c-peptide and Diabetes-Mellitus--Type-2

Diabetes is a heterogeneous and multifactorial disease. However, glycemia and glycated hemoglobin have been the focus of diabetes diagnosis and management for the last decades. As diabetes management goes far beyond glucose control, it has become clear that assessment of other biochemical parameters gives a much wider view of the metabolic state of each individual, enabling a precision medicine approach.. In this review, we summarize and discuss indexes that have been used in epidemiological studies and in the clinical practice.. Indexes of insulin secretion, sensitivity/resistance and metabolism have been developed and validated over the years to account also with insulin, C-peptide, triglycerides or even anthropometric measures. Nevertheless, each one has their own objective and consequently, advantages and disadvantages for specific cases. Thus, we discuss how new technologies, namely new sensors but also new softwares/applications, can improve the diagnosis and management of diabetes, both for healthcare professionals but also for caretakers and, importantly, to promote the empowerment of people living with diabetes.. In long-term, the solution for a better diabetes management would be a platform that allows to integrate all sorts of relevant information for the person with diabetes and for the healthcare practitioners, namely glucose, insulin and C-peptide or, in case of need, other parameters/indexes at home, sometimes more than once a day. This solution would allow a better and simpler disease management, more adequate therapeutics thereby improving patients' quality of life and reducing associated costs.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Insulin; Quality of Life

This systematic review and meta-analysis aimed to investigate the predictive ability of plasma connecting peptide (C-peptide) levels in discriminating type 1 diabetes (T1D) from type 2 diabetes (T2D) and to inform evidence-based guidelines in diabetes classification.. We conducted a holistic review and meta-analysis using PubMed, MEDLINE, EMBASE, and Scopus. The citations were screened from 1942 to 2021. The quality criteria and the preferred reporting items for systematic reviews and meta-analysis checklist were applied. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42022355088).. A total of 23,658 abstracts were screened and 46 full texts reviewed. Of the 46 articles screened, 12 articles were included for the meta-analysis. Included studies varied by race, age, time, and proportion of individuals. The main outcome measure in all studies was C-peptide levels. A significant association was reported between C-peptide levels and the classification and diagnosis of diabetes. Furthermore, lower concentrations and the cutoff of <0.20 nmol/L for fasting or random plasma C-peptide was indicative of T1D. In addition, this meta-analysis revealed the predictive ability of C-peptide levels in discriminating T1D from T2D. Results were consistent using both fixed- and random-effect models. The I. Plasma C-peptide levels are highly associated and predictive of the accurate classification and diagnosis of diabetes types. A plasma C-peptide cutoff of ≤0.20 mmol/L is indicative of T1D and of ≥0.30 mmol/L in the fasting or random state is indicative of T2D.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans

Among selected patients with type 2 diabetes mellitus (T2DM), simultaneous pancreas and kidney (SPK) transplants can be an effective option. However, data are limited about outcomes in T2DM SPK recipients based on the pretransplant C-peptide levels.. In this study, we reviewed all T2DM SPK recipients and categorized them based on the pretransplant fasting C-peptide levels into 3 groups: low (≤2 ng/mL), medium (>2-8 ng/mL), and high (>8 ng/mL). Several measures of graft failures (GFs), graft dysfunction, and composite outcomes were of interest.. There were a total of 76 SPK recipients (low, n = 14; medium, n = 47; high, n = 15). At the last follow-up, the low group did not reach any outcome; in contrast, 11 (23%) in the medium group and 5 (33%) in the high group reached the uncensored composite outcome; 6 (13%) in the medium group and 2 (13%) in the high group had GF; and 8 (17%) in the medium group and 4 (26.7%) in the high group reached the death-censored composite outcomes. In a fully adjusted model, each pretransplant C-peptide unit was not associated with an increased risk of the composite outcome, GF, or death-censored composite outcomes. However, in multivariate analysis with limited adjustment, pretransplant C-peptide was associated with the composite outcome (hazard ratio: 1.18, 95% confidence interval, 1.01-1.38; P = 0.03) and death-censored composite outcome (hazard ratio: 1.20; 95% confidence interval, 1.01-1.42; P = 0.03).. Although limited by the small sample size, we found excellent outcomes among T2DM SPK recipients overall. However, higher levels of pretransplant C-peptide may be associated with inferior posttransplant outcomes that include graft dysfunction.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Graft Survival; Humans; Kidney Transplantation; Pancreas; Pancreas Transplantation

Traditional medicines are recently being focused on to treat diabetes and its complications because of their lack of toxic and/or side effects. This report describes the effects of 7-O-galloyl-D-sedoheptulose (GS), a polyphenolic compound isolated from Corni Fructus, on type 2 diabetic db/db mice with hepatic and pancreatic damage. We examined several biochemical factors and oxidative stress- and inflammation-related markers. In the serum, levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, and interleukin-6 were down-regulated, while adiponectin was augmented by GS treatment. In addition, GS suppressed the reactive oxygen species and lipid peroxidation in the serum, liver, and pancreas, but increased the pancreatic insulin and pancreatic C-peptide contents. These results were derived from attenuating the expression of nicotinamide adenine dinucleotide phosphate oxidase subunit proteins, Nox-4 and p22

Topics: Animals; C-Peptide; Cornus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Insulin; Liver; Mice; NF-kappa B; Pancreas; Polyphenols

Bariatric surgery is the most effective treatment in individuals with obesity to achieve remission of type 2 diabetes. Post-bariatric surgery hypoglycaemia occurs frequently, and management remains suboptimal, because of a poor understanding of the underlying pathophysiology. The glucoregulatory hormone responses to nutrients in individuals with and without post-bariatric surgery hypoglycaemia have not been systematically examined.. The study protocol was prospectively registered with PROSPERO. PubMed, EMBASE, Web of Science and the Cochrane databases were searched for publications between January 1990 and November 2021 using MeSH terms related to post-bariatric surgery hypoglycaemia. Studies were included if they evaluated individuals with post-bariatric surgery hypoglycaemia and included measurements of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and/or glucagon concentrations following an ingested nutrient load. Glycated haemoglobin (HbA. From 377 identified publications, 12 were included in the analysis. In all 12 studies, the type of bariatric surgery was Roux-en-Y gastric bypass (RYGB). Comparing individuals with and without post-bariatric surgery hypoglycaemia following an ingested nutrient load, the standardised mean difference in peak GLP-1 was 0.57 (95% CI, 0.32, 0.82), peak GIP 0.05 (-0.26, 0.36), peak insulin 0.84 (0.44, 1.23), peak C-peptide 0.69 (0.28, 1.1) and peak glucagon 0.05 (-0.26, 0.36). HbA. Following RYGB, postprandial peak plasma GLP-1, insulin and C-peptide concentrations are greater in individuals with post-bariatric surgery hypoglycaemia, while HbA

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin

Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear.. To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach.. PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications.. The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was -27.3% (CI -36.5% to -18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose.. The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucose; Humans; Incretins; Insulin

The optimal therapy for latent autoimmune diabetes in adults (LADA) remains undefined. Increasing evidence has shown that sitagliptin and insulin treatment can benefit patients with LADA, but the efficacy still lacks systematic evaluation. We carried out this systematic review and meta-analysis to summarize the current data on the efficacy and safety of sitagliptin combined with insulin on LADA, providing a reliable reference for the effective therapeutic treatment of LADA patients.. We retrieved the literature in PubMed, Cochrane Library, Embase, Web of Science and CNKI from inception to August 2021. Randomized controlled trials comparing the effects of sitagliptin plus insulin with insulin alone in LADA patients were identified. The outcome measures included parameters of glycemic control, β-cell function, body mass index and adverse events. The Review Manager 5.2 and Stata 14.0 were utilized for data analysis.. Eight randomized controlled trials involving 295 participants were identified. Sitagliptin and insulin treatment lowered hemoglobin A1c (weighted mean difference -0.36, 95% confidence interval -0.61 to -0.10, I. Sitagliptin combined with insulin can achieve better glycemic control and improve islet β-cell function with lower incidence of hypoglycemia compared with insulin alone, which provides an effective and tolerated therapeutic regimen for LADA patients. However, further well-designed and rigorous randomized controlled trials are required to validate this benefit due to the limited methodology quality of included trials.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Latent Autoimmune Diabetes in Adults; Randomized Controlled Trials as Topic; Sitagliptin Phosphate

This study aims to investigate the effects of serum C-peptide levels on blood lipid and cardiovascular and cerebrovascular injury in patients with type 2 diabetes mellitus (T2DM).. China National Knowledge Infrastructure (CNKI), WanFang Data, PubMed, Web of Science, and Embase databases were searched for relevant studies published from January 2010 to June 2021. All retrieved randomized controlled trials that evaluated the effect of serum C-peptide levels on blood lipids or cardiovascular and cerebrovascular injuries in T2DM patients were included in our study. Patients in the included studies were divided into normal C-peptide group (control group) and low C-peptide group (treatment group) according to fasting C-peptide levels. Meta-analysis was performed using Stata16.0.. A total of 7 studies were included for the meta-analysis. Compared with the control group, the treatment group was associated with a higher incidence of coronary heart disease (OR = 4.89; 95% CI: 1.13, 21.24;. Low serum C-peptide level significantly increases the incidence of coronary heart disease and cerebral infarction. Additionally, low serum C-peptide increases blood lipid level and promotes lipid deposition. Collectively, low serum C-peptide has a negative impact on the occurrence and development of T2DM and therefore serum C-peptide level needs to be adjusted timely.

Topics: C-Peptide; Cerebral Infarction; Cholesterol; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Lipids; Randomized Controlled Trials as Topic

Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice, helping to classify types of diabetes, complication risk stratification and to guide treatment decisions. Because C-peptide secretion mirrors beta-cell function, it has emerged as a valuable clinical biomarker, mainly in autoimmune diabetes and especially in adult-onset diabetes. Nonetheless, the lack of robust evidence about the clinical utility of C-peptide measurement in type 2 diabetes, where insulin resistance is a major confounder, limits its use in such cases. Furthermore, problems remain in the standardization of the assay for C-peptide, raising concerns about comparability of measurements between different laboratories. To approach the heterogeneity and complexity of diabetes, reliable, simple and inexpensive clinical markers are required that can inform clinicians about probable pathophysiology and disease progression, and so enable personalization of management and therapy. This review summarizes the current evidence base about the potential value of C-peptide in the management of the two most prevalent forms of diabetes (type 2 diabetes and autoimmune diabetes) to address how its measurement may assist daily clinical practice and to highlight current limitations and areas of uncertainties to be covered by future research.

Topics: Adult; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion

The clinical manifestation of hepatocyte nuclear factor-1-alpha (

Topics: Adult; Autoantibodies; C-Peptide; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Male; Retrospective Studies; Triglycerides; Young Adult

This systematic literature review aims to compare the efficacy and safety of traditional and stem cell (SC) therapies for type 1 (T1DM) and type 2 (T2DM) diabetes mellitus patients.. The PubMed, SciELO, BVS, and Medline databases were searched, and 38 original articles were selected, which included 647 control cases and 654 treatments with three-, six- and twelve-month follow-ups of T1DM and T2DM patients. The efficacy of stem cell therapy was validated by comparing laboratory parameters such as fasting blood glucose and C-peptide levels before and after treatment. The REML model was chosen for random effects, and the inverse of variance was used for fixed effects. The statistical analysis was carried out using Bioestat 5.0 and STATA 16.0 software.. All SC treatments significantly reduced the need for insulin following six and twelve months of treatment, whereas there was no significant decrease after three months. Fasting blood glucose and glycosylated hemoglobin levels were significantly reduced in all follow-ups with SC. In addition, SC treatment caused a significant increase in C-peptide levels. Bone marrow hematopoietic stem cell therapy produced better results than the conventional drug treatment for diabetes mellitus (semagglutide).. The results with SC were significantly better, regardless of the follow-up period. Studies have proven cell therapy to be beneficial, safe, and effective.

Topics: Blood Glucose; C-Peptide; Cell- and Tissue-Based Therapy; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Treatment Outcome

Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.

Topics: Autoantibodies; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Humans; Insulin

In recent years, mesenchymal cellular therapies have received much attention in the treatment of diabetes. In this meta-analysis, we aimed to evaluate the efficacy of mesenchymal stem cell therapy in type 2 diabetes mellitus patients.. A comprehensive literature search was carried out using PubMed, Scopus, Web of Science and Central databases. A total of 1,721 articles were identified, from which nine full-text clinical trials were qualified to enter the current meta-analysis. The assessment groups included patients with type 2 diabetes, and levels of C-peptide, glycosylated hemoglobin and insulin dose were analyzed before and after mesenchymal stem cell infusion. Data analysis was carried out in Stata version 11, and the Jadad Score Scale was applied for quality assessment.. Changes in levels of C-peptide after mesenchymal stem cell therapy were: standardized mean difference 0.20, 95% confidence interval -0.61 to 1.00, glycosylated hemoglobin levels were: standardized mean difference -1.45, 95% confidence interval -2.10 to -0.79 and insulin dose were: standardized mean difference -1.40, 95% confidence interval -2.88 to 0.09.. This meta-analysis of prospective studies showed associations between mesenchymal stem cell therapy and control of glucose level in patients with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Insulin; Male; Mesenchymal Stem Cell Transplantation; Middle Aged; Prospective Studies; Treatment Outcome

Diabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs).. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to provide a reliable numerical summary and the most comprehensive assessment of therapeutic efficacy and safety with MSCs in diabetes. PubMed, Web of Science, Ovid, the Cochrane Library and CNKI were searched. The retrieval time was from establishment of these databases to January 4, 2020. Seven RCTs were eligible for analysis, including 413 participants. Meta-analysis results showed that there were no significant differences in the reduction of fasting plasma glucose (FPG) compared to the baseline [mean difference (MD) = -1.05, 95% confidence interval (CI) (-2.26,0.16), P<0.01, I2 = 94%] and the control group [MD = -0.62, 95%CI (-1.46,0.23), P<0.01, I2 = 87%]. The MSCs treatment group showed a significant decrease in hemoglobin (Hb) A1c [random-effects, MD = -1.32, 95%CI (-2.06, -0.57), P<0.01, I2 = 90%] after treatment. Additionally, HbA1c reduced more significantly in MSC treatment group than in control group [random-effects, MD = -0.87, 95%CI (-1.53, -0.22), P<0.01, I2 = 82%] at the end of follow-up. However, as for fasting C-peptide levels, the estimated pooled MD showed that there was no significant increase [MD = -0.07, 95%CI (-0.30, 0.16), P<0.01, I2 = 94%] in MSCs treatment group compared with that in control group. Notably, there was no significant difference in the incidence of adverse events between MSCs treatment group and control group [relative risk (RR) = 0.98, 95%CI (0.72, 1.32), P = 0.02, I2 = 70%]. The most commonly observed adverse reaction in the MSC treatment group was hypoglycemia (29.95%).. This meta-analysis revealed MSCs therapy may be an effective and safe intervention in subjects with diabetes. However, due to the limited studies, a number of high-quality as well as large-scale RCTs should be performed to confirm these conclusions.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemia; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Randomized Controlled Trials as Topic; Treatment Outcome

The classification of diabetes mellitus in 2020 still starts with 2 major types, ie, type 1 and type 2, but each of these now includes a few uncommon variants. Understanding the many faces of the diabetes syndrome can make a difference in how clinicians select glucose-lowering therapy.

Topics: Autoantibodies; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Latent Autoimmune Diabetes in Adults; Phenotype

It is well known that type 2 diabetes mellitus (T2D) is a globally increasing health burden. Despite recent therapeutic advances and the availability of many different classes of antihyperglycemic therapy, a large proportion of people do not achieve glycemic control. A decline in pancreatic beta-cell function has been defined as a key contributing factor to progression of T2D. In fact, a significant proportion of beta-cell secretory capacity is thought to be lost well before the diagnosis of T2D is made. Several models have been proposed to explain the reduction in beta-cell function, including reduced beta-cell number, beta-cell exhaustion, and dedifferentiation or transdifferentiation into other cell types. However, there have been reports that suggest remission of T2D is possible, and it is believed that beta-cell dysfunction may be, in part, reversible. As such, the question of whether beta cells are committed to failure in people with T2D is complex. It is now widely accepted that early restoration of normoglycemia may protect beta-cell function. Key to the successful implementation of this approach in clinical practice is the appropriate assessment of individuals at risk of beta-cell failure, and the early implementation of appropriate treatment options. In this review, we discuss the progression of T2D in the context of beta-cell failure and describe how C-peptide testing can be used to assess beta-cell function in primary care practice. In conclusion, significant beta-cell dysfunction is likely in individuals with certain clinical characteristics of T2D, such as long duration of disease, high glycated hemoglobin (≥9%), and/or long-term use of therapies that continuously stimulate the beta cell. In these people, measurement of beta-cell status could assist with choice of appropriate therapy to delay or potentially reverse beta-cell dysfunction and the progression of T2D.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Disease Progression; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Oxidative Stress

Long-term exposure to high dietary acid load has been associated with insulin resistance and type 2 diabetes in epidemiological studies. However, it remains unclear whether the acid load of the diet translates to mild metabolic acidosis and whether it is responsible for the impairment in glucose regulation in humans. Previously, in a cross-sectional study we have reported that dietary acid load was not different between healthy individuals with normal weight and those with overweight/obesity, irrespective of insulin sensitivity. However, 4-week high acid load diet increased plasma lactate (a small component of the anion gap) and increased insulin resistance in healthy participants. The change in plasma lactate correlated significantly with the change in insulin resistance. Because cause-and-effect could not be evaluated in these settings, we sought to directly test the effect of an alkalizing treatment preload on postprandial glucose regulation. In a randomized placebo-controlled study with a crossover design, we administered sodium bicarbonate (NaHCO

Topics: Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Postprandial Period; Randomized Controlled Trials as Topic

Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Humans; Inactivation, Metabolic; Insulin; Insulin Resistance; Liver

Current knowledge suggests a complex role of C-peptide in human physiology, but its mechanism of action is only partially understood. The effects of C-peptide appear to be variable depending on the target tissue, physiological environment, its combination with other bioactive molecules such as insulin, or depending on its concentration. It is apparent that C-peptide has therapeutic potential for the treatment of vascular and nervous damage caused by type 1 or late type 2 diabetes mellitus. The question remains whether the effect is mediated by the receptor, the existence of which is still uncertain, or whether an alternative non-receptor-mediated mechanism is responsible. The Institute of Endocrinology in Prague has been paying much attention to the issue of C-peptide and its metabolic effect since the 1980s. The RIA methodology of human C-peptide determination was introduced here and transferred to commercial production. By long-term monitoring of C-peptide oGTT-derived indices, the Institute has contributed to elucidating the pathophysiology of glucose tolerance disorders. This review summarizes the current knowledge of C-peptide physiology and highlights the contributions of the Institute of Endocrinology to this issue.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Nervous System Diseases; Vascular Diseases

The possibility that verapamil has new beneficial effects in diabetic patients in terms of an improvement in glycometabolic control has been put forward recently in several studies. However, to date the issue is still under debate. We conducted the first systematic review examining the impact of verapamil-based treatment on glycometabolic outcomes, in type 2 diabetes (T2D) patients.. We searched the PubMed, MEDLINE, Embase, Cochrane and ClinicalTrials.gov up to 9 October 2018, for all studies evaluating whether verapamil-based treatment is associated with changes in glycated haemoglobin (HbA1c), fasting plasma glucose levels, glucose and C-peptide areas from baseline in humans, without restrictions for study type.. Plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (mean change - 13 ± 5.29; P = 0.049); HbA1c values were instead not affected by the drug (mean change - 0.10 ± 0.12; P = 0.453). In five studies, groups exposed to verapamil achieved lower value of glycometabolic outcomes: comparison with values recorded in control groups showed a significant difference, in terms of both HbA1c and plasma glucose levels.. Despite the fact that plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (the HbA1c values were not affected by the drug), the clinical significance of the glycometabolic response induced by verapamil-based treatment remains unclear due to the high variety of sample size and type of studies presently available. Further experimental and clinical trials are needed to clarify unambiguously the role of verapamil in metabolic control.

Topics: B-Lymphocytes; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Male; Verapamil

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than "classical" type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis have been challenged. Despite the absence of a genetic background that is exclusive for LADA this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems to therapy and follow-up, perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

Topics: Adult; Age of Onset; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Humans; Islets of Langerhans; Latent Autoimmune Diabetes in Adults

C-peptide is a cleavage product of proinsulin that acts on different type of cells, such as blood and endothelial cells. C-peptide biological effects may be different in type 1 and type 2 diabetes. Besides, there are further evidence for a functional interaction between C-peptide and insulin. In this way, C-peptide has ambiguous effects, acting as an antithrombotic or thrombotic molecule, depending on the physiological environment and disease conditions. Moreover, C-peptide regulates interaction of leucocytes, erythrocytes, and platelets with the endothelium. The beneficial effects include stimulation of nitric oxide production with its subsequent release by platelets and endothelium, the interaction with erythrocytes leading to the generation of adenosine triphosphate, and inhibition of atherogenic cytokine release. The undesirable action of C-peptide includes the chemotaxis of monocytes, lymphocytes, and smooth muscle cells. Also, C-peptide was related with increased lipid deposits and elevated smooth muscle cells proliferation in the vessel wall, contributing to atherosclerosis. Purpose of this review is to explore these dual roles of C-peptide on the blood, contributing at one side to haemostasis and the other to atherosclerotic process.

Topics: Animals; Atherosclerosis; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelium, Vascular; Erythrocytes; Humans; Nitric Oxide

To evaluate the comparative effects of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), on β-cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM).. Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for β cell function (HOMA-β) and insulin resistance (HOMA-IR), fasting C-peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size.. A total of 360 RCTs (74% at least double-blinded) with 157 696 patients were included. Incretin-based therapies were compared with six other classes of glucose-lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA-β and fasting C-peptide was detected for GLP-1RAs (WMD = 20.31 [95% CI, 16.34-24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03-0.29] with low quality) and for DPP-4Is (WMD = 9.90 [95% CI, 8.27-11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04-0.14] with moderate quality) separately, while a significant reduction in HOMA-IR and FPG were found in favour of GLP-1RAs (WMD = -0.67 [95% CI, -1.08 to -0.27] with low quality; WMD = -1.04 mmol/L [95% CI, -1.26 to -0.83] with moderate quality) and DPP-4Is (WMD = -0.23 [95% CI, -0.38 to -0.08] with low quality; WMD = -0.77 mmol/L [95% CI, -0.98 to -0.57] with moderate quality), respectively.. Incretin-based therapies not only show an increase in HOMA-β and fasting C-peptide level, but also achieve a reduction in HOMA-IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin-based therapies seem to be an advisable option for long-term treatment to preserve β-cell function.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Network Meta-Analysis

The effect of bariatric surgery on the glycemic control of patients with obesity and type 2 diabetes mellitus is obvious. However, the effect in patients with body mass index (BMI) < 30 kg/m. We performed a literature search in Medline, Embase, and the Cochrane Library from January 2000 to March 2018. All the studies involving the effect of bariatric surgery on patients with type 2 diabetes and BMI < 30 kg/m. Asian patients with type 2 diabetes and BMI < 30 kg/m

Topics: Asian People; Bariatric Surgery; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin; Lipids; Postoperative Period; Waist Circumference

The Swedish study Better Diabetes Diagnosis (BDD) has now been ongoing for ten years and detailed information and blood samples have been collected from more than 8000 children and adolescents with newly diagnosed diabetes. We have been able to demonstrate that by means of HLA diabetes antibodies and C-peptide the discrimination between type one and type 2 diabetes is improved. These analyses are therefore included in the clinical check-up for all children and adolescents in Sweden who are diagnosed with diabetes. Type 1 diabetes is by far the most prevalent type of diabetes among Swedish children and adolescents. Type 2 diabetes is still relatively rare in Sweden but it is urgent to obtain a correct diagnosis as the long-term prognosis depends on a prompt pharmacological treatment. Monogenic diabetes (MODY) is also important to identify early. We therefore recommend that sequencing of MODY genes should be performed if an individual with newly-diagnosed diabetes is auto-antibody negative and has an HLA pattern associated with low risk for type 1 diabetes. However, despite these analytical tools it can be difficult to make the correct diabetes diagnosis initially. It is therefore prudent to re-evaluate the diabetes diagnosis after one year.

Topics: Adolescent; Autoantibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnostic Tests, Routine; Histocompatibility Testing; Humans; Infant; Sweden

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at

Topics: Alleles; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Genetic Variation; Genome-Wide Association Study; Genotype; Genotyping Techniques; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Linear Models; Liver; Transcription Factor 7-Like 2 Protein

The study evaluated the predictive role of preoperative fasting C-peptide, hemoglobin (Hb)A1c, fasting plasma glucose (FPG), and body mass index (BMI) levels on diabetes remission in patients with type 2 diabetes following bariatric surgery.. Medline, PubMed, Central, and Google Scholar databases of up to September 7, 2016 were searched using the following terms: type 2 diabetes mellitus, gastric bypass, Roux-en-Y, anastomosis, C-peptide, weight loss, HbA/HbA1c, predictive/predictor.. Meta-analysis of the pooled data indicated that fasting C-peptide was predictive of increased chance of remission of type 2 diabetes (pooled difference in means = 0.93, 95% confidence interval [CI] = 0.61 to 1.25, p < .001). The analysis also found that FPG (pooled standardized mean difference = -0.42, 95% CI: -0.64 to -0.20, p < .004) and HbA1c levels (pooled difference in means = -1.05, 95% CI: -1.48 to -0.62, p < .001) were associated with reduced odds of type 2 diabetes remission. BMI was not found to be associated with remission (pooled difference in means = 0.29, 95% CI: 0.30 to 0.88, p = .343). In general, subgroup analysis, which evaluated the pooled data from the retrospective and prospective studies separately, gave similar results.. Preoperative fasting plasma C-peptide was associated with increased type 2 diabetes remission after bariatric surgery, whereas baseline HbA1c and FPG levels were associated with reduced chance of remission. These parameters may be used as a guideline in weighing the risks and benefits for surgical intervention in patients with type 2 diabetes.

Topics: Bariatric Surgery; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Obesity, Morbid; Predictive Value of Tests; Risk Assessment; Treatment Outcome; Weight Loss

Diabetes is not a single homogeneous disease but composed of many diseases with hyperglycaemia as a common feature. Four factors have, historically, been used to identify this diversity: the age at onset; the severity of the disease, i.e. degree of loss of beta cell function; the degree of insulin resistance and the presence of diabetes-associated autoantibodies. Our broad understanding of the distinction between the two major types, type 1 diabetes mellitus and type 2 diabetes mellitus, are based on these factors, but it has become apparent that they do not precisely capture the different disease forms. Indeed, both major types of diabetes have common features, encapsulated by adult-onset autoimmune diabetes and maturity-onset diabetes of the young. As a result, there has been a repositioning of our understanding of diabetes. In this review, drawing on recent literature, we discuss the evidence that autoimmune type 1 diabetes has a broad clinical phenotype with diverse therapeutic options, while the term non-autoimmune type 2 diabetes obscures the optimal management strategy because it encompasses substantial heterogeneity. Underlying these developments is a general progression towards precision medicine with the need for precise patient characterisation, currently based on clinical phenotypes but in future augmented by laboratory-based tests.

Topics: Age Factors; Alleles; Autoantibodies; Autoimmunity; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Progression; Genotype; Humans; Hyperglycemia; Insulin; Insulin Resistance; Phenotype

C-peptide is secreted from pancreatic β cells at an equimolar ratio to insulin. Since, in contrast to insulin, C-peptide is not extracted by the liver and other organs, C-peptide reflects endogenous insulin secretion more accurately than insulin. C-peptide is therefore used as a marker of β cell function. C-peptide has been mainly used to assess the presence of an insulin-dependent state for the diagnosis of type 1 diabetes. However, recent studies have revealed that β cell dysfunction is also a core deficit of type 2 diabetes, and residual β cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. This review summarizes the role of C-peptide, especially the postprandial C-peptide to glucose ratio which likely better reflects maximum β cell secretory capacity compared with the fasting ratio in assessing β cell function, and discusses perspectives on its clinical utility for managing glycemic control in patients with type 2 diabetes.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Postprandial Period

Independent epidemiological studies have evaluated the association between markers of glucose metabolism (including fasting glucose, fasting insulin, homeostasis model of risk assessment-insulin resistance (HOMA-IR), glycated haemoglobin (HbA1c) and C peptide) and the risk of colorectal cancer (CRC). However, such associations have not been systematically analysed and no clear conclusions have been drawn. Therefore, we addressed this issue using a meta-analysis approach.. Systematic review and meta-analysis.. PubMed and EMBASE were searched up to May 2015.. Either a fixed-effects or random-effects model was adopted to estimate overall ORs for the association between markers of glucose metabolism and the risk of CRC. In addition, dose-response, meta-regression, subgroup and publication bias analyses were conducted.. 35 studies involving 25 566 patients and 5 706 361 participants were included. Higher levels of fasting glucose, fasting insulin, HOMA-IR, HbA1c and C peptide were all significantly associated with increased risk of CRC (fasting glucose, pooled OR=1.12, 95% CI 1.06 to 1.18; fasting insulin, pooled OR=1.42, 95% CI 1.19 to 1.69; HOMA-IR, pooled OR=1.47, 95% CI 1.24 to 1.74; HbA1c, pooled OR=1.22, 95% CI 1.02 to 1.47 (with borderline significance); C peptide, pooled OR=1.27, 95% CI 1.08 to 1.49). Subgroup analysis suggested that a higher HOMA-IR value was significantly associated with CRC risk in all subgroups, including gender, study design and geographic region. For the relative long-term markers, the association was significant for HbA1c in case-control studies, while C peptide was significantly associated with CRC risk in both the male group and colon cancer.. The real-time composite index HOMA-IR is a better indicator for CRC risk than are fasting glucose and fasting insulin. The relative long-term markers, HbA1c and C peptide, are also valid predictors for CRC risk. Considering the included case-control studies in the current analysis, more cohort studies are warranted to enhance future analysis.

Topics: Biomarkers; C-Peptide; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Insulin Resistance; Risk Assessment; Risk Factors

Our aim is to clarify the features of complete type 2 diabetes mellitus (T2DM) remission in patients who undergo Roux-en Y gastric bypass surgery, to better determine factors affecting the outcome of T2DM surgery. A search was conducted for original studies on Medline, PubMed and Elsevier from inception until October 28, 2014. All of the articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: Roux-en Y gastric bypass surgery for T2DM patients in remission or non-remission. The meta-analysis results demonstrated that fasting C-peptide values were significantly associated with increased remission (C-peptide: 95%CI = 0.2-1.0) whereas T2DM duration, patient age, preoperative insulin use, preoperative fasting blood glucose values and preoperative glycosylated haemoglobin values were significantly associated with reduced remission (T2DM duration: 95%CI = -1.2 - -0.7; age: 95%CI = -0.5 - -0.1; percentage of preoperative insulin users: odd ratio = 0.10, 95%CI = 0.07-0.15; preoperative fasting blood glucose: 95%CI = -0.9 - -0.5; preoperative glycosylated haemoglobin: 95%CI = -1.1 - -0.4). However, the results demonstrated that body mass index was not statistically different (body mass index: 95%CI = -0.2-0.6). The results of the systematic review demonstrated that smaller waist circumference; lower total cholesterol, triglycerides and low-density lipoprotein levels, increased higher high-density lipoprotein levels, shorter cardiovascular disease history and less preoperative prevalence of hypertension contribute to the increased postoperative remission rate. Better results are obtained in younger patients with less severe diabetes, a smaller waist circumference, higher preoperative high-density lipoprotein, lower preoperative total cholesterol, triglycerides and low-density lipoprotein levels and fewer other complications of shorter durations.

Topics: Age Factors; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Gastric Bypass; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Insulin; Lipoproteins, HDL; Lipoproteins, LDL; Obesity, Morbid; Prognosis; Remission Induction; Treatment Outcome; Triglycerides

In this study, we investigate whether bone marrow mononuclear cells (BM-MNC) or peripheral blood mononuclear cells (PB-MNC) have therapeutic efficacy in type 2 diabetes (T2D).. Search terms included stem cell, bone marrow cell, peripheral blood cell, umbilical cord blood and T2D in MEDLINE, the Cochrane Controlled Trials Register, EMBASE, the Wanfang Database, the China Science and Technology Periodical Database and China Journal Net.. Fifteen trials met our inclusion criteria (n = 497). One group included 266 cases with BM-MNC therapy and the other group contained 231 cases with PB-MNC treatment. Glycosylated hemoglobin was decreased after BM-MNC or PB-MNC therapy compared with that before (12 months: P < 0.001; 6 months: P < 0.001; 3 months: P < 0.05). Fasting plasma glucose was reduced in BM-MNC therapy group compared with control after 12-month follow-up (P < 0.001) and after BM-MNC therapy compared with that before (9 months: P < 0.001) but was not obvious in other stages. Meanwhile, the analysis showed that C-peptide level increased after BM-MNC and PB-MNC therapy compared with the control therapy (12 months: P < 0.001) and with that before therapy (6 months: P < 0.05). Insulin requirement reduction was also observed in patients receiving BM-MNC therapy (3, 6, 9 and 12 months: P < 0.05).. To a certain extent, BM-MNC or PB-MNC therapy for T2D demonstrated superiority of glycemic control, increased insulin biosynthesis and elevated insulin secretion from existing β-cells and might prevent islet cell loss.

Topics: Adult; Blood Glucose; Bone Marrow Cells; Bone Marrow Transplantation; C-Peptide; Cell- and Tissue-Based Therapy; Diabetes Mellitus, Type 2; Female; Fetal Blood; Glycated Hemoglobin; Humans; Insulin; Insulin-Secreting Cells; Leukocytes, Mononuclear; Male; Middle Aged; Stem Cell Transplantation; Stem Cells; Transplantation, Autologous; Treatment Outcome

C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to different requirements in the treatment of diabetes. An important clinical role of C-peptide is differentiating between type 1 and type 2 diabetes. Low basal C-peptide can be considered as criterion for transferring the patients, initially diagnosed as type 2 diabetes, in the type 1 diabetes group. C-peptide level may be a good predictor of the clinical partial remission during the first year of type 1 diabetes. Latent autoimmune diabetes in adults (LADA) is a special form of diabetes that is clinically similar to type 2 diabetes but with positivity for pancreatic autoantibodies and lower C-peptide levels. The measurement of C-peptide level and of immunological markers may represent important additional tools for establishing the correct diagnosis. The natural course of these patients shows that C-peptide will decrease with time in parallel with the curve for C-peptide in classical type 1 diabetic patients. Persistence of C-peptide is an important clinical feature of MODY. It is particularly important to identify these patients as they are commonly misdiagnosed as type 1 diabetes and treated with insulin, C-peptide can be used to assist in patient selection for islet cell transplantation and post-transplant monitoring. High uncorrected fasting C-peptid in the presence of hyperglycemia may suggest insulin resistance.. Peptyd C jest wytwarzany w ilości zależnej od ilości wytwarzanej insuliny i jest najlepszym wskaźnikiem do pomiaru endogennego wydzielania insuliny u chorych na cukrzycę. Pomiary wydzielania insuliny przy użyciu peptydu C mogą być pomocne w praktyce klinicznej do określania odpowiedniego leczenia cukrzycy. Peptyd C odgrywa ważną klinicznie rolę w różnicowaniu między typem 1 a typem 2 cukrzycy. Niskie podstawowe stężenie peptydu C może być kryterium zakwalifikowania pacjentów początkowo zdiagnozowanych jako chorych na cukrzycę typu 2 do grupy chorych na cukrzycę typu 1. Stężenie peptydu C to także dobry prognostyk częściowej remisji klinicznej w pierwszym roku zachorowania na cukrzycę typu 1. Utajona autoimmunologiczna cukrzyca u dorosłych (latent autoimmune diabetes in adults, LADA) jest szczególną formą tej choroby, która jest klinicznie podobna do cukrzycy typu 2, ale obecne są w niej autoprzeciwciała przeciwtrzustkowe. Pomiary stężenia peptydu C i markerów immunologicznych mogą stanowić ważne dodatkowe narzędzia do ustalenia prawidłowej diagnozy. Trwałość peptydu C jest ważną cechą kliniczną MODY (maturity onset diabetes of the young), ponieważ pacjenci są często błędnie diagnozowani jako chorzy na cukrzycę typu 1 i leczeni insuliną. Peptyd C może być również wykorzystany przy selekcji pacjentów do przeszczepu komórek wysp i do monitorowania po przeszczepie. Wysokie stężenie peptydu C, które nie ulega korekcie przy hiperglikemii, może sugerować insulinooporność.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion

The impact of bariatric surgery beyond its effect on weight loss has entailed a change in the way of regarding it. The term metabolic surgery has become more popular to designate those interventions that aim at resolving diseases that have been traditionally considered as of exclusive medical management, such as type 2 diabetes mellitus (T2D). Recommendations for metabolic surgery have been largely addressed and discussed in worldwide meetings, but no definitive consensus has been reached yet. Rates of diabetes remission after metabolic surgery have been one of the most debated hot topics, with heterogeneity being a current concern. This review aims to identify and clarify controversies regarding metabolic surgery, by focusing on a critical analysis of T2D remission rates achieved with different bariatric procedures, and using different criteria for its definition. Indications for metabolic surgery for patients with T2D who are not morbidly obese are also discussed.

Topics: Age Factors; Bariatric Surgery; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Obesity, Morbid; Patient Selection; Prognosis; Remission Induction; Sex Factors; Treatment Outcome; Weight Loss

Type 2 Diabetes is a heterogeneous disease which harbors several different pathomechanistic entities. For a successful prevention, it is important to understand the exact pathomechanisms. Overt type 2 Diabetes usually develops through an intermediary state called prediabetes, which is also heterogeneous. This state is especially important, because it already confers a higher risk for diabetes-associated complications. Therefore, detection of prediabetes and prevention of its progression to diabetes would be desirable. In this review, we describe the phenotypes of prediabetes and type 2 diabetes. We also try to envision the first steps of a future phenotype-oriented diabetes therapy.

Topics: Blood Glucose; C-Peptide; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Progression; Early Diagnosis; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Prediabetic State; Prognosis; Risk Factors; Transcription Factor 7-Like 2 Protein

Transplantation of the whole vascularized pancreas can provide insulin secretion in patients with insulin-dependent, type 1 diabetes mellitus (T1D). It restores euglycemia in most patients, with the potential to impact the chronic diabetic complications and quality of life. Pancreas transplantation (PT) is presently controversial for type 2 diabetes mellitus (T2D). For those patients with severe glycemic dysregulation, T2D can be associated with the same life-threatening sequelae as T1D such as severe hypoglycemia and kidney failure that could be corrected by pancreas (and kidney) transplantation. Thus, clinical indications and patient selection criteria are very important. This chapter will review the current status of PT for T2D and discuss the options and evolution of transplant perspectives.

Topics: Bariatric Surgery; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Insulin; Insulin Secretion; Pancreas Transplantation; Patient Selection; Quality of Life; Risk Reduction Behavior; Survival Rate

Lack of C-peptide, along with insulin, is the main feature of Type 1 diabetes mellitus (DM) and is also observed in progressive β-cell loss in later stage of Type 2 DM. Therapeutic approaches to hyperglycaemic control have been ineffective in preventing diabetic vasculopathy, and alternative therapeutic strategies are necessary to target both hyperglycaemia and diabetic complications. End-stage organ failure in DM seems to develop primarily due to vascular dysfunction and damage, leading to two types of organ-specific diseases, such as micro- and macrovascular complications. Numerous studies in diabetic patients and animals demonstrate that C-peptide treatment alone or in combination with insulin has physiological functions and might be beneficial in preventing diabetic complications. Current evidence suggests that C-peptide replacement therapy might prevent and ameliorate diabetic vasculopathy and organ-specific complications through conservation of vascular function, as well as prevention of endothelial cell death, microvascular permeability, vascular inflammation, and neointima formation. In this review, we describe recent advances on the beneficial role of C-peptide replacement therapy for preventing diabetic complications, such as retinopathy, nephropathy, neuropathy, impaired wound healing, and inflammation, and further discuss potential beneficial effects of combined C-peptide and insulin supplement therapy to control hyperglycaemia and to prevent organ-specific complications.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hypoglycemic Agents; Signal Transduction; Treatment Outcome

C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to the different treatment requirements of Type 1 and Type 2 diabetes. This article reviews the use of C-peptide measurement in the clinical management of patients with diabetes, including the interpretation and choice of C-peptide test and its use to assist diabetes classification and choice of treatment. We provide recommendations for where C-peptide should be used, choice of test and interpretation of results. With the rising incidence of Type 2 diabetes in younger patients, the discovery of monogenic diabetes and development of new therapies aimed at preserving insulin secretion, the direct measurement of insulin secretion may be increasingly important. Advances in assays have made C-peptide measurement both more reliable and inexpensive. In addition, recent work has demonstrated that C-peptide is more stable in blood than previously suggested or can be reliably measured on a spot urine sample (urine C-peptide:creatinine ratio), facilitating measurement in routine clinical practice. The key current clinical role of C-peptide is to assist classification and management of insulin-treated patients. Utility is greatest after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes. Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of Type 1 diabetes management strategies regardless of apparent aetiology.

Topics: C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin Secretion; Prognosis

Despite years of research in the field of type 1 diabetes, patients with the disease remain without a therapeutic agent that can alter the underlying immune response in a clinically beneficial way. Glucagon-like peptide 1 agonist therapies have shown some promising effects in terms of positively affecting overall beta cell health and increasing beta cell mass, primarily in mouse models. The three agents of this class currently available for patients with type 2 diabetes have shown beneficial clinical effects on glucose control in this patient population. The purpose of this article is to review the preclinical and clinical data of these agents to date with a focus on the potential immunological and clinical benefits these drugs may have on patients with type 1 diabetes.

Topics: Animals; Biomarkers; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Liraglutide; Peptides; Venoms

In the recent years there were numerous evidences that C-peptide, which was previously considered as a product of insulin biosynthesis, is one of the key regulators of physiological processes. C-peptide via heterotrimeric G(i/o) protein-coupled receptors activates a wide range of intracellular effector proteins and transcription factors and, thus, controls the inflammatory and neurotrophic processes, pain sensitivity, cognitive function, macro- and microcirculation, glomerular filtration. These effects of C-peptide are mainly expressed in its absolute or relative deficiency occurred in type 1 diabetes mellitus and they are less pronounced when the level of C-peptide is close to normal. Replacement therapy with C-peptide prevents many complications of type 1 diabetes, such as atherosclerosis, diabetic peripheral neuropathy, and nephropathy. C-peptide interacts with the insulin hexamer complexes and induces their dissociation and, as a result, regulates the functional activity of the insulin signaling system. At the same time, C-peptide at the concentrations above physiological may demonstrate pro-inflammatory effects on the endothelial cells and cause atherosclerotic changes in the vessels, which should be considered in the study of pathogenic mechanisms of complications of type 2 diabetes mellitus, where the level of C peptide is increased, as well as in the development of approaches for C-peptide application in clinic. This review is devoted contemporary achievements and unsolved problems in the study of C-peptide, as an important regulator of physiological and biochemical processes.

Topics: C-Peptide; Cell Communication; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelial Cells; Humans; Inflammation; Insulin; Microcirculation; Pain; Signal Transduction

C-peptide, which is formed during the biosynthesis of insulin, has long been considered as a biologically inactive substance. However in the recent years there is convincing evidence that the deficit of C-peptide in type 1 diabetes mellitus (DM) or its excess in DM2 lead to the development of disorders in the cardiovascular, nervous, excretory, and other systems of organism. It is shown than C-peptide in the physiological concentrations has anti-inflammatory, immunomodulatory and neuroprotective effects, so that it and its synthetic analogs can be widely used to treat diabetic patients and to prevent DM complications diabetes. To effectively use C-peptide in medicine it is necessary to study its structural-functional organization and the molecular mechanisms of regulatory action of C-peptide on the fundamental cellular processes. It is established that C-peptide coupled with Gi/o protein-coupled receptors of the serpentine type regulates the functional activity of many intracellular signaling pathways, which include phospholipase Cbeta, different forms of protein kinase C, phosphatidylinositol 3-kinases and mitogen-activated protein kinases, endothelial NO-synthase, Na+/K+-ATPase, a wide range of transcription factors and nuclear receptors. C-peptide controls the stability of the insulin hexamer complexes, and, thus,affects on the activity of insulin and insulin-regulated signaling pathways. The present review analyse the current state of the problem of structural-functional organization of C-peptide and its mechanism of action on the intracellular signaling pathways, as well as the prospects for the use of C-peptide in the fundamental biology and clinical medicine.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Extracellular Signal-Regulated MAP Kinases; Humans; Phosphatidylinositol 3-Kinases; Phospholipase C beta; Receptors, G-Protein-Coupled; Signal Transduction; Structure-Activity Relationship

Gradually, the C-peptide part of proinsulin has evolved from being viewed upon as a side product of insulin synthesis and secretion to being considered as a bioactive peptide with endocrine functions. Independent of these, its biophysical properties and peptide interactions point to still further roles of C-peptide, in particular regarding possible links to diabetes-related protein aggregations. Insulin, which can deposit at the injection sites in the treatment of diabetes, and islet amyloid polypeptide (IAPP), which can form amyloid fibrils in the islets of Langerhans in diabetes type 2, are kept nonaggregated by charge-based interactions with C-peptide at defined stoichiometries. It is possible that the conformational stabilization of insulin and IAPP by C-peptide may also counterbalance their aggregational tendencies at the high peptide concentrations in the pancreatic β-cell secretory granules. The concentration imbalances of C-peptide, insulin, and IAPP from the hyperpeptidism early in T2DM patients and the insulin-only injections in T1DM patients may distort equilibria of these peptide interactions and promote protein aggregation. Additionally, the chaperone-like actions of C-peptide may increase bioavailability of insulin supplements given to T1DM patients and prevent the formation of insulin deposits. Similarly, peptide interactions may influence depository tendencies in additional peptide systems. In short, biophysical studies are relevant to establish all roles of peptide imbalances in T1DM and T2DM and associated depository diseases.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Islet Amyloid Polypeptide; Molecular Chaperones

Type LADA diabetes is a form of autoimmune-mediated diabetes in adults. The progression of beta-cell failure is slower than in childhood type 1 diabetes. Patients with LADA present with more preserved beta cell function than those with classic type l diabetes. The diagnosis of LADA according to Immunology Diabetes Society is based on three features: age over 35 years, the presence at least one of four circulating autoantibodies to pancreatic islet cell antigens and lack of requirement for insulin at least 6 month after diagnosis. The level of C-peptide secretion after stimulation with intravenous glucagon administration helped to diagnosis. The optimal treatment of latent autoimmune diabetes in adults (LADA) is not established. Consider that early insulin treatment would result in better preservation of beta-cell function and metabolic control.

Topics: Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Disease Progression; Glucagon; Humans; Insulin; Islets of Langerhans

Diabetes results from insulin deficiency but despite this endogenous insulin secretion is infrequently measured. C-peptide is not present in synthetic insulin so it's presence indicates endogenous secretion. One of the key roles for measuring C-peptide in childhood is to assist in the diagnosis of diabetes subtypes, which in turn determines appropriate management. It is also useful in Type 1 diabetes to monitor disease course, both in clinical practice and in trials following intervention with disease modifying agents. Measuring C-peptide routinely in Type 1 diabetes provides valuable information to the patient and clinician about glucose variability, risk of hypoglycemia and ketoacidosis. Newer more practical methods of C-peptide determination are now available to allow assessment of endogenous insulin secretion in routine clinical practice. We review the physiology of insulin secretion, the essential roles and methods for C-peptide determination in blood and in urine.

Topics: Adolescent; Biomarkers; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Proinsulin

C-peptide is secreted from proinsulin and over the recent decade is considered as an active peptide that leads to different capillary actions and macrovascular complications in patients with type 2 diabetes mellitus. Results of the recent researches showed the C-peptide uptake in the blood vessel walls, in the juxtaglomerular apparatus of malpighian tuft, induction of local inflammation, proliferative effect on mesangial cell. The given effects showed an atherogenic role of C-peptide. Authors consider C-peptide as a possible predicator of cardiovascular complications and mortality in patients with type 2 diabetes mellitus and without diabetes.

Topics: Animals; C-Peptide; Capillaries; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans

Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5' flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox- 1(PDX-1), MafA, and β-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling- dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes.

Topics: Basic Helix-Loop-Helix Transcription Factors; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eye Proteins; Female; Gene Expression Regulation; Homeodomain Proteins; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Maf Transcription Factors, Large; Male; Paired Box Transcription Factors; PAX6 Transcription Factor; Protein Precursors; Repressor Proteins; RNA, Messenger; Trans-Activators

Proinsulin C-peptide, released in equimolar amounts with insulin by pancreatic β cells, since its discovery in 1967 has been thought to be devoid of biological functions apart from correct insulin processing and formation of disulfide bonds between A and B chains. However, in the last two decades research has brought a substantial amount of data indicating a crucial role of C-peptide in regulating various processes in different types of cells and organs. C-peptide acts presumably via either G-protein-coupled receptor or directly inside the cell, after being internalized. However, a receptor binding this peptide has not been identified yet. This peptide ameliorates pathological changes induced by type 1 diabetes mellitus, including glomerular hyperfiltration, vessel endothelium inflammation and neuron demyelinization. In diabetic patients and diabetic animal models, C-peptide substitution in physiological doses improves the functional and structural properties of peripheral neurons and protects against hyperglycemia-induced apoptosis, promoting neuronal development, regeneration and cell survival. Moreover, it affects glycogen synthesis in skeletal muscles. In vitro C-peptide promotes disaggregation of insulin oligomers, thus enhancing its bioavailability and effects on metabolism. There are controversies concerning the biological action of C-peptide, particularly with respect to its effect on Na⁺/K⁺-ATPase activity. Surprisingly, the excess of circulating peptide associated with diabetes type 2 contributes to atherosclerosis development. In view of these observations, long-term, large-scale clinical investigations using C-peptide physiological doses need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to diabetic patients.

Topics: Animals; Apoptosis; Atherosclerosis; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Disease Models, Animal; Glycogen; Humans; Hyperglycemia; Muscle, Skeletal; Peripheral Nervous System

This review focuses on recent literature on insulin resistance in youth with type 2 diabetes mellitus (T2DM). Insulin resistance is associated with a variety of cardiometabolic problems leading to increased morbidity and mortality across the lifespan.. Functional pancreatic β-cell changes play a role in the transition from obesity to impaired glucose tolerance (IGT). Insulin resistance drives islet cell upregulation, manifested by elevated glucagon and c-peptide levels, early in the transition to IGT. Surrogate measurements of insulin resistance and insulin secretion exist but their accuracy compared to clamp data is imperfect. Recent large longitudinal studies provide detailed information on the progression from normoglycemia to T2DM and on the phenotype of T2DM youth. Defining prediabetes and T2DM remains a challenge in youth. Lifestyle interventions do not appear as effective in children as in adults. Metformin remains the only oral hypoglycemic agent approved for T2DM in youth.. New insights exist regarding the conversion from insulin resistance to T2DM, measurement of insulin resistance and phenotypes of insulin resistance youth, but more information is needed. Surrogate measurements of insulin resistance, additional treatment options for insulin resistance and individualization of treatment options for T2DM adolescents in particular require further investigation.

Topics: Adolescent; Body Mass Index; C-Peptide; Child; Diabetes Mellitus, Type 2; Exercise Tolerance; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Metformin; Obesity; Phenotype; Young Adult

A large body of epidemiologic evidence provides strong support for the notion that type-2 diabetics are at decreased risk for prostate cancer. In this review article, we summarize the epidemiologic literature that explores the role of diabetes mellitus and related biomarkers in prostate cancer risk and detection, in order to create a better understanding of the potential mechanisms that underlie this inverse association. The bulk of the data supporting this association comes from the USA, as evidence for this association is less consistent in many other regions of the world. The relationship between diabetes and prostate cancer is suspected to be causal due to evidence of decreasing prostate cancer risk with increasing diabetes duration and lack of evidence for any confounding of this association. Hypothesized mechanisms for decreased prostate cancer risk among diabetics include (1) decreased levels of hormones and other cancer-related growth factors among diabetics, (2) the impact of diabetes on detection-related factors, such as prostate size, circulating prostate-specific antigen (PSA), and health-care seeking behaviors, (3) protective effects of diabetes medications, and (4) a protective effect of diabetes-induced vascular damage in the prostate. The evidence for screening-related factors is compelling, as diabetics appear to have reduced PSA and lower levels of health-care seeking behavior compared with nondiabetics. Furthermore, the inverse association between diabetes and prostate cancer is much less apparent in populations that do not perform biopsies based on PSA levels and in studies restricted to biopsied individuals. The inverse association appears to be stronger for low-grade disease, as compared with high-grade (Gleason >7), which is consistent with the observation that among patients receiving biopsy or prostate cancer treatment, diabetics are more likely to have high-grade disease as compared to nondiabetics, potentially resulting in worse outcomes for diabetics. Epidemiological research has reveals a great deal regarding the relationship between diabetes and prostate cancer risk, but additional research is needed to further clarify the mechanisms underlying this inverse association.

Topics: Androgens; C-Peptide; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; United States

Topics: C-Peptide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins

This article reviews the outcome of pancreas transplantations in diabetic recipients according to risk factors, surgical techniques, and immunosuppression management that evolved over the course of a decade at Wake Forest Baptist Medical Center. A randomized trial of alemtuzumab versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous kidney-pancreas transplantation (SKPT) at our institution demonstrated lower rates of acute rejection and infection in the alemtuzumab group. Consequently, alemtuzumab induction has been used exclusively in all pancreas transplantations since February 2009. Early steroid elimination has been feasible in the majority of patients. Extensive experience with surveillance pancreas biopsies in solitary pancreas transplantation (SPT) is described. Surveillance pancreas biopsy-directed immunosuppression has contributed to equivalent long-term pancreas graft survival rates in SKPT and SPT recipients at our center, in contrast to recent registry reports of persistently higher rates of immunologic pancreas graft loss in SPT. Furthermore, the impact of donor and recipient selection on outcomes is explored. Excellent results have been achieved with older (extended) donors and recipients, in recipients of organs from donation after cardiac death donors managed with extracorporeal support, and in African-American patients. Type 2 diabetics with detectable C-peptide levels have been transplanted successfully with outcomes comparable to those of insulinopenic diabetics. Our experiences are discussed in the light of findings reported in the literature.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Kidney Transplantation; Pancreas; Pancreas Transplantation; Randomized Controlled Trials as Topic

Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes.. To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN.. Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-kappaB and peroxisome proliferator-activated receptor-gamma.. Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Fibrosis; Humans; Hyperglycemia; Models, Biological; NF-kappa B; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Protein Kinase C; Sodium-Potassium-Exchanging ATPase

This article emphasizes (1) the utility of routine measurement of pro-insulin to insulin ratio as a specific marker of insulin resistance and predictor of future T2DM, HT and CAD, (2) routine C-Peptide estimation to determine which T2DM needs insulin and to monitor the effect of newer drugs which promote beta cell regeneration, (3) routine estimation of adiponectin and TNF alpha and monitor response to thiozolidine drugs which increases adiponectin and decreases TNF alpha production by adipocytes, (4) crucial role of AMPK--Cellular energy sensor in mediating the beneficial effects of exercise as well as drugs (adiponectin, metformin) in T2DM, (5) Availability of glucogon suppressors will eliminate the need for giving insulin to T2 DM with normal C Pepetide levels which inevitably causes undesirable weight gain & hypoglycemia.

Topics: Adipocytes; Adiponectin; AMP-Activated Protein Kinases; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Tumor Necrosis Factor-alpha

Topics: Albuminuria; Animals; Biomarkers; C-Peptide; Calmodulin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Insulin; Insulin-Secreting Cells; Metabolic Syndrome; Receptors, G-Protein-Coupled; Sodium-Potassium-Exchanging ATPase

In recent years, accumulating evidence indicates a biological function for proinsulin C-peptide. These results challenge the traditional view that C-peptide is essentially inert and only useful as a surrogate marker of insulin release. Accordingly, it is now clear that C-peptide binds with high affinity to cell membranes, probably to a pertussis-toxin-sensitive G-protein-coupled receptor. Subsequently, multiple signalling pathways are potently and dose-dependently activated in multiple cell types by C-peptide with the resulting activation of gene transcription and altered cell phenotype. In diabetic animals and Type 1 diabetic patients, short-term studies indicate that C-peptide also enhances glucose disposal and metabolic control. Furthermore, results derived from animal models and clinical studies in Type 1 diabetic patients suggest a salutary effect of C-peptide in the prevention and amelioration of diabetic nephropathy and neuropathy. Therefore a picture of Type 1 diabetes as a dual-hormone-deficiency disease is developing, suggesting that the replacement of C-peptide alongside insulin should be considered in its management.

Topics: Animals; Blood Glucose; C-Peptide; Cell Membrane; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Humans; Mice

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Diabetic subjects show a remarkable increase in vascular complications, including myocardial infarction and strokes. The accelerated atherosclerosis in these patients is likely to be multifactorial. In this review, we focus on the advanced glycation end product (AGE)-receptor for AGE (RAGE) axis and the role of C-peptide as a mediator of lesion development. AGEs are proteins or lipids that become glycated after exposure to sugars. By engaging the RAGEs, AGEs induce the expression of proinflammatory mediators in various vascular cell types and are involved in a variety of microvascular and macrovascular complications. In animal models, interruption of the AGE-RAGE interaction reduces lesion size and plaque development and RAGE deficiency in a RAGE(-/-)/apolipoprotein E(-/-) double knockout mouse attenuates the development of atherosclerosis in diabetes. On the other side, patients with type 2 diabetes show increased levels of C-peptide and over the last years various groups examined the effect of C-peptide in vascular cells as well as its potential role in lesion development. Recent data suggest that the proinsulin cleavage product C-peptide could play a causal role in atherogenesis by promoting monocyte and CD4-positive lymphocyte recruitment in early arteriosclerotic lesions and by inducing the proliferation of vascular smooth muscle cells. The following review will summarize these two pathophysiological aspects and discuss on the one hand the potential role of the activated AGE-RAGE axis in diabetes-accelerated atherogenesis and on the other hand the role of C-peptide as a mediator in lesion development in patients with type 2 diabetes.

Topics: Animals; Apolipoproteins E; Atherosclerosis; C-Peptide; CD4-Positive T-Lymphocytes; Cell Proliferation; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Expression Regulation; Glycation End Products, Advanced; Humans; Inflammation Mediators; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Monocytes; Myocardial Infarction; Myocytes, Smooth Muscle; Receptor for Advanced Glycation End Products; Stroke

To assess the effects of 24-week treatment with vildagliptin on measures of beta-cell function in a broad spectrum of drug-naïve patients with type 2 diabetes (T2DM).. Data from all double-blind, multicentre, randomized, placebo- or active-controlled trials conducted in drug-naïve patients with T2DM were pooled from all patients receiving monotherapy with vildagliptin (100 mg daily: 50 mg twice daily or 100 mg once daily, n = 1855) or placebo (n = 347). Fasting measures of beta-cell function [homeostasis model assessment of beta-cell function (HOMA-B) and proinsulin : insulin ratio] were assessed in the overall pooled monotherapy population. Standard meal tests were performed at baseline and week 24 in a subset of patients, and effects of vildagliptin (100 mg daily, n = 227) on dynamic (meal test-derived) measures of beta-cell function [insulin secretion rate relative to glucose (ISR/G) and insulinogenic indices] were assessed relative to baseline and vs. placebo (n = 29).. In the overall population, vildagliptin significantly increased HOMA-B both relative to baseline [adjusted mean change (AMDelta) = 10.3 +/- 1.5] and vs. placebo (between-treatment difference in AMDelta = 11.5 +/- 4.5, p = 0.01) and significantly decreased the proinsulin : insulin ratio relative to baseline (AMDelta = -0.05 +/- 0.01) and vs. placebo (between-treatment difference in AMDelta = -0.09 +/- 0.02, p < 0.001). Relative to baseline, vildagliptin monotherapy significantly increased all meal test-derived parameters, and ISR/G (between-treatment difference in AMDelta = 9.8 +/- 2.8 pmol/min/m(2)/mM, p < 0.001) and the insulinogenic index(0-peak glucose) (between-treatment difference in AMDelta = 0.24 +/- 0.05 pmol/mmol, p = 0.045) were significantly increased vs. placebo.. Vildagliptin monotherapy consistently produced robust improvements in both fasting and meal test-derived measures of beta-cell function across a broad spectrum of drug-naïve patients with T2DM. All Phase III trials described (NCT 00099905, NCT 00099866, NCT 00099918, NCT 00101673, NCT 00101803 and NCT 00120536) are registered with ClinicalTrials.gov.

Topics: Adamantane; Aged; Biomarkers; Blood Glucose; C-Peptide; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Multicenter Studies as Topic; Nitriles; Pyrrolidines; Vildagliptin

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show increased levels of C-peptide and over the last years various groups examined the effect of C-peptide in vascular cells as well as its potential role in lesion development. While some studies demonstrated beneficial effects of C-peptide, for example, by showing an inhibition of smooth muscle cell proliferation, others suggested proatherogenic mechanisms in patients with type 2 diabetes. Among them, C-peptide may facilitate the recruitment of inflammatory cells into early lesions and promote lesion progression by inducing smooth muscle cell proliferation. The following review will summarize the effects of C-peptide in vascular cells and discuss the potential role of C-peptide in atherogenesis in patients with type 2 diabetes.

Topics: Atherosclerosis; C-Peptide; Cell Division; Chemotaxis, Leukocyte; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Muscle, Smooth, Vascular

The prevalence of latent autoimmune diabetes of the adult (LADA) varies according to the population studied, criteria used and antibodies analyzed. In a series of 256 patients > 25 years, we found that 26 (10.2%) were anti-GAD antibody (GADA) positive and 16 of them (6.3%) progressed without initial insulin requirement. Although controversy exists, the following diagnostic criteria for LADA are suggested: age between 25 and 65 years; absence of ketoacidosis or symptomatic hyperglycemia at diagnosis or immediately thereafter, without insulin requirement for 6-12 months; and presence of autoantibodies (especially GADA). Autoimmunity and insulin resistance coexist in LADA and the contribution of these factors seems to be reflected in GADA titers. A subgroup, which is phenotypically and in terms of insulin requirement similar to type 2 diabetic patients, seems to be better identified based on the presence of low GADA titers, especially when these antibodies are present alone. On the other hand, subjects with high GADA titers and multiple antibodies show a phenotype close to that of classical DM 1 and are at a higher risk of premature beta-cell failure. Compared to GADA-negative diabetics, patients with LADA present a higher prevalence of other autoantibodies (anti-TPO, anti-21-hydroxylase and antibodies associated with celiac disease) and a higher frequency of genotypes and haplotypes indicating a risk for DM 1. Patients with high GADA titers may benefit from early insulinization and avoiding the use of sulfonylureas, delaying beta-cell failure. In contrast, patients with low GADA titers do not seem to have any disadvantage when managed as type 2 diabetic patients (GADA negative).

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmunity; Biomarkers; Brazil; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Genetic Predisposition to Disease; Glutamate Decarboxylase; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Middle Aged; Prevalence; Young Adult

Latent autoimmune diabetes in Adults (LADA) is a slowly developing type 1 diabetes which presents as non-insulin dependent diabetes and progresses to insulin dependence. However, the best treatment strategy for LADA is unclear.. To compare interventions used for LADA.. Studies were obtained from searches of electronic databases (including MEDLINE, EMBASE), supplemented by hand searches, conference proceedings and consultation with experts.. Selection was in duplicate by two independent reviewers. RCT and controlled clinical trials evaluating interventions for LADA or type 2 diabetes with antibodies were included.. Two reviewers independently extracted data and assessed study quality. Studies were summarised in a descriptive manner.. Searches identified 8067 citations. Eight publications (seven studies) were included, involving 735 participants. All studies had high risk of bias. There were no data on use of metformin or glitazones alone. Rosiglitazone or sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone. SU alone gave either poorer (one study, mean difference in HbA1c 2.8% (95% confidence interval (CI) 0.9 to 4.7) or equivalent metabolic control compared to insulin alone (two studies). There was evidence that SU caused earlier insulin dependence (insulin treated at two years: 60% (SU) and 5% (conventional care) (P < 0.001); classified insulin dependent: 64% (SU) and 12.5% (insulin group) (P = 0.007)). No interventions influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5) and insulin with rosiglitazone was superior to insulin alone (one study) at maintaining stimulated C-peptide. A pilot study showed better metabolic control at six months with subcutaneously administered glutamic acid decarboxylase (GAD) GAD65, a major autoantigen in autoimmune diabetes, compared to placebo. There was no information regarding quality of life, mortality, complications or costs in any of the publications. Time from diagnosis varied between recruitment at diagnosis to recruitment at nine years of disease duration and there was a great deal of variation in the selection criteria for LADA patients, making it difficult to generalise findings from these studies.. There are few studies on this topic and existing studies have a high risk of bias. However, there does seem to be an indication that SU should not be a first line treatment for antibody positive type 2 diabetes. There is no significant evidence for or against other lines of treatment of LADA.

Topics: Adult; Autoimmune Diseases; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Randomized Controlled Trials as Topic; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones

Type 2 diabetes mellitus (T2DM) has dramatically increased throughout the world in many ethnic groups and among people with diverse social and economic backgrounds. This increase has also affected the young such that over the past decade, the increase in the number of children and youth with T2DM has been labeled an 'epidemic'. Before the 1990s, it was rare for most pediatric centers to have significant numbers of patients with T2DM. However, by 1994, T2DM patients represented up to 16% of new cases of diabetes in children in urban areas and by 1999, depending on geographic location, the range of percentage of new cases because of T2DM was 8-45% and disproportionately represented among minority populations. Although the diagnosis was initially regarded with skepticism, T2DM is now a serious diagnostic consideration in all young people who present with signs and symptoms of diabetes in the USA.

Topics: Adolescent; Age of Onset; C-Peptide; Child; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diet, Diabetic; Exercise; Humans; Hypoglycemic Agents; Insulin; Obesity; Patient Education as Topic; Sex Factors

Diabetic polyneuropathy (DPN) is the most common late diabetic complication, and is more frequent and severe in the type 1 diabetic population. Currently, no effective therapy exists to prevent or treat this complication. Hyperglycemia remains a major therapeutic target when dealing with DPN in both type 1 and type 2 diabetes, and should be supplemented by aldose reductase inhibition and antioxidant treatment. However, in the past few years, preclinical and clinical data have indicated that factors other than hyperglycemia contribute to DPN, and these factors account for the disproportionality of prevalence of DPN between the two types of diabetes. Insulin and C-peptide deficiencies have emerged as important pathogenetic factors and underlie the acute metabolic abnormalities, as well as serious chronic perturbations of gene regulatory mechanisms, impaired neurotrophism, protein-protein interactions and specific degenerative disorders that characterize type 1 DPN. It has become apparent that in insulin-deficient conditions, such as type 1 diabetes and advanced type 2 diabetes, both insulin and C-peptide must be replaced in order to gain hyperglycemic control and to combat complications. As with any chronic ailment, emphasis should be on the prevention of DPN; as the disease progresses, metabolic interventions, be they directed against hyperglycemia and its consequences or against insulin/ C-peptide deficiencies, are likely to be increasingly ineffective.

Topics: Aldehyde Reductase; Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Hyperglycemia; Lipid Metabolism; Nerve Degeneration; Nerve Growth Factor; Oxidative Stress; Polymers

Topics: Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Postprandial Period; Severity of Illness Index; Time Factors

Topics: Adiponectin; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Intercellular Signaling Peptides and Proteins; Leptin

Topics: Biomarkers; C-Peptide; Chromatography, Gel; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Factitious Disorders; Humans; Hypoglycemia; Immunoassay; Insulin Resistance; Insulin-Secreting Cells; Insulinoma; Kidney Diseases; Pancreatic Function Tests; Pancreatic Neoplasms; Proinsulin; Reference Values; Specimen Handling

Topics: Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Markers; Genetic Predisposition to Disease; Glutamate Decarboxylase; Humans; Insulin; Islets of Langerhans; Predictive Value of Tests; Terminology as Topic

Diabetes is an increasingly common disorder which causes and contributes to a variety of central nervous system (CNS) complications which are often associated with cognitive deficits. There appear to be two types of diabetic encephalopathy. Primary diabetic encephalopathy is caused by hyperglycemia and impaired insulin action, which evolves in a diabetes duration-related fashion and is associated with apoptotic neuronal loss and cognitive decline. This appears to be particularly associated with insulin-deficient diabetes. Secondary diabetic encephalopathy appears to arise from hypoxic-ischemic insults due to underlying microvascular disease or as a consequence of hypoglycemia. This type of cerebral diabetic complication is more common in the type 2 diabetic population. Here, we will review the clinical and experimental data supporting this conceptual division of diabetic CNS complications and discuss the underlying metabolic, molecular, and functional aberrations.

Topics: Animals; Apoptosis; C-Peptide; Central Nervous System Diseases; Cognition; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Insulin

The incretin hormone glucagon-like peptide 1 (GLP-1) has a promising potential for the treatment of type 2 diabetes due to its glucose-dependent insulinotropic and glucagonostatic properties. In addition, the peptide potently decelerates gastric emptying and inhibits appetite, thereby leading to reduced food intake. In animal studies, GLP-1 has been demonstrated to increase B-cell mass via inhibition of apoptosis and stimulation of B-cell replication and neogenesis. However, an in vivo half-life in the range of minutes limits the therapeutic use of the native peptide GLP-1. Different pharmacological approaches to overcome these problems are currently being evaluated. They include the continuous parenteral administration of the peptide via infusion pumps, the inhibition of its in vivo degradation and the generation or use of modified derivatives/analogs of GLP-1 displaying prolonged biological activity. The physiological effects of GLP-1 and its pharmacokinetic limitations will be reviewed here, and the current therapeutic approaches based on GLP-1 discussed.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Injections, Intravenous; Injections, Subcutaneous; Insulin; Peptide Fragments; Protein Precursors

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Humans; Neural Conduction; Nitric Oxide Synthase; Randomized Controlled Trials as Topic; Sodium-Potassium-Exchanging ATPase

Autoimmune markers such as islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and islet antigen-2 antibodies (IA-2A) are found in high frequencies among type 1 patients and especially among younger patients. Presence of these autoantibodies confirms the destructive process of the beta cells associated with immune-mediated type 1 diabetes. Type 2 diabetes is characterised by peripheral insulin resistance and a relative deficiency in insulin production. However, when autoimmune markers are analysed these are found in about 10% of patients clinically classified as type 2 diabetes, indicating that the frequency of type 1 diabetes is underestimated. GADA is the most frequent marker both among patients clinically classified as type 1 and type 2. GADA is also highly predictive for insulin treatment in patients not classified as type 1 diabetes. C-peptide is the best marker of the endogenous insulin production. Sampling of C-peptide is preferably done in the non-fasting condition since these values differentiate better between autoimmune and non-autoimmune diabetes. The presence of autoimmune markers at diagnosis predicts a course of further deteriorating beta cell function, whereas absence of autoimmune markers predicts stable beta cell function for the first two years in adults. Presence of GADA and in particular in high levels are prognostic for a low beta cell function within the next few years after diagnosis. Positivity only for ICA indicates a more preserved beta cell function for the first three years compared to positivity for other autoimmune markers.

Topics: Autoantibodies; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans

A loss of early-phase insulin response is common in Type II diabetic patients and in people with impaired glucose metabolism. It is hypothesized that this alteration is not simply a marker for the risk of developing diabetes, rather it is a an important pathogenetic mechanism causing excessive postprandial hyperglycaemia.. Relevant literature on the epidemiology, physiopathology, and therapeutic intervention related to loss of early insulin secretion and postprandial hyperglycaemia has been analysed.. In response to intravenous glucose, insulin secretion is biphasic. This behaviour translates as a rapid release of insulin into the blood stream in response to the ingestion of carbohydrates or a mixed meal. The rapid increase in portal insulin concentration and the avid binding of the hormone to its receptor on liver cell membranes, account for a prompt suppression of endogenous glucose production and reduction of the rate of increase in plasma glucose concentrations. This has been supported by experimental studies carried out in both animals and humans: the selective abolition of early insulin secretion in healthy subjects results in impaired glucose tolerance, excessive glucose excursions, and possible hampering of the thermic effects of ingested carbohydrates. In non-diabetic subjects, the loss of early insulin secretion is a determinant for developing diabetes. The critical role of the early-phase insulin response in determining postprandial hyperglycaemia, is supported by an amelioration of glucose tolerance by restoring the acute rise in plasma insulin concentrations after the ingestion of both glucose and a mixed meal. This amelioration in plasma glucose profile can prevent late hyperglycaemia and hyperinsulinaemia.. Therapeutic approaches aimed at restoring a physiological pattern of insulin secretion could prove effective in reducing postprandial glucose excursions particularly in the early stage of Type II diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Food; Homeostasis; Humans; Hyperglycemia; Insulin; Insulin Secretion

Diabetic polyneuropathy (DPN) is the most common chronic complication of diabetes and affects Type 1 diabetic patients disproportionately. In the last two decades it has become increasingly evident that underlying metabolic, molecular and functional mechanisms and, ultimately, structural changes differ in DPN between the two major types of diabetes. In Type 1 diabetes, impaired insulin/C-peptide action has emerged as a prominent pathogenetic factor. C-peptide was long considered to be biologically inactive. During the last number of years it has been shown to have a number of insulin-like effects but without affecting blood glucose levels. Preclinical studies have demonstrated effects on Na(+)/K(+)-ATPase activity, endothelial nitric oxide synthase, expression of neurotrophic factors and regulation of molecular species underlying the degeneration of the nodal apparatus in Type 1 diabetic nerves, as well as DNA binding of transcription factors and modulation of apoptotic phenomena. In animal studies, these effects have translated into protection and improvement of functional abnormalities, promotion of nerve fibre regeneration, protection of structural changes and amelioration of apoptotic phenomena targeting central and peripheral nerve cell constituents. Several small-scale clinical trials confirm these beneficial effects on autonomic and somatic nerve function and blood flow in a variety of tissues. Therefore, evidence to date indicating that replacement of C-peptide in patients with Type 1 diabetes will retard and prevent chronic complication is real and encouraging. Large-scale clinical trials necessary to bring this natural substance into the clinical arena should, therefore, be encouraged and accelerated.

Topics: C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Insulin

After the ingestion of fat- and glucose-rich meals, gut hormones are secreted into the circulation in order to stimulate insulin secretion. This so-called "incretin effect" is primarily conferred by Glucagon-like peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP). In contrast to GLP-1, GIP has lost most of its insulinotropic effect in type 2 diabetic patients. In addition to its main physiological role in the regulation of endocrine pancreatic secretion, GIP exerts various peripheral effects on adipose tissue and lipid metabolism, thereby leading to increased lipid deposition in the postprandial state. In some animal models, an influence on gastrointestinal functions has been described. However, such effects do not seem to play an important role in humans. During the last years, the major line of research has focussed on GLP-1, due to its promising potential for the treatment of type 2 diabetes mellitus. However, the physiological importance of GIP in the regulation of insulin secretion has been shown to even exceed that of GLP-1. Furthermore, work from various groups has provided evidence that GIP contributes to the pathogenesis of type 2 diabetes to a considerable degree. Recent data with modified GIP analogues further suggested a possibility of therapeutic use in the treatment of type 2 diabetes. Thus, it seems worthwhile to refocus on this important and-sometimes-neglected incretin hormone. The present work aims to review the physiological functions of GIP, to characterize its role in the pathogenesis of type 2 diabetes, and to discuss possible clinical applications and future perspectives in the light of new findings.

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Lipids; Models, Biological; Molecular Sequence Data; Pancreatic Hormones; Peptide Fragments; Postprandial Period; Protein Precursors; Secretin; Sequence Homology, Amino Acid; Stomach

Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Glucoregulatory abnormalities have also been associated with the use of antipsychotic medications themselves. While antipsychotics may increase adiposity, which can decrease insulin sensitivity, disease- and medication-related differences in glucose regulation might also occur independent of differences in adiposity.. Modified oral glucose tolerance tests were performed in schizophrenic patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical antipsychotics, and untreated healthy control subjects (n = 31), excluding subjects with diabetes and matching groups for adiposity and age. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load.. Significant time x treatment group interactions were detected for plasma glucose (F(12,222) = 4.89, P<.001) and insulin (F(12,171) = 2.10, P =.02) levels, with significant effects of treatment group on plasma glucose level at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at all time points, in comparison with patients receiving typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75 minutes after load, again in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose level were detected when comparing risperidone-treated vs typical antipsychotic-treated patients and when comparing typical antipsychotic-treated patients vs untreated control subjects.. Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Brief Psychiatric Rating Scale; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose; Humans; Hydrocortisone; Insulin; Male; Obesity; Schizophrenia

The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has substantially increased over the past decade. This is attributed to obesity, insulin resistance and deficient beta-cell function. In children a pubertal increase in insulin resistance and an inability to mount an adequate beta-cell insulin response results in hyperglycemia. Adults with T2DM have a diminished first phase response to intravenous glucose and a delayed early insulin response to oral glucose. Long-term studies show progressive loss of beta-cell function in T2DM in adults; however, such long-term studies are not available in children. To characterize beta- and alpha-cell function in African-American adolescents with established T2DM, we used mixed meal, intravenous glucagon and oral glucose tolerance testing and compared them to obese non-diabetic controls. T2DM was defined as fasting C-peptide >0.232 nmol/l and absent autoimmune markers. BETA-CELL FUNCTION: Meal testing in 24 children and adolescents with T2DM, mean age 14 years, BMI 30 kg/m2, Tanner stage II-V, HbA1c 8.9%, were compared with BMI- and age-matched controls. Forty percent presented with DKA. Half were treated with insulin and half with diet/oral anti-diabetic agents. Although absolute C-peptide response in both groups was similar, the incremental rise in C-peptide relative to plasma glucose in the patients with T2DM compared to controls was 40% and 35% lower 30 and 60 min after the meal, p <0.007 and p <0.026. Glucagon testing in 20 pediatric patients with T2DM compared with 15 matched controls showed significantly lower 6 min stimulated C-peptide relative to the ambient plasma glucose in patients with T2DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p <0.05). The clinical utility is that 78% of patients with a 6 min C-peptide <1.4 nmol required insulin, while 81% of those >1.4 nmol required oral anti-diabetic agents, p <0.0001. Furthermore, the duration of T2DM up to 5 years after diagnosis was associated with lower fasting and glucagon-stimulated C-peptide levels, implying worsening beta-cell function over time, even in children and adolescents. ALPHA-CELL FUNCTION: During meal testing, children and adolescents with T2DM had less suppression of plasma glucagon than non-diabetic controls; this was more severe with longer duration of T2DM and poorer glycemic control. BETA-CELL RECOVERY: In African-American and Hispanic adults, intensive treatment of blood glucose may achieve beta-cell. T2DM in children, as in adults, is characterized by insulin deficiency relative to insulin resistance. Plasma C-peptide levels may be clinically useful in guiding therapeutic choices, since patients with lower levels required insulin treatment; beta-cell function is also diminished with longer duration of T2DM. The possibility exists that in children, as in adults, intensive glycemic regulation may allow for beta-cell recovery and preservation. Thus, optimum beta- and alpha-cell function are central to the prevention of DM and maintenance of good glycemic control in African-American and Hispanic children and adolescents with T2DM.

Topics: Adolescent; Adult; Black People; Body Mass Index; C-Peptide; Child; Diabetes Mellitus, Type 2; Food; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Puberty

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Humans; Hypoglycemia; Immunoassay; Insulin; Proinsulin; Reagent Kits, Diagnostic

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Humans; Hypoglycemic Agents; Insulin; Liver; Reference Values; Tolbutamide

The classification of newly diagnosed diabetic patients as type I (insulin-dependent) or type II (non-insulin-dependent) diabetes and the implied therapeutical consequences there of are based on clinical observations and laboratory tests. In case differential diagnosis is difficult, the measurement of the c-peptide secretion to assess beta-cell capacity can be helpful. For adequate control especially after long-standing diabetes in obese patients it is important to identify patients with potential secondary drug failure. Poor compliance with diet is thought to be a major reason for poor response to treatment. On the other hand, diabetics with poor control because of deterioration of beta-cell function must be distinguished. In these situations the measurement of c-peptide concentrations may contribute to identify the need for insulin treatment. As a result the development of diabetic complications can be retarded and beta-cell function can be preserved by adequate insulin therapy, whereas the consequences of hyperinsulinaemia in insulin treated patients not needing insulin can be avoided. In our opinion the c-peptide/glucose-quotient serves as simple, cost-effective and non-invasive method in the assessment of beta-cell capacity. Insulin therapy is indispensable in the case of inadequate insulin secretion.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Male; Middle Aged; Predictive Value of Tests

This review is meant to give to the readers an overview of the pharmacokinetics, pharmacodynamics, mechanism(s) of action and therapeutical indications of the sulfonylurea compound glibenclamide, which is a cardinal drug in the treatment of type 2 diabetes mellitus. Data produced in our own laboratory over the past 15 years will be presented, along with reference to the main literature in the field. As pharmacokinetics is concerned, special emphasis will be placed on the detrimental effect of hyperglycemia in the intestinal absorption of this class of drugs. Both beta-cell and extrapancreatic effects of glibenclamide will be highlighted. The mechanism of action of the drug consists in the inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells and insulin secretion. Based on the same mechanism are also the extrapancreatic action of the drug at the liver, skeletal muscle, heart muscle and smooth muscle sites. The newly discovered possible physiological actions of the C-peptide molecule [suggesting a stimulatory effect of C-peptide on the Na+, K+ (ATPase) pump and on diabetic complications], cast a new light on all therapeutic approaches (like sulfonylurea class of compounds and whole pancreas or islet of Langerhans transplantation), which induce/replace both insulin and C-peptide secretion.

Topics: Adipose Tissue; C-Peptide; Central Nervous System; Diabetes Mellitus, Type 2; Glyburide; Heart; Humans; Hypoglycemic Agents; Islets of Langerhans; Liver; Muscle, Skeletal; Potassium Channels

Numerous studies demonstrate the efficacy of the combination therapy of insulin and sulfonylurea in subjects with type II diabetes mellitus. However, two recent meta-analyses of randomized trials during the last decade provided inconsistent conclusions and failed to resolve the controversy.. To assess the efficacy of insulin and sulfonylurea combination therapy in type II diabetes mellitus by performing meta-analysis of only the controlled studies selected according to specific strict criteria.. A computerized literature survey was conducted using the MEDLINE database from January 1980 through March 1992 with the search headings of "sulfonylurea" and "insulin" and "combination therapy in diabetes mellitus. "A manual search was also performed using references from each retrieved report. Case reports, review articles, editorials, and citations reported in non-English-language journals without English translations were excluded. Forty-three citations were obtained. Four strict inclusion criteria were used to select studies: randomized, placebo-controlled trials (oral agent plus insulin vs placebo plus insulin); homogeneous target population (subjects with type II diabetes); intervention using the same sulfonylurea agent in a combination therapy; and uniform outcome measures to evaluate efficacy such as body weight; values for serum glucose, glycohemoglobin, and C peptide; daily insulin dosage; and lipid concentrations. More stringent qualitative subcriteria were then used to eliminate bias in the final unanimous selection by two blinded reviewers. Data were pooled and analyzed using Student's t test and Winer's combined test.. Sixteen studies satisfied the inclusion criteria. Metabolic control improved with the combination therapy as reflected by a significant lowering of fasting serum glucose values (P < .01) and glycohemoglobin concentrations (P < .025). Moreover, improved metabolic control was achieved with a significantly smaller daily insulin dose (P < .01) and without a significant change in body weight. Finally, the combination therapy enhanced the endogenous insulin secretion as expressed by an increase in fasting serum C peptide concentration (P < .05).. Combination therapy with insulin and sulfonylurea may be a more appropriate and a suitable option to insulin monotherapy in subjects with non-insulin-dependent diabetes in whom primary or secondary failure to sulfonylurea developed. It may also be a more cost-effective way of long-term management in this group of subjects, especially in the elderly.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Male; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Treatment Outcome

The hormone insulin remains the cornerstone of diabetic therapy since it is required for almost all cases of Type 1 and many cases of Type 2 diabetes. Since the discovery of insulin in 1921, much has been learned about its chemistry, structure and action as well as its production in the beta cell. Insulin is formed through a series of precursors, beginning with preproinsulin, the protein encoded in the insulin gene. These precursors direct the prohormone into the secretory pathway and ultimately into the secretory granules where it is converted into insulin and C-peptide. These products are stored and secreted together in a highly regulated manner in response to glucose and other stimuli. This review focuses on the recently discovered prohormone convertases, PC2 and PC3 (PC1), the enzymes responsible for the endoproteolytic processing of proinsulin to insulin and C-peptide in the beta cell as well as for the selective processing of proglucagon to glucagon in the alpha cell or GLP1 in intestinal L-cells. PC2 and PC3 are calcium-dependent serine proteases related to the bacterial enzyme subtilisin. They cleave selectively at Lys-Arg or Arg-Arg sites in precursors, generating products with C-terminal basic residues that are then removed by carboxypeptidase E, an exopeptidase. All 3 enzymes are expressed mainly in secretory granules of neuroendocrine cells throughout the body and in the brain. Inherited defects affecting the prohormone-processing enzymes have recently been found in association with unusual syndromes of obesity and other metabolic disorders.

Topics: Animals; Aspartic Acid Endopeptidases; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Islets of Langerhans; Obesity; Organ Specificity; Proinsulin; Proprotein Convertase 2; Proprotein Convertases; Subtilisins

Major genes for NIDDM appear to be rare. Therefore, phenotypic characterization of the pathophysiological changes contributing to hyperglycaemia are assuming increasing importance. Assessment of beta-cell function has been hampered by two major confounding factors during functional testing: variable insulin sensitivity and plasma glucose levels. These and other methodological variables are discussed with recommendations for ameliorating or accounting for their impact. A group of tests as used by the Seattle Group for phenotypic characterization is described including basal immunoreactive insulin (IRI), proinsulin, and proinsulin intermediates (PI); the acute insulin response to glucose (AIRg); maximal (AIRmax), and half-maximal (PG50) capacity to potentiate a non-glucose secretagogue; and insulin-sensitivity (S1). Specific examples in the use of this battery of tests are given. It is concluded that such phenotyping will be an important tool for studies of the epidemiology and genetics of NIDDM.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Phenotype; Proinsulin; Risk Factors

The search for the genetic basis of NIDDM has magnified the need for an efficient representation of the pre-NIDDM phenotype. The overall goal is to relate specific mutations on the genome to specific changes in physiologic function which lead to NIDDM. Unfortunately, there is still not a clear understanding of the molecular cause of NIDDM in most individuals. Therefore, one must take an alternative approach: to express in quantitative terms the various tissue processes which determine the ability to regulate the blood glucose in fasting and after carbohydrate administration. A minimal list of such processes includes the provision of glucose by the liver, insulin sensitivity, insulin secretion, and glucose effectiveness. The latter function is the ability of glucose per se to enhance glucose disappearance from blood, independent of a dynamic insulin response. Approaches to measuring the list of functions which determine the glucose tolerance are reviewed: they include the minimal model method, which quantitates insulin sensitivity (Sl) and glucose effectiveness (SG), and a combined model approach, which measures insulin secretion. These methods are being developed for large populations. Such a development is important for elucidating the causes of reduced glucose tolerance in populations, and examining the relation between such causes and outcomes including diabetes and cardiovascular disease. Of particular importance for diabetes development is the characteristic hyperbolic relationship between insulin secretion and insulin action. This relationship, the "hyperbolic law of glucose tolerance' indicates that insulin secretion can only be assessed in terms of the ambient degree of insulin sensitivity. By applying this principle, it is clear that latent pancreatic islet-cell dysfunction has been underestimated, and may be significant even in subjects with impaired glucose tolerance. Finally, new explorations of insulin control of liver glucose output indicate that this process may be under the control of free fatty acids. The latter realization indicates that the insulin effect on lipolysis is what is critical for determination of glucose output in the fasting state, and that insulin resistance at the level of the adipocyte may determine the extent of fasting hyperglycaemia, and may be an important factor in the overall phenotype in prediabetic and NIDDM individuals.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Models, Biological; Phenotype; Prediabetic State; Risk Factors; Tolbutamide

Defective insulin secretion plays a crucial role in insulin-dependent (Type 1) and non-insulin-dependent (Type 2) diabetes mellitus as well as in many secondary forms of the disease. Glucagon is a potent stimulus for the islet beta-cell, and intravenous bolus injection of 1 mg glucagon has been widely used to assess endogenous insulin secretion for clinical or research purposes. Plasma C-peptide levels (less commonly insulin) are usually measured immediately before and 6 min after glucagon injection. The C-peptide response to glucagon is well-correlated with the beta-cell response to mixed meals or other stimuli commonly used to characterize endogenous insulin secretion (oral or intravenous glucose, standard meals, arginine, etc.) and has the advantage of shorter duration and simple standardization. The glucagon test shows good intra-subject reproducibility, although in diabetic patients it may be influenced by variable prevailing blood glucose levels. Several applications of the glucagon test have been developed. In Type 1 diabetes, the glucagon test has been used to discriminate between patients with and without residual insulin secretion. This can be especially important during the first few months, or even years, following initiation of insulin therapy when attempts to stop the immunological destruction of the beta-cell are made. Assessment of endogenous insulin secretion is also important after pancreas or islet transplantation. In patients with Type 2 diabetes mellitus, in which residual endogenous insulin secretion is common, characterization of the disease may help in the choice of therapy for the individual patient (insulin, sulphonylureas or combined therapy). Thus, the glucagon test is a simple, reliable and useful tool for clinical evaluation of diabetes mellitus.

Topics: Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion

Pancreatic insulin secretion rates can be accurately derived by mathematical deconvolution of peripheral C-peptide concentrations either by using individual C-peptide kinetic parameters obtained by analysis of the decay curve of biosynthetic human C-peptide or by using published group parameters with appropriate adjustments for age and degree of obesity. Since the cross-reactivity of proinsulin and related peptides is low (< 10%) in many C-peptide assays, this experimental approach avoids the spurious increase in insulin immunoreactivity resulting from cross-reactivity with proinsulin and related peptides in the insulin assay. Application of this technique has demonstrated that the phenotypic expression of beta-cell dysfunction differs in subjects with different genetic mechanisms of non-insulin-dependent diabetes mellitus (NIDDM). Subjects who have maturity-onset diabetes of the young (MODY) due to mutations in the glucokinase gene demonstrate different patterns of altered insulin secretion when compared with subjects who have mutations in the MODY1 gene on chromosome 20. Glucokinase mutations affect the ability of the beta-cell to detect and respond to small increases in glucose above the basal level. However, compensatory mechanisms operative in vivo, which include a priming effect of glucose on insulin secretion, limit the severity of the observed insulin secretory defect, resulting in a generally mild clinical course in these subjects. In contrast, mutations in the MODY1 gene are associated with an inability to increase insulin secretion as the plasma glucose concentration increases above 7-8 mmol/l and the normal priming effect of glucose on insulin secretion is lost. These characteristics of the dose-response relationships between glucose and insulin secretion result in a more severe degree of hyperglycemia than observed in subjects with glucokinase mutations, and these subjects more frequently need insulin treatment. These alterations are evident in prediabetic subjects with normal glucose levels who carry the MODY1 mutation, suggesting that defective beta-cell function is the primary pathogenetic defect in the diabetic syndrome in these subjects. Studies performed in the classic form of NIDDM demonstrate that subjects with mild glucose intolerance and normal fasting glucose concentrations and glycosylated hemoglobin levels consistently demonstrate defective beta-cell function. These results are consistent with studies in the Zucker diabetic fatty

Topics: Adult; Animals; Blood Glucose; C-Peptide; Chromosomes, Human, Pair 20; Diabetes Mellitus, Type 2; Genes; Glucokinase; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Mutation; Rats; Rats, Zucker

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Radioimmunoassay

Topics: C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Prognosis; Radioimmunoassay

Topics: C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Insulin

To assess the efficacy of combination therapy with insulin and sulfonylurea in the treatment of NIDDM.. Studies published between January 1966 and January 1991 were identified through a computerized Medline search and by hand searching the bibliographies of identified articles. We identified 17 eligible randomized, controlled trials of combination therapy in NIDDM. These trials had a minimum duration of 8 wk and at least one of three outcome measures (fasting glucose, HbA1, or C-peptide) with SD or SE of the mean reported to do metaanalysis. With standardized forms, three independent reviews abstracted measures of study quality and specific descriptive information about population, intervention, and outcome measurements.. We calculated effect size and weighted mean changes of the three outcome measures for control and treatment groups. In the treatment group, the fasting plasma glucose decreased from a mean of 11.4 mM (206 mg/dl) at baseline to a mean of 9.16 mM (165 mg/dl) posttreatment, whereas the control group decreased from (11.3 to 10.8 mM) (204 to 194 mg/dl) (effect size 0.39, P less than 0.0001). For HbA1, the treatment group decreased from a baseline of 11.0 to 10.2% compared to 11.0 and 11.2% in the control group (effect size 0.43, P less than 0.0001). For fasting C-peptide, the treatment group increased from 0.49 to 0.58 nM (1.45 to 1.75 ng/ml) compared with 0.47 and 0.43 (1.42 and 1.30) for the control group (effect size 0.26, P less than 0.017).. Combined insulin-sulfonylurea therapy leads to modest improvement in glycemic control compared with insulin therapy alone. With combined therapy, lower insulin doses may be used to achieve similar control. Obese patients with higher fasting C-peptides may be more likely to respond than others.

Topics: Blood Glucose; C-Peptide; Chlorpropamide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Gliclazide; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; MEDLINE; Meta-Analysis as Topic; Middle Aged; Periodicals as Topic; Sulfonylurea Compounds; Tolazamide; Treatment Outcome; United States

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Humans; Insulin; Insulin Secretion; Islets of Langerhans

This review examines recent epidemiological data about the prevalence and incidence of and risk factors for proliferative diabetic retinopathy. In addition, the relation of proliferative retinopathy to other systemic complications associated with diabetes is reviewed.. The data come mostly from the baseline and 4-yr follow-up examinations of a large population-based study, the WESDR, which involved 996 younger-onset insulin-dependent people whose diabetes was diagnosed at < 30 yr of age and 1370 older-onset people whose diabetes was diagnosed at > or = 30 yr of age, and who were taking or not taking insulin.. The major finding is that proliferative retinopathy is a prevalent complication (23% in the WESDR younger-onset group, 10% in the WESDR older-onset group that takes insulin, and 3% in the group that does not take insulin). Hyperglycemia, longer duration of diabetes, and more severe retinopathy at baseline were associated with an increased 4-yr risk of developing proliferative retinopathy. However, higher blood pressure at baseline was associated only with the development of proliferative retinopathy in the younger-onset group. The presence of proliferative diabetic retinopathy was associated with an increased 4-yr risk of loss of vision, cardiovascular disease, diabetic nephropathy, and mortality. In the WESDR, a significant number of diabetic people with proliferative retinopathy at risk for vision loss were not under the care of an ophthalmologist or had not undergone panretinal photocoagulation.. These data suggest that hyperglycemia and, possibly, high blood pressure are related to proliferative retinopathy. They also suggest that once proliferative diabetic retinopathy is detected, people should have a medical evaluation, because it is a strong indicator for the presence and development of systemic disease. These data also indicate that diabetic patients and their physicians should be aware of the need for routine ophthalmological examinations to detect and treat proliferative retinopathy.

Topics: Age Factors; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Incidence; Morbidity; Prevalence; Risk Factors; Sex Factors

Topics: Alcohol Drinking; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Evaluation Studies as Topic; Humans; Hypoglycemia; Insulin; Insulin Secretion

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Infections; Insulin; Insulin Resistance; Myocardial Infarction

Since the introduction of glyburide in 1984, many studies have evaluated the effects of this oral hypoglycemic agent on beta cell function in patients with non-insulin-dependent diabetes mellitus. The early studies, which were performed in patients receiving concomitant insulin therapy, may have underestimated the true effect of glyburide on insulin secretion. The more recent studies demonstrate that both short- and long-term glyburide therapy increase C-peptide levels in diabetic as well as nondiabetic subjects and that the effects of glyburide are comparable to those of the other second-generation sulfonylurea, glipizide. The effects of glyburide on insulin secretory rates calculated from plasma C-peptide levels were recently evaluated using individually derived C-peptide kinetic parameters and a validated open two-compartment model of peripheral C-peptide kinetics. Glyburide did not influence fasting insulin secretion (196 +/- 34 versus 216 +/- 23 pmol/min) but did cause an increase in the total amount of insulin secreted over a 24-hour period (447 +/- 58 versus 561 +/- 55 nmol). This increase in the production of insulin was generated by an increase in amplitude of secretory pulses occurring after lunch and dinner rather than by a greater number of pulses. The full effect of glyburide on the beta cell became evident when glucose concentrations were clamped at the hyperglycemic level of 300 mg/dL both before and during treatment for a 3-hour period. During that time, insulin secretion rates increased by 221 percent in response to glyburide. Glyburide did not, however, completely reverse the beta cell secretory defect characteristic of non-insulin-dependent diabetes mellitus. In the patients receiving glyburide, the sluggish insulin secretory response to breakfast persisted, and the insulin secretory response during the hyperglycemic clamping was less than the response normally seen in nondiabetic subjects. These experiments suggest that the primary effect of glyburide on the beta cell is to increase its responsiveness to glucose. Although the precise mechanism of action of glyburide at the cellular level is unclear, in vitro studies suggest that its effect is mediated through binding with specific receptors on the beta cell membrane, which in turn leads to alterations in the cellular efflux of potassium ions and influx of calcium ions.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Glucose; Glyburide; Humans; Insulin; Insulin Secretion; Islets of Langerhans

Type II diabetes is a frequent disease among older people (approximately 7% of 60-year-olds in the US). Genetic factors play a more important role in the etiology of type II than of type I diabetes. The metabolic derangements of type II diabetes are due to the combination of a diminished effect of insulin (insulin resistance due to a decreased number of insulin receptors and a postreceptor defect the nature of which is not clear) and a disturbance of insulin secretion. Type II diabetes is associated with a more than doubling of the age-specific mortality, mainly due to diabetic macroangiopathy (myocardial infarctions, cerebrovascular insults). Diet remains the basis of treatment for type II diabetes. The composition of the diet, however, has been altered in that the proportion of carbohydrates has been increased, the proportion of fat decreased and the fibre content increased. If necessary, oral antidiabetics or insulin are added to the dietary treatment. Measurement of C-peptide may help to decide when insulin therapy is required. Measuring HbA1c permits assessment of the mean blood sugar value of the last 1 1/2-2 months. The greatest progress recently made in the treatment of the chronic complications of type II diabetes has been in the field of diabetic retinopathy (photocoagulation for retinopathy lesions, vitrectomy).

Topics: Aged; Aging; Albuminuria; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Exercise; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Middle Aged

A structural mathematical model of glucose-insulin relationships based on known quantitative responses of the major organs involved with glucose metabolism has been computed. Different degrees of beta-cell function and insulin sensitivity can be included, and the effect of their interaction assessed (i) in a steady state, basal homeostasis after an overnight fast and (ii) in response to a glucose infusion. By comparing a patient's basal plasma glucose and insulin (or C-peptide) concentrations with the predictions of a basal homeostatic model, the degree of impairment of beta-cell function and insulin sensitivity can be assessed. Similarly, the plasma glucose and insulin (or C-peptide) concentrations after a continuous glucose infusion can also be compared with predictions from the model to estimate beta-cell function and insulin sensitivity. These assessments of pathophysiology can be applied to data from individual patients or to patient populations.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Glucose Clamp Technique; Homeostasis; Humans; Insulin; Mathematics; Models, Biological

C-peptide and insulin are secreted in equimolar amounts from the beta-cells in the pancreas. Therefore, measurement of C-peptide in plasma can be used to estimate endogenous insulin secretion also in insulin treated diabetic subjects. From a clinical point of view, it is of especial interest to use measurements of C-peptide in the discrimination between diabetic subjects with and without insulin requirements. Such measurements are, however, difficult to interpret. Thus, plasma C-peptide values depend apart from C-peptide secretion also on C-peptide clearence, technical procedures, and during unsteady state conditions also on the C-peptide volume of distribution. In clinical practice, it is recommended only to measure basal plasma C-peptide and these values should be interpreted with caution. Generally, values below 0.2 nmol/l suggest insulin requirement while values above 0.5 nmol/l suggest non-insulin requirement. Patients with intermediate basal plasma C-peptide values should be evaluated more closely for example in hospital. Measurement of C-peptide should, however, be restricted to certain selected patients in whom the clinical classification is uncertain.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin

Our knowledge of the effects of n-3 fatty acids on the glucose homeostasis in diabetes mellitus is at present incomplete. The results are in certain respects conflicting. Several studies have shown that addition of n-3 fatty acids, especially in type-2 diabetes, may increase blood glucose concentrations without a concomitant increase of insulin or C-peptide concentrations. The glucose/insulin ratio is increased in fasting as well as after meals. On the other hand, some data indicate that, in spite of increased or unchanged glucose concentrations, there may be an improved peripheral insulin sensitivity. The stimulated insulin response may be reduced after mixed meals, although there are no indications of significant impairments of the response to intravenous glucose. The reasons for the observed changes are still obscure. More controlled studies, during prolonged periods of time, are needed. At present it would seem important to closely follow diabetic patients with respect to glucose and lipid metabolism if treated with n-3 fatty acids. As for now, diabetic patients are recommended to increase their intake of fish in the diet. The use of pharmacological doses of n-3 fatty acids remains investigational.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Unsaturated; Fish Oils; Humans; Insulin; Male

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Glucose; Humans; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Models, Biological; Rats; Research Design

Diabetes mellitus is a heterogeneous disorder. About 80% of the patients with this disease are categorized as having non-insulin-dependent diabetes mellitus, a disorder resulting from varied degrees of insulin resistance and impaired insulin secretion; the causes for these abnormalities are unknown. The remaining 15 to 20% of patients have insulin-dependent diabetes mellitus, a disorder caused by the destruction of insulin-producing endocrine cells within the pancreas and currently considered to be the result of an autoimmune process. During the course of both types of diabetes mellitus, the so-called long-term complications of diabetes invariably occur to some extent in all patients. These complications include retinopathy, nephropathy, neuropathy, and premature atherosclerosis. The molecular basis for these complications is not completely understood, but recent evidence obtained from both experiments in animals and prospective clinical studies indicates that metabolic derangements associated with poor glycemic control are a major determinant of the frequency and severity of these complications. Such evidence is the rationale for current attempts to maintain near-normal glycemia in patients with diabetes mellitus.

Topics: Autoimmune Diseases; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Diagnosis, Differential; Glucagon; Humans; Insulin; Insulin Resistance

Proinsulin is the single chain precursor of insulin. It consists of insulin, plus a peptide which connects the A and B chains of insulin. This peptide is termed C-peptide. C-peptide an insulin are secreted in equimolar amounts from pancreatic beta-cells, Hence, circulating C-peptide levels provide a measure of beta-cell secretory activity. C-peptide measurements are preferable to insulin measurements because of lack of hepatic extraction, slower metabolic clearance rate, and lack of cross reactivity with antibodies to insulin. This article reviews the methods for determination of C-peptide levels in body fluids, and discusses the applications of C-peptide measurement. These include the investigation of hypoglycemia and the assessment of insulin secretory function in insulin-treated and non-insulin-dependent diabetics. The contribution of C-peptide measurement to the understanding of the interrelationships between insulin secretory function and age, sex, obesity, blood lipids, and blood glucose concentrations will also be evaluated.

Topics: Amniotic Fluid; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Islets of Langerhans; Kidney; Liver; Male; Obesity; Pregnancy; Proinsulin; Radioimmunoassay; Reference Values

The large and variable hepatic extraction of insulin is a major obstacle to our ability to quantitate insulin secretion accurately in human subjects. The evidence that C-peptide is secreted from the beta cell in equimolar concentration with insulin, but not extracted by the liver to any significant degree, has provided a firm scientific basis for the use of peripheral C-peptide concentrations as a semiquantitative marker of beta cell secretory activity in a variety of clinical situations. Thus, plasma C-peptide has proved to be extremely valuable in the study of the natural history of type 1 diabetes, to monitor insulin secretion in patients with insulin antibodies, and as an adjunct in the investigation of patients with hypoglycemic disorders. The use of the peripheral C-peptide concentration to accurately quantitate the rate of insulin secretion is more controversial. This is mainly because understanding of the kinetics and metabolism of C-peptide under different conditions is incomplete. Unfortunately, sufficient quantities of human C-peptide are not available to allow the experimental validation of the mathematical formulae that have been proposed for the calculation of insulin secretion from peripheral C-peptide concentrations. Until it is possible to perform such experiments, the accuracy of studies that have derived insulin secretion rates from peripheral C-peptide levels will remain uncertain. The assumption that the peripheral C-peptide:insulin molar ratio can be used as a reflection of hepatic insulin extraction has not been experimentally validated. The marked difference in the plasma half-lives of insulin and C-peptide complicates the interpretation of changes in their ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Glucose Tolerance Test; Half-Life; Humans; Insulin; Insulin Secretion; Kidney Diseases; Kinetics; Liver; Male; Metabolic Clearance Rate; Obesity; Tissue Distribution

Topics: Adolescent; Adult; Animals; Blood Glucose; C-Peptide; Child; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Time Factors

Rapid conversion from prediabetes to diabetes and frequent postprandial hyperglycemia (PPHG) is seen in Asian Indians. These should be the target of dietary strategies.. We hypothesized that dietary intervention of preloading major meals with almonds in participants with prediabetes will decrease overall glycemia and PPHG.. The study included two phases: (1) an oral glucose tolerance test (OGTT)-based crossover randomized control study, the effect of a single premeal almond load (20 g) given before OGTT was evaluated (n = 60, 30 each period). (2) The continuous glucose monitoring system (CGMS)-based study for 3 days including premeal almond load before three major meals was a free-living, open-labeled, crossover randomized control trial, where control and premeal almond load diets were compared for glycaemic control (n = 60, 30 in each period). The study was registered at clinicaltrials.gov (registration no. NCT04769726).. In the OGTT-based study phase, the overall AUC for blood glucose, serum insulin, C-peptide, and plasma glucagon post-75 g oral glucose load was significantly lower for treatment vs. control diet (p < 0.001). Specifically, with the former diet, PPHG was significantly lower (18.05% in AUC on OGTT, 24.8% at 1-h, 28.9% at 2-h post OGTT, and 10.07% during CGMS). The CGMS data showed that premeal almond load significantly improved 24-glucose variability; SD of mean glucose concentration and mean of daily differences. Daily glycaemic control improved significantly as per the following: mean 24-h blood glucose concentration (M), time spent above 7.8 mmol/L of blood glucose, together with the corresponding AUC values. Premeal almond load significantly decreased following: overall hyperglycemia (glucose AUC), PPHG, peak 24-h glycaemia, and minimum glucose level during night.. Incorporation of 20 g of almonds, 30 min before each major meal led to a significant decrease in PPHG (as revealed in OGTT-based study phase) and also improved insulin, C-peptide, glucagon levels, and improved glucose variability and glycemic parameters on CGMS in participants with prediabetes.. The study was registered at clinicaltrials.gov (registration no. NCT04769726).

Topics: Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Postprandial Period; Prediabetic State; Prunus dulcis

Increased glucose level and insulin resistance are major factors in Type 2 diabetes mellitus (T2M), which is chronic and debilitating disease worldwide. Submerged culture medium of Ceriporia lacerata mycelium (CLM) is known to have glucose lowering effects and improving insulin resistance in a mouse model in our previous studies. The main purpose of this clinical trial was to evaluate the functional efficacy and safety of CLM in enrolled participants with impaired fasting blood sugar or mild T2D for 12 weeks.. A total of 72 participants with impaired fasting blood sugar or mild T2D were participated in a randomized, double-blind, placebo-controlled clinical trial. All participants were randomly assigned into the CLM group or placebo group. Fasting blood glucose (FBG), HbA1c, insulin, C-peptide, HOMA-IR, and HOMA-IR by C-peptide were used to assess the anti-diabetic efficacy of CLM for 12 weeks.. In this study, the effectiveness of CLM on lowering the anti-diabetic indicators (C-peptide levels, insulin, and FBG) was confirmed. CLM significantly elicited anti-diabetic effects after 12 weeks of ingestion without showing any side effects in both groups of participants. After the CLM treatment, FBG levels were effectively dropped by 63.9% (ITT), while HOMA-IR level in the CLM group with FBG > 110 mg/dL showed a marked decrease by 34% up to 12 weeks. Remarkably, the effect of improving insulin resistance was significantly increased in the subgroup of participants with insulin resistance, exhibiting effective reduction at 6 weeks (42.5%) and 12 weeks (61%), without observing a recurrence or hypoglycemia. HbA1c levels were also decreased by 50% in the participants with reduced indicators (FBG, insulin, C-peptide, HOMA-IR, and HOMA-IR). Additionally, it is noteworthy that the levels of insulin and C-peptide were significantly reduced despite the CLM group with FBG > 110 mg/dL. No significant differences were detected in the other parameters (lipids, blood tests, and blood pressure) after 12 weeks.. The submerged culture medium of CLM showed clinical efficacy in the improvement of FBG, insulin, C-peptide, HbAc1, and HOMA-index. The microbiome-based medium could benefit patients with T2D, FBG disorders, or pre-diabetes, which could guide a new therapeutic pathway in surging the global diabetes epidemic.

Topics: Blood Glucose; C-Peptide; Culture Media; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Polyporales

Disease modifying therapies aiming to preserve β-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the β-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of β-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic β-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Vitamin D

Dietary sugars are often linked to the development of overweight and type 2 diabetes (T2D) but inconsistencies remain.. We investigated associations of added, free, and total sugars, and glycaemic index (GI) with indices of glucose metabolism (IGM) and indices of body fatness (IBF) during a 3-year weight loss maintenance intervention.. Total sugars were inversely associated with fasting insulin and C-peptide in all centres, and free sugars were inversely associated with fasting glucose and HbA1c (Model B: all. Our findings suggest that added sugars and GI were independently associated with 3-y weight regain, but only GI was associated with 3-y changes in glucose metabolism in individuals at high risk of T2D.

Topics: Adipose Tissue; Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Sugars; Glucose; Glycated Hemoglobin; Glycemic Index; Humans; Immunoglobulin M; Insulin; Middle Aged; Overweight

Empagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and β-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM.. Forty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and β-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit.. After 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and β-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline.. Empagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia.. EudraCT number 2015-004571-73.

Topics: Acute Coronary Syndrome; Aged; Benzhydryl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Male; Mannose

glucagon secretion and inhibition should be mainly determined by glucose and insulin levels, but the relative relevance of each factor is not clarified, especially following ingestion of different macronutrients. We aimed to investigate the associations between plasma glucagon, glucose, and insulin after ingestion of single macronutrients or mixed-meal.. thirty-six participants underwent four metabolic tests, based on administration of glucose, protein, fat, or mixed-meal. Glucagon, glucose, insulin, and C-peptide were measured at fasting and for 300 min following food ingestion. We analyzed relationships between time samples of glucagon, glucose, and insulin in each individual, as well as between suprabasal area-under-the-curve of the same variables (ΔAUC. in individuals, time samples of glucagon and glucose were related in only 26 cases (18 direct, 8 inverse relationships), whereas relationship with insulin was more frequent (60 and 5,. glucose and insulin are not general and exclusive determinants of glucagon secretion/inhibition after mixed-meal or macronutrients ingestion.

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Male; Meals; Middle Aged; Nutrients; Time Factors

We sought association between serum Lipoprotein(a) and C-Peptide levels as two predictors with cardiometabolic biomarkers in patients with type 2 diabetes mellitus. This nested case-control study was conducted on 253 participants with type 2 diabetes mellitus and control from the second phase of the KERCADR cohort study. The participants were randomly allocated into case and control groups. The quantitative levels of Lipoprotein(a) and C-Peptide were measured by ELISA. Atherogenic indices of plasma were measured. The plasma Atherogenic Index of Plasma significantly decreased (P = 0.002) in case-male participants, and plasma Castelli Risk Index II level significantly increased (P = 0.008) in control-male participants with the highest dichotomy of Lipoprotein(a). The plasma Atherogenic Index of Plasma level in case-female participants significantly increased (P = 0.023) with the highest dichotomy of C-Peptide. Serum C-Peptide level significantly increased (P = 0.010 and P = 0.002, respectively) in control-male participants with the highest dichotomies of Atherogenic Index of Plasma and Castelli Risk Index I. There was a significant association between the highest quartile of C-Peptide and higher anthropometric values in case participants; and higher atherogenic indices of plasma and anthropometric values in control participants. Raised serum C-peptide than raised Lipoprotein(a) can be a prior predictor for cardiometabolic disease risk in healthy participants and patients with type 2 diabetes mellitus with increased cardiometabolic biomarkers. Case and control males with general and visceral obesity and case and control females with visceral obesity are exposure to increased C-peptide, respectively. Lipoprotein(a) may be risk independent biomarker for type 2 diabetes mellitus. Reducing raised Lipoprotein(a) levels to less than 30ng/ml with strict control of low density lipoprotein cholesterol would be the best approach to prevent coronary artery disease consequences. It is suggested that a screening system be set up to measure the Lp(a) levels in the community for seemingly healthy people or individuals with one or more cardiometabolic biomarkers.

Topics: Biomarkers; C-Peptide; Case-Control Studies; Cohort Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Lipoprotein(a); Male; Obesity, Abdominal; Risk Factors

Metabolic dysfunction-associated fatty liver disease (MAFLD) reflects the multifactorial pathogenesis of fatty liver disease in metabolically sick patients. The effects of metabolic surgery on MAFLD have not been investigated. This study assesses the impact of Roux-en-Y gastric bypass (RYGB) on MAFLD in a prototypical cohort outside the guidelines for obesity surgery.. Twenty patients were enrolled in this prospective, single-arm trial investigating the effects of RYGB on advanced metabolic disease (DRKS00004605). Inclusion criteria were an insulin-dependent type 2 diabetes, body mass index of 25 to 35 kg/m 2 , glucagon-stimulated C-peptide of >1.5 ng/mL, glycated hemoglobin >7%, and age 18 to 70 years. A RYGB with intraoperative liver biopsies and follow-up liver biopsies 3 years later was performed. Steatohepatitis was assessed by expert liver pathologists. Data were analyzed using the Wilcoxon rank sum test and a P value <0.05 was defined as significant.. MAFLD completely resolved in all patients 3 years after RYGB while fibrosis improved as well. Fifty-five percent were off insulin therapy with a significant reduction in glycated hemoglobin (8.45±0.27% to 7.09±0.26%, P =0.0014). RYGB reduced systemic and hepatic nitrotyrosine levels likely through upregulation of NRF1 and its dependent antioxidative and mitochondrial genes. In addition, central metabolic regulators such as SIRT1 and FOXO1 were upregulated while de novo lipogenesis was reduced and β-oxidation was improved in line with an improvement of insulin resistance. Lastly, gastrointestinal hormones and adipokines secretion were changed favorably.. RYGB is a promising therapy for MAFLD even in low-body mass index patients with insulin-treated type 2 diabetes with complete histologic resolution. RYGB restores the oxidative balance, adipose tissue function, and gastrointestinal hormones.

Topics: Adipokines; Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Gastric Bypass; Gastrointestinal Hormones; Glucagon; Glycated Hemoglobin; Humans; Insulin; Liver Diseases; Middle Aged; Obesity, Morbid; Prospective Studies; Sirtuin 1; Young Adult

Rebaudioside A, a steviol glycoside, is deglycosylated by intestinal microflora prior to the absorption of steviol and conjugation to steviol glucuronide. While glucose-lowering properties are observed for rebaudioside A in mice, they have been attributed to the metabolites steviol and steviol glucuronide. We aimed to characterize the pharmacokinetic and pharmacodynamic properties of rebaudioside A and its metabolites in patients with early-onset type 2 diabetes mellitus (T2DM).. This randomized, placebo-controlled, open-label, two-way crossover trial was performed in subjects with T2DM on metformin or no therapy at the University Hospitals Leuven, Belgium. Following oral rebaudioside A (3 g), plasma concentrations of rebaudioside A, steviol and steviol glucuronide were determined. The effect on glucose homeostasis was examined by an oral glucose tolerance test (OGTT) performed 19 h following rebaudioside A administration, i.e. the presumed time of maximal steviol and steviol glucuronide concentrations. The primary pharmacodynamic endpoint was the difference in area under the blood glucose concentration-time curve during the first 2 h of the OGTT (AUC. Rebaudioside A is readily absorbed after oral administration and metabolized to steviol and steviol glucuronide. However, no effect on glucose nor insulin or C-peptide excursion was observed during the OGTT at the time of maximal metabolite concentrations. Thus, no antidiabetic properties of rebaudioside A could be observed in patients with T2DM after single oral use.. Registered on ClinicalTrials.gov (NCT03510624).

Topics: Animals; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucose; Glucuronides; Homeostasis; Male; Mice

Diabetic ketosis (DK) is one of the leading causes of hospitalization among patients with diabetes. Failure to recognize DK symptoms may lead to complications, such as diabetic ketoacidosis, severe neurological morbidity, and death.. This study aimed to develop and validate a model to predict DK in patients with type 2 diabetes mellitus (T2DM) based on both clinical and biochemical characteristics.. A cross-sectional study was conducted by evaluating the records of 3,126 patients with T2DM, with or without DK, at The Affiliated Hospital of Qingdao University from January 2015 to May 2022. The patients were divided randomly into the model development (70%) or validation (30%) cohorts. A risk prediction model was constructed using a stepwise logistic regression analysis to assess the risk of DK in the model development cohort. This model was then validated using a second cohort of patients.. The stepwise logistic regression analysis showed that the independent risk factors for DK in patients with T2DM were the 2-h postprandial C-peptide (2hCP) level, age, free fatty acids (FFA), and HbA1c. Based on these factors, we constructed a risk prediction model. The final risk prediction model was L= (0.472. This study identified independent risk factors for DK in patients with T2DM and constructed a prediction model based on these factors. The present findings provide an easy-to-use, easily interpretable, and accessible clinical tool for predicting DK in patients with T2DM.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Glycated Hemoglobin; Humans

The benefits of once-daily insulin degludec/aspart (IDegAsp) compared with basal insulin in type 2 diabetes patients have not been established.. This was a retrospective observational study. From a basal insulin cohort from three referral hospitals, patients were enrolled who initiated once-daily IDegAsp. A control group maintaining basal insulin was selected by propensity score matching. Glycated hemoglobin (HbA1c) changes over a period of 6 months and associated clinical factors were evaluated.. The IDegAsp group and the control group comprised of 87 patients, respectively. Baseline HbA1c was comparable between the two groups (8.7 ± 0.9 vs 8.6 ± 0.9%, mean and standard deviation). After 6 months with matched insulin doses, HbA1c in the IDegAsp group was lower than that in the control group (8.1 ± 1.0 vs 8.4 ± 1.1%, P = 0.029). Among baseline variables, fasting plasma glucose (FPG) and fasting C-peptide in the IDegAsp were lower than that in the control (FPG 124.2 ± 38.4 vs 148.0 ± 50.6 mg/dL, P < 0.001). Considering that the lower FPG despite the comparable HbA1c could be related with the efficacy of IDegAsp, subgroup analysis was carried out according to a ratio of FPG-to-estimated average glucose, which is calculated from HbA1c. When compared with each control group, the superiority of IDegAsp in the reduction of HbA1c was significant only in the patients with a lower FPG-to-estimated average glucose ratio (0.49 ± 0.09), but not in those with a higher FPG-to-estimated average glucose ratio (0.79 ± 0.20).. We observed that IDegAsp was more effective than basal insulin in patients with an FPG lower than predicted by HbA1c, which might be related with insulin deficiency and postprandial hyperglycemia in patients on basal insulin therapy.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Combinations; Fasting; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Retrospective Studies

This study is aimed at investigating whether dapagliflozin adjunct to insulin therapy further improves glycemic control compared to insulin therapy alone in patients with newly diagnosed type 2 diabetes (T2D).. This single-centre, randomized, controlled, open-labeled trial recruited newly diagnosed T2D patients. Subjects were randomized 1 : 1 to the dapagliflozin add-on to continuous subcutaneous insulin infusion (CSII) group (DAPA) or the CSII therapy group for 5 weeks. Standard meal tests were performed 3 times at days -3, 7, and 35 for glucose, C-peptide, and insulin level determination. Two-time continuous glucose monitoring (CGM) was performed at baseline and at the end of the study. The primary endpoint was the difference in the mean amplitude of glycemic excursions (MAGEs) between the groups.. A total of 66 subjects completed the study, with 34 and 32 patients in the DAPA and CSII groups, respectively. Patients in the DAPA group exhibited significant decreases in MAGE levels at the endpoint. We also observed that patients in the DAPA group had a lower homoeostasis model assessment insulin resistance (HOMA-IR) and a higher homoeostasis model assessment B (HOMA-B) value at 1 week and 5 weeks compared to those with insulin therapy, respectively. In addition, our data showed that patients in the DAPA group showed a significantly lower insulin dose (0.07 U/kg) and weighed less than those in the CSII group.. Our data indicate that dapagliflozin adjunct to insulin is a safe and effective therapy for improving glycemic variations, insulin sensitivity, and weight loss in newly diagnosed T2D patients.

Topics: Benzhydryl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Subcutaneous; Insulin; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

Imigliptin is a novel dipeptidyl peptidase-4 inhibitor. In the present study, we aimed to evaluate the effects of imigliptin and alogliptin on insulin resistance and beta-cell function in Chinese patients with type-2 diabetes mellitus (T2DM).. A total of 37 Chinese T2DM patients were randomized to receive 25 mg imigliptin, 50 mg imigliptin, placebo, and 25 mg alogliptin (positive drug) for 13 days. Oral glucose tolerance tests were conducted at baseline and on day 13, followed by the oral minimal model (OMM).. Imigliptin or alogliptin treatment, compared with their baseline or placebo, was associated with higher beta-cell function parameters (. After 13 days of treatment, imigliptin and alogliptin could decrease glycemic levels by improving beta-cell function. By comparing OMM with HOMA or SUIT results, glucose stimulation might be more sensitive for detecting changes in beta-cell function.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; China; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Imidazoles; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Piperidines; Pyridines; Treatment Outcome; Uracil; Young Adult

Pinolenic acid, a major component (~20%) of pine nut oil, is a dual agonist of the free fatty acid receptors, FFA1 and FFA4, which may regulate release of incretins and ghrelin from the gut. Here, we investigated the acute effects of hydrolyzed pine nut oil (PNO-FFA), delivered to the small intestine by delayed-release capsules, on glucose tolerance, insulin, incretin and ghrelin secretion, and appetite.. In two cross-over studies, we evaluated 3 g unhydrolyzed pine nut oil (PNO-TG) or 3 g PNO-FFA versus no oil in eight healthy, non-obese subjects (study 1), and 3 g PNO-FFA or 6 g PNO-FFA versus no oil in ten healthy, overweight/obese subjects (study 2) in both studies given in delayed-release capsules 30 min prior to a 4-h-oral glucose tolerance test (OGTT). Outcomes were circulating levels of glucose, insulin, GLP-1, GIP, ghrelin, appetite and gastrointestinal tolerability during OGTT.. Both 3 g PNO-FFA in study 1 and 6 g PNO-FFA in study 2 markedly increased GLP-1 levels (p < 0.001) and attenuated ghrelin levels (p < 0.001) during the last 2 h of the OGTT compared with no oil. In study 2, these effects of PNO-FFA were accompanied by an increased satiety and fullness (p < 0.03), and decreased prospective food consumption (p < 0.05). PNO-FFA caused only small reductions in glucose and insulin levels during the first 2 h of the OGTT.. Our results provide evidence that PNO-FFA delivered to the small intestine by delayed-release capsules may reduce appetite by augmenting GLP-1 release and attenuating ghrelin secretion in the late postprandial state.. NCT03062592 and NCT03305367.

Topics: Adult; Aged; Appetite; Blood Glucose; C-Peptide; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hydrolysis; Incretins; Insulin; Intestine, Small; Linolenic Acids; Male; Middle Aged; Pinus; Plant Oils; Seeds

To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion.. A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (ΔMAGE) was carried out in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median.. ΔMAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2 ± 28.3 vs -20.0 ± 24.6, respectively; P = 0.60). However, ΔMAGE was not ameliorated in the low CPR SWITCH group, and the ΔMAGE was significantly smaller than that in the high CPR COMB group (P < 0.01).. COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Secretion; Japan; Male; Middle Aged; Prospective Studies; Pyrazoles; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidines; Young Adult

The rate of gastric emptying and glucoregulatory hormones are key determinants of postprandial glycaemia. Intragastric administration of L-tryptophan slows gastric emptying and reduces the glycaemic response to a nutrient drink in lean individuals and those with obesity. We investigated whether tryptophan decreases postprandial glycaemia and slows gastric emptying in type 2 diabetes (T2D).. Twelve men with T2D (age: 63 ± 2 years, HbA1c: 49.7 ± 2.5 mmol/mol, BMI: 30 ± 1 kg/m. Tryptophan alone stimulated C-peptide (P = 0.002) and glucagon (P = 0.04), but did not affect fasting glucose. In response to the drink, Trp-3 lowered plasma glucose from t = 15-30 min and from t = 30-45 min compared with control and Trp-1.5, respectively (both P < 0.05), with no differences in peak glucose between treatments. Gastric emptying tended to be slower after Trp-3, but not Trp-1.5, than control (P = 0.06). Plasma C-peptide, glucagon and 3-OMG increased on all days, with no major differences between treatments.. In people with T2D, intragastric administration of 3 g tryptophan modestly slows gastric emptying, associated with a delayed rise, but not an overall lowering of, postprandial glucose.

Topics: 3-O-Methylglucose; Aged; Beverages; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Routes; Gastric Emptying; Glucagon; Glucose; Humans; Insulin; Intestinal Absorption; Male; Middle Aged; Nutrients; Obesity; Postprandial Period; Tryptophan

The results of the present study demonstrate that beta cell function in newly diagnosed T2DM patients is the key predictor of response to glucose lowering medications and provides a practical tool (C-Pep120 /C-Pep0) to guide the choice of glucose lowering agent.. This work aims to identify predictors for individualization of antidiabetic therapy in patients with new-onset type 2 diabetes mellitus (T2DM).. A total of 261 drug-naive participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, with new-onset diabetes, were randomly assigned in a single-center study to receive 1) metformin followed by glipizide and then insulin glargine on failure to achieve glycated hemoglobin A1c (HbA1c) less than 6.5%, or 2) initial triple therapy with metformin/pioglitazone/exenatide. Each patient received a 75-g oral glucose tolerance test (OGTT) prior to start of therapy. Factors that predicted response to therapy were identified using the area under the receiver operating characteristic curve method.. Thirty-nine patients started and maintained the treatment goal (HbA1c < 6.5%) on metformin only, and did not require intensification of antihyperglycemic therapy; 54 patients required addition of glipizide to metformin; and 47 patients required insulin addition to metformin plus glipizide for glucose control. The plasma C-peptide concentration (C-Pep)120/C-Pep0 ratio during the OGTT was the strongest predictor of response to therapy. Patients with a ratio less than 1.78 were more likely to require insulin for glucose control, whereas patients with a ratio greater than 2.65 were more likely to achieve glucose control with metformin monotherapy. In patients started on initial triple therapy, the HbA1c decreased independently of the C-Pep120/C-Pep0 ratio.. The increase in C-Pep above fasting following glucose load predicts the response to antihyperglycemic therapy in patients with new-onset diabetes. C-Pep120/C-Pep0 provides a useful tool for the individualization of antihyperglycemic therapy in patients with new-onset T2DM.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Prognosis

It was observed that type II diabetes mellitus associated with chronic liver failure improved after stem cell transplantation. However, there were no adequate studies regarding this issue. The aim of this study was to evaluate the effect of stem cell transplantation on associated type II diabetes mellitus and on the liver function tests.. This pilot study included 30 patients of post-hepatitis chronic liver failure who were classified into two groups: Group I included patients with chronic liver cell failure associated with type 2 diabetes. Group II included patients without type II diabetes. Autologous CD34+ and CD133+ stem cells were percutaneously infused into the portal vein. Responders (regarding the improvement of diabetes as well as improvement of liver condition) and non-responders were determined. Patients were followed up for one, three and six months after the intervention evaluating their three-hour glucose tolerance test, C- peptide (Fasting and postprandial), Child-Pugh score and performance score one month, three months, and six months after stem cell therapy.. Both synthetic and excretory functions of the liver were improved in 10 patients (66.66 %) of group I and in 12 patients (80 %) of group II. Significant improvement in the Oral Glucose Tolerance Test in the responders of both the groups was well defined from the 3rd month and this was comparable to changes in liver function tests and Child-Pugh score.. Successful stem cell therapy in chronic liver cell failure patients can improve but not cure the associating type 2 diabetes by improving insulin resistance.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Egypt; End Stage Liver Disease; Fasting; Female; Follow-Up Studies; Glucose Tolerance Test; Hepatitis C; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Pilot Projects; Stem Cell Transplantation; Treatment Outcome

To evaluate the change in insulin sensitivity, β-cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon-like peptide-1 receptor/glucagon receptor agonist, versus placebo.. Thirty-six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low-dose SAR425899 (0.03, 0.06 and 0.09 mg) and high-dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day -1) and on days 1 and 28. Oral glucose and C-peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β-cell responsiveness and glucose absorption.. With low-dose SAR425899, high-dose SAR425899 and placebo, β-cell function from day -1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was -32%, -20% and 8%, respectively.. After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β-cell function and slowing glucose absorption rate.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Receptors, Glucagon

Type 2 diabetes mellitus (T2DM) is frequently misdiagnosed in children and treated as type 1 DM (T1DM) with insulin. Urinary C-peptide to creatinine ratio (UCPCR) can be used to measure ß cell function and endogenous insulin. We aimed to assess the value of UCPCR to differentiate T2DM from T1DM in pediatric patients. We assessed UCPCR from urine sample taken 2 h after lunch in 50 children with T1DM and 30 children with T2DM (duration of the disease ≥ 2 years and without renal impairment). Fasting and postprandial C-peptide levels were also evaluated in all included children. Receiver operating characteristic (ROC) curve was performed to assess the optimal UCPCR cutoff level to differentiate T2DM from T1DM in children. UCPCR was significantly lower in children with T1DM compared with those with T2DM (P < 0.001). There was a significant positive correlation between UCPCR and fasting C-peptide, postprandial C-peptide, and age of onset. There was a significant negative correlation between the UCPCR and both HbA1c and duration of DM in T1DM. Fasting C-peptide had a sensitivity of 63%, a specificity of 84% at a cutoff point ≥ 1.3 ng/ml to differentiate T2DM from T1DM. Postprandial C-peptide had a sensitivity of 87%, a specificity of 86% at a cutoff point ≥ 3.2 ng/ml to differentiate T2DM from T1DM. Finally, UCPCR had a sensitivity of 97%, a specificity of 88% at a cutoff point ≥ 0.28 nmol/nmol to differentiate T2DM from T1DM in pediatric patients.Conclusion: UCPCR is an easy noninvasive reliable marker to differentiate T2DM from T1DM in pediatric patients.What is Known:• Type 2 DM (T2DM) is frequently misdiagnosed in children and treated as type 1 DM (T1DM) with insulin.• Urinary C-peptide to creatinine ratio (UCPCR) can be used to measure ß cell function and endogenous insulin.What is New:• We revealed that UCPCR had a sensitivity of 97%, a specificity of 88% at a cutoff point ≥ 0.28 nmol/nmol to differentiate T2DM from T1DM.• UCPCR is an easy noninvasive dependable marker to diagnose T2DM from T1DM in pediatric patients.

Topics: Adolescent; Biomarkers; C-Peptide; Case-Control Studies; Child; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Male; Prospective Studies; ROC Curve; Sensitivity and Specificity

For those with type 2 diabetes mellitus (T2DM), impact of short-term high-dose glucocorticoid exposure on beta-cell function is unknown. This study aims to compare the impact on beta-cell function and insulin resistance of prednisone 40 mg between adults with newly diagnosed T2DM and healthy adults.. Five adults with T2DM and five healthy adults, all between 18-50 years, were enrolled. T2DM diagnosis was less than one year prior, HbA1c<75 mmol/mol (9.0%), with metformin treatment only. Pre- and post-therapy testing included 75-g oral glucose tolerance, plasma glucose, C-peptide, and insulin. Intervention therapy was prednisone 40mg daily for 3 days.. Upon therapy completion, HOMA-IR did not increase or differ between groups. Percentile difference for HOMA-%B and insulinogenic index in those with T2DM was significantly lower statistically (50.4% and 69.2% respectively) compared to healthy subjects (19% and 32.2%).. Contrary to the assumption that insulin resistance is the main driver of glucocorticoid-induced hyperglycemia, results indicate that decreased beta-cell insulin secretion is the more likely cause in those with T2DM. This is evidenced by significant drops in C-peptide AUC and HOMA-%B and increased glucose AUC in T2DM group only. These results may be caused by increased beta-cell fragility along with reduced recovery ability after glucocorticoid exposure. ClinicalTrials.gov NCT03661684.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Prednisone; Young Adult

The aim of this study was to explore the association of 1,5-anhydroglucitol with acute C peptide response (ACPR) to arginine among patients with type 2 diabetes.. Patients with type 2 diabetes were enrolled from the Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital. ACPR was assessed using arginine stimulation test. Decreased. Finally, 623 patients with type 2 diabetes were enrolled into the analysis. Multivariable-adjusted odds ratios for decreased. We demonstrated a dose-response linear association between 1,5-anhydroglucitol and ACPR. 1,5-Anhydroglucitol was likely to be associated with

Topics: Adult; Arginine; Biomarkers; Blood Glucose; C-Peptide; Deoxyglucose; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin-Secreting Cells; Male; Middle Aged; Pancreatic Function Tests; Predictive Value of Tests

The aim of this study is to investigate the effects of a low-carbohydrate staple food (i.e., low-carbohydrate bread) on glucose and lipid metabolism and pancreatic and enteroendocrine hormone secretion in comparison with meals containing normal-carbohydrate bread, without consideration of the carbohydrate content of the side dishes.. T2DM patients (n = 41) were provided meals containing low-carbohydrate bread (LB) together with side dishes or normal-carbohydrate bread (NB) together with side dishes every other day as a breakfast. Blood glucose levels were evaluated by using a continuous glucose monitoring system; blood samples were collected before and 1 and 2 h after the breakfast.. Postprandial blood glucose levels, plasma insulin, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma triglyceride were significantly lower and plasma glucagon levels were significantly higher in LB compared with those in NB. Plasma glucagon-like peptide-1 (GLP-1) levels did not differ in the LB and NB groups.. These results indicate that changing only the carbohydrate content of the staple food has benefits on glucose and lipid metabolism in T2DM patients concomitant with the decrease of insulin and GIP secretion, which ameliorate body weight gain and insulin resistance.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Bread; Breakfast; C-Peptide; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glycemic Load; Humans; Hypoglycemic Agents; Lipid Metabolism; Lipids; Male; Meals; Middle Aged; Postprandial Period

Postprandial hypoglycaemia (PPHG) is a complication of Roux-en-Y gastric bypass (RYGB) surgery in normoglycaemic individuals. In type 2 diabetes, RYGB improves glucose metabolism, but whether this improvement is related to the later development of PPHG is not known. We investigated the presence and mechanisms of PPHG in individuals with type 2 diabetes undergoing RYGB.. A total of 35 obese individuals with type 2 diabetes underwent an OGTT before and 24 months after surgery. PPHG was defined as a plasma glucose level of ≤3.3 mmol/l when not taking glucose-lowering agents. Insulin sensitivity was assessed by oral glucose insulin sensitivity index and beta-cell function by mathematical modelling of the plasma glucose, insulin and C-peptide concentrations.. After surgery, PPHG occurred in 11 of 35 individuals who underwent RYGB. Before surgery, BMI was lower, glycaemic control less good and time of glucose peak earlier in the PPHG vs No PPHG group, and the duration of diabetes was shorter with PPHG (all p ≤ 0.05). In addition, insulin sensitivity was greater in the PPHG than No PPHG group (p = 0.03). After surgery, BMI and fasting glucose and insulin levels decreased similarly in the two groups; insulin secretion during the first hour of the OGTT increased more in the PPHG than No PPHG group (p = 0.04). Beta-cell glucose sensitivity increased more in individuals with PPHG than those without (p = 0.002). Over the same time interval, the glucagon-like peptide 1 (GLP-1) response was lower in individuals with PPHG before surgery (p = 0.05), and increased more after surgery. At 2 h after glucose ingestion in the OGTT, postsurgery plasma glucagon level was significantly lower in the PPHG than No PPHG group.. In morbidly obese individuals with type 2 diabetes, spontaneous PPHG may occur after bariatric surgery independently of a remission of diabetes. Before surgery, individuals had a shorter duration and were more insulin sensitive. Two years after surgery, these individuals developed greater beta-cell glucose sensitivity, and showed greater insulin and GLP-1 release early in the OGTT.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucose Tolerance Test; Humans; Hypoglycemia; Male; Obesity, Morbid

Liraglutide is associated with blood pressure reduction in patients with type 2 diabetes. However, it is not known whether this blood pressure reduction can be predicted prior to treatment initiation, and to what extent it correlates with weight loss and with improved glycemic control during follow-up. We analyzed data from a double-blind, placebo-controlled trial, in which 124 insulin-treated patients with type 2 diabetes were randomized to liraglutide or placebo. We evaluated various baseline variables as potential predictors of systolic blood pressure (SBP) reduction, and evaluated whether changes in SBP correlated with weight loss and with improved glycemic control. A greater reduction in SBP among liraglutide-treated patients was predicted by higher baseline values of SBP (P < 0.0001) and diastolic blood pressure (P = 0.012), and by lower baseline values of mean glucose measured by continuous glucose monitoring (CGM; P = 0.044), and serum fasting C-peptide (P = 0.015). The regression coefficients differed significantly between the liraglutide group and the placebo group only for diastolic blood pressure (P = 0.037) and mean CGM (P = 0.021). During the trial period, SBP reduction correlated directly with change in body weight and BMI, but not with change in HbA1c. We conclude that patients with lower mean CGM values at baseline responded to liraglutide with a larger reduction in SBP, and that improved HbA1c during follow-up was not associated with reductions of SBP. Our data suggest that some patients with type 2 diabetes may benefit from liraglutide in terms of weight and SBP reduction.

Topics: Adult; Aftercare; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged; Placebos; Sweden; Weight Loss

It may be difficult to distinguish between adults with type 1 diabetes and type 2 diabetes by clinical assessment. In patients undergoing bariatric surgery, it is critical to correctly classify diabetes subtype to prevent adverse perioperative outcomes including diabetic ketoacidosis. This study aimed to determine whether testing for C-peptide and islet cell antibodies during preoperative evaluation for bariatric surgery could improve the classification of type 1 versus type 2 diabetes compared to clinical assessment alone.. The participant with type 1 diabetes was similar to the 11 participants with type 2 diabetes in age at diagnosis, adiposity, and glycemic control but had the lowest C-peptide levels. Among insulin-treated participants, fasting and stimulated C-peptide correlated strongly with the C-peptide area-under-the-curve on mixed meal tolerance testing (R = 0.86 and 0.88, respectively). Three participants, including the one with type 1 diabetes, were islet cell antibody positive.. Clinical characteristics did not correctly identify type 1 diabetes in this study. Preoperative C-peptide testing may improve diabetes classification in patients undergoing bariatric surgery; further research is needed to define the optimal C-peptide thresholds.

Topics: Adult; Autoantibodies; Bariatric Surgery; Blood Glucose; C-Peptide; Clinical Laboratory Techniques; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Fasting; Female; Humans; Male; Middle Aged; Obesity; Postoperative Period; Retrospective Studies; Weight Loss

This study aimed to determine whether L-arginine supplementation lasting for 18 months maintained long-lasting effects on diabetes incidence, insulin secretion and sensitivity, oxidative stress, and endothelial function during 108 months among subjects at high risk of developing type 2 diabetes.. One hundred and forty-four middle-aged subjects with impaired glucose tolerance and metabolic syndrome were randomized in 2006 to an L-arginine supplementation (6.4 g orally/day) or placebo therapy lasting 18 months. This period was followed by a 90-month follow-up. The primary outcome was a diagnosis of diabetes during the 108 month study period. Secondary outcomes included changes in insulin secretion (proinsulin/c-peptide ratio), insulin sensitivity (IGI/HOMA-IR), oxidative stress (AOPPs), and vascular function. After the 18 month participation, subjects that were still free of diabetes and willing to continue their participation (104 subjects) were further followed until diabetes diagnosis, with a time span of about 9 years from baseline.. Although results derived from the 18 month of the intervention study demonstrated no differences in the probability of becoming diabetics, at the end of the study, the cumulative incidence of diabetes was of 40.6% in the L-arginine group and of 57.4% in the placebo group. The adjusted HR for diabetes (L-arginine vs. placebo) was 0.66; 95% CI 0.48, 0.91; p < 0.02). Proinsulin/c-peptide ratio (p < 0.001), IGI/HOMA-IR (p < 0.01), and AOPP (p < 0.05) levels were ameliorated in L-arginine compared to placebo.. These results may suggest that the administration of L-arginine could delay the development of T2DM for a long period. This effect could be mediated, in some extent, by L-arginine-induced reduction in oxidative stress.

Topics: Administration, Oral; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet; Endothelial Cells; Exercise; Follow-Up Studies; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Middle Aged; Oxidative Stress; Sample Size; Surveys and Questionnaires; Treatment Outcome

The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide vs basal/bolus insulin therapy in T2DM patients who are poorly controlled with maximum/near-maximum doses of metformin plus a sulfonylurea. Participants in the Qatar study received a 75-g OGTT with measurement of plasma glucose, insulin and C-peptide concentration at baseline and were then randomized to receive either treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤ 7.0%) with pioglitazone plus exenatide. A 54% increase in 2-hour plasma C-peptide concentration above the fasting level identified subjects who achieved the glycaemic goal (HbA1c < 7.0%) with 82% sensitivity and 79% specificity. Only baseline HbA1c was a predictor of response to basal/bolus insulin therapy. Thus, the increment in 2-hour plasma C-peptide concentration above the fasting level provides a useful tool to identify poorly controlled T2DM patients who can achieve glycaemic control without insulin therapy, and thereby, can be used to individualize antihyperglycaemic therapy in poorly controlled T2DM patients.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Fasting; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Peptides; Pioglitazone; Qatar; Thiazolidinediones; Treatment Outcome; Venoms

To examine whether lowering plasma glucose concentration with the sodium-glucose transporter-2 inhibitor empagliflozin improves β-cell function in patients with type 2 diabetes mellitus (T2DM).. Patients with T2DM (N = 15) received empagliflozin (25 mg/d) for 2 weeks. β-Cell function was measured with a nine-step hyperglycemic clamp (each step, 40 mg/dL) before and at 48 hours and at 14 days after initiating empagliflozin.. Glucosuria was recorded on days 1 and 14 [mean ± standard error of the mean (SEM), 101 ± 10 g and 117 ± 11 g, respectively] after initiating empagliflozin, as were reductions in fasting plasma glucose levels (25 ± 6 mg/dL and 38 ± 8 mg/dL, respectively; both P < 0.05). After initiating empagliflozin and during the stepped hyperglycemic clamp, the incremental area under the plasma C-peptide concentration curve increased by 48% ± 12% at 48 hours and 61% ± 10% at 14 days (both P < 0.01); glucose infusion rate increased by 15% on day 3 and 16% on day 14, compared with baseline (both P < 0.05); and β-cell function, measured with the insulin secretion/insulin resistance index, increased by 73% ± 21% at 48 hours and 112% ± 20% at 14 days (both P < 0.01). β-cell glucose sensitivity during the hyperglycemic clamp was enhanced by 42% at 14 hours and 54% at 14 days after initiating empagliflozin (both P < 0.01).. Lowering the plasma glucose concentration with empagliflozin in patients with T2DM augmented β-cell glucose sensitivity and improved β-cell function.

Topics: Adult; Benzhydryl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glucosides; Glycosuria; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged

Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.. In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed.. Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed.. Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.

Topics: Aged; Area Under Curve; Bile Acids and Salts; Blood Glucose; C-Peptide; Chelating Agents; Cholecystokinin; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Energy Metabolism; Female; Fibroblast Growth Factors; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Microbiome; Glucagon; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; RNA, Ribosomal, 16S; Sequestering Agents; Sevelamer; Triglycerides

Glucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide-treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles. Changes in glycaemic measures in response to treatment with once-weekly dulaglutide were evaluated in each HOMA2-%B tertile. Patients with low HOMA2-%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB-2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; -1.55% vs. -0.98% [-16.94 vs. -10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; -1.00 vs. -1.18% [-10.93 vs. -12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C-peptide were observed in the low tertile. Similar increases in HOMA2-%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta-cell function.

Topics: Aged; Biomarkers; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Recombinant Fusion Proteins

Transcription factor 7-like 2 (TCF7L2) is the main susceptibility gene for type 2 diabetes, primarily through impairing the insulin secretion by pancreatic β cells. However, the exact in vivo mechanisms remain poorly understood. We performed a family study and determined if the T risk allele of the rs7903146 in the TCF7L2 gene increases the risk of type 2 diabetes based on real-time stable isotope measurements of insulin synthesis during an Oral Glucose Tolerance Test. In addition, we performed oral minimal model (OMM) analyses to assess insulin sensitivity and β cell function indices. Compared to unaffected relatives, individuals with type 2 diabetes had lower OMM indices and a higher level of insulin synthesis. We found a T allele-dosage effect on insulin synthesis and on glucose tolerance status, therefore insulin synthesis was higher among T-allele carriers with type 2 diabetes than in wild-type individuals. These results suggest that hyperinsulinemia is not only an adaptation to insulin resistance, but also a direct cause of type 2 diabetes.

Topics: Adult; Alleles; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide; Regression Analysis; Transcription Factor 7-Like 2 Protein

The aim of the study was to assess whether a simple substitution of carbohydrate in the conventionally recommended diet with protein and fat would result in a clinically meaningful reduction in postprandial hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). In all, sixteen subjects with T2DM treated with metformin only, fourteen male, with a median age of 65 (43-70) years, HbA1c of 6·5 % (47 mmol/l) (5·5-8·3 % (37-67 mmol/l)) and a BMI of 30 (sd 4·4) kg/m2 participated in the randomised, cross-over study. A carbohydrate-reduced high-protein (CRHP) diet was compared with an iso-energetic conventional diabetes (CD) diet. Macronutrient contents of the CRHP/CD diets consisted of 31/54 % energy from carbohydrate, 29/16 % energy from protein and 40/30 % energy from fat, respectively. Each diet was consumed on 2 consecutive days in a randomised order. Postprandial glycaemia, pancreatic and gut hormones, as well as satiety, were evaluated at breakfast and lunch. Compared with the CD diet, the CRHP diet reduced postprandial AUC of glucose by 14 %, insulin by 22 % and glucose-dependent insulinotropic polypeptide by 17 % (all P<0·001), respectively. Correspondingly, glucagon AUC increased by 33 % (P<0·001), cholecystokinin by 24 % (P=0·004) and satiety scores by 7 % (P=0·035), respectively. A moderate reduction in carbohydrate with an increase in fat and protein in the diet, compared with an energy-matched CD diet, greatly reduced postprandial glucose excursions and resulted in increased satiety in patients with well-controlled T2DM.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Proteins; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged

Sodium-glucose co-transporter-2 inhibitors are newly established anti-diabetic agents with a unique glucose-lowering mechanism. In the present study, we investigated the efficacy and safety of the sodium-glucose co-transporter-2 inhibitor ipragliflozin (Ipra) for metabolic markers and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus (T2DM). This study was an investigator-initiated, open-label, single-arm, multicenter prospective study. Patients with T2DM were treated with 50 mg Ipra for 24 and 52 weeks. The primary outcome investigated was the reduction of glycated hemoglobin (HbA1c) level. The secondary outcome was the change in other metabolic and cardiovascular parameters by 24 weeks. Before and after 52 weeks of treatment, carotid intima-media thickening (IMT) was measured by echography. A total of 134 patients were recruited in the study. A 24-week treatment with 50 mg Ipra daily significantly reduced HbA1c level (-0.6%, p < 0.01). Body mass index (BMI), blood pressure and serum C-peptide were reduced significantly (p < 0.05), while serum glucagon level was unchanged. Interestingly, the serum adiponectin and high-density lipoprotein (HDL) cholesterol levels were significantly increased by Ipra. However, 52 weeks of Ipra treatment did not change carotid IMT. Multiple regression analysis revealed that the only significant contributing factor for HbA1c reduction by Ipra was baseline HbA1c level. These data suggest that Ipra decreased not only glucose level but also BMI, blood pressure and serum C-peptide, and the contributing factor for HbA1c reduction by Ipra was baseline HbA1c level. Further, Ipra improved serum adiponectin and HDL cholesterol levels.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucosides; Humans; Hypoglycemic Agents; Male; Middle Aged; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Treatment Outcome; Young Adult

Fasting C-peptide levels are used to differentiate type 1 from type 2 diabetes (T2D), thereby determining eligibility for coverage of continuous subcutaneous insulin infusion (CSII) for patients with T2D.. A total of 168 patients (74 female/94 male, aged 55.5 ± 9.7 years) were randomized to CSII, and 163 patients (77 female/86 male, aged 56.4 ± 9.5 years) were randomized to multiple daily injections (MDI) of insulin and grouped by baseline C-peptide level: group A (≤183 pmol/L [≤0.55 ng/mL]); group B (>183 pmol/L [>0.55 ng/mL]). At 6 months, the MDI group crossed over to CSII. Within- and between-group comparisons were recorded at 6 and 12 months in the entire group and separately for those patients aged ≥65 years.. CSII reduced hemoglobin A1c (A1c) equally in groups A ( P = .0006, P = .0022) and B ( P<.0001, P<.0001) at 6 and 12 months, respectively. There was an increase in weight in group A versus group B at 6 months but not 12 months ( P<.03). CSII therapy reduced total daily dose (TDD) of insulin and improved treatment satisfaction similarly in groups A and B. The results for patients aged ≥65 years displayed a similar trend as the entire group.. A1c, TDD of insulin, and treatment satisfaction improved for T2D patients using CSII versus MDI therapy, irrespective of baseline C-peptide level. A subgroup of patients aged ≥65 years displayed a similar trend. These results support abandoning C-peptide as a criterion for reimbursing CSII therapy in patients with diabetes.. A1c = hemoglobin A1c; CMS = Centers for Medicare and Medicaid Services; CSII = continuous subcutaneous insulin infusion; DTSQ = Diabetes Treatment Satisfaction Questionnaire; MDI = multiple daily injections; RCT = randomized controlled trials; T1D = type 1 diabetes; T2D = type 2 diabetes; TDD = total daily dose.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Male; Middle Aged; Patient Satisfaction

Despite their widespread use in this population, data on the pharmacodynamic (PD) properties of the insulin analogs detemir and glargine in severely obese patients with type 2 diabetes are lacking.. The primary objective of the study was to compare the PD properties of two different doses of the basal insulin analogs detemir and glargine in patients with type 2 diabetes and a BMI > 35 kg/m2. PD data were derived from euglycemic clamp studies over 30 hours and each subject was studied for four times after the subcutaneous injection of a lower (0.8 U/kg body weight) and higher (1.6 U/kg body weight) dose of both detemir and glargine using a single-blind, randomised cross-over design.. Six male and four female patients with type 2 diabetes and a mean BMI of 43.2±5.1 kg/m2 (mean age 55.7±2 years, mean HbA1c 7.2±0.3%) completed the study. The total GIRAUC0-30 (mean difference 1224 mg/kg, 95%CI 810-1637, p = 0.00001), GIRAUC0-24 (mean difference 1040 mg/kg, 95%CI 657-1423; p = 0.00001), GIRAUC24-30 (mean difference 181 mg/kg, 95%CI 64-298; p = 0.004), GIRmax (mean difference 0.93 mg/kg/min, 95%CI 0.22-1.64, p = 0.01) and time to GIRmax (+1.9 hours, 95%CI 0.5-3.2; p = 0.009) were higher after the higher doses of both insulins, without significant differences between detemir and glargine. However, during the last 6 hours of the clamp the GIRAUC24-30 was significantly increased with glargine (mean difference 122 mg/kg, 95%CI 6-237, p = 0.043), reflecting a more pronounced late glucose lowering effect.. A clear dose-response relationship can be demonstrated for both insulin analogs, even at very high doses in severely obese patients with type 2 diabetes. Compared to detemir, glargine has a more pronounced late glucose lowering effect 24-30 h after its injection.. Controlled-Trials.com ISRCTN57547229.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucose Clamp Technique; Humans; Insulin Detemir; Insulin Glargine; Male; Middle Aged; Obesity

GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients.. We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD2 pathway biomarkers were performed.. We found (1) that PGD2 is produced in human islet in response to high glucose or IL-1beta, but likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean ratios vs placebo of 0.94 (80% CI of 0.90-0.98, p = 0.12) and 0.99 (90% CI of 0.94-1.05, p = 0.45), despite reaching the expected antagonist exposure.. Pharmacological inhibition of the PGD2-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients.. ClinicalTrials.gov NCT02367066.

Topics: Acetates; Blood Glucose; C-Peptide; Cell Line; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Female; Gene Expression Regulation; Humans; Indoles; Insulin; Islets of Langerhans; Male; Middle Aged; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Transcription Factors

The aim of the study was to investigate the different B-cell responses after a glucagon stimulation test (GST) versus mixed meal tolerance test (MMTT).. We conducted GST and MMTT in 10 healthy people (aged 25-40 years) and measured C-peptide, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) at different time points after the administration of 1 mg i.v. glucagon for GST or a liquid mixed meal for MMTT.. The GST stimulated C-peptide showed a mean increase of 147.1%, whereas the mean increase of MMTT stimulated C-peptide was 99.82% (Δincrease = 47.2%). Maximum C-peptide level reached with the MMTT was greater than that obtained with the GST (C-pept max MMTT = 2.35 nmol/L vs C-pep max GST = 1.9 nmol/L). A positive and linear correlation was found between the GST incremental area under the curve C-peptide and the MMTT incremental area under the curve C-peptide (r = 0.618, P = .05). After GST, there was no increment of GIP and glucagon like peptide-1 levels compared to baseline levels. A positive and linear correlation between GIP and C-peptide levels was observed only for the MMTT (r = 0.922, P = .008) indicating that in the GST, the C-peptide response is independent of the incretin axis response.. Although the 2 stimulation tests may elicit a similar response in C-peptide secretion, B-cell response to MMTT depends on a functionally normal incretin axis. These results may have implications when investigating the B-cell response in people with diabetes and for studies in which stimulated C-peptide secretion is used as primary or secondary outcome for response to therapy.

Topics: Adult; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Eating; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells; Male; Meals; Stimulation, Chemical

We investigated whether intake of non-glutinous brown rice (BR) or glutinous brown rice (GBR) for 1 day had an influence on the daily glucose profile measured by continuous glucose monitoring (CGM) when compared with intake of non-glutinous white rice (WR).. A total of 37 inpatients with type 2 diabetes mellitus (T2DM) were recruited for a 3-day randomized triple cross-over trial in which they ate WR, BR, or GBR for 1 day each. One of the three types of rice was eaten at breakfast, lunch, and dinner on the first day, before switching to the other types on the second and third days. Each meal had the same energy content and the same side dishes. The main outcome measures were the blood glucose profile determined by continuous glucose monitoring (CGM) and the profile of serum C-peptide (CPR) for 3 hours after breakfast. A self-administered questionnaire was used to assess the palatability of each type of rice.. According to the CGM data, the mean 24-hour glucose concentration was lowest with GBR (p<0.01). Serum Cpeptide showed no significant differences among the three diets. Regarding palatability, BR was assigned significantly lower scores than WR and GBR (p<0.05), while there was no difference between WR and GBR.. GBR intake suppressed the whole-day glucose profile of patients with T2DM, mainly by reducing postprandial glucose excursion, and GBR was preferred over BR with respect to palatability. GBR may be worth adding to the diet of patients with T2DM.

Topics: Aged; Blood Glucose; Body Mass Index; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Monitoring, Physiologic; Oryza; Surveys and Questionnaires

We recently reported that eating glutinous brown rice (GBR) for 1 day improved the whole-day glucose profile and postprandial plasma glucose level compared with eating white rice (WR) or standard brown rice. However, it was unknown whether eating GBR could maintain improvement of glycemic control for a longer period. Therefore, we evaluated the effect of GBR intake for 8 weeks on glycemic control in outpatients with diabetes mellitus.. This was an open-label randomized crossover study in outpatients with type 2 diabetes. Among the 18 subjects registered in this study, 2 were excluded from analysis. After a 1-week observation period while eating WR twice a day, the patients were randomly assigned to two groups. One group ate GBR as a staple food twice a day for 8 weeks and then switched to WR for the next 8 weeks, while the other group ate WR first and then switched to GBR. A mixed meal tolerance test was performed at baseline and after 8 and 16 weeks of dietary intervention to evaluate plasma glucose and serum C-peptide.. None of the subjects failed to complete the study because of disliking the taste of GBR. Hemoglobin A1c (7.5-7.2%, P=0.014) and glycoalbumin (20.4-19.4%, P=0.029) both decreased significantly when the patients were eating GBR. Additionally, the 30-min postprandial plasma glucose level (194-172 mg dl. We confirmed that GBR was well tolerated for 8 weeks and improved glycemic control in patients with type 2 diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Female; Food; Glycated Hemoglobin; Humans; Male; Middle Aged; Oryza; Treatment Outcome

The discovery of gut sweet taste receptors has led to speculations that non-nutritive sweeteners, including sucralose, may affect glucose control. A double-blind, parallel, randomized clinical trial, reported here and previously submitted to regulatory agencies, helps to clarify the role of sucralose in this regard. This was primarily an out-patient study, with 4-week screening, 12-week test, and 4-week follow-up phases. Normoglycemic male volunteers (47) consumed ∼333.3 mg encapsulated sucralose or placebo 3x/day at mealtimes. HbA1c, fasting glucose, insulin, and C-peptide were measured weekly. OGTTs were conducted in-clinic overnight, following overnight fasting twice during screening phase, twice during test phase, and once at follow-up. Throughout the study, glucose, insulin, C-peptide and HbA1c levels were within normal range. No statistically significant differences between sucralose and placebo groups in change from baseline for fasting glucose, insulin, C-peptide and HbA1c, no clinically meaningful differences in time to peak levels or return towards basal levels in OGTTs, and no treatment group differences in mean glucose, insulin, or C-peptide AUC change from baseline were observed. The results of other relevant clinical trials and studies of gastrointestinal sweet taste receptors are compared to these findings. The collective evidence supports that sucralose has no effect on glycemic control.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Male; Sucrose; Sweetening Agents

Shift-work is associated with circadian rhythm disruption and an increased risk of obesity and type 2 diabetes. We sought to determine the effect of rotational shift-work on glucose metabolism in humans.. We studied 12 otherwise healthy nurses performing rotational shift-work using a randomised crossover study design. On each occasion, participants underwent an isotope-labelled mixed meal test during a simulated day shift and a simulated night shift, enabling simultaneous measurement of glucose flux and beta cell function using the oral minimal model. We sought to determine differences in fasting and postprandial glucose metabolism during the day shift vs the night shift.. Postprandial glycaemic excursion was higher during the night shift (381±33 vs 580±48 mmol/l per 5 h, p<0.01). The time to peak insulin and C-peptide and nadir glucagon suppression in response to meal ingestion was also delayed during the night shift. While insulin action did not differ between study days, the beta cell responsivity to glucose (59±5 vs 44±4 × 10. Impaired beta cell function during the night shift may result from normal circadian variation, the effect of rotational shift-work or a combination of both. As a consequence, higher postprandial glucose concentrations are observed during the night shift.

Topics: Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucagon; Health Personnel; Humans; Insulin; Male; Postprandial Period; Shift Work Schedule; Young Adult

The role of glucose effectiveness (S. Fourteen participants with type 2 diabetes underwent three trials (IWT, CWT and no training) in a crossover study. Exclusion criteria were exogenous insulin treatment, smoking, pregnancy, contraindications to structured physical activity and participation in recurrent training (>90 min/week). The trials were performed in a randomised order (computerised-generated randomisation). IWT and CWT consisted of ten supervised treadmill walking sessions, each lasting 60 min, over 2 weeks. IWT was performed as repeated cycles of 3 min slow walking and 3 min fast walking (aiming for 54% and 89% of [Formula: see text], respectively, which was measured during the last minute of each interval), and CWT was performed aiming for a moderate walking speed (73% of [Formula: see text]). A two-step (pancreatic and hyperinsulinaemic) hyperglycaemic clamp was implemented before and after each trial. All data were collected in a hospitalised setting. Neither participants nor assessors were blinded to the trial interventions.. Thirteen individuals completed all procedures and were included in the analyses. IWT improved S. Two weeks of IWT, but not CWT, improves S. ClinicalTrials.gov NCT02320526 FUNDING: CFAS is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of DD2-the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724).

Topics: Aged; Blood Glucose; Body Composition; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Energy Metabolism; Exercise; Female; Humans; Insulin; Insulin Resistance; Kinetics; Male; Middle Aged; Walking

We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.. We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.. At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.. Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.

Topics: Adamantane; Aged; Blood Glucose; C-Peptide; Deoxyglucose; Diabetes Mellitus, Type 2; Dipeptides; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Middle Aged; Placebo Effect; Treatment Outcome

A personalized antidiabetic therapy is not yet part of the official guidelines of professional societies for clinical practice. The aim of this study was to evaluate the serum C-peptide and plasma glucose levels in patients with type 2 diabetes mellitus (T2DM) after oral administration of whey proteins. Sixteen overweight T2DM Caucasians with good glycemic control and with preserved fasting serum C-peptide levels (>200 nmol/l) were enrolled in this study. Two oral stimulation tests - one with 75 g of glucose (OGTT) and the other with 75 g of whey proteins (OWIST) - were administered for assessing serum C-peptide and plasma glucose levels in each participant. Both oral tests induced similar pattern of C-peptide secretion, with a peak at 90 min. The serum C-peptide peak concentration was 2.91+/-0.27 nmol/l in OWIST, which was 22 % lower than in OGTT. Similarly, the C-peptide iAUC(0-180) were 32 % lower in the OWIST than in the OGTT (p<0.01). Contrary to OGTT the OWIST did not cause a significant increase of glycemia (p<0.01). Our study showed that the OWIST represents a useful tool in estimation of stimulated serum C-peptide levels in patients with T2DM.

Topics: Administration, Oral; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Czech Republic; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Male; Middle Aged; Predictive Value of Tests; Time Factors; Whey Proteins

The aim of the randomized present study was to compare the therapeutic efficacy and safety of a combination of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, plus insulin glargine (GL + sita) with that of premixed insulin aspart 30 (NOV) for type 2 diabetes (T2D) patients controlled with oral hypoglycemic drugs (HbA1c 7 %-9 %).. Sixty-five patients were randomized (1:  1) to the GL + sita (n = 33) and NOV (n = 32) groups and were treated with the combination regimen or premixed insulin twice a day for 16 weeks. The primary endpoint was mean change in HbA1c. Secondary endpoints included fasting blood glucose, blood glucose profiles (seven time points), rate of achieving target HbA1c (<7 % or ≤6.5 %), insulin dose, incidence of hypoglycemia, and body weight.. After 16 weeks, there was no significant difference in HbA1c between the two groups, although more patients achieved HbA1c <7.0 % in the GL + sita group. There was a significant difference in body weight changes between the GL + sita and NOV groups (-0.45 vs 1.52 kg, respectively; P < 0.001). Mean plasma glucose and the mean amplitude of glycemic excursion were significantly lower in the GL + sita than NOV group (P < 0.005), as was the incidence of symptomatic hypoglycemia (2.85 % vs. 13.3 %, respectively; P < 0.001).. The combination of GL + sita greatly improved HbA1c in T2D patients (HbA1c 7 %-9 %) with an efficacy that was equal to that of premixed insulin. Thus, GL + sita treatment is a viable option for patients who fail to achieve glycemic control using oral hypoglycemic drugs.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged; Sitagliptin Phosphate; Treatment Outcome

A bidirectional relationship exists between diabetes and periodontitis. In the present clinical trial, we evaluated the effects of non-surgical periodontal therapy (NSPT) on insulin resistance in patients with type II diabetes mellitus (DM) and chronic periodontitis.. Forty chronic periodontitis patients with type II DM were selected and equally allocated to case and control groups. All patients were assessed for periodontal parameters and systemic parameters. The case group received NSPT, and both groups were re-evaluated after 3 months.. All periodontal parameters were found to be significantly improved in the case group compared to the control group 3 months after NSPT. The mean differences in systemic parameters, such as fasting serum C-peptide, Homeostasis Assessment (HOMA) Index-insulin resistance, and HOMA-insulin sensitivity, from baseline to 3 months for the case group were 0.544 ± 0.73, 0.54 ± 0.63, and -25.44 ± 36.81, respectively; for the control group, they were significant at -1.66 ± 1.89, -1.48 ± 1.86, and 31.42 ± 38.82 respectively (P < 0.05). There was a significant decrease in fasting blood glucose and glycosylated hemoglobin A1c from baseline to 3 months in the case group (P < 0.05).. The present study showed that periodontal inflammation could affect glycemic control and insulin resistance. Effective periodontal therapy reduced insulin resistance and improved periodontal health status and insulin sensitivity in patients with type II DM and chronic periodontitis.

Topics: C-Peptide; Chronic Periodontitis; Diabetes Mellitus, Type 2; Homeostasis; Humans; Insulin Resistance

Gemigliptin is a new dipeptidyl peptidase-IV inhibitor. We investigated the efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes (T2D).. A total of 433 T2D patients with a glycosylated haemoglobin (HbA1c) level of 7.5% to 11.0% and a fasting plasma glucose (FPG) concentration <270 mg/dL were randomly assigned to 3 groups: (1) gemigliptin 50 mg qd + metformin 1000 to 2000 mg qd (titrated individually), (2) gemigliptin 50 mg qd, or (3) metformin 1000 to 2000 mg qd. The primary end-point was the change in HbA1c level after 24 weeks. Secondary end-points were the changes in FPG, insulin, proinsulin and C-peptide levels. The percentages of responders who achieved an HbA1c level <7% (or <6.5%) were compared between treatment groups.. Baseline HbA1c levels were 8.7% in all groups. The mean changes in HbA1c level from baseline to week 24 were -2.06%, -1.24% and -1.47% in the combination, gemigliptin monotherapy and metformin monotherapy groups, respectively. The 95% confidence intervals for between-group differences in HbA1c changes were -1.02 to -0.63 in the combination group vs the gemigliptin group and -0.82 to -0.41 vs the metformin group, which confirmed the superiority of combination therapy. A significantly higher percentage of patients in the combination therapy group reached the target HbA1c level <7% (or <6.5%) compared with the monotherapy groups. No severe side effects were observed.. In T2D patients, the initial combination of gemigliptin and metformin had superior efficacy without safety concerns compared with monotherapy with either drug.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Piperidones; Proinsulin; Pyrimidines; Republic of Korea; Thailand; Treatment Outcome

To examine the lipid and glycaemic effects of 52 weeks of treatment with evolocumab.. The Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES) was a 52-week placebo-controlled trial of evolocumab that randomized 905 patients from 88 study centres in 9 countries, with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status: type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS) or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDL-cholesterol (LDL-C) at week 52 and safety.. A total of 413 patients had dysglycaemia (120, type 2 diabetes; 293, IFG), 289 had MetS (194 also had IFG) and 393 had none of these conditions. At week 52, evolocumab reduced LDL-C by >50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients.. Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Blood Glucose; C-Peptide; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypercholesterolemia; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Treatment Outcome; Triglycerides

To determine whether the addition of sitagliptin to pre-existing therapy with liraglutide changes glycaemic excursions after a mixed meal.. A total of 16 patients with type 2 diabetes treated with metformin and liraglutide (1.2 mg/d for ≥2 weeks) were randomized (sealed envelopes), within a cross-over design, to be studied on two occasions, after an overnight fast, with (1) sitagliptin (100 mg orally) and (2) placebo (patients and care givers blinded) administered 60 minutes before a mixed meal, or vice versa. Glucose excursions (incremental area under the curve [AUC]; primary endpoint) and insulin, C-peptide, glucagon and incretin concentrations were measured. The study setting was a metabolic study unit at a specialized diabetes hospital.. All 16 patients completed the study and were analysed. Glucose (AUC. Sitagliptin, in patients already treated with a GLP-1 receptor agonist (liraglutide), increased intact GLP-1 and GIP concentrations, but with marginal, non-significant effects on glycaemic control. GLP-1 receptors have probably been maximally stimulated by liraglutide. Our findings do not support combination treatment with GLP-1 receptor agonists and DPP-4 inhibitors, but longer-term trials are needed to support clinical recommendations.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Treatment Outcome

The purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM).. At baseline, Taiwanese participants had a lower BMI, younger age, and shorter duration of T2DM than American participants. At 24 months, weight loss was greater in the RYGB group in both populations than in the IMM group. No IMM participant of either population had partial or complete remission of T2DM. In the RYGB group, a substantial proportion of the subjects achieved complete or partial remission (57 % in Taiwanese and 27 % in American participants, P = 0.08). Logistic regression revealed stimulated C-peptide (Odds ratio 2.22, P = 0.02) but not nationality as a significant predictor of diabetes remission.. Adding RYGB to lifestyle and medical management was associated with a greater likelihood of remission of T2DM in both Taiwanese and American subjects with mild obesity with type 2 diabetes. Residual beta-cell function at baseline appears to be the major factor predicting remission of T2DM. Trial registry number: clinicaltrials.gov Identifier: NCT00641251.

Topics: Adult; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Hypoglycemic Agents; Life Style; Male; Middle Aged; Obesity; Remission Induction; Taiwan; Time Factors; Treatment Outcome; United States

Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as 'glucotoxicity'. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.. This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.. After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10. These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucosides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Middle Aged; Proinsulin; Prospective Studies; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes

To determine if reduction in serum insulin with dapagliflozin plus saxagliptin or dapagliflozin add-on to metformin contributed to increased insulin clearance and to assess the effects of these treatments on β-cell function.. Patients (glycated hemoglobin, 8 to 12%; 64 to 108 mmol/mol) were randomized to 24-week, double-blind treatment with saxagliptin 5 mg/day plus dapagliflozin 10 mg/day (n = 179), saxagliptin 5 mg/day plus placebo (n = 176), or dapagliflozin 10 mg/day plus placebo (n = 179) added to metformin. C-peptide to insulin ratio was used as an index of insulin clearance during a meal tolerance test, and β-cell function was evaluated by Homeostasis Model Assessment 2.. Increased C-peptide to insulin ratio with saxagliptin + dapagliflozin and dapagliflozin + placebo add-on to metformin compared with saxagliptin + placebo add-on to metformin suggests that dapagliflozin increases insulin clearance and may contribute to lower circulating insulin. All treatments improved β-cell function, with the greatest improvements with saxagliptin + dapagliflozin and dapagliflozin + placebo.. A1c = glycated hemoglobin AUC

Topics: Adamantane; Aged; Area Under Curve; Benzhydryl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptides; Double-Blind Method; Drug Therapy, Combination; Female; Glucose Tolerance Test; Glucosides; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

To evaluate the effects of dulaglutide 1.5 mg on first- and second-phase insulin secretion in response to an intravenous (i.v.) glucose bolus challenge, in subjects with type 2 diabetes mellitus (T2DM; primary objective) and in healthy subjects.. In this randomized, double-blind, placebo-controlled, 2-period crossover study, subjects received a single subcutaneous injection of dulaglutide 1.5 mg or placebo on day 1 of each period. On day 3, subjects underwent a 6-hour insulin infusion, followed by an i.v. glucose bolus and a glucagon challenge during hyperglycaemia. Areas under the concentration-time curve and maximum concentrations for first- (AUC. In 20 subjects with T2DM, dulaglutide increased mean insulin AUC. In subjects with T2DM, a single dulaglutide 1.5-mg dose restored the first-phase insulin secretion in response to an i.v. glucose bolus, increased the second-phase insulin response and enhanced β-cell function.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Glucagon; Glucagon-Like Peptides; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Infusions, Intravenous; Injections, Subcutaneous; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Recombinant Fusion Proteins; Treatment Outcome

To investigate efficacy and safety of the sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin administered as add-on therapy to the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin in patients with type 2 diabetes mellitus (T2DM).. We conducted a multicentre, randomized, double-blind, placebo-controlled, phase 3 clinical trial in Japanese patients with T2DM who had inadequate glycaemic control with teneligliptin. Patients were randomized to receive teneligliptin 20 mg plus either canagliflozin 100 mg (T + C, n = 70) or placebo (T + P, n = 68) once daily. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. Other endpoints included changes in fasting plasma glucose, body weight, proinsulin/C-peptide ratio, homeostatic model assessment 2-%B and adverse events. Patients also underwent mixed-meal tolerance tests.. The difference between the T + C and T + P groups for HbA1c change from baseline to week 24 was -0.88% (least-squares mean, P < .001). Fasting plasma glucose, body weight and the proinsulin/C-peptide ratio were significantly lower in the T + C group than in the T + P group. Homeostatic model assessment 2-%B improved with T + C compared with T + P. The T + C group exhibited a decrease in the 2-hour postprandial plasma glucose and plasma glucose area under the curve (AUC). Canagliflozin administered as add-on therapy to teneligliptin was effective and well tolerated in Japanese T2DM patients.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Pyrazoles; Thiazolidines; Treatment Outcome

: Postprandial hypotension (PPH) is a common condition that occurs primarily in elderly patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the effectiveness of acarbose for PPH; it also investigated possible mechanisms behind PPH development. This single-blind, randomized controlled trial included 91 elderly patients with T2DM, aged between 60 and 80 years, who were inpatients at Beijing Hospital between March 2012 and November 2014. The patients were included into one of three groups: Group A, patients with T2DM without PPH; Group B, patients with T2DM with PPH receiving placebo; and Group C, patients with T2DM with PPH receiving acarbose. After an overnight fast, patients received a single dose of acarbose (100 mg) or placebo and then consumed a standardized 450 kcal meal. Blood pressure, glucose levels, heart rate (HR), and catecholamine levels were evaluated. Acarbose ameliorated PPH as determined by significant improvements in the duration and maximal fall in blood pressure (both p<0.001); however, no differences in HR and blood glucose levels were observed. In patients with PPH, blood pressure was correlated with blood glucose and HR variability values (p<0.05). Correlations between epinephrine and glucagon-like peptide-1 with blood pressure in groups A and C were largely lost in group B. Acarbose reduced postprandial blood pressure fluctuations in elderly patients with diabetes. PPH may be related to impaired autonomic nervous system function, reduced catecholamine secretion, and postprandial fluctuations in blood glucose levels.. Chinese Clinical Trial Registry ChiCTR-IPR-15006177.

Topics: Acarbose; Aged; Aged, 80 and over; Blood Glucose; Blood Glucose Self-Monitoring; Blood Pressure; C-Peptide; Catecholamines; Demography; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Rate; Humans; Hypotension; Postprandial Period; Treatment Outcome

Children whose parents have diabetes are at increased risk for developing type 2 diabetes. This report assessed relationships between parental diabetes status and baseline demographics, anthropometrics, metabolic measurements, insulin sensitivity, and β-cell function in children recently diagnosed with type 2 diabetes.. The sample included 632 youth (aged 10-17 years) diagnosed with type 2 diabetes for <2 years who participated in the TODAY clinical trial. Medical history data were collected at baseline by self-report from parents and family members. Youth baseline measurements included an oral glucose tolerance test and other measures collected by trained study staff.. Youth exposed to maternal diabetes during pregnancy (whether the mother was diagnosed with diabetes prior to pregnancy or had gestational diabetes mellitus) were diagnosed at younger ages (by 0.6 years on average), had greater dysglycemia at baseline (HbA1c increased by 0.3% [3.4 mmol/mol]), and had reduced β-cell function compared with those not exposed (C-peptide index 0.063 vs. 0.092). The effect of maternal diabetes on β-cell function was observed in non-Hispanic blacks and Hispanics but not whites. Relationships with paternal diabetes status were minimal.. Maternal diabetes prior to or during pregnancy was associated with poorer glycemic control and β-cell function overall but particularly in non-Hispanic black and Hispanic youth, supporting the hypothesis that fetal exposure to aberrant metabolism may have long-term effects. More targeted research is needed to understand whether the impact of maternal diabetes is modified by racial/ethnic factors or whether the pathway to youth-onset type 2 diabetes differs by race/ethnicity.

Topics: Adolescent; Black or African American; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 2; Diabetes, Gestational; Ethnicity; Family Health; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Linear Models; Male; Parents; Pregnancy; Risk Factors; White People

Investigation of dietary therapy for diabetes has focused on meal size and composition; examination of the effects of meal sequence on postprandial glucose management is limited. The effects of fish or meat before rice on postprandial glucose excursion, gastric emptying and incretin secretions were investigated.. The experiment was a single centre, randomised controlled crossover, exploratory trial conducted in an outpatient ward of a private hospital in Osaka, Japan. Patients with type 2 diabetes (n = 12) and healthy volunteers (n = 10), with age 30-75 years, HbA1c 9.0% (75 mmol/mol) or less, and BMI 35 kg/m(2) or less, were randomised evenly to two groups by use of stratified randomisation, and subjected to meal sequence tests on three separate mornings; days 1 and 2, rice before fish (RF) or fish before rice (FR) in a crossover fashion; and day 3, meat before rice (MR). Pre- and postprandial levels of glucose, insulin, C-peptide and glucagon as well as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide were evaluated. Gastric emptying rate was determined by (13)C-acetate breath test involving measurement of (13)CO2 in breath samples collected before and after ingestion of rice steamed with (13)C-labelled sodium acetate. Participants, people doing measurements or examinations, and people assessing the outcomes were not blinded to group assignment.. FR and MR in comparison with RF ameliorated postprandial glucose excursion (AUC-15-240 min-glucose: type 2 diabetes, FR 2,326.6 ± 114.7 mmol/l × min, MR 2,257.0 ± 82.3 mmol/l × min, RF 2,475.6 ± 87.2 mmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 1,419.8 ± 72.3 mmol/l × min, MR 1,389.7 ± 69.4 mmol/l × min, RF 1,483.9 ± 72.8 mmol/l × min) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, FR 1.94 ± 0.22 mmol/l, MR 1.68 ± 0.18 mmol/l, RF 2.77 ± 0.24 mmol/l [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 0.95 ± 0.21 mmol/l, MR 0.83 ± 0.16 mmol/l, RF 1.18 ± 0.27 mmol/l). FR and MR also enhanced GLP-1 secretion, MR more strongly than FR or RF (AUC-15-240 min-GLP-1: type 2 diabetes, FR 7,123.4 ± 376.3 pmol/l × min, MR 7,743.6 ± 801.4 pmol/l × min, RF 6,189.9 ± 581.3 pmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 3,977.3 ± 324.6 pmol/l × min, MR 4,897.7 ± 330.7 pmol/l × min, RF 3,747.5 ± 572.6 pmol/l × min [p < 0.05 for MR vs RF and MR vs FR]). FR and MR delayed gastric emptying (Time50%: type 2 diabetes, FR 83.2 ± 7.2 min, MR 82.3 ± 6.4 min, RF 29.8 ± 3.9 min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 66.3 ± 5.5 min, MR 74.4 ± 7.6 min, RF 32.4 ± 4.5 min [p < 0.05 for FR vs RF and MR vs RF]), which is associated with amelioration of postprandial glucose excursion (AUC-15-120 min-glucose: type 2 diabetes, r = -0.746, p < 0.05; healthy, r = -0.433, p < 0.05) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, r = -0.578, p < 0.05; healthy, r = -0.526, p < 0.05), as well as with increasing GLP-1 (AUC-15-120 min-GLP-1: type 2 diabetes, r = 0.437, p < 0.05; healthy, r = 0.300, p = 0.107) and glucagon (AUC-15-120 min-glucagon: type 2 diabetes, r = 0.399, p < 0.05; healthy, r = 0.471, p < 0.05). The measured outcomes were comparable between the two randomised groups.. Meal sequence can play a role in postprandial glucose control through both delayed gastric emptying and enhanced incretin secretion. Our findings provide clues for medical nutrition therapy to better prevent and manage type 2 diabetes.. UMIN Clinical Trials Registry UMIN000017434.. Japan Society for Promotion of Science, Japan Association for Diabetes Education and Care, and Japan Vascular Disease Research Foundation.

Topics: Adult; Aged; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Japan; Male; Meals; Middle Aged; Postprandial Period

C-peptide allows estimation of insulin secretion even in the presence of insulin treatment. C-peptide may be suitable for the differential diagnosis of type 1 and type 2 diabetes, and, within type 2 diabetes, of insulin-requiring vs. non-insulin-requiring patients. Relating C-peptide concentrations to ambient glucose levels might improve its diagnostic potential.. The diagnostic value (a) fasting C-peptide, (b) C-peptide/glucose ratios, and (c) the HOMA-ßC-peptide-index for predicting a diagnosis of type 1 (vs. type 2) diabetes were assessed.. Specialised hospital for the care of diabetic patients (inpatient treatment). 303 patients with type 1 diabetes and 841 patients with type 2 diabetes.. Odds ratios and 95% confidence intervals for a clinical diagnosis of type 1 diabetes or for insulin treatment by deciles of (a) fasting C-peptide, (b) C-peptide/glucose ratios, and (c) HOMA-ßC-peptide-index.. Low C-peptide concentrations were associated with a high odds ratio for type 1 diabetes and vice versa (p<0.0001). Concentrations of 0.13-0.36 nmol/l did not discriminate. C-peptide/glucose ratios or HOMA-ßC-Peptide did not perform better. The ability of all 3 parameters to predict the necessity for insulin treatment within the population of type 2-diabetic patients was low.. Fasting C-peptide and derived parameters help to differentiate type 1 from type 2 diabetes, but there is a range of C-peptide concentrations that does not help discriminate. Relating C-peptide to glucose did not improve diagnostic accuracy. C-peptide does not help predicting a need for insulin treatment in patients with type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Male; Middle Aged

To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake.. On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled.. In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups.. CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.

Topics: Aged; Bile Acids and Salts; Blood Glucose; C-Peptide; Chenodeoxycholic Acid; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Placebos

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM).. Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured.. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated.. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.

Topics: Adult; Aged; Alanine Transaminase; Amino Acids; Aspartate Aminotransferases; beta-Alanine; Blood Glucose; C-Peptide; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Pyrazoles; Receptors, Glucagon; Sulfonylurea Compounds

To determine whether interrupting prolonged sitting with brief bouts of light-intensity walking (LW) or simple resistance activities (SRA) improves postprandial cardiometabolic risk markers in adults with type 2 diabetes (T2D).. In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men 62 ± 6 years old) underwent the following 8-h conditions on three separate days (with 6-14 days washout): uninterrupted sitting (control) (SIT), sitting plus 3-min bouts of LW (3.2 km · h(-1)) every 30 min, and sitting plus 3-min bouts of SRA (half-squats, calf raises, gluteal contractions, and knee raises) every 30 min. Standardized meals were consumed during each condition. Incremental areas under the curve (iAUCs) for glucose, insulin, C-peptide, and triglycerides were compared between conditions.. Compared with SIT, both activity-break conditions significantly attenuated iAUCs for glucose (SIT mean 24.2 mmol · h · L(-1) [95% CI 20.4-28.0] vs. LW 14.8 [11.0-18.6] and SRA 14.7 [10.9-18.5]), insulin (SIT 3,293 pmol · h · L(-1) [2,887-3,700] vs. LW 2,104 [1,696-2,511] and SRA 2,066 [1,660-2,473]), and C-peptide (SIT 15,641 pmol · h · L(-1) [14,353-16,929] vs. LW 11,504 [10,209-12,799] and SRA 11,012 [9,723-12,301]) (all P < 0.001). The iAUC for triglycerides was significantly attenuated for SRA (P < 0.001) but not for LW (SIT 4.8 mmol · h · L(-1) [3.6-6.0] vs. LW 4.0 [2.8-5.1] and SRA 2.9 [1.7-4.1]).. Interrupting prolonged sitting with brief bouts of LW or SRA attenuates acute postprandial glucose, insulin, C-peptide, and triglyceride responses in adults with T2D. With poor adherence to structured exercise, this approach is potentially beneficial and practical.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Exercise Therapy; Female; Humans; Insulin; Male; Middle Aged; Obesity; Overweight; Postprandial Period; Posture; Resistance Training; Sedentary Behavior; Triglycerides; Walking

We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study.. In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean ± SD) 64 ± 6 years; BMI 30 ± 7 kg/m(2); diabetes duration 8 ± 5 years; glycated haemoglobin 6.6 ± 0.6 % (57.3 ± 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records.. Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen's d = -1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), -2.3 (-5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed.. Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet.. ClinicalTrials.gov NCT00435240.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Humans; Insulin; Leptin; Male; Middle Aged

Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans.. ClinicalTrials.gov NCT01434901.

Topics: Administration, Oral; Adult; Bethanechol; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Hormones; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Muscarinic Agonists; Neurotensin; Non-Randomized Controlled Trials as Topic; Pancreatic Polypeptide; Postprandial Period

To examine the efficacy and safety of add-on ipragliflozin in Japanese patients with type 2 diabetes in the early stage of insulin therapy.. Patients treated with insulin (bolus component <30% of total daily dose) with/without a dipeptidyl peptidase-4 (DPP-4) inhibitor were randomized to receive placebo (n = 87) or ipragliflozin (n = 175) for 16 weeks. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline. Secondary endpoints included changes in fasting plasma glucose (FPG) and metabolic hormones. Safety endpoints were also examined.. The changes in HbA1c were 0.27% and -0.79% (2.9 and -8.7 mmol/mol) in the placebo and ipragliflozin groups, respectively (baseline: 8.62% vs 8.67% [70.8 vs 71.2 mmol/mol]), corresponding to an adjusted mean difference of -1.07% (95% confidence interval -1.24, -0.91) or -11.7 mmol/mol (-13.5, -9.9), p < .001. Ipragliflozin reduced FPG and serum C-peptide levels and body weight (all p < .001), and increased serum adiponectin levels (p = .022). There was a statistically significant interaction for use/non-use of a DPP-4 inhibitor × treatment group for the change in HbA1c (p = .042). Hypoglycaemia was the only treatment-related adverse event reported in >5% of patients (14.9% vs 29.1%). Events consistent with urinary tract infection (placebo 1.1% vs ipragliflozin 2.3%) or genital infection (0.0% and 4.0%, respectively) occurred in <5% of patients.. Ipragliflozin was well tolerated and effective in insulin-treated patients, especially when used with a DPP-4 inhibitor.

Topics: Adiponectin; Aged; Asian People; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Middle Aged; Reproductive Tract Infections; Thiophenes; Treatment Outcome; Urinary Tract Infections

Water-soluble dietary fibers intake may help control blood glucose and body weight.. The objective of the study was to determine whether soluble fiber supplementation from psyllium improves glycemic control indicators and body weight in type 2 diabetic patients.. Forty type 2 diabetes patients, non-smoker, aged >35 years were stratified to different strata according to sex, age, body mass index (BMI) and fasting blood sugar level (FBS) and randomly assigned into two groups; The intervention group which consists of 20 participants was on soluble fiber (10.5 g daily), and the control group which consist of 20 participants continued on their regular diet for eight weeks duration.. After 8 weeks of intervention, soluble fiber supplementation showed significant reduction in the intervention group in BMI (p < 0.001) when compared with the control group. Moreover, water soluble fiber supplementation proven to improve FBS (163 to 119 mg/dl), HbA1c (8.5 to 7.5 %), insulin level (27.9 to 19.7 μIU/mL), C-peptide (5.8 to 3.8 ng/ml), HOMA.IR (11.3 to 5.8) and HOMA-β % (103 to 141 %).. The reduction in glycemic response was enhanced by combining soluble fiber to the normal diet. Consumption of foods containing moderate amounts of these fibers may improve glucose metabolism and lipid profile in type 2 diabetes patients.. Current Controlled Trials PHRC/HC/28/15 .

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet; Dietary Fiber; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Psyllium; Waist Circumference

This study aimed to examine the association between changes in objectively measured overall physical activity (PA) and changes in fasting and postprandial plasma insulin, C-peptide, and glucose concentrations in type 2 diabetes-prone immigrant Pakistani men living in Norway and to examine whether this association is explained by changes in moderate and vigorous PA (MVPA) or changes in sedentary time.. The current study is a secondary cohort analysis on data collected from the Physical Activity and Minority Health study, a randomized controlled trial aimed at increasing the PA level, and not sedentary time per se, in a group of sedentary immigrant Pakistani men (n = 150). For the present analyses, the two groups were merged and a cohort analysis was performed. Overall PA (counts per minute) and its subcomponents, sedentary time and MVPA, were measured with accelerometry. Outcome variables were measured after a 2-h standardized glucose tolerance test.. Change in overall PA was significantly associated with postprandial log-transformed plasma insulin (β = -0.002; 95% confidence interval (CI), -0.003 to 0.000; P = 0.008), C-peptide (β = -2.7; 95% CI, -4.9 to -0.5; P = 0.01), and glucose concentration (β = -0.006; 95% CI, -0.01 to -0.002; P = 0.002). Change in sedentary time was significantly and beneficially associated with changes in postprandial log-transformed plasma insulin (β = 0.002; 95% CI, 0.001-0.003; P = 0.001), C-peptide (β = 3.7; 95% CI, 1.5-6.0; P = 0.001), and glucose concentration (β = 0.006; 95% CI, 0.002-0.1; P = 0.002), independent of changes in MVPA, waist circumference, and other confounders.. Increasing overall PA by reducing sedentary time seems as important as increasing time spent at MVPA in relation to postprandial plasma insulin and glucose levels in diabetes-prone immigrant men.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Emigrants and Immigrants; Fasting; Humans; Insulin; Male; Middle Aged; Motor Activity; Norway; Pakistan; Postprandial Period; Risk Factors; Sedentary Behavior; Young Adult

To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM).. A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100 mg once daily) or placebo as add-on therapy to metformin [sitagliptin group (n = 12): mean ± standard error of the mean (s.e.m.) age 54 ± 2.5 years, mean ± s.e.m. HbA1c 7.8 ± 0.2%; placebo group (n = 13): mean ± s.e.m. age: 57 ± 3.0 years, mean ± s.e.m. HbA1c 7.9 ± 0.2 %]. In weeks 1 and 12, the patients underwent three 2-h 15-mM hyperglycaemic clamp experiments with infusion of either saline, GLP-1 or GIP. β-cell function was evaluated according to first-phase, second-phase, incremental and total insulin and C-peptide responses.. In the sitagliptin group, the mean HbA1c concentration was significantly reduced by 0.9% (p = 0.01). The total β-cell response during GIP infusion improved significantly from week 1 to week 12, both within the sitagliptin group (p = 0.004) and when compared with the placebo group (p = 0.04). The total β-cell response during GLP-1 infusion was significantly higher (p = 0.001) when compared with saline and GIP infusion, but with no improvement from week 1 to week 12. No significant changes in β-cell function occurred in the placebo group.. Treatment with the DPP-4 inhibitor sitagliptin over 12 weeks in patients with T2DM partially restored the lost insulinotropic effect of GIP, whereas the preserved insulinotropic effect of GLP-1 was not further improved. A gradual enhancement of the insulinotropic effect of GIP, therefore, possibly contributes to the antidiabetic actions of DPP-4 inhibitors.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles; Up-Regulation

Artificial sweeteners were thought to be metabolically inactive, but after demonstrating that the gustatory mechanism was also localized in the small intestine, suspicions about the metabolic effects of artificial sweeteners have emerged. The objective of this study was to determine the effect of artificial sweeteners (aspartame and sucralose) on blood glucose, insulin, c-peptide and glucagon-like peptide-1 (GLP-1) levels.. Eight newly diagnosed drug-naive type 2 diabetic patients (mean age 51.5±9.2 years; F/M: 4/4) and eight healthy subjects (mean age 45.0±4.1 years; F/M: 4/4) underwent 75 g oral glucose tolerance test (OGTT). During OGTT, glucose, insulin, c-peptide and GLP-1 were measured at 15- min intervals for 120 min. The OGTTs were performed at three settings on different days, where subjects were given 72 mg of aspartame and 24 mg of sucralose in 200 ml of water or 200 ml of water alone 15 min before OGTT in a single-blinded randomized order.. In healthy subjects, the total area under the curve (AUC) of glucose was statistically significantly lower in the sucralose setting than in the water setting (P=0.002). There was no difference between the aspartame setting and the water setting (P=0.53). Total AUC of insulin and c-peptide was similar in aspartame, sucralose and water settings. Total AUC of GLP-1 was significantly higher in the sucralose setting than in the water setting (P=0.04). Total AUC values of glucose, insulin, c-peptide and GLP-1 were not statistically different in three settings in type 2 diabetic patients.. Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in newly diagnosed type 2 diabetic patients.

Topics: Adult; Area Under Curve; Aspartame; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Male; Middle Aged; Sucrose; Sweetening Agents

Few studies have focused on postprandial incretin responses to different carbohydrate meals. Therefore, we designed a study to compare the different effects of two carbohydrates (75 g oral glucose, a monosaccharide and 100 g standard noodle, a polysaccharide, with 75 g carbohydrates equivalently) on postprandial glucose, insulin and incretin responses in different glucose tolerance groups.. This study was an open-label, randomized, two-way crossover clinical trial. 240 participants were assigned to take two carbohydrates in a randomized order separated by a washout period of 5-7 days. The plasma glucose, insulin, c-peptide, glucagon and active glucagon-like peptide-1 (AGLP-1) were measured. The incremental area under curve above baseline from 0 to 120 min of insulin (iAUC(0 -120 min)- INS) and AGLP-1(iAUC(0 -120 min)- AGLP-1) was calculated.. Compared with standard noodles, the plasma glucose and insulin after consumption of oral glucose were higher at 30 min (both P < 0.001) and 60 min (both P < 0.001), while lower at 180 min (both P < 0.001), but no differences were found at 120 min. The glucagon at 180 min was higher after consumption of oral glucose (P = 0.010). The AGLP-1 response to oral glucose was higher at 30 min (P < 0.001), 60 min (P < 0.001) and 120 min (P = 0.022), but lower at 180 min (P = 0.027). In normal glucose tolerance (NGT), oral glucose elicited a higher insulin response to the corresponding AGLP-1 (P < 0.001), which was represented by iAUC(0 -120 min) -INS /iAUC(0 -120 min)- AGLP-1, while in type 2 diabetes mellitus (T2DM), standard noodles did (P = 0.001).. Monosaccharide potentiated more rapid and higher glycemic and insulin responses. Oral glucose of liquid state would elicit a more potent release of AGLP-1. The incretin effect was amplified after consumption of standard noodles in T2DM.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; China; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Postprandial Period; Predictive Value of Tests; Time Factors; Young Adult

Hyperglycemia improves when patients with type 2 diabetes are placed on a weight-loss diet. Improvement typically occurs soon after diet implementation. This rapid response could result from low fuel supply (calories), lower carbohydrate content of the weight-loss diet, and/or weight loss per se. To differentiate these effects, glucose, insulin, C-peptide and glucagon were determined during the last 24 h of a 3-day period without food (severe calorie restriction) and a calorie-sufficient, carbohydrate-free diet.. Seven subjects with untreated type 2 diabetes were studied. A randomized-crossover design with a 4-week washout period between arms was used.. Results from both the calorie-sufficient, carbohydrate-free diet and the 3-day fast were compared with the initial standard diet consisting of 55% carbohydrate, 15% protein and 30% fat.. The overnight fasting glucose concentration decreased from 196 (standard diet) to 160 (carbohydrate-free diet) to 127 mg/dl (fasting). The 24 h glucose and insulin area responses decreased by 35% and 48% on day 3 of the carbohydrate-free diet, and by 49% and 69% after fasting. Overnight basal insulin and glucagon remained unchanged.. Short-term fasting dramatically lowered overnight fasting and 24 h integrated glucose concentrations. Carbohydrate restriction per se could account for 71% of the reduction. Insulin could not entirely explain the glucose responses. In the absence of carbohydrate, the net insulin response was 28% of the standard diet. Glucagon did not contribute to the metabolic adaptations observed.

Topics: Aged; Blood Glucose; C-Peptide; Caloric Restriction; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Diet, Reducing; Fasting; Glucagon; Hospitals, Veterans; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Weight Loss

To compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration.. Ten T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the morning (1000 h).. The 24-h glucose infusion rate area under the curve (AUC0-24h) was similar in the evening and morning studies (1,058 ± 571 and 995 ± 691 mg/kg × 24 h, P = 0.503), but the first 12 h (AUC0-12h) was lower with evening versus morning glargine (357 ± 244 vs. 593 ± 374 mg/kg × 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC12-24h 700 ± 396 vs. 403 ± 343 mg/kg × 24 h, P = 0.002). The glucose infusion rate differences were totally accounted for by different rates of endogenous glucose production, not utilization. Plasma insulin and C-peptide levels did not differ in evening versus morning studies. Plasma glucagon levels (AUC0-24h 1,533 ± 656 vs. 1,120 ± 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC0-24h 7.5 ± 1.6 vs. 8.9 ± 1.9 mmol/L/h, P = 0.005; β-OH-butyrate AUC0-24h 6.8 ± 4.7 vs. 17.0 ± 11.9 mmol/L/h, P = 0.005; glycerol, P < 0.020) were overall more suppressed after evening versus morning glargine administration.. The PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0-12 h, while with evening administration the activity is greater in the 12-24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM (lower in the night-early morning vs. afternoon hours) rather than glargine per se.

Topics: Aged; Blood Glucose; C-Peptide; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Injections; Insulin Glargine; Insulin Resistance; Insulin, Long-Acting; Male; Middle Aged

The study of endogenous insulin secretion may provide relevant insight into the comparison of the natural history of adult onset latent autoimmune diabetes (LADA) with types 1 and 2 diabetes mellitus. The aim of this study was to compare the results of the C-peptide response to mixed-meal stimulation in LADA patients with different disease durations and subjects with type 2 and adult-onset type 1 diabetes.. Stimulated C-peptide secretion was assessed using the mixed-meal tolerance test in patients with LADA (n = 32), type 1 diabetes mellitus (n = 33) and type 2 diabetes mellitus (n = 30). All patients were 30 to 70 years old at disease onset. The duration of diabetes in all groups ranged from 6 months to 10 years. The recruitment strategy was predefined to include at least 10 subjects in the following 3 disease onset categories for each group: 6 to 18 months, 19 months to 5 years and 5 to 10 years.. At all time-points of the mixed-meal tolerance test, patients with LADA had a lower stimulated C-peptide response than the type 2 diabetes group and a higher response than the type 1 diabetes group. The same results were found when the peak or area under the C-peptide curve was measured. When the results were stratified by time since disease onset, a similar pattern of residual insulin secretory capacity was observed.. The present study shows that the magnitude of stimulated insulin secretion in LADA is intermediate between that of type 1 and type 2 diabetes mellitus.

Topics: Adult; Aged; Autoimmune Diseases; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Progression; Female; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Meals; Middle Aged; Postprandial Period; Time Factors

The effects of 12 weeks of supplementation with a dieckol-rich extract (AG-dieckol) from brown algae, Ecklonia cava, on glycemic parameters, serum biochemistry, and hematology were investigated in this study. Eighty pre-diabetic male and female adults were enrolled in a randomized, double-blind, placebo-controlled trial with parallel-group design. Subjects were randomly allocated into two groups designated as placebo and AG-dieckol (1500 mg per day). Compared with the placebo group, the AG-dieckol group showed a significant decrease in postprandial glucose levels after 12 weeks. The AG-dieckol group also showed a significant decrease in insulin and C-peptide levels after 12 weeks, but there was no significant difference between the AG-dieckol and placebo groups. There were no significant adverse events related to the consumption of AG-dieckol, and biochemical and hematological parameters were maintained within the normal range during the intervention period. In conclusion, these results demonstrate that AG-dieckol supplementation significantly contributes to lowering postprandial hyperglycemia and in reducing insulin resistance. Furthermore, we believe that based on these results the consumption of phlorotannin-rich foods such as marine algae may be useful for the treatment of diabetes.

Topics: Benzofurans; Biological Products; C-Peptide; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Pacific Ocean; Phaeophyceae; Prediabetic State; Republic of Korea; Seaweed

In patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesised that insulin deficiency and islet autoantibodies would be associated with severe hypoglycaemia and failure to achieve near-normal glycaemia (HbA1c <6.0% [42 mmol/mol]).. A nested case-control design was used. Cases (n = 326) were defined as participants having severe hypoglycaemia and failure to achieve an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death. Controls (n = 1,075) were those who achieved an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death without severe hypoglycaemia. Each case was matched (for race, age and BMI) by up to four controls. Baseline insulin deficiency (fasting C-peptide ≤0.15 nmol/l) and islet autoantibodies (glutamic acid decarboxylase [GAD], tyrosine phosphatase-related islet antigen 2 [IA2], insulin [IAA] and zinc transporter 8 [ZnT8]) were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used on the full cohort and after removal of patients who died and their respective controls.. Severe hypoglycaemia accompanied by an inability to achieve an HbA1c level of <6.0% (42 mmol/mol) was associated with insulin deficiency (adjusted OR 23.2 [95% CI 9.0, 59.5], p < 0.0001), the presence of IAA autoantibodies or baseline insulin use (adjusted OR 3.8 [95% CI 2.7, 5.3], p < 0.0001), GAD autoantibodies (OR 3.9 [95% CI 2.5, 6.0], p < 0.0001), IA2 autoantibodies (OR 16.7 [95% CI 3.9, 71.6], p = 0.0001) and ZnT8 autoantibodies (adjusted OR 3.9 [95% CI 1.2, 12.4], p = 0.02).. C-peptide and islet autoantibodies may serve as biomarkers to predict the risk of severe hypoglycaemia during intensification of type 2 diabetes treatment.. ClinicalTrials.gov NCT00000620 (original ACCORD study).

Topics: Aged; Autoantibodies; Biomarkers; Body Mass Index; C-Peptide; Cardiovascular Diseases; Case-Control Studies; Cation Transport Proteins; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Male; Microcirculation; Middle Aged; Receptor-Like Protein Tyrosine Phosphatases, Class 8; Zinc Transporter 8

To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes.. We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug-naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. β-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated.. Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved β-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion.. In patients with type 2 diabetes, imeglimin improves β-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucose Clamp Technique; Hepatobiliary Elimination; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Triazines

β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-cell function in T2DM individuals.. Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (OGTT) and insulin clamp were performed before and after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured during the OGTT.. Dapagliflozin significantly lowered both the fasting and 2-hour plasma glucose concentrations and the incremental area under the plasma glucose concentration curve (ΔG0-120) during OGTT by -33 ± 5 mg/dL, -73 ± 9 mg/dL, and -60 ± 12 mg/dL · min, respectively, compared to -13 ± 9, -33 ± 13, and -18 ± 9 reductions in placebo-treated subjects (both P < .01). The incremental area under the plasma C-peptide concentration curve tended to increase in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects. Thus, ΔC-Pep0-120/ΔG0-120 increased significantly in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects (0.019 ± 0.005 vs 0.002 ± 0.006; P < .01). Dapagliflozin significantly improved whole-body insulin sensitivity (insulin clamp). Thus, β-cell function, measured as ΔC-Pep0-120/ ΔG0-120 ÷ insulin resistance, increased by 2-fold (P < .01) in dapagliflozin-treated vs placebo-treated subjects.. Lowering the plasma glucose concentration with dapagliflozin markedly improves β-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on β-cell function.

Topics: Benzhydryl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Glucosides; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Treatment Outcome

High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet).. In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (<10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner.. Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUCglucose) throughout the day was 20% lower, whereas AUCinsulin, AUCC-peptide and AUCtGLP-1 were 20% higher for the Bdiet than the Ddiet. Glucose AUC0-180min and its peak were both lower by 24%, whereas insulin AUC0-180min was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet.. High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes. Trial registration ClinicalTrials.gov NCT01977833 Funding No specific funding was received for the study.

Topics: Adult; Aged; Blood Glucose; Breakfast; C-Peptide; Diabetes Mellitus, Type 2; Energy Intake; Female; Humans; Hyperglycemia; Insulin; Male; Meals; Middle Aged; Postprandial Period; Treatment Outcome

The previous meal modulates the postprandial glycemic responses to a subsequent meal; this is termed the second-meal phenomenon.. This study examined the effects of high-protein vs. high-carbohydrate breakfast meals on the metabolic and incretin responses after the breakfast and lunch meals.. Twelve type 2 diabetic men and women [age: 21-55 y; body mass index (BMI): 30-40 kg/m(2)] completed two 7-d breakfast conditions consisting of 500-kcal breakfast meals as protein (35% protein/45% carbohydrate) or carbohydrate (15% protein/65% carbohydrate). On day 7, subjects completed an 8-h testing day. After an overnight fast, the subjects consumed their respective breakfast followed by a standard 500-kcal high-carbohydrate lunch meal 4 h later. Blood samples were taken throughout the day for assessment of 4-h postbreakfast and 4-h postlunch total area under the curve (AUC) for glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1).. Postbreakfast glucose and GIP AUCs were lower after the protein (17%) vs. after the carbohydrate (23%) condition (P < 0.05), whereas postbreakfast insulin, C-peptide, glucagon, and GLP-1 AUCs were not different between conditions. A protein-rich breakfast may reduce the consequences of hyperglycemia in this population. Postlunch insulin, C-peptide, and GIP AUCs were greater after the protein condition vs. after the carbohydrate condition (second-meal phenomenon; all, P < 0.05), but postlunch AUCs were not different between conditions. The overall glucose, glucagon, and GLP-1 responses (e.g., 8 h) were greater after the protein condition vs. after the carbohydrate condition (all, P < 0.05).. In type 2 diabetic individuals, compared with a high-carbohydrate breakfast, the consumption of a high-protein breakfast meal attenuates the postprandial glucose response and does not magnify the response to the second meal. Insulin, C-peptide, and GIP concentrations demonstrate the second-meal phenomenon and most likely aid in keeping the glucose concentrations controlled in response to the subsequent meal. The trial was registered at www.clinicaltrials.gov/ct2/show/NCT02180646 as NCT02180646.

Topics: Adult; Blood Glucose; Body Mass Index; Breakfast; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Diet Records; Dietary Carbohydrates; Dietary Proteins; Energy Intake; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Lunch; Male; Middle Aged; Postprandial Period; Single-Blind Method; Young Adult

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.

Topics: Adiponectin; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Treatment Outcome; Weight Loss

Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of glucagon-like peptides (GLP)-1 and -2.. A prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 ± 7 years, BMI 23.6 ± 1.7 kg/m(2); 10 obese: age 51 ± 7 years, BMI 35.5 ± 4.9 kg/m(2)). Participants ingested 10(10) b.i.d. L. reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-(2)H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by (1)H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays.. In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines.. Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic approach to improve glucose-dependent insulin release.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Limosilactobacillus reuteri; Male; Middle Aged; Obesity; Oxidative Stress; Pilot Projects; Probiotics; Prospective Studies; Protein Precursors

To compare long term effects of two bariatric procedures for Chinese type 2 diabetes mellitus (T2DM) patients with a body mass index (BMI) of 28-35 kg/m(2).. Sixty four T2DM patients with Glycated hemoglobin A1c (HbA1c) ≧ 7.0 % were randomly assigned to receive laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) procedure. Weight, percentage of excess weight loss (%EWL), BMI, waist circumference, HbA1c, fasting blood glucose (FBG), and C-peptide were measured. Serum lipid levels were also measured during three-year postoperative follow-up visits.. Fifty five patients completed the 36-month follow-up. Both groups had similar baseline anthropometric and biochemical measures. At the end point, 22 patients (78.6 %) in SG group and 23 patients (85.2 %) in RYGB group achieved complete remission of diabetes mellitus with HbA1c < 6.0 % (P = 0.525) and without taking diabetic medications, and 25 patients in each group (89.3 % vs. 92.6 %) gained successful treatment of diabetes with HbA1c≦6.5 % (P = 0.100). Change in HbA1c, FBG and C peptide were comparable in the two groups. The RYGB group had significantly greater weight loss than the SG group [percentage of total weight loss (%TWL) of 31.0 % vs. 27.1 % (P = 0.049), %EWL of 92.3 % vs. 81.9 % (P = 0.003), and change in BMI of 11.0 vs. 9.1 kg/m(2)(P = 0.017), respectively]. Serum lipids in each group were also greatly improved.. In this three-year study, SG had similar positive effects on diabetes and dyslipidemia compared to RYGB in Chinese T2DM patients with BMI of 28-35 kg/m(2). Longer term follow-ups and larger sample studies are needed to confirm these outcomes, however.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Glycated Hemoglobin; Humans; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Treatment Outcome; Weight Loss

Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner.. In a crossover design, 22 patients with diabetes with a mean diabetes duration of 8.4 ± 0.7 years, age 56.9 ± 1.0 years, BMI 28.2 ± 0.6 kg/m(2), and HbA1c 7.7 ± 0.1% (61 ± 0.8 mmol/mol) were randomly assigned to two test days: one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) were assessed.. Compared with YesB, lunch area under the curves for 0-180 min (AUC0-180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day.. Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Breakfast; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Lunch; Male; Meals; Middle Aged; Postprandial Period

It remains unknown whether dipeptidyl peptidase-4 (DPP-4) inhibitors improve early-phase insulin secretion in Japanese patients with type 2 diabetes (T2D), a disease characterized by impaired insulin secretion. We investigated the changes in insulin secretion before and after treatment with the DPP-4 inhibitor teneligliptin in patients with T2D with a low insulinogenic index (IGI) determined by the oral glucose tolerance test (OGTT).. An open-label, prospective clinical study was conducted. Thirteen drug-naïve patients (mean age 55.5 ± 3.9 years) with T2D underwent OGTT before and after teneligliptin 20 mg/day monotherapy. Plasma levels of glucose (PG), insulin, and C-peptide were measured at 0, 30, 60, 90, and 120 min after glucose loading in the OGTT. Homeostasis model assessment (HOMA)-β, IGI, and the total or incremental area under the curve (AUC) for PG and insulin were measured. AUC120min for the secretory units of islets in transplantation (SUIT) index was also measured.. HbA1c significantly decreased from 8.3 ± 0.4% at baseline to 6.3 ± 0.2% after 12 weeks of teneligliptin treatment (p < 0.05). Incremental AUC120min PG also significantly decreased, and β-cell function assessed by IGI30min, AUC120min insulin, and the AUC120min SUIT index significantly increased (0.16 ± 0.05 vs. 0.28 ± 0.06, 2692 ± 333 µU·2h/mL vs. 3537 ± 361 µU·2h/mL, and 4261 ± 442 vs. 8290 ± 1147, respectively; all p < 0.05). HOMA-β was unchanged. The reduction in incremental AUC120min PG was significantly associated with the augmentation of IGI30min and the AUC120min SUIT index. No severe adverse events were observed.. Twelve weeks of teneligliptin treatment improved IGI30min, AUC120min, and the SUIT index in drug-naïve Japanese patients with T2D.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Pyrazoles; Thiazolidines; Young Adult

In patients with type 2 diabetes (T2DM), impaired suppression of postprandial glucagonemia is a metabolic defect that contributes to hyperglycemia. Treatment with a glucagon-like peptide-1 agonist can reduce hyperglucagonemia in the acute setting, but little is known about the durability of this effect with long-term treatment.. The purpose of this study was to evaluate the impact of chronic liraglutide therapy on glucagon regulation in early T2DM. Design/Setting/Participants/Intervention: In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration were randomized to either daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial assessment of the glucose, insulin, C-peptide, and glucagon responses to a 75-g oral glucose tolerance test every 12 weeks.. The glucagon response was assessed with the incremental area under the glucagon curve (iAUCglucagon) from measurements at 0, 30, 60, 90, and 120 minutes on each oral glucose tolerance test.. As expected, compared with placebo, liraglutide induced a robust enhancement of the postchallenge insulin and C-peptide response at each of the 12-, 24-, 36-, and 48-week time points, with a concomitant reduction in glycemic excursion. However, liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12 weeks and persisted over the 48-week treatment period. Indeed, baseline-adjusted iAUCglucagon was significantly higher in the liraglutide group compared with placebo at 12 weeks (170.2 ± 34.9 vs 65.4 ± 36.4 pg/mL · 2 hours, P = .04), 36 weeks (162.2 ± 27.9 vs 55.7 ± 30.4 pg/mL · 2 hours, P = .01), and 48 weeks (155.5 ± 26.5 vs 45.7 ± 27.0 pg/mL · 2 hours, P = .006).. In contrast to its acute glucagon-lowering effect, chronic treatment with liraglutide is associated with increased postchallenge hyperglucagonemia in patients with early T2DM.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged; Treatment Outcome

The effects of twice-daily GLP-1 analogue injections added on continuous subcutaneous insulin infusion (CSII) in patients with poorly controlled type 2 diabetes (T2DM) were unknown. After optimization of blood glucose in the first 3 days by CSII during hospitalization, patients with poorly controlled T2DM were randomized to receive CSII combined with injections of exenatide or placebo for another 3 days. A total of 51 patients (30 in exenatide and 21 in placebo groups) with mean A1C 11% were studied. There was no difference in mean glucose but a significant higher standard deviation of plasma glucose (SDPG) was found in the exenatide group (50.51 ± 2.43 vs. 41.49 ± 3.00 mg/dl, p = 0.027). The improvement of incremental area under the curve (AUC) of glucose and insulinogenic index (Insulin 0-peak/ Glucose 0-peak) in 75 g oral glucose tolerance test was prominent in the exenatide group (p < 0.01). The adiponectin level was significantly increased with exenatide added on (0.39 ± 0.32 vs. -1.62 ± 0.97 μg/mL, in exenatide and placebo groups, respectively, p = 0.045). In conclusion, the add-on of GLP-1 analogue to CSII increased glucose variability and the β - cell response in patients with poorly controlled T2DM.

Topics: Adiponectin; Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endpoint Determination; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Peptides; Risk Factors; Venoms

There is a growing interest in cell-based therapies in T2DM as β-cell failure is progressive and inexorable with the advancing duration of disease. This prospective, randomized, single-blinded placebo-controlled study evaluates the efficacy and safety of autologous bone marrow-derived stem cell transplantation (ABMSCT) in T2DM. Twenty-one patients with triple oral antidiabetic drug failure and requiring insulin ≥0.4 IU per kg per day with HbA1c <7.5% were randomly assigned to an intervention (n = 11) and control group (n = 10) and followed for 12 months. Patients in the intervention group received ABMSCT through a targeted approach, and after 12 weeks, a second dose of stem cells was administered through the antecubital vein after mobilization with G-CSF, while the control group underwent a sham procedure. The primary end point was a reduction in insulin requirement by ≥50% from baseline while maintaining HbA1c <7%. Nine out of the 11 (82%) patients in the intervention group achieved the primary end point, whereas none of the patients in the control group did over the study period (p = 0.002). The insulin requirement decreased by 66.7% in the intervention group from 42.0 (31.0‐64.0) IU per day to 14.0 (0.0‐30.0) IU per day (p = 0.011), while in controls it decreased by 32.1% from 40.5 (31.8‐44.3) IU per day to 27.5 (23.5‐33.3) IU per day (p = 0.008) at 12 months. The reduction in insulin requirement was significantly more in the intervention group compared to controls at both 6 (p = 0.001) and 12 months (p = 0.004). There was a modest but nonsignificant increase in HbA1c (%) in cases from 6.9% (6.4‐7.2%) to 7.1% (6.6‐7.5%) as well as in controls from 6.9% (6.2‐7.0%) to 7.0% (6.9‐7.5%). Ten out of 11 (91%) patients could maintain HbA1c <7% in the intervention group, whereas 6 out of 10 did (60%) in the control group (p = 0.167). The glucagon-stimulated C-peptide significantly increased in treated cases compared to controls (p = 0.036). The decrease in insulin requirement positively correlated with stimulated C-peptide (r = 0.8, p = 0.001). In conclusion, ABMSCT results in a significant decrease in the insulin dose requirement along with an improvement in the stimulated C-peptide levels in T2DM. However, a greater number of patients with a longer duration of follow-up are required to substantiate these observations.

Topics: Adult; Aged; Bone Marrow Cells; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Placebo Effect; Transplantation, Autologous

T-emerge 2 was a randomized, open-label, 24-week trial comparing subcutaneous taspoglutide 10 mg weekly (Taspo10), taspoglutide 20 mg weekly (Taspo20; titrated after 4 weeks of Taspo10), with exenatide 10 mcg BID (Exe; after 4 weeks of Exe 5 mcg) in patients inadequately controlled on metformin, a thiazolidinedione, or both. T-emerge 2 showed that once-weekly Taspo provided better glycaemic control than Exe. This report focuses on a subset of T-emerge 2 participants undergoing a standardized liquid meal comparing Taspo to Exe, which has been previously shown to lower postprandial glucose.. Meal tolerance tests (MTT) were performed at baseline and at week 24 in a subset of Taspo10, Taspo20 and Exe patients (n = 42, 39 and 67, respectively). Blood samples for glucose, insulin, glucagon and C-peptide were obtained before and after (30, 60, 90, 120 and 180 min) ingestion of a standardized liquid meal.. The 2-h postprandial, mean 0-3 h and iAUC0-3 h glucose during the MTT was reduced to a similar extent in all groups and the time profile of the postprandial glucose showed a similar pattern. Taspo10 and Taspo20, but not Exe, significantly increased insulin from baseline (both mean and iAUC0-3 h). Although changes from baseline in C-peptide were not significant within any treatment group, the mean change from baseline (both mean 0-3 h and iAUC0-3 h) was significantly increased in Taspo10 vs. Exe. Mean glucagon showed significant decreases in all groups.. Taspoglutide and Exe improved postprandial glucose tolerance to a similar extent but possibly with different intimate mechanisms.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Meals; Metformin; Middle Aged; Peptides; Postprandial Period; Receptors, Glucagon; Treatment Outcome; Venoms

To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus.. This parallel-group, open-label, dose-escalation study examined the PK and GD of basal insulin LY2605541 after single and multiple-dose administration. Fixed doses of LY2605541 (0.33-1.00 U/kg) were given once-daily (QD) for 14 days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14.. PK steady state was achieved within 7-10 days and the peak-to-trough fluctuation was <2, translating to a nearly 'peakless' glucose infusion rate at steady state and with a duration of action of at least 24 h. Across dose levels t1/2 ranged from 44.7 to 75.5 h (~2-3 days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100 mg/dl across dose levels. Within-patient variability was <14 and <26% for the area under the concentration versus time curve (AUC) of the 8-point blood glucose profile and fasting blood glucose, respectively. The nocturnal glucose control between 03:00 and 09:00 hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event.. In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.

Topics: Adolescent; Adult; Aged; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Lispro; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome

The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.. β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95-125 mg/dL (5.3-6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c 5.8-7.0% (40-53 mmol/mol), and BMI 25-40 kg/m(2). Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30-40 kg/m(2), HbA1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m(2), 10-19 years of age, and diabetes <6 months.. Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.. RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.

Topics: Adolescent; Adult; Aged; Arginine; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gastroplasty; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liraglutide; Male; Metformin; Middle Aged; Prediabetic State; Young Adult

This randomized, double-blind, placebo-controlled parallel-group study assessed the effects of sodium glucose cotransporter 2 inhibition by dapagliflozin on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM), who had inadequate glycemic control with metformin (with or without an insulin secretagogue).. Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks. Subjects continued stable doses of background antidiabetes medication throughout the study. Insulin sensitivity was assessed by measuring the glucose disappearance rate (GDR) during the last 40 min of a 5-h hyperinsulinemic, euglycemic clamp. Insulin secretion was determined as the acute insulin response to glucose (AIRg) during the first 10 min of a frequently sampled intravenous glucose tolerance test. Where noted, data were adjusted for baseline values and background antidiabetes medication.. An adjusted mean increase from baseline in GDR (last observation carried forward), at Week 12, was observed with dapagliflozin (7.98%) versus a decrease with placebo (-9.99%). The 19.97% (95% confidence interval 5.75-36.10) difference in GDR versus placebo was statistically significant (P=0.0059). A change from baseline in adjusted mean AIRg of 15.39 mU/L min was observed with dapagliflozin at Week 12, versus -12.73 mU/L min with placebo (P=0.0598). Over 12 weeks, numerical reductions from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and body weight were observed with dapagliflozin (-0.38%, -0.39 mmol/L, and -1.58%, respectively) versus slight numerical increases with placebo (0.03%, 0.26 mmol/L, and 0.62%, respectively).. In patients with T2DM and inadequate glycemic control, dapagliflozin treatment improved insulin sensitivity in the setting of reductions in HbA1c and weight.

Topics: Adult; Aged; Benzhydryl Compounds; Blood Glucose; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucose Tolerance Test; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Male; Metformin; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles

Topics: Adult; Aged; Autoimmunity; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Middle Aged; Missouri; Neurotensin; Postprandial Period; Receptors, Neurotensin; Time Factors; Treatment Outcome

The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of β-cells compared with glimepiride when metformin alone was failed. This was an open-label and multi-center study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the endpoint. Glargine was not superior to glimepiride in other β-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining β-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Chi-Square Distribution; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Republic of Korea; Sulfonylurea Compounds; Young Adult

In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes.. Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin + sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin + sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide.. In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min(-1) m(-2) (mmol/l)(-1) with canagliflozin 100 and 300 mg, respectively (p < 0.002, Study 1), and 16 (8) and 10 (9) pmol min(-1) m(-2) (mmol/l)(-1) (p < 0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min(-1) m(-2), respectively; p < 0.05 for both].. Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies.. Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3).

Topics: Adult; Aged; Blood Glucose; C-Peptide; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucosides; Humans; Insulin-Secreting Cells; Least-Squares Analysis; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Sodium-Glucose Transporter 2; Sulfonylurea Compounds; Thiophenes; Time Factors; Triazoles

The aim of this study was to test the hypothesis that intensive glycaemic control (INT) and higher plasma C-peptide levels in patients with poorly controlled diabetes would be associated with better eye outcomes.. The incidence and progression of diabetic retinopathy (DR) was assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later in 858 of 1,791 participants in the Veterans Affairs Diabetes Trial (VADT).. After adjustment for all covariates, risk of progression (but not incidence) of DR increased by 30% for each 1% increase in baseline HbA1c (OR 1.3; 95% CI 1.123, 1.503; p = 0.0004). Neither assignment to INT nor age was independently associated with DR in the entire cohort. However, INT showed a biphasic interaction with age. The incidence of DR was decreased in INT participants ≤55 years of age (OR 0.49; 95% CI 0.24, 1.0) but increased in those ≥70 years old (OR 2.88; 95% CI 1.0, 8.24) (p = 0.0043). The incidence of DR was reduced by 67.2% with each 1 pmol/ml increment in baseline C-peptide (OR 0.328; 95% CI 0.155, 0.7; p = 0.0037). Baseline C-peptide was also an independent inverse risk factor for the progression of DR, with a reduction of 47% with each 1 pmol/ml increase in C-peptide (OR 0.53; 95% CI 0.305, 0.921; p = 0.0244).. Poor glucose control at baseline was associated with an increased risk of progression of DR. INT was associated with a decreased incidence of DR in younger patients but with an increased risk of DR in older patients. Higher C-peptide at baseline was associated with reduced incidence and progression of DR.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Pancreas; Veterans

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.. Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Mesylates; Metformin; Middle Aged; Oxadiazoles; Peptide YY; Prognosis; Pyrazines; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Triazoles

Type 2 diabetic (T2D) patients exhibit fasting relative hyperproinsulinemia owing to pancreatic β-cell dysfunction. To clarify the mechanism underlying this hyperproinsulinemic state, we evaluated the activities of the endopeptidases prohormone convertase (PC) 1/3 and PC2 in T2D patients. Fasting blood levels of intact proinsulin (IPI), total proinsulin (t-PI) and C-peptide were measured simultaneously, and intravenous glucagon loading was performed to investigate the dynamics of circulating proinsulin-related molecules released from pancreatic β-cells in 12 healthy volunteers and 18 T2D patients. Taking advantage of the 95% cross-reactivity between proinsulin and des-31,32-proinsulin (des-31,32-PI) with the human proinsulin radioimmunoassay kit used in this study, we estimated PC1/3 and PC2 activities using the following formulas: des-31,32-PI = (t-PI-IPI)/0.95; PC1/3 activity = des-31,32-PI/IPI; and PC2 activity = C-peptide/des-31,32-PI. C-peptide responses to glucagon were slightly lower among T2D patients. IPI and the IPI/C-peptide ratio were significantly higher in T2D patients (p<0.05 and p<0.01, respectively). There was no difference in des-31,32-PI levels or PC2 activity between the two groups. However, PC1/3 activity was significantly lower in T2D patients than in the control group (p<0.01). We propose that decreased activity of PC1/3 rather than PC2 in pancreatic β-cells is involved in the impaired proinsulin processing, resulting in elevated IPI levels in T2D patients.

Topics: Administration, Intravenous; Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin-Secreting Cells; Middle Aged; Proinsulin; Proprotein Convertase 1; Proprotein Convertase 2; Protein Processing, Post-Translational; Statistics as Topic

We assessed safety and efficacy of two selective 11β-HSD1 inhibitors (RO5093151/RO-151 and RO5027383/RO-838) in this randomized, controlled study in metformin-treated patients with type 2 diabetes.. Patients either received placebo (N = 21), RO-151 BID 5 mg (N = 24) or 200 mg (N = 20) or RO-838 QD 50 mg (N = 21) or 200 mg (N = 24) for 28 days. Metabolic assessments comprising of nine-point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C-peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment.. Despite the short treatment duration, both RO-151 and RO-838 showed trends for improved HbA1c and consistent reductions in body weight (-0.86 to -1.67 kg) exceeding those observed with placebo (-0.28 kg, p = 0.019 for 200 mg RO-151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA-IR and Matsuda-Index) improved non-significantly with 200 mg RO-151. Lipid parameters did not consistently improve with either compound, but RO-838 led to non-significant increases in triglycerides and VLDL-cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11β-HSD1 activity based on urinary corticosteroid excretion. As reported for other 11β-HSD1-inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO-151, but not with RO-838.. Slight metabolic improvements were seen, in particular with RO-151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adult; Aged; Austria; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Germany; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metformin; Middle Aged; Risk Assessment; Treatment Outcome; United States

The aim of the study was to compare the effect of six (A6 regimen) vs two meals a day, breakfast and lunch (B2 regimen), on body weight, hepatic fat content (HFC), insulin resistance and beta cell function.. In a randomised, open, crossover, single-centre study (conducted in Prague, Czech Republic), we assigned 54 patients with type 2 diabetes treated with oral hypoglycaemic agents, both men and women, age 30-70 years, BMI 27-50 kg/m(2) and HbA1c 6-11.8% (42-105 mmol/mol), to follow two regimens of a hypoenergetic diet, A6 and B2, each for 12 weeks. Randomisation and allocation to trial groups (n = 27 and n = 27) were carried out by a central computer system. Individual calculations of energy requirements for both regimens were based on the formula: (resting energy expenditure × 1.5) - 2,092 kJ. The diet in both regimens had the same macronutrient and energy content. HFC was measured by proton magnetic resonance spectroscopy. Insulin sensitivity was measured by isoglycaemic-hyperinsulinaemic clamp and calculated by mathematical modelling as oral glucose insulin sensitivity (OGIS). Beta cell function was assessed during standard meal tests by C-peptide deconvolution and was quantified with a mathematical model. For statistical analysis, 2 × 2 crossover ANOVA was used.. The intention-to-treat analysis included all participants (n = 54). Body weight decreased in both regimens (p < 0.001), more for B2 (-2.3 kg; 95% CI -2.7, -2.0 kg for A6 vs -3.7 kg; 95% CI -4.1, -3.4 kg for B2; p < 0.001). HFC decreased in response to both regimens (p < 0.001), more for B2 (-0.03%; 95% CI -0.033%, -0.027% for A6 vs -0.04%; 95% CI -0.041%, -0.035% for B2; p = 0.009). Fasting plasma glucose and C-peptide levels decreased in both regimens (p < 0.001), more for B2 (p = 0.004 and p = 0.04, respectively). Fasting plasma glucagon decreased with the B2 regimen (p < 0.001), whereas it increased (p = 0.04) for the A6 regimen (p < 0.001). OGIS increased in both regimens (p < 0.01), more for B2 (p = 0.01). No adverse events were observed for either regimen.. Eating only breakfast and lunch reduced body weight, HFC, fasting plasma glucose, C-peptide and glucagon, and increased OGIS, more than the same caloric restriction split into six meals. These results suggest that, for type 2 diabetic patients on a hypoenergetic diet, eating larger breakfasts and lunches may be more beneficial than six smaller meals during the day. Trial registration ClinicalTrials.gov number, NCT01277471, completed. Funding Grant NT/11238-4 from Ministry of Health, Prague, Czech Republic and the Agency of Charles University - GAUK No 702312.

Topics: Adult; Aged; Blood Glucose; Breakfast; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Glucagon; Humans; Hypoglycemic Agents; Insulin; Lunch; Male; Meals; Middle Aged; Treatment Outcome

The pathogenesis of type 2 diabetes is characterized by insulin resistance and insulin secretory dysfunction. Few existing metabolic tests measure both characteristics, and no such tests are inexpensive enough to enable widespread use. A hierarchical approach uses 2 down-sampled tests in the dynamic insulin sensitivity and secretion test (DISST) family to first determine insulin sensitivity (SI) using 4 glucose measurements. Second the insulin secretion is determined for only participants with reduced SI using 3 C-peptide measurements from the original test. The hierarchical approach is assessed via its ability to classify 214 individual test responses of 71 females with an elevated risk of type 2 diabetes into 5 bins with equivalence to the fully sampled DISST. Using an arbitrary SI cut-off, 102 test responses were reassayed for C-peptide and unique insulin secretion characteristics estimated. The hierarchical approach correctly classified 84.5% of the test responses and 94.4% of the responses of individuals with increased fasting glucose. The hierarchical approach is a low-cost methodology for measuring key characteristics of type 2 diabetes. Thus the approach could provide an economical approach to studying the pathogenesis of type 2 diabetes, or in early risk screening. As the higher cost test uses the same clinical protocol as the low-cost test, the cost of the additional information is limited to the assay cost of C-peptide, and no additional procedures or callbacks are required.

Topics: Algorithms; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Reference Values; Reproducibility of Results; Risk Assessment

Saxagliptin reduced glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose (PPG) in Asian patients with type 2 diabetes mellitus (T2DM). To understand the physiology of this effect, indices of α- and β-cell function were measured in a subpopulation of Chinese patients following a noodle mixed-meal tolerance test.. Data from Chinese patients were pooled from two phase 3, 24-week studies of saxagliptin 5mg/d as monotherapy in drug-naive patients and as add-on to metformin in patients inadequately controlled with metformin alone. The end points for β- and α-cell function were change from baseline in C-peptide, insulin, and glucagon areas under the curve from 0 to 180 min (AUC0-180), insulinogenic index, and insulin sensitivity from Matsuda index after a mixed meal. Also glycemic variables, HbA1c, FPG, and PPG (AUC0-180), and homeostasis model assessment (HOMA) 2β were measured.. At 24 weeks, greater improvements in adjusted mean change from baseline HbA1c (difference vs placebo [95% CI], -0.33% [-0.50%, -0.17%], [-4 (-5.5, -1.9) mmol/mol], P<0.0001), FPG (-0.41 [-0.78, -0.03] mmol/L, P=0.03), PPG AUC0-180 (-168 [-245, -91.8] mmol min/L, P<0.0001), C-peptide AUC0-180 (19.7 [5.2, 34.2] nmol min/L, P=0.008), insulinogenic index (0.06% [0.02%, 0.09%], P=0.002), and greater suppression of glucagon secretion (glucagon AUC0-180, -322 [-493.6, -150.7] pmol min/L, P=0.0003) were observed with saxagliptin versus placebo.. In Chinese patients with T2DM, saxagliptin as monotherapy or as add-on to metformin improved glycemic control by modulating α- and β-cell function.

Topics: Adamantane; Asian People; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Postprandial Period

Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1(GCG)) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility.. In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined.. Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals.. In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

Topics: Adult; Aged; Area Under Curve; Bile; Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Cholecystokinin; Denmark; Diabetes Mellitus, Type 2; Dietary Fats; Female; Gallbladder Emptying; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrins; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Postprandial Period; Receptors, G-Protein-Coupled

Isomaltulose attenuates postprandial glucose and insulin concentrations compared with sucrose in patients with type 2 diabetes mellitus (T2DM). However, the mechanism by which isomaltulose limits postprandial hyperglycemia has not been clarified.. The objective was therefore to assess the effects of bolus administration of isomaltulose on glucose metabolism compared with sucrose in T2DM.. In a randomized, double-blind, crossover design, 11 participants with T2DM initially underwent a 3-h euglycemic-hyperinsulinemic (0.8 mU · kg(-1) · min(-1)) clamp that was subsequently combined with 1 g/kg body wt of an oral (13)C-enriched isomaltulose or sucrose load. Hormonal responses and glucose kinetics were analyzed during a 4-h postprandial period.. Compared with sucrose, absorption of isomaltulose was prolonged by ∼50 min (P = 0.004). Mean plasma concentrations of insulin, C-peptide, glucagon, and glucose-dependent insulinotropic peptide were ∼10-23% lower (P < 0.05). In contrast, glucagon-like peptide 1 (GLP-1) was ∼64% higher (P < 0.001) after isomaltulose ingestion, which results in an increased insulin-to-glucagon ratio (P < 0.001) compared with sucrose. The cumulative amount of systemic glucose appearance was ∼35% lower after isomaltulose than after sucrose (P = 0.003) because of the reduction in orally derived and endogenously produced glucose and a higher first-pass splanchnic glucose uptake (SGU). Insulin action was enhanced after isomaltulose compared with sucrose (P = 0.013).. Ingestion of slowly absorbed isomaltulose attenuates postprandial hyperglycemia by reducing oral glucose appearance, inhibiting endogenous glucose production (EGP), and increasing SGU compared with ingestion of rapidly absorbed sucrose in patients with T2DM. In addition, GLP-1 secretion contributes to a beneficial shift in the insulin-to-glucagon ratio, suppression of EGP, and enhancement of SGU after isomaltulose consumption. This trial was registered at clinicaltrials.gov as NCT01070238.

Topics: Blood Glucose; C-Peptide; Carbohydrate Metabolism; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Double-Blind Method; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Isomaltose; Male; Middle Aged; Postprandial Period; Sucrose

Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes.. A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 μg daily for 2 weeks, 140 μg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples.. Serum-25(OH) vitamin D and serum-1,25(OH)₂ vitamin D increased significantly after 12 weeks in the intervention group (p=0.01, p=0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p=0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass.. Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

Topics: Aged; Biomarkers; C-Peptide; Calcifediol; Calcitriol; Cholecalciferol; Denmark; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Kinetics; Male; Middle Aged; Seasons; Severity of Illness Index; Vitamin D Deficiency

To examine counterregulatory glucose kinetics and test the hypothesis that β-adrenergic blockade impairs these in patients with type 2 diabetes mellitus (T2DM) and advanced β-failure.. Nine insulin-requiring T2DM subjects and six matched nondiabetic control subjects were studied. β-Cell function was assessed by the C-peptide response to arginine stimulation. Counterregulatory hormonal responses and glucose kinetics were assessed by hyperinsulinemic euglycemic-hypoglycemic clamps with [3-(3)H]glucose infusion. T2DM subjects underwent two clamp experiments in a randomized crossover fashion: once with infusion of the β-adrenergic antagonist propranolol and once with infusion of normal saline.. Compared with the control subjects, T2DM subjects had threefold reduced C-peptide responses to arginine stimulation. During the hypoglycemic clamp, glucagon responses were markedly diminished (16.0 ± 4.2 vs. 48.6 ± 6.0 ng/L, P < 0.05), but other hormonal responses and the decrement in the required exogenous glucose infusion rate (GIR) from the euglycemic clamp were normal (-10.4 ± 1.1 vs. -7.8 ± 1.9 µmol · kg(-1) · min(-1) in control subjects); however, endogenous glucose production (EGP) did not increase (-0.8 ± 1.0 vs. 2.2 ± 0.7 µmol · kg(-1) · min(-1) in control subjects, P < 0.05), whereas systemic glucose disposal decreased normally. β-Adrenergic blockade in the T2DM subjects increased GIR ∼20% during the euglycemic clamp (P < 0.01), but neither increased GIR during the hypoglycemic clamp or decreased its decrement from the euglycemic clamp to the hypoglycemic clamp.. Overall glucose counterregulation is preserved in advanced T2DM, but the contribution of EGP is diminished. β-Adrenergic blockade may increase insulin sensitivity at normoglycemia but does not impair glucose counterregulation in T2DM patients, even those with advanced β-cell failure.

Topics: Adrenergic beta-Antagonists; C-Peptide; Case-Control Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Single-Blind Method

This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after (L)-N(G)-monomethyl arginine (L-NMMA) infusion. At Week 12, ACh-mediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant (p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant (p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted.

Topics: Acetylcholine; Aged; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Lipids; Liraglutide; Male; Middle Aged; Nitroprusside; Plethysmography

To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, β-cell function, inflammation and metabolic markers.. 6-month randomized, placebo-controlled trial.. Ninety-five adults with serum 25-hydroxyvitamin D [25(OH)D] ≤55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score ≥15) were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45).. Daily calcium carbonate (1,200 mg) and cholecalciferol [2,000-6,000 IU to target 25(OH)D >75 nmol/L] or matching placebos for 6 months.. Insulin sensitivity (HOMA2%S, Matsuda index), insulin secretion (insulinogenic index, area under the curve (AUC) for C-peptide) and β-cell function (Matsuda index x AUC for C-peptide) derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-α; IL-6; adiponectin; total and undercarboxylated osteocalcin.. Participants were middle-aged adults (mean age 54 years; 69% Europid) at risk of type 2 diabetes (48% with prediabetes). Compliance was >80% for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L), but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and β-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda) was observed.. Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes. However, in participants with prediabetes, supplementation with vitamin D and calcium may improve insulin sensitivity.. Australian New Zealand Clinical Trials Registry ACTRN12609000043235.

Topics: Adiponectin; Adult; Aged; Blood Glucose; C-Peptide; C-Reactive Protein; Calcium, Dietary; Cholecalciferol; Diabetes Mellitus, Type 2; Dietary Supplements; Female; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Interleukin-6; Male; Middle Aged; Osteocalcin; Pilot Projects; Prediabetic State; Tumor Necrosis Factor-alpha; Vitamin D Deficiency

Vitamin D insufficiency has been associated with impaired pancreatic beta-cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes.. Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n=26) or placebo (n=24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C-peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR).. In the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (-0.08) was not different (P=0.112). However, change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.. Oral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Time Factors; Vitamin D; Vitamin D Deficiency

Plasma calprotectin is a potential biomarker of cardiovascular disease (CVD), insulin resistance (IR), and obesity. We examined the relationship between plasma calprotectin concentrations, CVD manifestations and the metabolic syndrome (MetS) in patients with type 2 diabetes mellitus (T2DM) in order to evaluate plasma calprotectin as a risk assessor of CVD in diabetic patients without known CVD.. An automated immunoassay for determination of plasma calprotectin was developed based on a fecal Calprotectin ELIA, and a reference range was established from 120 healthy adults. Plasma calprotectin concentrations were measured in 305 T2DM patients without known CVD. They were screened for carotid arterial disease, peripheral arterial disease (PAD), and myocardial ischemia (MI) by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy.. The reference population had a median plasma calprotectin concentration of 2437 ng/mL (2.5-97.5% reference range: 1040-4262 ng/mL). The T2DM patients had significantly higher concentrations (3754 ng/mL, p < 0.0001), and within this group plasma calprotectin was significantly higher in patients with MetS (p < 0.0001) and also in patients with autonomic neuropathy, PAD, and MI compared with patients without (p < 0.001, p = 0.021 and p = 0.043, respectively). Plasma calprotectin was by linear regression analysis found independently associated with BMI, C-reactive protein, and HDL cholesterol. However, plasma calprotectin did not predict autonomic neuropathy, PAD, MI or CVD when these variables entered the multivariable regression analysis as separate outcome variables.. T2DM patients had higher concentrations of plasma calprotectin, which were associated with obesity, MetS status, autonomic neuropathy, PAD, and MI. However, plasma calprotectin was not an independent predictor of CVD, MI, autonomic neuropathy or PAD.. NCT00298844.

Topics: Adult; Aged; Biomarkers; Body Mass Index; C-Peptide; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leukocyte L1 Antigen Complex; Male; Metabolic Syndrome; Middle Aged; Obesity; Reference Values; Young Adult

Type 2 diabetes mellitus (T2DM) is a serious threat to human health and remains incurable. Insulin deficiency seems to be attributed to the progressive failure of pancreatic islet β-cells and immune cells such as T cells mediated cytotoxicity may be involved in the loss of pancreatic islet β-cells in T2DM. Targeting on the immune system to maintain functional activity of pancreatic islet β-cells could be an attractive way to treat T2DM. Mesenchymal stem cells (MSCs) exert potent capacity of immunomodulation. MSCs have been successfully applied for the treatment of several types of autoimmune diseases. So, the aim of this study is to evaluate the safety and potential therapeutic effects of UMSC on T2DM.. UMSCs were separated, expanded, and identified on the basis of the previous description. 18 patients of T2DM were recruited according to our experimental protocol. UMSC was intravenously transfused three times. All patients were followed up in the first, third, and sixth month. Age, gender, diabetes duration and medications as well as weight, height, and BMI were recorded. Fasting plasma glucose (FPG), postprandial blood glucose (PBG), HbA1c, C-peptide, and subsets of T cells were measured. All adverse reactions were carefully documented. Effective criteria were made and data was analyzed using SPSS 19.0 software.. UMSCs were successful obtained. Baseline clinical characteristics between the efficacy and inefficacy groups were not statistically different (p > 0.05). FBG and PBG of the patients in efficacy group were significantly reduced (p < 0.05) after UMSC transfusion. Plasma C-peptide levels and regulatory T (Treg) cell number in the efficacy group were numerically higher after UMSC transfusion; however, the difference of both parameters did not reach significance (p > 0.05). During the treatment course only 4 out of 18 patients (22.2%) had slight transient fever. Up to 6 months after UMSC transfusion, all patients continued to have a feeling of well-being and were physically more active.. UMSC transfusion is safe and well tolerated, effectively alleviates blood glucose, and increases the generation of C-peptide levels and Tregs in a subgroup of T2DM patients. This pilot study provides fundamental data for further study of UMSC transfusion on control of blood glucose as well as morbidity of T2DM in a larger cohort.

Topics: Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; Cells, Cultured; China; Cord Blood Stem Cell Transplantation; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Mesenchymal Stem Cell Transplantation; Middle Aged; Pilot Projects; T-Lymphocytes, Regulatory; Time Factors; Treatment Outcome; Young Adult

The glucose tolerance test demonstrates that content of unesterified fatty acids in blood plasma decreases up to three times and the content of oleic and linoleic acids is more decreased in the pool of fatty acids lipids. Out of resistance to insulin, hormone secretion increases up to three times. The decreasing of level of individual fatty acids occurs in a larger extent. Under resistance to insulin secretion of insulin is increasing up to eight times. The decreasing of level of each fatty acid is less expressed. The effect of insulin reflects decreasing of content of double bonds in blood plasma. The number of double bonds characterizes the degree of unsaturation of fatty acids in lipids of blood plasma. The higher number of double bonds is in the pool of unesterified fatty acids the more active is the effect of insulin. The hyper-secretion of insulin is directly proportional to content of palmitic fatty acid in lipids of blood plasma on fasting. According the phylogenetic theory of general pathology, the effect of insulin on metabolism of glucose is mediated by fatty acids. The insulin is blocking lipolysis in insulin-depended subcutaneous adipocytes and decreases content of unesterified fatty acids in blood plasma. The insulin is depriving all cells of possibility to absorb unesterified fatty acids and "forces" them to absorb glucose increasing hereby number of GLUT4 on cell membrane. The resistance to insulin is manifested in high concentration of unesterfied fatty acids, hyperinsulinemia, hyperalbuminemia and increasing of concentration of C-reactive protein-monomer. The resistance to insulin is groundlessly referred to as a symptom of diabetes mellitus type II. The resistance to insulin is only a functional disorder lasting for years. It can be successfully arrested. The diabetes mellitus is developed against the background of resistance to insulin only after long-term hyper-secretion of insulin and under emaciation and death of β-cells. The diabetes mellitus type I and not type II is an undesirable outcome of resistance to insulin.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids, Unsaturated; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male

Postprandial glucagon secretion was shown to be dysregulated in patients with type 2 diabetes. However, the differences in secretory patterns between obese and non-obese patients and their physiological effects on plasma glucose levels are not fully understood. This study population consisted of 21 (10 obese and 11 non-obese) consecutive patients with type 2 diabetes admitted for glycemic control. A 3-hour mixed-meal tolerance test was performed after glycemic control improved. Six non-diabetic subjects were also enrolled in the test. Postprandial glucagon levels increased after 30 min in diabetic patients but not in non-diabetic subjects. The glucagon levels in obese diabetic patients were significantly higher than those in non-obese diabetic patients, while the percent values of postprandial glucagon levels were not different between these groups. In diabetic patients, there were significant positive correlations between the percent value at 30 min and the early postprandial glucose levels at 0, 15 and 30 min and the areas under the curve (AUC0-30 and AUC30-90). Interestingly, the ratio of this percent glucagon value to the C-peptide level at 30 min was significantly associated with the late half of the postprandial glucose levels at 90, 120, 150 and 180 min and the AUC90-180. This is the first report that demonstrates the glucagon secretory patterns and the close correlations in detailed time course between the early postprandial glucagon response and the early and the late half of the postprandial glucose levels in obese and non-obese patients with type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Meals; Middle Aged; Obesity; Postprandial Period; Up-Regulation

After approval of sitagliptin and >750 mg of metformin in Japan, a triple oral antidiabetes drug (OAD) regimen including sulfonylurea, metformin, and sitagliptin was sometimes described. However, in the real world of clinical practice, the daily dose of sulfonylurea tended to be decreased according to the warning from the Japan Diabetes Society for avoiding hypoglycemia, instead of increasing the dose of metformin for maintaining hemoglobin A1c (HbA1c) levels with this regimen. This study examined the impact of either a small dose of glimepiride or a high dose of metformin on HbA1c in triple OAD therapy with sitagliptin in a 3-month, single-center, open-label, randomized controlled study.. Fifty-six type 2 diabetes mellitus patients who had been treated with 50 mg of sitagliptin, ≥ 1,000 mg of metformin, and ≤ 1 mg of glimepiride with an HbA1c level of <7.4% during at least 3 months were enrolled in the study. The patients were randomly assigned to two treatment groups who either received a 50% reduced dose of metformin (n = 27) or discontinued glimepiride (n = 29), while sitagliptin administration continued in both groups. Twenty-six patients from the reduced metformin group and 27 patients from the discontinued glimepiride group completed the study.. Significantly greater changes were observed in HbA1c and glycated albumin levels in patients who discontinued glimepiride than in patients with a 50% reduced metformin dose, during the 2-3-month period than in the 1-3-month period.. Glimepiride is important for good glycemic control in triple OAD therapy with sitaglitpin and metformin. This regimen may be useful for those patients who do not achieve satisfactory glycemic control with dual combination therapy.

Topics: Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Male; Metformin; Middle Aged; Prospective Studies; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome; Triazoles

To assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S).. We randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments with placebo (P), M, S, and M+S. After each period, subjects received a 6-h meal tolerance test (MTT) with [(14)C]glucose to calculate glucose kinetics. Fasting plasma glucose (FPG), fasting plasma insulin, C-peptide (insulin secretory rate [ISR]), fasting plasma glucagon, and bioactive glucagon-like peptide (GLP-1) and gastrointestinal insulinotropic peptide (GIP) were measured.. FPG decreased from P, 160 ± 4 to M, 150 ± 4; S, 154 ± 4; and M+S, 125 ± 3 mg/dL. Mean post-MTT plasma glucose decreased from P, 207 ± 5 to M, 191 ± 4; S, 195 ± 4; and M+S, 161 ± 3 mg/dL (P < 0.01). The increase in mean post-MTT plasma insulin and in ISR was similar in P, M, and S and slightly greater in M+S. Fasting plasma glucagon was equal (≈ 65-75 pg/mL) with all treatments, but there was a significant drop during the initial 120 min with S 24% and M+S 34% (both P < 0.05) vs. P 17% and M 16%. Fasting and mean post-MTT plasma bioactive GLP-1 were higher (P < 0.01) after S and M+S vs. M and P. Basal endogenous glucose production (EGP) fell from P 2.0 ± 0.1 to S 1.8 ± 0.1 mg/kg · min, M 1.8 ± 0.2 mg/kg · min (both P < 0.05 vs. P), and M+S 1.5 ± 0.1 mg/kg · min (P < 0.01 vs. P). Although the EGP slope of decline was faster in M and M+S vs. S, all had comparable greater post-MTT EGP inhibition vs. P (P < 0.05).. M+S combined produce additive effects to 1) reduce FPG and postmeal plasma glucose, 2) augment GLP-1 secretion and β-cell function, 3) decrease plasma glucagon, and 4) inhibit fasting and postmeal EGP compared with M or S monotherapy.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Metformin; Pyrazines; Sitagliptin Phosphate; Triazoles

To determine the effects of lixisenatide, a new once-daily (QD) glucagon-like peptide-1 receptor agonist, on postprandial glucose (PPG) and gastric emptying, and the relationship between these effects in patients with type 2 diabetes mellitus (T2DM).. Data were obtained from a randomized, double-blind, placebo-controlled, parallel-group study with treatment duration of 28 days in patients with T2DM receiving ≤2 oral antidiabetic drugs. Lixisenatide was injected subcutaneously using an ascending dose range (5-20 μg) increased every fifth day in increments of 2.5 μg. Blood glucose was determined before and after three standardized meals (breakfast, lunch, and dinner). Gastric emptying of the standardized breakfast was determined by a (13)C-octanoic acid breath test at baseline (Day-1) and at Day 28.. A total of 21 and 22 patients were randomized to lixisenatide 20 μg QD and placebo, respectively. With lixisenatide 20 μg QD, there was a reduction in PPG when compared with placebo after breakfast (p<0.0001), lunch (p<0.001) and dinner (p<0.05). Hence, lixisenatide 20 μg administered in the morning exhibited a pharmacodynamic effect on blood glucose throughout the day. Gastric emptying (50% emptying time) increased substantially from baseline with lixisenatide 20 μg QD, but not with placebo (change from baseline ± SD: -24.1 ± 133.1 min for placebo and 211.5 ± 278.5 min for lixisenatide; p<0.01). There was an inverse relationship between PPG area under the curve after breakfast and gastric emptying with lixisenatide 20 μg QD (n=17, r(2)=0.51, p<0.05), but not with placebo.. In this study, lixisenatide at a dose of 20 μg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Gastric Emptying; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptides; Postprandial Period

This clinical trial assessed whether a potent, selective GPR109A agonist, GSK256073, could, through inhibition of lipolysis, acutely improve glucose homeostasis in subjects with type 2 diabetes mellitus.. Thirty-nine diabetic subjects were enrolled in the randomized, single-blind, placebo-controlled, three-period crossover trial. Each subject received placebo and two of four regimens of GSK256073 for 2 days. GSK256073 was dosed 5 mg every 12 h before breakfast and supper (BID), 10 mg every 24 h before breakfast (QD), 25 mg BID and 50 mg QD.. The change from baseline weighted mean glucose concentration for an interval from 24 to 48 h after the initial drug dose was significantly reduced for all GSK256073 regimens, reaching a maximum of -0.87 mmol/l (-1.20, -0.52) with the 25 mg BID dose. Sustained suppression of non-esterified fatty acid (NEFA) and glycerol concentrations was observed with all GSK256073 doses throughout the 48-h dosing period. Serum insulin and C-peptide concentrations fell in concert with glucose concentrations and calculated HOMA-IR scores decreased 27-47%, consistent with insulin sensitization. No marked differences were evident between either 10 and 50 mg total daily doses or QD versus BID dosing.. Administration of a GPR109A agonist for 2 days significantly decreased serum NEFA and glucose concentrations in diabetic subjects. Glucose improvements were associated with decreased insulin concentrations and measures of enhanced insulin sensitivity. Improved glucose control occurred with GSK256073 doses that were generally safe and not associated with events of flushing or gastrointestinal disturbances.

Topics: C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Investigational; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Glycerol; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Male; Middle Aged; Receptors, G-Protein-Coupled; Receptors, Nicotinic; Single-Blind Method

To evaluate the effects of exenatide on some inflammatory markers and to quantify the effect of exenatide on β-cell function.. A randomized, double-blind, placebo-controlled trial.. Seven hospitals in Italy.. A total of 174 white treatment-naive adults with type 2 diabetes and a glycated hemoglobin (HbA(1c)) level higher than 7.5%.. After an open-label run-in period of 8 ± 2 months with metformin, patients were randomized to take exenatide (5 μg twice/day for the first 4 weeks, 10 μg twice/day thereafter) or a placebo volume equivalent for 12 months.. Body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index, homeostasis model assessment β-cell function index (HOMA-β), fasting plasma proinsulin (FPPr), proinsulin-to-fasting plasma insulin ratio (Pr:FPI ratio), C-peptide, glucagon, vaspin, chemerin, and resistin were evaluated at baseline, at randomization, and at 3, 6, 9, and 12 months. Patients also underwent a combined euglycemic, hyperinsulinemic, and hyperglycemic clamp with subsequent arginine stimulation to assess insulin sensitivity and insulin secretion. HbA(1c) was significantly improved with exenatide plus metformin compared with placebo plus metformin. Exenatide plus metformin was also significantly more effective than placebo plus metformin in increasing HOMA-β C-peptide, and all measures of β-cell function after the euglycemic hyperinsulinemic and hyperglycemic clamp. We observed that exenatide plus metformin also reduced resistin compared with placebo plus metformin. No variations in vaspin and chemerin were noted in group-to-group comparisons. We observed a significant correlation between M value increase, an index of insulin sensitivity, and a decrease in inflammatory parameters in the exenatide plus metformin group.. The combination of exenatide plus metformin was more effective than metformin alone in improving glycemic control, β-cell function, and inflammatory parameters.

Topics: Aged; Arginine; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Chimerin Proteins; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Exenatide; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Male; Metformin; Middle Aged; Peptides; Resistin; Risk Factors; Serpins; Venoms

We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 10(4) and +5.8 × 10(4) copies, respectively) but decreased in healthy subjects during hyperglycemia (-1.4 × 10(4) copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 10(5) copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.

Topics: 3-O-Methylglucose; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Epithelial Cells; Fasting; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Receptors, G-Protein-Coupled

The effects of sitagliptin and pioglitazone, alone and in combination, on α- and β-cell function were assessed in patients with type 2 diabetes.. Following a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4 mmol/l were randomized (1 :1 :1 : 1) to sitagliptin, pioglitazone, sitagliptin + pioglitazone or placebo. At baseline and after 12 weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon.. After 12 weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with sitagliptin + pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with sitagliptin versus all other treatments and increased with sitagliptin + pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with sitagliptin versus placebo and decreased with sitagliptin + pioglitazone versus pioglitazone or placebo. Φ(s), a measure of dynamic β-cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with sitagliptin + pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and sitagliptin + pioglitazone versus placebo. The disposition index, a measure of the relationship between β-cell function and insulin sensitivity, improved with all active treatments versus placebo.. Sitagliptin and pioglitazone enhanced β-cell function (increasing postmeal Φ(s)), and sitagliptin improved α-cell function (decreasing postmeal glucagon) after 12 weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glucagon; Glucagon-Secreting Cells; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Middle Aged; Pioglitazone; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles

The pharmacodynamic properties of a single dose of 0.5 U/kg insulin detemir and insulin glargine were compared during two 24-h isoglycaemic clamps, one week apart.. The order of treatments was randomised. At approximately 0830 h, persons with T2DM received subcutaneous administration of a 0.5 U/kg dose of either insulin detemir or insulin glargine into the anterior abdominal wall. Plasma glucose was measured at 10-min intervals throughout the 24-h clamp period and isoglycaemia was maintained by variable infusion of 20% glucose. Glucose infusion rates (GIR) and plasma C-peptide were determined throughout each 24-h period.. Eleven persons with type 2 diabetes (8 male) with mean (SD) age 58.5 years (8.5), BMI 30.8 kg/m² (2.8) and HbA1c 7.5% (0.6) were studied. Plasma glucose remained constant during the clamp (CV: insulin detemir 3.7%; insulin glargine 3.8%). Following injection of insulin detemir, GIR increased, reaching a mean peak of 2.29 mg/kg/min (95% CI 1.64, 2.94) at 11.6h (range 8.9 to 14.3) compared to 1.71 mg/kg/min (95% CI 1.4, 2.0) at 10.2 h (8.1 to 12.3) for insulin glargine (P=0.025 for GIR(max)). Plasma C-peptide decreased during the study period, remaining significantly lower than the fasting level at the study end after both analogues, insulin detemir (P=0.01) and insulin glargine (P=0.02).. In persons with T2DM, no difference in duration of action following a single subcutaneous dose of insulin detemir and insulin glargine could be observed. Insulin detemir showed greater between subject variability and achieved a significantly higher maximum GIR than insulin glargine.

Topics: Adolescent; Adult; Aged; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Young Adult

An elevated PI/I ratio is attributable to increased secretory demand on β-cells. However, the effect of postprandial targeting therapy on proinsulin level is unknown. We evaluated the metabolic effect of glinide and sulfonylurea (SU) using the meal tolerance test (MTT).. MTT was applied to previously untreated Type 2 Diabetes Mellitus (T2DM) subjects. Twenty-two participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum proinsulin and C-peptide immunoreactivity (CPR) were measured at 0 and 120 min. Postprandial profile was assessed at baseline and following 3 months treatment with either mitiglinide or glimepiride.. Plasma glucose level at 30, 60, 120, and 180 min was significantly improved by mitiglinide. Whereas, glimepiride showed a significant improve plasma glucose at 0, 180 min. Peak IRI shifted from 120 to 30 min by mitiglinide treatment. The pattern of insulin secretion was not changed by glimepiride treatment. Whereas mitiglinide did not affect the PI/I ratio, glimepiride tended to increase the PI/I ratio. Moreover, although mitiglinide did not affect PI/I ratio as a whole, marked reduction was noted in some patients treated by mitiglinide. PI/I ratio was reduced significantly in the responder group. The responder subgroup exhibited less insulin resistance and higher insulinogenic index at baseline than non-responders. Moreover, the triglyceride level of responders was significantly lower than that of non-responders.. Mitiglinide improved postprandial insulin secretion pattern and thereby suppressed postprandial glucose spike. In T2DM patients with low insulin resistance and low triglyceride, mitiglinide recovered impaired β-cell function from the viewpoint of the PI/I ratio.. UMIN000010467.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Isoindoles; Male; Middle Aged; Molecular Targeted Therapy; Postprandial Period; Proinsulin; Sulfonylurea Compounds; Triglycerides

Basal-supported oral therapy (BOT) is often used to treat poorly controlled type 2 diabetes. However, patients sometimes experience nocturnal and early morning hypoglycemia. Thus, maintaining targeted glycemic control by BOT is limited in some patients. We assessed the efficacy and safety of replacing basal insulin by sitagliptin therapy in Japanese type 2 diabetes patients on BOT. Forty-nine subjects were sequentially recruited for the 52-week, prospective, single arm study. Patients on BOT therapy were switched from basal insulin to sitagliptin. The primary endpoint was change in HbA1c in 52 weeks. The secondary endpoints were dropout rate, changes in body weight, frequency of hypoglycemia, and relationship between change in HbA1c and insulin secretion capacity evaluated by glucagon loading test. The average dose of basal insulin was 15.0±8.4 units. Sixteen subjects (31.3%) were dropped because replacement by sitagliptin was less effective for glycemic control. In these subjects, diabetes duration was longer, FPG and HbA1c at baseline were higher, and insulin secretion capacity was lower. Change in HbA1c in 52 weeks was - 4 mmol/mol (95% CI - 5 to - 4 mmol/mol) (p<0.05). Change in body weight was - 0.71 kg (95% CI - 1.42 to - 0.004 kg) (p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month. HbA1c level was improved if C-peptide index (CPI) was over 1.19. In conclusion, basal insulin in BOT can be replaced by sitagliptin with a decrease in HbA1c level and frequency of hypoglycemia in cases where insulin secretion capacity was sufficiently preserved.

Topics: Aged; Asian People; Body Mass Index; Body Weight; C-Peptide; Demography; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Pyrazines; ROC Curve; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated.. After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72 h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin.. CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28 h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group.. CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example.

Topics: Adolescent; Adult; Aged; Area Under Curve; Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Carriers; Female; Glycated Hemoglobin; Glycoproteins; Half-Life; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin, Long-Acting; Male; Middle Aged; Oligosaccharides; Young Adult

To compare the safety and tolerability of metformin to insulin for glycemic control among women with preexisting type 2 and early A2 gestational diabetes.. Women with preexisting type 2 diabetes and those diagnosed with gestational diabetes who required medical management prior to 20 weeks were randomly assigned to metformin or insulin. Glycemic control, defined as >50% capillary blood glucose within target range, was compared between groups. Other outcomes included patient tolerance, neonatal and obstetric complications, maternal weight gain, neonatal cord blood C-peptide, and patient satisfaction with therapy.. Twenty-eight women completed the study, with 14 in each group. Of the 15 women assigned to metformin, 100% continued to receive metformin until delivery, although 43% required supplemental insulin to achieve glycemic control. Glucose measures did not differ between the groups, and the proportion who met fasting and postprandial glycemic target values did not differ between the groups. Women treated with metformin had significantly fewer subjective episodes of hypoglycemia compared with those using insulin (0% versus 36%; p = 0.04) as well as reported glucose values < 60 mg/dL (7.1% versus 50%; p = 0.03).. Metformin should be considered for treatment of overt diabetes and early A2 gestational diabetes in pregnancy.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Blood; Humans; Hypoglycemic Agents; Insulin; Metformin; Patient Satisfaction; Pregnancy; Pregnancy in Diabetics

Reducing the dietary glycaemic response has been proposed as a means of reducing the risk of diabetes.. To evaluate the effects of a new diabetes-specific formula (DSF) enriched with resistant starch type IV and fructose-free on postprandial glycaemia, insulinaemia and gastrointestinal hormones in healthy volunteers and in outpatient type 2 diabetics.. (1) Twenty-four healthy volunteers were divided into two groups: Group 1 ( n = 10) was provided 50 g of the carbohydrate (CHO) constituent of the new product and 50 g of glucose separated by 1 week; Group 2 ( n = 14) was provided 400 ml of the new DSF (T-Diet Plus(®) Diabet NP) and 400 ml of a control product separated by 1 week. (2) Ten type 2 diabetic patients received 400 ml of the new DSF and two other commercially available DSF (Glucerna(®) SR and Novasource(®) Diabet) on three occasions separated by 1 week. Venous blood samples were drawn at time 0 and at different times until 120 min. Glucose, insulin and gastrointestinal hormones were determined. Glycaemic and insulinaemic indices and glycaemic load were calculated.. The CHO constituent and the new DSF showed low glycaemic index and glycaemic load. In healthy subjects, insulin and C-peptide release were lower after administration of the CHO constituent as well as after the new DSF (P < 0.001). Ghrelin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) production were lower after intake of the CHO constituent (P ranging from <0.001 to 0.019) compared with glucose, and GIP was lower after ingestion of the new DSF (P = 0.002) than after the control product. In type 2 diabetic patients, glucose AUC was lower after the administration of the new DSF (P = 0.037) compared with the others.. Our results indicate that this new product could be beneficial for diabetic patients.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats, Unsaturated; Dietary Supplements; Enteral Nutrition; Fatty Acids, Omega-3; Female; Fructose; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glycemic Index; Healthy Volunteers; Humans; Insulin; Lipids; Male; Middle Aged; Postprandial Period; Starch; Young Adult

We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and β-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 ± 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model-derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 μmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose.

Topics: Allylamine; Anticholesteremic Agents; Blood Glucose; C-Peptide; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Postprandial Period

The clinical efficacy of peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists in cell-mediated autoimmune diseases results from down-regulation of inflammatory cytokines and autoimmune effector cells. T cell islet autoimmunity has been demonstrated to be common in patients with phenotypic type 2 diabetes mellitus (T2DM) and islet-specific T cells (T(+) ) to be correlated positively with more severe beta cell dysfunction. We hypothesized that the beneficial effects of the PPAR-γ agonist, rosiglitazone, therapy in autoimmune T2DM patients is due, in part, to the immunosuppressive properties on the islet-specific T cell responses. Twenty-six phenotypic T2DM patients positive for T cell islet autoimmunity (T(+) ) were identified and randomized to rosiglitazone (n = 12) or glyburide (n = 14). Beta cell function, islet-specific T cell responses, interleukin (IL)-12 and interferon (IFN)-γ responses and islet autoantibodies were followed for 36 months. Patients treated with rosiglitazone demonstrated significant (P < 0·03) down-regulation of islet-specific T cell responses, although no change in response to tetanus, a significant decrease (P < 0·05) in IFN-γ production and significantly (P < 0·001) increased levels of adiponectin compared to glyburide-treated patients. Glucagon-stimulated beta cell function was observed to improve significantly (P < 0·05) in the rosiglitazone-treated T2DM patients coinciding with the down-regulation of the islet-specific T cell responses. In contrast, beta cell function in the glyburide-treated T2DM patients was observed to drop progressively throughout the study. Our results suggest that down-regulation of islet-specific T cell autoimmunity through anti-inflammatory therapy may help to improve beta cell function in autoimmune phenotypic T2DM patients.

Topics: Adult; Aged; Autoantibodies; Autoimmunity; C-Peptide; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Progression; Female; Follow-Up Studies; Glyburide; Humans; Hypoglycemic Agents; Immunosuppression Therapy; Interferon-gamma; Interleukin-12; Islets of Langerhans; Male; Middle Aged; PPAR gamma; Rosiglitazone; T-Cell Antigen Receptor Specificity; T-Lymphocytes; Thiazolidinediones

Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin.. In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal.. Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported.. Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Resistance; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Metformin; Middle Aged; Peptides

The aim of the study was to evaluate circulatory AGE-peptide levels in diabetic nephropathy and to observe the effects of thiamine (vitamin B1) and pyridoxine (vitamin B6) therapy.. Type 2 diabetic patients (N.=57) were divided into two groups as "with nephropathy" (N.=27) and "without nephropathy" (N.=30). Diabetic nephropathy patients were treated with either B6 (N.=12) (250 mg/day) or B1+B6 (N.=15) (250 mg/day, each) for five months. At the beginning and the end of the experimentation period, glucose, HbA1c, triglyceride, cholesterol, insulin, C-peptide, thiamine pyrophosphate, pyridoxal phosphate and AGE- peptides were measured.. AGE-peptides were higher in the diabetic group with nephropathy than without nephropathy (P=0.005). Within five months AGE-peptides increased in the diabetic group without nephropathy (P=0.042) but not in the group with nephropathy treated either with B1+B6 or B6. In B6 treated group a substantial decrease was observed in HbA1c (P=0.033). B1+B6 or B6 treatment both caused an increase in C-peptide (P=0.006, P=0.004).. Among the parameters measured, plasma AGE-peptides was the only parameter found to be higher in type 2 diabetes mellitus patients "with nephropathy" than "without nephropathy". However, patients with nephropathy treated with B1+B6 or B6 did not display any further increase in AGE-peptides within five months. Both of the treatments caused an increase in C-peptide.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Male; Middle Aged; Pyridoxal Phosphate; Pyridoxine; Thiamine; Thiamine Pyrophosphate; Triglycerides; Vitamin B Complex

To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA).. A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUC(G) ) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed.. Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m(2) and 25.4 ± 4.2 kg/m(2) , respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6-34] and 19 mg/liter [interquartile range 3-39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUC(G) with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179-4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210-4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUC(G) did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUC(G) (β = 3.626 [95% confidence interval 1.077-6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017-1.122], P = 0.009).. In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Early Diagnosis; Female; Glucocorticoids; Glucose Tolerance Test; Health Status; Humans; Inflammation; Insulin Resistance; Joints; Male; Middle Aged; Prednisolone; Severity of Illness Index

This study was performed to determine the effect of a single, large, intramuscular injection of vitamin D post-partum on glucose tolerance and insulin resistance in women with gestational diabetes.. Forty-five participants in a randomized controlled trial on gestational diabetes mellitus were divided into an intervention group and a control group. Only subjects in the intervention group received one intramuscular injection of 300,000 IU of vitamin D3. HbA(1c), serum 25-hydroxyvitamin D3, fasting insulin and blood glucose, C-peptide, homeostasis model assessment insulin resistance index (HOMA-IR), β-cell function, insulin sensitivity and the Quantitative Insulin Sensitivity Check Index (QUICKI) were measured at baseline and after 3 months of intervention.. Approximately 80% of the mothers had a degree of vitamin D deficiency. Post-intervention, this was found in 4.2 and 71.4% in the intervention and control groups, respectively. The medians of HOMA-IR indices before and after intervention were 0.6 and 0.5 (P = 0.7), respectively, in subjects in the intervention group, and 0.5 and 0.9 (P = 0.01) in subjects in the control group. The mean of the QUICKI fell only in the control group (P = 0.008). In the control group, β-cell function increased by ~8% (P = 0.01) and insulin sensitivity decreased after 3 months (P = 0.002). Post-intervention, the median C-peptide decreased in the intervention group and increased in the control group, but the change was significant only in the control group (P = 0.03).. A single injection of 300,000 IU of vitamin D3 achieves a 3-month serum 25-hydroxyvitamin D range of 50-80 nmol/l and is an efficient, effective and safe procedure for improving the vitamin status and indices of insulin resistance in mothers with gestational diabetes after delivery.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Fasting; Female; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Injections, Intramuscular; Insulin Resistance; Postpartum Period; Pregnancy; Treatment Outcome; Vitamin D

To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β-cell function in patients with type 2 diabetes.. The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI.. At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β-cell function relative to their respective monotherapy groups.. After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β-cell function were found with treatments for up to 2 years.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Pinitol is thought to mediate insulin action and improve insulin resistance. We evaluated the effects of pinitol on glycemic control, insulin resistance and adipocytokine levels in type 2 diabetic patients.. A total of 66 patients with type 2 diabetes who had been taking oral hypoglycemic agents for at least 3 months were enrolled and randomized to receive pinitol (n = 33) or matching placebo (n = 33). All subjects took 1,200 mg pinitol or placebo and maintained their current oral hypoglycemic agents throughout the study.. Mean HbA1c, fasting plasma glucose, and HOMA-IR were significantly lowered more in patients taking pinitol than in those given a placebo. Patients who had an HbA1c over 8.0% showed a greater reduction (p < 0.01) than those who had an HbA1c below 8.0% (p =0.16). In addition, in the group of patients with a HOMA-IR over 2.5, there was a significant decrease in HbA1c compared to that in the group of patients with a HOMA-IR below 2.5. There were no differences in the changes in adiponectin, FFA and CRP between the two groups.. Pinitol can mediate insulin action to improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus, especially in patients with insulin resistance.

Topics: Adipokines; Adiponectin; Adult; Aged; Blood Glucose; C-Peptide; C-Reactive Protein; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Insulin Resistance; Male; Middle Aged; Milk Proteins; Treatment Outcome; Whey Proteins

Cardiovascular events and death are better predicted by postprandial glucose (PPG) than by fasting blood glucose or HbA(1c). While chronic exercise reduces HbA(1c) in patients with type 2 diabetes, short-term exercise improves measures of insulin sensitivity but does not consistently alter responses to the OGTT. The purpose of this study was to determine whether short-term exercise training improves PPG and glycaemic control in free-living patients with type 2 diabetes, independently of the changes in fitness, adiposity and energy balance often associated with chronic exercise training.. Using continuous glucose monitors, PPG was quantified in previously sedentary patients with type 2 diabetes not using exogenous insulin (n = 13, age 53 ± 2 years, HbA(1c) 6.6 ± 0.2% (49.1 ± 1.9 mmol/mol)) during 3 days of habitual activity and during the final 3 days of a 7 day aerobic exercise training programme (7D-EX) which does not elicit measurable changes in cardiorespiratory fitness or body composition. Diet was standardised across monitoring periods, with modifications during 7D-EX to offset increases in energy expenditure. OGTTs were performed on the morning following each monitoring period.. 7D-EX attenuated PPG (p < 0.05) as well as the frequency, magnitude and duration of glycaemic excursions (p < 0.05). Conversely, average 24 h blood glucose did not change, nor did glucose, insulin or C-peptide responses to the OGTT.. 7D-EX attenuated glycaemic variability and PPG in free-living patients with type 2 diabetes but did not significantly alter responses to the laboratory-based OGTT. These effects appeared to be independent of changes in fitness, body composition or energy balance. ClinicalTrials.gov numbers: NCT00954109 and NCT00972452.. This project was funded by the University of Missouri Institute for Clinical and Translational Sciences (CRM), NIH grant T32 AR-048523 (CRM), Diabetes Action Research and Education Foundation (JPT). Medtronic supplied CGMS sensors at a discounted rate.

Topics: Adiposity; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diet; Exercise; Exercise Therapy; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Postprandial Period

In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes.. Subjects aged 12-25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects.. GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group.. Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Carbonated Beverages; Child; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose; Humans; Male; Peptide YY; Young Adult

This study evaluated the effect of vildagliptin + metformin on glycemic control and β-cell function in type 2 diabetes patients.. One hundred seventy-one type 2 diabetes patients, naive to antidiabetes therapy and with poor glycemic control, were instructed to take metformin for 8±2 months up to a mean dosage of 2,500±500 mg/day; then they were randomly assigned to add vildaglipin 50 mg twice a day or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index, glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment β-cell function index (HOMA-β), fasting plasma proinsulin, proinsulin/fasting plasma insulin ratio, C-peptide, glucagon, adiponectin, and high-sensitivity C-reactive protein. Before and at 12 months after the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation, to assess insulin sensitivity and insulin secretion.. After 12 months of treatment, vildagliptin + metformin gave a better decrease of body weight, glycemic control, HOMA-IR, and glucagon and a better increase of HOMA-β compared with placebo + metformin. Regarding the measures of β-cell function, treatment-induced changes in M-value, first- and second-phase C-peptide response to glucose, and C-peptide response to arginine were significantly higher in the vildagliptin + metformin group compared with the placebo + metformin group.. The addition of vildagliptin to metformin gave a better improvement of glycemic control, insulin resistance, and β-cell function compared with metformin alone.

Topics: Adamantane; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Nitriles; Pyrrolidines; Vildagliptin; Weight Loss

The additive effect of α-glucosidase inhibitors (α-GIs) was investigated in patients with type 2 diabetes (T2D) under control with rapid-acting insulin analog.. Thirty-six poorly controlled T2D patients were recruited, and plasma glucose (PG) was controlled by three times daily injection of insulin lispro mix 50/50 (Mix50) to maintain fasting PG <130 mg/dL and 2-h postprandial PG (PPG) <180 mg/dL. Another group of 20 patients was randomly assigned to either 0.3 mg of voglibose or 50 mg of miglitol, which was administered at breakfast every other day. Another group of 16 patients was assigned to a crossover study, in which each α-GI was switched every day during the 6-day study. PPG, C-peptide, and lipid profile were analyzed.. The addition of voglibose had no effect on PPG, but miglitol blunted the PPG rise and significantly decreased 1-h and 2-h postprandial C-peptide levels compared with Mix50 alone. In addition, miglitol significantly decreased the 1-h postprandial triglyceride rise and the remnant-like particle-cholesterol rise, while it increased the 1-h postprandial high-density lipoprotein-cholesterol and apolipoprotein A-I levels in the crossover study.. Miglitol appears to have rapid action, which appears earlier than that of lispro. The combination of miglitol and Mix50 seems effective for the control of PPG and lipid profile in T2D.

Topics: 1-Deoxynojirimycin; Apolipoprotein A-I; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Inositol; Insulin Lispro; Lipids; Lipoproteins, HDL; Male; Middle Aged; Postprandial Period; Treatment Outcome; Triglycerides

Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion (GSIS). This response is blunted in type 2 diabetes (T2DM). Xenin-25 is a 25-amino acid neurotensin-related peptide that amplifies GIP-mediated GSIS in hyperglycemic mice. This study determines if xenin-25 amplifies GIP-mediated GSIS in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or T2DM. Each fasting subject received graded glucose infusions to progressively raise plasma glucose concentrations, along with vehicle alone, GIP, xenin-25, or GIP plus xenin-25. Plasma glucose, insulin, C-peptide, and glucagon levels and insulin secretion rates (ISRs) were determined. GIP amplified GSIS in all groups. Initially, this response was rapid, profound, transient, and essentially glucose independent. Thereafter, ISRs increased as a function of plasma glucose. Although magnitudes of insulin secretory responses to GIP were similar in all groups, ISRs were not restored to normal in subjects with IGT and T2DM. Xenin-25 alone had no effect on ISRs or plasma glucagon levels, but the combination of GIP plus xenin-25 transiently increased ISR and plasma glucagon levels in subjects with NGT and IGT but not T2DM. Since xenin-25 signaling to islets is mediated by a cholinergic relay, impaired islet responses in T2DM may reflect defective neuronal, rather than GIP, signaling.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucose; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Neurotensin

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (D(β-GS): β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(β-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.

Topics: Adult; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Obesity, Morbid; Postprandial Period; Time Factors

Fibroblast growth factor 21 (FGF21), an endocrine factor predominantly secreted from liver, possesses multiple beneficial effect on energy metabolism and insulin sensitivity in animals. This study aimed to investigate the acute change of serum FGF21 in response to glucose challenge in humans.. A 75-g oral glucose tolerance test was performed among 20 healthy subjects, 18 with impaired glucose tolerance (IGT) and 21 with type 2 diabetes mellitus (T2DM). Blood samples were collected for measurement of FGF21 and other biochemical parameters. The associations of FGF21 with insulin and other metabolic parameters were analyzed.. Fasting serum FGF21 levels increased progressively from healthy, IGT to T2DM subjects (P < 0.05 for global trend). After oral glucose administration, the serum FGF21 level showed a similar biphasic change in all three groups. It declined to a nadir level at 60 min and then increased gradually to its peak level at 180 min. FGF21 levels at different time points of oral glucose tolerance test negatively correlated with glucose levels in all subjects, and the fold change of serum FGF21 at different time points (compared with the basal level) were inversely associated with fold changes of insulin (P = 0.012) and C-peptide (P = 0.043) levels in healthy subjects but not in IGT and T2DM patients.. The dynamic change of circulating FGF21 was associated with alterations in insulin levels in response to glucose challenge in humans. These findings support the role of FGF21 as a potential regulator of insulin secretion and glucose metabolism in humans.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Fibroblast Growth Factors; Glucose; Glucose Intolerance; Glucose Tolerance Test; Health; Humans; Insulin; Insulin Resistance; Male; Matched-Pair Analysis

The present analysis tests the hypothesis that quantifiable disruption of the glucose-stimulated insulin-secretion dose-response pathway mediates impaired fasting glycemia (IFG) and type 2 diabetes mellitus (DM). To this end, adults with normal and impaired fasting glycemia (NFG, n = 30), IFG (n = 32), and DM (n = 14) were given a mixed meal containing 75 g glucose. C-peptide and glucose were measured over 4 h, 13 times in NFG and IFG and 16 times in DM (age range 50-57 yr, body mass index 28-32 kg/m(2)). Wavelet-based deconvolution analysis was used to estimate time-varying C-peptide secretion rates. Logistic dose-response functions were constructed analytically of the sensitivity, potency, and efficacy (in the pharmacological sense of slope, one-half maximal stimulation, and maximal effect) of glucose's stimulation of prehepatic insulin (C-peptide) secretion. A hysteresis changepoint time, demarcating unequal glucose potencies for onset and recovery pathways, was estimated simultaneously. According to this methodology, NFG subjects exhibited distinct onset and recovery potencies of glucose in stimulating C-peptide secretion (6.5 and 8.5 mM), thereby defining in vivo hysteresis (potency shift -2.0 mM). IFG patients manifested reduced glucose onset potency (8.6 mM), and diminished C-peptide hysteretic shift (-0.80 mM). DM patients had markedly decreased glucose potency (18.8 mM), reversal of C-peptide's hysteretic shift (+4.5 mM), and 30% lower C-peptide sensitivity to glucose stimulation. From these data, we conclude that a dynamic dose-response model of glucose-dependent control of C-peptide secretion can identify disruption of in vivo hysteresis in patients with IFG and DM. Pathway-defined analytic models of this kind may aid in the search for prediabetes biomarkers.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Fasting; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Logistic Models; Male; Middle Aged; Osmolar Concentration; Prediabetic State; Secretory Pathway; Time Factors

G-protein-coupled receptor 40 (GPR40), highly expressed in pancreatic β-cells, mediates free fatty acid (FFA)-induced insulin secretion. This phase I, double-blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose-lowering GPR40 agonist, TAK-875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose-proportional increases in AUC(0-24) and C(max) occurred. TAK-875 showed good tolerability with no dose-limiting side effects. Two subjects (on TAK-875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK-875 showed reductions from baseline in fasting (2 to -93 mg/dl) and post-OGTT glucose (26 to -172 mg/dl), with an apparent dose-dependent increase in post-OGTT C-peptide over 14 days. Consistent with preclinical data, TAK-875 apparently acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once-daily oral administration.

Topics: Administration, Oral; Benzofurans; Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Fatty Acids, Nonesterified; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Receptors, G-Protein-Coupled; Sulfones; Treatment Outcome

To evaluate the impact on glycemic control, insulin resistance, and insulin secretion of sitagliptin+metformin compared to metformin in type 2 diabetic patients.. Patients were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to sitaglipin 100 mg or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, adiponectin (ADN), and high sensitivity-C reactive protein (Hs-CRP). Before, and after 12 months since the addition of sitagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation.. Both treatments similarly decreased body weight, and BMI; on the other hand, they both improved glycemic control, glucagon and HOMA-IR, but sitagliptin+metformin were more effective in reducing these parameters. Sitagliptin+metformin, but not placebo+metformin, decreased FPPr, FPPR/FPI ratio, and increased C-peptide values, even if no differences between the groups were recorded. Sitaglitin+metformin gave also a greater increase of HOMA-β, M value, C-peptide response to arginine and disposition index compared to placebo+metformin group.. Other than improving glycemic control, sitagliptin+metformin also improved β-cell function better than metformin alone.

Topics: Blood Glucose; C-Peptide; C-Reactive Protein; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exercise; Fasting; Female; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Italy; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Postprandial hyperglycemia is associated with platelet activation. We thus investigated if meal-induced platelet activation could be attenuated by meal insulin. A randomized, double-blind, cross-over study was performed to compare postprandial platelet activation after premeal injections of placebo or insulin aspart (0.1 and 0.2 units/kg) in 18 patients with type 2 diabetes mellitus (T2DM). Platelet activation was assessed by flow cytometry, without and with stimulation by the thromboxane analog U46619 or ADP. Measurements were before and after premeal blood glucose standardization (to 6-7 mmol/L by insulin infusion, if needed) and at 90 min after the meal. Premeal insulin reduced postprandial hyperglycemia by 2-3 mmol/L compared with placebo. Postmeal insulin levels were doubled with placebo and further elevated with insulin injections. The standardized meal enhanced U46619-induced platelet P-selectin expression by 23% after placebo; this response was more than doubled after premeal insulin. U46619-induced fibrinogen binding was unchanged after meal intake with placebo but was markedly enhanced (by ~50-60%) after premeal insulin. Postprandial platelet activation correlated positively to postprandial insulin levels and inversely to glucose levels. Premeal insulin infusion was also associated with platelet activation. Our results suggest that postprandial insulin rather than glucose accounts for postprandial platelet activation in T2DM patients.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Insulin; Insulin Aspart; Male; Middle Aged; P-Selectin; Platelet Activation; Postprandial Period

The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism.. Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight.. We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients.. Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study.. Roflumilast 500 μg or placebo was administered once daily.. We evaluated mean change in blood glycated hemoglobin levels.. We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters.. Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = -0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [-0.7 (0.4) kg] was not statistically significant (P = 0.0584).. Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis.

Topics: Adult; Aged; Aminopyridines; Area Under Curve; Benzamides; Blood Glucose; Body Weight; C-Peptide; Cyclopropanes; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glycated Hemoglobin; Glycerol; Homeostasis; Humans; Insulin; Male; Middle Aged; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Sample Size

No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters.. Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI), C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1) levels, and urinary CPR levels, were measured.. The mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin.. CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and sitagliptin.. UMIN000007687.

Topics: Adamantane; Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Deoxyglucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Japan; Male; Middle Aged; Monitoring, Ambulatory; Natriuretic Peptide, Brain; Nitriles; Pilot Projects; Plasminogen Activator Inhibitor 1; Postprandial Period; Predictive Value of Tests; Pyrazines; Pyrrolidines; Serum Albumin; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles; Vildagliptin

Insulin-mediated glucose disposal rates (R(d)) are reduced in type 2 diabetic patients, a process in which intrinsic signalling defects are thought to be involved. Phosphorylation of TBC1 domain family, member 4 (TBC1D4) is at present the most distal insulin receptor signalling event linked to glucose transport. In this study, we examined insulin action on site-specific phosphorylation of TBC1D4 and the effect of exercise training on insulin action and signalling to TBC1D4 in skeletal muscle from type 2 diabetic patients.. During a 3 h euglycaemic-hyperinsulinaemic (80 mU min⁻¹ m⁻²) clamp, we obtained M. vastus lateralis biopsies from 13 obese type 2 diabetic and 13 obese, non-diabetic control individuals before and after 10 weeks of endurance exercise-training.. Before training, reductions in insulin-stimulated R (d), together with impaired insulin-stimulated glycogen synthase fractional velocity, Akt Thr³⁰⁸ phosphorylation and phosphorylation of TBC1D4 at Ser³¹⁸, Ser⁵⁸⁸ and Ser⁷⁵¹ were observed in skeletal muscle from diabetic patients. Interestingly, exercise-training normalised insulin-induced TBC1D4 phosphorylation in diabetic patients. This happened independently of increased TBC1D4 protein content, but exercise-training did not normalise Akt phosphorylation in diabetic patients. In both groups, training-induced improvements in insulin-stimulated R(d) (~20%) were associated with increased muscle protein content of Akt, TBC1D4, α2-AMP-activated kinase (AMPK), glycogen synthase, hexokinase II and GLUT4 (20-75%).. Impaired insulin-induced site-specific TBC1D4 phosphorylation may contribute to skeletal muscle insulin resistance in type 2 diabetes. The mechanisms by which exercise-training improves insulin sensitivity in type 2 diabetes may involve augmented signalling of TBC1D4 and increased skeletal muscle content of key insulin signalling and effector proteins, e.g., Akt, TBC1D4, AMPK, glycogen synthase, GLUT4 and hexokinase II.

Topics: Blood Glucose; Blotting, Western; C-Peptide; Diabetes Mellitus, Type 2; Electrophoresis, Polyacrylamide Gel; Exercise; Glucose Clamp Technique; Glycated Hemoglobin; Glycogen Synthase; GTPase-Activating Proteins; Humans; Insulin; Male; Middle Aged; Muscle, Skeletal; Phosphorylation

To investigate the efficacy of continuing glimepiride in combination with basal-prandial insulin therapy in type 2 diabetes.. An open crossover study was performed with arms of discontinuation and continuation of glimepiride in 25 subjects with mean diabetes duration of 17 years and 5 years of insulin treatment combined with glimepiride plus metformin. At entry and at the end of each 3-month arm, meal tolerance tests were performed for measurements of blood glucose and C-peptide.. In terms of between-treatment differences (discontinuation vs. continuation arm of glimepiride) during meal tolerance tests performed at the ends of arms, significant increases in plasma glucose were seen on the discontinuation arm at 0-, 30-, and 60-min, while significant decreases in serum C-peptide were observed at 60- and 120-min. A1C values of the discontinuation arm significantly increased (from 6.6 ± 0.6 at baseline to 7.7 ± 0.8 at 3-months, p<0.0001). Increases in A1C were closely correlated with decreases in area under the curve of meal-stimulated serum C-peptide (r=-0.61, p<0.0001).. Since endogenous insulin secretion is more physiological than subcutaneous insulin injection, continuing glimepiride may remain beneficial, partly through enhancing insulin secretion, in individuals with a long duration of diabetes and basal-prandial insulin therapy.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin, Long-Acting; Male; Middle Aged; Sulfonylurea Compounds

Glucose is the major stimulus for insulin release. Time course and amount of insulin secreted after glycemic stimulus are different between type 2 diabetes mellitus (T2DM) patients and healthy subjects. In rodents, it was demonstrated that insulin can modulate its own release. Previous studies in humans yielded contrasting results: Insulin was shown to have an enhancing effect, no effect, or a suppressive effect on its own secretion. Thus, we aimed to evaluate short-term effects of human insulin infusion on insulin secretion during normoglycemia in healthy humans and T2DM subjects of both sex.. Hyperinsulinemic-isoglycemic clamps with whole-body insulin-sensitivity (M) and C-peptide measurements for insulin secretion modeling were performed in 65 insulin-sensitive (IS) subjects (45 ± 1 year, BMI: 24.8 ± 0.5 kg/m(2)), 17 insulin-resistant (IR) subjects (46 ± 2 years, 28.1 ± 1.3 kg/m(2)), and 20 T2DM patients (56 ± 2 years, 28.0 ± 0.8 kg/m(2); HbA(1c) = 6.7 ± 0.1%).. IS subjects (M = 8.8 ± 0.3 mg · min(-1) · kg(-1)) had higher (P < 0.00001) whole-body insulin sensitivity than IR subjects (M = 4.0 ± 0.2) and T2DM patients (M = 4.3 ± 0.5). Insulin secretion profiles during clamp were different (P < 0.00001) among the groups, increasing in IS subjects (slope: 0.56 ± 0.11 pmol/min(2)) but declining in IR (-0.41 ± 0.14) and T2DM (-0.87 ± 0.12, P < 0.00002 IR and T2DM vs. IS) subjects. Insulin secretion changes during clamp directly correlated with M (r = 0.6, P < 0.00001).. Insulin release during normoglycemia can be modulated by exogenous insulin infusion and directly depends on whole-body insulin sensitivity. Thus, in highly sensitive subjects, insulin increases its own secretion. On the other hand, a suppressive effect of insulin on its own secretion occurs in IR and T2DM subjects.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Predictive Value of Tests

Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes.. Adults with diabetes for ≥ 5 years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes.. UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (<0.02 nmol/mmol [<0.02 to <0.02] vs. 1.72 nmol/mmol [0.98-2.90]; P < 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of ≥ 0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98-2.90] vs. 2.47 nmol/mmol [1.4-4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64).. UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years' duration, UCPCR could be used to determine whether genetic testing is indicated.

Topics: Adult; Aged; Biomarkers; C-Peptide; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4; Humans; Insulin; Male; Middle Aged; Outpatients; ROC Curve

To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles.. In a double-blind, parallel, placebo-controlled trial, 47 patients were randomized to placebo or rGLP-1 (1.25, 2.5, 5.0 or 8.5 pmol/kg/min) by CSCI for 7 days. On day 1 (pretreatment) and on day 8, patients underwent monitoring of fasting, postprandial, and 11-h profiles of glucose and hormones.. Fasting serum glucose decreased by 76.2, 53.9, 37.0 and 22.7 mg/dl for the 8.5, 5.0, 2.5 and 1.25 pmol/kg/min rGLP-1 groups, respectively, compared to a decrease of 1.1 mg/dl for placebo (p = 0.0002, 0.005, 0.064 and 0.27, respectively). Mean 11-h serum glucose area under the curve decreased by 36.3, 23.3, 16.9 and 10.0% for 8.5, 5.0, 2.5 and 1.25 pmol/kg/min rGLP-1, respectively, compared to no change for placebo (p = 0.0001, 0.0019, 0.012 and 0.14, respectively). Mean fasting C-peptide increased dose dependently with rGLP-1 (p = 0.0023 for the highest dose) and decreased with placebo. There were no serious safety concerns and no instances of hypoglycaemia.. rGLP-1 produced continuous improvements in glycaemic control across a broad dose range of up to 8.5 pmol/kg/min.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infusions, Subcutaneous; Male; Middle Aged; Peptide Fragments; Placebos; Postprandial Period

Diabetic patients have a markedly increased risk of cardiovascular disease compared with non-diabetics. Two drug groups today target insulin resistance; biguanides and thiazolidinediones. In addition, these may have other effects on cardiovascular risk factors. The aim of this study was to evaluate the effects of metformin and rosiglitazone on non-traditional cardiovascular risk factors. Forty type 2 diabetic patients were randomized into metformin and rosiglitazone groups. After receiving the optimal doses, the patients were monitored for 12 weeks. Biochemical parameters, lipid parameters, CRP, insulin, c-peptide, and HbA1c levels were analyzed. VWF, PAI-1, ICAM-1, TNF-α, IL-6, E-selectin, and fibrinogen levels were measured in order to assess coagulation status and endothelial dysfunction. In the metformin group, body mass index, PPG, HbA1c, IL-6, ICAM-1, and TNF-α levels were significantly decreased after 12 weeks compared with the basal levels. IL-6 levels decreased from 75 pg/ml ± 20 to 42 pg/ml ± 9 (P 0.023) and TNF- α levels from 61 pg/ml ± 31 to 39 pg/ml ± 10 (P 0.018). In the rosiglitazone group, FPG, PPG, HbA1c, insulin, HOMA-IR, IL-6, and TNF-α levels decreased significantly after 12 weeks compared with the basal levels. IL-6 levels decreased from 78 pg/ml ± 21 to 41 pg/ml ± 9 (P 0.028) and TNF-α levels from 62 pg/ml ± 19 to 37 pg/ml ± 10 (P 0.012). At the end of the study, no significant differences were determined between groups. Insulin resistance and type 2 diabetes are strongly associated with low grade inflammation. Both metformin and rosiglitazone were effective in controlling inflammatory markers in addition to metabolic parameters.

Topics: Adult; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelial Cells; Female; Humans; Interleukin-6; Male; Metformin; Middle Aged; Rosiglitazone; Thiazolidinediones; Tumor Necrosis Factor-alpha

To compare the efficacy of a fixed-dose triple oral diabetes polypill containing 1 or 2 mg glimepiride, 500 mg sustained-release metformin, and 15 mg pioglitazone (GMP) administered once daily with human insulin 70/30 mix and 500 mg sustained-release metformin administered twice daily (IM) in insulin-naÏve subjects with type 2 diabetes mellitus inadequately controlled [haemoglobin A1c (HbA1c) over 8.0%] on a combination of glimepiride and metformin.. One hundred and one subjects were randomized to GMP or IM regimens for 12 weeks. The primary outcome was the change in HbA1c and secondary outcomes were changes in fasting plasma, and postprandial plasma glucoses and the number of patients achieving a drop in HbA1c of over 1%. Other secondary outcomes were changes in the lipid profile, C-peptide level, body weight as well as physician assessments of efficacy and patient assessment of tolerability.. The primary outcome of a change in HbA1c showed a trend towards a lower HbA1c with GMP therapy (-1.33% vs. -0.83%; p = 0.059). The number of subjects achieving a decrease in HbA1c of greater than 1.0% was significantly greater in the GMP therapy (72.5% vs. 22%; p = 0.0001). Both regimens equally and significantly reduced fasting and postprandial glucose levels (p = 0.05). Weight gain was nonsignificantly greater with IM (2.69 vs. 0.92 kg; p = 0.223). Investigator assessment of efficacy was significantly better with GMP (p = 0.001) as was tolerability as assessed by patients (p = 0.0001).. When compared with suboptimally titrated IM there was a trend towards a lower HbA1c with GMP and significantly more GMP subjects obtained an HbA1c under 7%. Global assessments by investigators and subjects showed both a greater efficacy and tolerability with GMP.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Patient Satisfaction; Pioglitazone; Postprandial Period; Prospective Studies; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Ingestion of high doses of casein hydrolysate stimulates insulin secretion in healthy subjects and patients with type 2 diabetes. The effects of low doses have not been studied. The aim of this study was to assess the effect of lower doses of a casein hydrolysate on the glucose and insulin responses to an oral glucose tolerance test in patients with type 2 diabetes.. In this randomized, placebo-controlled, double-blind study, thirteen patients with type 2 diabetes (age: 58±1 years) were studied. Glucose, insulin and C-peptide responses were determined after the oral administration of 0 (control), 6 or 12 g protein hydrolysate in combination with 50 g carbohydrate.. Twelve grams of casein hydrolysate, but not 6g, elevated insulin levels and decreased glucose levels post-challenge. These changes over time were not large enough to also affect the total area under the curve of glucose and insulin. C-peptide levels did not change after both treatments.. Ingestion of six grams of casein hydrolysate did not affect glucose or insulin responses. Intake of 12 g of casein hydrolysate has a small positive effect on post-challenge insulin and glucose levels in patients with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Caseins; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Treatment Outcome

Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 ± 0.6%). Participants ingested a low-fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln-30), 15 g L-glutamine (Gln-15), 100 mg SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0-60 min) postprandial glycemic response compared with control. All Gln treatments enhanced the postprandial insulin response from t = 60-180 min but had no effect on the C-peptide response compared with control. The postprandial glucagon concentration was increased by Gln-30 and Gln-15 compared with control, but the insulin:glucagon ratio was not affected by any treatment. In contrast to Gln-30, which tended to increase the total GLP-1 AUC, SIT tended to decrease the total GLP-1 AUC relative to control (both P = 0.03). Gln-30 and SIT increased the active GLP-1 AUC compared with control (P = 0.008 and P = 0.01, respectively). In summary, Gln-30 decreased the early postprandial glucose response, enhanced late postprandial insulinemia, and augmented postprandial active GLP-1 responses compared with control. These findings suggest that glutamine may be a novel agent for stimulating GLP-1 concentration and limiting postprandial glycemia in type 2 diabetes.

Topics: Administration, Oral; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glutamine; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Triazoles

Addition of fibre or protein to carbohydrate-rich foods can reduce the glycaemic response to those foods. This may assist with glycaemic management in individuals with type 2 diabetes. Lupin is a legume rich in fibre and protein. We assessed the acute effects of lupin- and soya-based beverages on glucose and insulin responses in type 2 diabetic individuals. We hypothesised that the lupin and soya beverages would lower the acute glycaemic response compared with a control beverage containing no protein or fibre, and that lupin would reduce the postprandial glucose more than soya. In a randomised, controlled, cross-over trial, twenty-four diabetic adults (nineteen men and five women) attended three testing sessions, each 1 week apart. At each session, participants consumed a beverage containing 50 g glucose (control), 50 g glucose plus lupin kernel flour with 12·5 g fibre and 22 g protein (lupin), or 50 g glucose plus 12·5 g fibre and 22 g protein from soya isolates (soya). Serum glucose, insulin and C-peptide were measured periodically for 4 h following beverage consumption. Compared with the control beverage, the 4 h post-beverage glucose response was lower (P < 0·001), and the 4 h post-beverage insulin and C-peptide responses were higher (P < 0·001) for lupin and soya. Glucose (P = 0·25) and C-peptide (P = 0·07) responses did not differ significantly between lupin and soya, but lupin resulted in a lower insulin response compared with soya (P = 0·013). Adding lupin or soya to a carbohydrate-rich beverage reduces glycaemia acutely in type 2 diabetic individuals. This may have a beneficial role in glycaemic management.

Topics: Adult; Aged; Beverages; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Flour; Humans; Insulin; Lupinus; Male; Middle Aged; Soybean Proteins

Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions.. We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention.. We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year.. In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.

Topics: Adult; C-Peptide; Cation Transport Proteins; Chromans; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Male; Metformin; Middle Aged; Polymorphism, Genetic; Proinsulin; Thiazolidinediones; Troglitazone; Zinc Transporter 8

This study compares the effects of glibenclamide and creatine in type II diabetics. In a 14-day symmetrically randomized crossover trial recently detected type II diabetics received either creatine (3 g) or glibenclamide (3.5 mg) for five successive days, followed by two days of washout, and crossover to the opposite treatment. Glucose, insulin, c-peptide, and creatine were measured. Creatine and glibenclamide decreased glucose concentrations vs. basal glucose [-15, 60, 90, 120, 180, and 240 min; mol/l]: 12.6±0.83 vs. 12.2±0.56 vs. 12.1±0.57, 15.3±0.63 vs. 13.5± 0.70(a ) vs. 13.0±0.57(a), 14.8±0.57 vs. 13.8±0.59(a) vs. 13.4±0.46(a), 14.6±0.61 vs. 12.3±0.49(b) vs. 12.4±0.61(a), 12.8±0.76 vs. 10.0± 0.40(c) vs. 10.3±0.41(c), and 11.4±0.67 vs. 8.3±0.40(c) vs. 8.5±0.36(c); ((a) p<0.05; (b) p<0.01; (c) p<0.001 vs. basal glucose). Treatment with both creatine and glibenclamide increased insulin and c-peptide concentrations after 120 and 240 min (p<0.05 and p<0.01). At the doses applied short-term treatment with creatine and glibenclamide elicits similar glucose lowering effects.

Topics: Adult; Blood Glucose; C-Peptide; Creatine; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Postprandial Period

We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure.. Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI).. At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (-7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and -0.99 ± 0.65, respectively; P = 0.028).. EXE and GLAR sustained HbA(1c) over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin-Secreting Cells; Insulin, Long-Acting; Male; Metformin; Middle Aged; Peptides; Venoms

Food composition and style is changing dramatically now, which causes inappropriate secretion of hormones from brain, gastrointestinal and endo-pancreas, may be related to unbalance of glucose in blood. The aim of this study was to explore the fast response of C-peptide, glucagon-like peptide-1 (GLP-1), ghrelin and endomorphin-1 (EM-1) to the eastern and western style meals in patients with type 2 diabetes mellitus.. The study enrolled 57 patients with type 2 diabetes (20 men and 37 women, mean age (67.05 ± 8.26) years). Eastern style meal (meal A) and western style meal (meal B) were designed to produce the fullness effect. C-peptide, GLP-1, ghrelin and EM-1 were assessed before (0 hour) and after (2 hours) each diet.. The delta (2h - 0h) of C- peptide in meal A was significantly lower than that in meal B (P = 0.0004). C-peptide, GLP-1, ghrelin and EM-1 were obviously higher before meal B than those before meal A (P < 0.0001, < 0.0001, = 0.001, = 0.0004 respectively). Blood glucose 2 hours and 3 hours after meal B were higher than those after meal A (P = 0.0005, 0.0079 respectively). Correlations between GLP-1 and ghrelin were strongly positive before both meals and 2 hours after both meals and also in relation to the delta of meal A and meal B (r(A0h) = 0.7836, r(B0h) = 0.9368, r(A2h) = 0.7615, r(B2h) = 0.9409, r(A(2h-0h)) = 0.7531, r((2h-0h))B = 0.9980, respectively, P < 0.0001).. Western style meal (high fat and protein food) could make more response of C-peptide than eastern style meal, and could stimulate more gut hormones (GLP-1, ghrelin) and brain peptide (EM-1) at the first phase of digestion.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 2; Diet; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Oligopeptides; Postprandial Period

Sleeve gastrectomy is a new bariatric surgery, and many reports have showed that patients who have undergone sleeve gastrectomy have experienced rapid resolution of type 2 diabetes. The mechanisms accounting for the beneficial effects of sleeve gastrectomy on glucose homeostasis are not well understood and remain speculative. This trial assessed prospectively the effect of sleeve gastrectomy on type 2 diabetes and the serial changes of insulin secretion to oral glucose loads.. Prospective study on the response of insulin secretion to oral glucose loads in 20 severe diabetic patients (body mass index [BMI] >25 and <35, HbA1C >7.5%) before and at 1, 4, 12, 26, and 52 weeks after sleeve gastrectomy. The insulin secretion was measured by insulinogenic index and area under the curve (AUC) during a standard oral glucose tolerance test (OGTT). Remission of type 2 diabetes was defined as fasting glucose level <126 mg/dL and HbA1C <6.5% without any glycemic therapy.. Of the 20 patients enrolled, the mean age was 46.3 + or - 8.0 years, mean BMI was 31.0 + or - 2.9 kg/m(2), and mean HbA1C was 10.1 + or - 2.2. The mean BMI and excess body weight loss at 1, 4, 12, 26, and 52 weeks after operation were 28.9 (22.1%), 27.4 (43.0%), 25.7 (55.1%), 24.9 (71.9%), and 24.6 (69.1%), respectively. The mean HbA1C at 1, 4, 12, 26, and 52 weeks after operation were 9.2, 8.4, 7.7, 7.3, and 7.1, respectively. Resolution of type 2 diabetes was achieved in 2 (20%) patients at 4 weeks, 6 (30%) at 12 weeks, 8 (40%) at 26 weeks, and 10 (50%) at 52 weeks after sleeve gastrectomy. Before operation, the mean fasting plasma glucose and insulin levels were 240.1 + 80.9 mg/dL and 16.8 + or - 15.4 uIU/mL, respectively. The OGTT test showed a blunted insulin secretion pattern with an AUC of 3,135 uIU x min/mL. At 1 week after operation, the fasting plasma glucose and insulin levels significantly decreased to 158 + or - 52 mg/dL and 5.6 + or - 3.2 uIU/mL, respectively. The AUC decreased to 2,988.7 uIU x min/mL. The AUC at 4, 12, 26, and 52 weeks after operation was 2,211, 1,584, 3,621, and 3,351 uIU x min/mL, respectively. The diabetes resolution rates for those with pre-operative C-peptide <3, 3-6, and >6 ng/mL were 1/7 (14.3%), 7/11 (63.6%), and 2/2 (100%), respectively (P < .05).. Laparosopic gastric sleeve gastrectomy resulted in remission of poorly controlled nonmorbidly obese T2DM patients up to 50% at 1 year after operation. The effect is related more to the decreasing of insulin resistance because of calorie restriction and weight loss rather than to the increasing of insulin secretion. C-peptide >3 ng/mL is the most important predictor for a successful treatment.

Topics: Adult; Bariatric Surgery; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastrectomy; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Secretion; Laparoscopy; Male; Middle Aged; Obesity; Prospective Studies; Remission Induction; Weight Loss

This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (P<0.001). The AUC amylin/C-peptide ratio was similar on both days, while AUC proinsulin/C-peptide ratio was higher with GLP-1 (P=0.02). In the patients, amylin, C-peptide and proinsulin AUCs were unaltered by near-normoglycaemia per se. Proinsulin responses to GLP-1 were unchanged, but amylin and C-peptide AUCs increased (P<0.05) after insulin treatment, and AUC amylin/C-peptide ratios rose to control levels. Near-normoglycaemia tended to reduce AUC proinsulin/C-peptide ratio, which was significant (P=0.04) with GLP-1, but still higher than with saline (P=0.004). In conclusion, amylin, C-peptide and proinsulin responses to glucose were unaffected by four weeks of near-normoglycaemia, whereas GLP-1 increased amylin and C-peptide secretion and amylin/C-peptide ratio. Near-normoglycaemia reduced proinsulin/C-peptide ratio during stimulation with GLP-1, suggesting that strict glycaemic control might ameliorate some of the disturbances in beta-cell function characterizing T2DM.

Topics: Amyloid; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Male; Middle Aged; Proinsulin; Time Factors

A progressive weight gain is associated with various pharmacological options improving glycemic control in type 2 diabetes mellitus (T2DM). Ghrelin has been implicated in the regulation of feeding behavior and energy balance in humans. Based on evidence that functional ATP-sensitive channels are present in ghrelin-producing cells, we hypothesized that meglitinides may affect circulating ghrelin levels in subjects with type 2 diabetes.. In a single-blinded randomized three-period crossover study (n = 20), repaglinide or nateglinide was given in combination with metformin for two treatment periods over a 1-week period, respectively, separated by a 1-week treatment with placebo. Liquid meal challenge tests (LMCTs) with single preprandial doses of repaglinide (2 mg), nateglinide (120 mg), or placebo were performed at the end of each treatment period. Ten control subjects without diabetes underwent a single LMCT without any medication.. Fasting ghrelin concentrations were not different between all treatments and between patients with diabetes and control subjects. Subjects with T2DM treated with placebo showed no suppression of ghrelin in the LMCT. After administration of meglitinides a nadir of serum ghrelin was observed at 60 min (8.6% of baseline [P = 0.038] for repaglinide and 7.5% of baseline [P = 0.081] for nateglinide), which was similar to the secretion pattern seen in control subjects. No correlations between postprandial insulin or glucose levels and circulating ghrelin concentrations were observed.. Treatment with meglitinides reconstructed postprandial ghrelin secretion patterns to those of controls without diabetes. This observation may help to improve the control of feeding behavior in patients with T2DM.

Topics: Adult; Aged; Benzamides; Blood Glucose; Body Mass Index; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Feeding Behavior; Ghrelin; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Piperidines; Reference Values; Single-Blind Method

To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.. Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 +/- 3 years, with BMI 36 +/- 2 kg/m(2) and A1C 8.3 +/- 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and beta-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 mumol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.. A single subcutaneous injection of glargine at a dose of >or=0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

Glucose-dependent insulinotropic peptide (GIP) contributes to incretin effect of insulin secretion which is impaired in Type 2 diabetes mellitus. The aim of this study was to introduce a simple meal test for evaluation of GIP secretion and action and to examine GIP changes in Type 2 diabetic patients. Seventeen Type 2 diabetic patients, 10 obese non-diabetic and 17 non-obese control persons have been examined before and after 30, 60 and 90 min stimulation by meal test. Serum concentrations of insulin, C-peptide and GIP were estimated during the test. Impaired GIP secretion was found in Type 2 diabetic patients as compared with obese non-diabetic and non-obese control persons. The AUCGIP during 90 min of the meal stimulation was significantly lower in diabetic patients than in other two groups (p<0.03). Insulin concentration at 30 min was lower in diabetic than in non-diabetic persons and the GIP action was delayed. The deltaIRI/deltaGIP ratio increased during the test in diabetic patients, whereas it progressively decreased in obese and non-obese control persons. Simple meal test could demonstrate impaired GIP secretion and delayed insulin secretion in Type 2 diabetic patients as compared to obese non-diabetic and non-obese healthy control individuals.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Dietary Fats; Dietary Proteins; Dietary Sucrose; Gastric Inhibitory Polypeptide; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Middle Aged; Obesity

The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding.. We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp).. Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ individuals having gained significantly more weight than FH- individuals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001).. Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding.. ClinicalTrials.gov NCT00562393. The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).

Topics: Adult; Analysis of Variance; Australia; Body Composition; C-Peptide; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Genetic Predisposition to Disease; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overnutrition; Risk Factors; Sedentary Behavior; Weight Gain

To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.. Children (10-17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations.. Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects.. Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.

Topics: Adolescent; Autoantibodies; C-Peptide; Child; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Islets of Langerhans; Male

The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin.. The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C-peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN-105 administration were also compared against those of placebo.. Changes in glucose from baseline (mean +/- s.d.) at 140 min (2 h postprandial) were 94.84 +/- 22.3, 79.45 +/- 43.00, 70.68 +/- 35.71, 63.47 +/- 42.75 and 53.06 +/- 47.27 mg/dL, respectively, and exhibited linear dose-response. The insulin C(max) values were found to be 50.8 +/- 26.0 mU/L for placebo, 100.3 +/- 66.7 with 10 mg IN-105, 177.69 +/- 150.3 with 15 mg IN-105, 246.2 +/- 245.2 with 20 mg IN-105 and 352.5 +/- 279.3 mU/L with 30 mg of IN-105.. IN-105 absorption is proportional to the dose administered. The 2-h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C-peptide levels were found to be suppressed in proportion to the IN-105 exposure. IN-105 reduces glucose excursion despite lower endogenous insulin secretion. IN-105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied.

Topics: Administration, Oral; Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Postprandial Period; Tablets; Treatment Outcome

MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.

Topics: Administration, Inhalation; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Delivery Systems; Energy Intake; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptide Fragments

Dicarboxylic acids are natural products with the potential of being an alternate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (Ra) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro.. Subjects ingested a mixed meal (50% carbohydrates, 15% proteins, and 35% lipids) containing 0 g (control) or 10 g C10 in addition to the meal or 23 g C10 as a substitute of fats.. In type 2 diabetic subjects, the incremental glucose area under the curve (AUC) decreased by 42% (P<0.05) and 70% (P<0.05) in the 10 g C10 and 23 g C10 groups, respectively. At the largest amounts used, C10 reduced the glucose AUC in healthy volunteers also. When fats were substituted with 23 g C10, AUC of Ra was significantly reduced on the order of 18% (P<0.05) in both healthy and diabetic subjects. The insulin-dependent glucose uptake by L6 cells was increased in the presence of C10 (38.7±10.3 vs. 11.4±5.4%; P=0.026). This increase was associated with a 1.7-fold raise of GLUT4.. Sebacic acid significantly reduced hyperglycemia after a meal in type 2 diabetic subjects. This beneficial effect was associated with a reduction in glucose Ra, probably due to lowered hepatic glucose output and increased peripheral glucose disposal.

Topics: Absorptiometry, Photon; Animals; Biological Transport; Blood Glucose; Blotting, Western; Body Composition; C-Peptide; Cell Line; Decanoic Acids; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Female; Gas Chromatography-Mass Spectrometry; Humans; Immunoprecipitation; Insulin; Male; Middle Aged; Postprandial Period; Rats

Glucokinase plays a key role in glucose homeostasis. Glucokinase activators can lower glucose levels in both animal and human type 2 diabetes, but their mechanism of action has never been explored in humans.. The objective of the study was to investigate the effects of the glucokinase activator piragliatin (RO4389620) on β-cell function and glucose fluxes in both fasting and fed (oral glucose tolerance test) states in patients with type 2 diabetes.. This was a phase Ib randomized, double-blind, placebo-controlled crossover trial of two (25 and 100 mg) doses of piragliatin.. This study was conducted at a clinical research center.. Patients included 15 volunteer ambulatory patients with mild type 2 diabetes.. Interventions included three 10-h (-300' to +300') studies, with an interval of at least 14 d. Administration of a single dose of placebo or piragliatin 25 mg or piragliatin 100 mg at -120'. Oral glucose tolerance test (at 0') with dual (iv and oral routes) tracer dilution technique was conducted.. The primary measure was plasma glucose concentration. The secondary measure was model assessed β-cell function and tracer-determined glucose fluxes.. Piragliatin caused a dose-dependent reduction of glucose levels in both fasting and fed states (P < 0.01). In the fasting state, piragliatin caused a dose-dependent increase in β-cell function, a fall in endogenous glucose output, and a rise in glucose use (all P < 0.01). In the fed state, the primary effects of piragliatin were on β-cell function (P < 0.01).. The glucokinase activator piragliatin has an acute glucose-lowering action in patients with mild type 2 diabetes, mainly mediated through a generalized enhancement of β-cell function and through fasting restricted changes in glucose turnover.

Topics: Analysis of Variance; Benzeneacetamides; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Glucokinase; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells

The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.

Topics: Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Pulmonary Disease, Chronic Obstructive

To evaluate the effect of a prebreakfast high-protein snack upon postbreakfast hyperglycemia.. We studied 10 men and women with diet- and/or metformin-controlled type 2 diabetes. Metabolic changes after breakfast were compared between 2 days: breakfast taken only and soya-yogurt snack taken prior to breakfast.. There was a significant lower rise in plasma glucose on the snack day. The incremental area under the glucose curve was 450 ± 55 mmol · min/l on the snack day compared with 699 ± 99 mmol · min/l on the control day (P = 0.013). The concentration of plasma free fatty acids immediately before breakfast correlated with the increment in plasma glucose (r = 0.50, P = 0.013).. Consuming a high-protein prebreakfast snack results in almost 40% reduction of postprandial glucose increment. The second-meal effect can be applied simply and practically to improve postbreakfast hyperglycemia in people with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dietary Proteins; Fatty Acids, Nonesterified; Female; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Postprandial Period; Yogurt

Insulin resistance is a significant risk factor in the pathogenesis of type 2 diabetes. This article presents pilot study results of the dynamic insulin sensitivity and secretion test (DISST), a high-resolution, low-intensity test to diagnose insulin sensitivity (IS) and characterize pancreatic insulin secretion in response to a (small) glucose challenge. This pilot study examines the effect of glucose and insulin dose on the DISST, and tests its repeatability.. DISST tests were performed on 16 subjects randomly allocated to low (5 g glucose, 0.5 U insulin), medium (10 g glucose, 1 U insulin) and high dose (20 g glucose, 2 U insulin) protocols. Two or three tests were performed on each subject a few days apart.. Average variability in IS between low and medium dose was 10.3% (p=.50) and between medium and high dose 6.0% (p=.87). Geometric mean variability between tests was 6.0% (multiplicative standard deviation (MSD) 4.9%). Geometric mean variability in first phase endogenous insulin response was 6.8% (MSD 2.2%). Results were most consistent in subjects with low IS.. These findings suggest that DISST may be an easily performed dynamic test to quantify IS with high resolution, especially among those with reduced IS.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Feasibility Studies; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; New Zealand; Pancreas; Pilot Projects; Predictive Value of Tests; Reproducibility of Results; Research Design; Time Factors; Young Adult

Early insulin treatment is considered more beneficial than anti-diabetic medication with sulphonylureas, because the latter may exert negative effects on beta-cell function, while the former may help preserve it. In a previous study, we found that C-peptide response was increased in the insulin-treated group, whereas it was decreased in the glibenclamide group. However, it was not certain whether the advantage remained in the longer term.. In this study, we tested whether early insulin treatment is more beneficial than glibenclamide against a 6-year follow-up perspective.. We designed a randomized clinical trial in subjects with newly diagnosed type 2 diabetes. Glucagon stimulatory tests, measuring C-peptide and islet amyloid polypeptide (IAPP), were performed after 2, and 3, days of temporary insulin and glibenclamide withdrawal.. 18 subjects initially randomized to glibenclamide, and 16 randomized to two daily injections of insulin, participated in end-of-study investigations. C-peptide response to glucagon deteriorated (p < 0.01 vs. baseline) in initially glibenclamide-treated patients (n = 18), but not in insulin-treated patients (p < 0.05 for difference between groups, after 2 days of treatment withdrawal). The IAPP response to glucagon declined in the glibenclamide group (p < 0.001), but not in insulin-treated subjects (p = 0.05 for difference between groups).. Early insulin treatment preserves beta-cell secretory function better than glibenclamide even in a 6-year perspective.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucagon; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged

Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

Topics: Aged; Apolipoproteins; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Lipids; Lipoproteins; Male; Middle Aged; Piperidines; Proinsulin

The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations.. We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S(I)), glucose effectiveness, and beta-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously.. Vildagliptin reduced postprandial glucose concentrations (905 +/- 94 vs. 1,008 +/- 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net S(I) (7.71 +/- 1.28 vs. 6.41 +/- 0.84 10(-4) dl x kg(-1) x min(-1) x muU(-1) x ml(-1), P = 0.13) or glucose effectiveness (0.019 +/- 0.002 vs. 0.018 +/- 0.002 dl x kg(-1) x min(-1), P = 0.65). However, the net beta-cell responsivity index was increased (35.7 +/- 5.2 vs. 28.9 +/- 5.2 10(-9) min(-1), P = 0.03) as was total disposition index (381 +/- 48 vs. 261 +/- 35 10(-14) dl x kg(-1) x min(-2) x pmol(-1) x l(-1), P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 +/- 1.1 vs. 29.7 +/- 1.5 microg x l(-1) x 6 h(-1), P = 0.03), especially after administration of exogenous insulin (81.5 +/- 6.4 vs. 99.3 +/- 5.6 ng/l, P = 0.02).. Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters alpha-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

Topics: Adamantane; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Digestion; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glucagon; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nitriles; Placebos; Postprandial Period; Pyrrolidines; Satiety Response; Vildagliptin

Traditional blood glucose-lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in beta-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp-derived measures of beta-cell function, glycemic control, and body weight.. Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). beta-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety.. Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09-2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: -0.8 +/- 0.1 and -0.7 +/- 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference -4.6 kg, P < 0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy.. Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Topics: Arginine; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Secretion; Insulin-Secreting Cells; Insulin, Long-Acting; Kinetics; Male; Metformin; Middle Aged; Peptides; Venoms

To compare the compliance and efficacy among three treatment modalities in patients of type 2 diabetes with fairly good islet function.. This 38-month open, randomized, prospective study enrolled 536 subjects (HbA1c 9.4+/-0.8%). Patients were divided into three groups including continual insulin injection (I), continual secretagogue administration (S) and alternation of two-month insulin injection and four-month secretagogue treatment (A). At baseline and every three months, HbA1c was measured and a standard bread meal test (100g) was performed.. HbA1c were better controlled in both groups I and A than in S (6.9+/-0.3%, 6.8+/-0.3% vs. 7.6+/-0.5%). Hypoglycemia incidence was much lower in group A than that in I (0.8 times/patient/month vs. 2.4 times/patient/month) also with less weight gain (1.6 kg vs. 2.8 kg/patient/year). From the standard bread meal test, patients in group A got the greatest increment of 2-h C-peptide. Inquiry from all subjects showed that alternate strategy was welcomed by most of them considering for convenience and efficacy.. Alternate insulin-secretagogue treatment can effectively reduce HbA1c and help to improve islet function with reduced risk of hypoglycemia and weight gain under good compliance.

Topics: Administration, Oral; Age of Onset; Alanine Transaminase; Blood Urea Nitrogen; Body Mass Index; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections; Insulin; Male; Middle Aged; Patient Selection; Prospective Studies

Glycemic control of type 2 diabetes mellitus (T2DM) remains a dilemma to physicians. Although gastric bypass surgery undertaken for morbid obesity has been shown to resolve this disease well, data on the effectiveness of duodenojejunal bypass in improving or resolving T2DM and the metabolic syndrome (MS), especially in nonobese patients are scarce. This study was intended to evaluate the clinical effects of laparoscopic duodenojejunal bypass (LDJB) in patients with T2DM and a body mass index of <35 kg/m(2).. We conducted a 12-month prospective study on the changes in glucose homeostasis and the MS in seven T2DM subjects undergoing LDJB with similar DM duration, type of DM treatment, and glycemic control. Laboratory values including glycosylated hemoglobin A (HbA1c), fasting blood glucose, cholesterol, triglyceride, and C-peptide were followed throughout the 12 months. Serum levels of gastric inhibitory peptide and ghrelin were followed for 1 month. Serum levels of gastrin and glucagon-like peptide were followed for 3 months.. At 12 months after surgery, all subjects consistently felt relief from fatigue, pain and/or numbness in the extremities, polyuria, and polydypsia. Clinical resolution was obtained for one patient, and the preoperative diabetic medication requirements decreased for most of the other patients. The subjects demonstrated an overall improved HbA1c (from 9.4% to 8.5%) and fasting blood glucose level (from 209 to 154 mg/dl). Although the change in fasting blood glucose approached statistical significance, these measures of glucose homeostasis did not achieve significance. Cholesterol and triglycerides increased slightly, and C-peptide decreased slightly over 1 year. These changes were not statistically significant.. Although this is a small series, our data show that at 12 months after surgery, clinical improvement was obvious in all of our seven patients, but LDJB may not be effective at inducing remission of T2DM and the MS in certain patients undergoing this operation. This suggests that larger patient studies should be conducted, before concluding that surgery may offer clinical and biochemical resolution to a disease once treated only medically. Longer follow-up is required for better evaluation.

Topics: Adult; Anastomosis, Roux-en-Y; Bariatric Surgery; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Duodenum; Glycated Hemoglobin; Humans; Jejunum; Laparoscopy; Middle Aged; Prospective Studies; Treatment Outcome; Triglycerides

The aim of this study was to study the effects of pioglitazone on several diabetic parameters with subjects possessing distinct levels of insulin. Treatment naive patients with type 2 diabetes received 15-30 mg/day pioglitazone monotherapy. At 3 months, levels of insulin, C-peptide, HbA1c, HOMA-R, HOMA-B and BMI were compared with those at baseline between the low (below 5.9 microU/ml, n = 48), medium (11.9-6 microU/ml n = 39) and high (above 12 microU/ml, n = 33) insulin groups. At baseline, differences existed in the levels of HbA1c, insulin, C-peptide, HOMA-R, HOMA-B, and BMI between these groups. In the high-insulin group significant reductions of insulin/C-peptide levels were observed, while in the low-insulin group significant increases of insulin/C-peptide were observed. In the medium-insulin group, no significant changes were observed. In contrast, the HbA1c levels significantly and similarly decreased in all the groups. Significant correlations between the changes of insulin/C-peptide levels with pioglitazone and the baseline insulin/C-peptide levels were observed. HOMA-R showed greater reductions in the high-insulin group, while HOMA-B showed greater increases in the low-insulin group in comparison to other groups. Multiple regression analysis revealed that the baseline insulin level is the predominant determinant of the changes of insulin levels with pioglitazone. These results suggest that pioglitazone appears to have two effects: to reduce insulin resistance (and lower insulin) and to improve beta-cell function (and increase insulin). The predominance of these effects appears to be determined by the insulin levels. Based on these data, a novel physiological model showing that pioglitazone may shift the natural history of diabetes toward an earlier stage (rejuvenation of beta-cell function) will be presented.

Topics: Adult; Aged; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Models, Biological; Pioglitazone; Thiazolidinediones

Studies have suggested that vitamin D may be important for both insulin sensitivity and insulin secretion, and that supplementation with vitamin D may subsequently prevent development of type 2 diabetes.. The objective of the current study was to test the hypothesis that supplementation with vitamin D would improve glycaemic control in subjects with type 2 diabetes.. Thirty-six subjects with type 2 diabetes, treated with metformin and bed-time insulin, were randomised to supplementation with cholecalciferol (40,000 IU per week) versus placebo for 6 months. Thirty-two subjects participated throughout the entirety of the study. Fasting blood samples were drawn before and at the end of the 6 month study without the previous bed-time insulin injection. The insulin and metformin doses were not changed throughout the study.. After 6 months, the fasting glucose, insulin, C-peptide, fructosamine, and HbA(1c) levels were not significantly different from baseline values. In addition, changes in these parameters (values at 6 months minus values at baseline) did not differ between the vitamin D and the placebo group.. We were not able to demonstrate that vitamin D supplementation had a significant effect on glucose metabolism in subjects with type 2 diabetes but without vitamin D deficiency. Further studies are needed in larger groups of subjects with type 2 diabetes or impaired glucose tolerance, who also exhibit low serum 25-hydroxyvitamin D levels.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Calcifediol; Calcium; Cholecalciferol; Diabetes Mellitus, Type 2; Dietary Supplements; Female; Fructosamine; Glycated Hemoglobin; Humans; Insulin; Insulin, Long-Acting; Male; Metformin; Middle Aged; Young Adult

To provide an initial evaluation of insulin sensitivity and secretion indices derived from a standard liquid meal tolerance test protocol in subjects with normal (NFG), impaired fasting glucose (IFG) or type 2 diabetes mellitus.. Areas under the curve (AUC) for glucose, insulin and C-peptide from pre-meal to 120 min after consumption of a liquid meal were calculated, as were homeostasis model assessments of insulin resistance (HOMA2-IR) and the Matsuda index of insulin sensitivity.. Subjects with NFG (n = 19), IFG (n = 19), and diabetes (n = 35) had mean +/- SEM HOMA2-IR values of 1.0 +/- 0.1, 1.6 +/- 0.2 and 2.5 +/- 0.3 and Matsuda insulin sensitivity index values of 15.6 +/- 2.0, 8.8 +/- 1.2 and 6.0 +/- 0.6, respectively. The log-transformed values for these variables were highly correlated overall and within each fasting glucose category (r = -0.91 to -0.94, all p < 0.001). Values for the product of the insulin/glucose AUC ratio and the Matsuda index, an indicator of the ability of the pancreas to match insulin secretion to the degree of insulin resistance, were 995.6 +/- 80.7 (NFG), 684.0 +/- 57.3 (IFG) and 188.3 +/- 16.1 (diabetes) and discriminated significantly between fasting glucose categories (p < 0.001 for each comparison).. These results provide initial evidence to support the usefulness of a standard liquid meal tolerance test for evaluation of insulin secretion and sensitivity in clinical and population studies.

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged

To compare blood glucose control when using biphasic insulin aspart (BIAsp) three times a day (using 70/30 high-mix before breakfast and lunch), with biphasic human insulin (BHI, 30/70) twice daily in adults with type 2 diabetes already treated with insulin.. In a 60-day, open-label, crossover study, people with insulin-treated type 2 diabetes [n = 38, baseline haemoglobin A1c 8.3 +/- 0.9 (s.d.) %] were randomized to BIAsp three times a day before meals, as BIAsp 70 (70% insulin aspart and 30% protamine-complexed insulin aspart) before breakfast and lunch and BIAsp 30 (30/70 free and protamine-complexed insulin aspart) before dinner, or to human premix insulin (BHI) 30/70 twice a day before meals. A 24-h in-patient plasma glucose profile was performed at the end of each 30-day treatment period. The total daily insulin dose of BIAsp regimen was 110% of BHI and the doses were not changed during the study.. There was no difference between BIAsp and BHI in geometric weighted average serum glucose over 24 h [7.3 vs. 7.7 mmol/l, BIAsp/BHI ratio 0.95 (95% CI 0.88-1.02), not significant (NS)], but daytime geometric weighted average glucose concentration was significantly lower with the BIAsp regimen than with BHI [8.3 vs. 9.2 mmol/l, BIAsp/BHI ratio 0.90 (0.84-0.98), p = 0.014]. The mealtime serum glucose excursion was also lower with BIAsp than with BHI with statistically significant differences at lunchtime [difference -4.9 (-7.0 to -2.7) mmol/l, p = 0.000); the difference in glucose excursions above 7.0 mmol/l was also significant [-5.8 (-8.3 to -3.2) mmol/l, p = 0.000). The proportion of participants experiencing confirmed hypoglycaemic episodes was similar between regimens (42 vs. 43%, NS).. An insulin regimen using high-mix BIAsp (BIAsp 70) before breakfast and lunch and BIAsp 30 before dinner can achieve lower blood glucose levels during the day through reduced mealtime glucose excursions in particular at lunchtime than a twice-daily premix regimen.

Topics: Adult; Aged; Biphasic Insulins; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; England; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin, Isophane; Male; Middle Aged; Treatment Outcome; Young Adult

In type 2 diabetes (T2D), insulin-induced weight gain may stem from a reduction in resting energy expenditure (REE). We sought to determine the early effects of insulin introduction on REE in 20 poorly controlled T2D patients.. After improving the glycaemia, REE was measured on Day 0 and Day 4 during two treatment regimens: bedtime insulin (n=10, group 1); and one off (3-day) intravenous insulin infusion (n=10, group 2).. Both groups were similar in age, gender, BMI, C-peptide, HbA(1c) and initial REE. By Day 4, fasting glycaemia had similarly improved in both groups: group 1: -5.3+/-2.7mmol/L vs group 2: -5.8+/-4.2 mmol/L. In group 2, the second REE was measured 12h after stopping the intravenous insulin infusion, whereas subcutaneous insulin was maintained in group 1. REE did not change in group 2 (-1.3+/-6.5%), whereas it decreased significantly in group 1 (-8.0+/-7.0%; P<0.05).. Bedtime insulin led to an early and specific reduction in REE.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Glycated Hemoglobin; Humans; Infusions, Intravenous; Injections, Subcutaneous; Insulin; Male; Middle Aged; Respiration; Rest; Statistics, Nonparametric; Time Factors; Weight Gain

This study assessed the efficacy of add-on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide.. This multicentre, double-blind, parallel-group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA(1c)) 6.5%), or placebo for a further 4 months. The primary efficacy end-point was improvement in HbA(1c) (per cent change). Secondary end-points included changes in fasting plasma glucose (FPG), insulin, C-peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-B) were calculated.. Pioglitazone add-on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between-group difference after 7 months of triple therapy was 1.18% in HbA(1c) and -2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA(1c) level of <8.5% achieved the HbA(1c) target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA(1c) level was >or= 8.5%, 13% achieved the HbA(1c) target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA-IR, insulin, proinsulin and C-peptide decreased and HOMA-B increased in the pioglitazone group relative to the placebo group.. In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA(1c), FPG and surrogate measures of beta-cell function. Patients were more likely to reach target HbA(1c) levels (< 7.0%) with pioglitazone treatment if their baseline HbA(1c) levels were < 8.5%, highlighting the importance of early triple therapy.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Metformin; Middle Aged; Pioglitazone; Proinsulin; Sulfonylurea Compounds; Thiazolidinediones

Islet neogenesis associated protein (INGAP) has beta cell regenerating effects in experimental models.. Subjects with T1DM (N = 63) and T2DM (N = 126) received 300 or 600 mg/day of INGAP peptide in a 90 day, randomized, double-blind, placebo-controlled trial.. In T1DM, on-treatment Arginine-stimulated C-peptide (AUC(0-30)) significantly increased from baseline in the 600 mg group (p = 0.0058 versus placebo); no significant changes were seen in the 300 mg group. In T2DM, stimulated C-peptide was significantly better preserved in the 600 mg group compared to placebo at day 120, 30 days after washout (p = 0.031 versus placebo), but did not reach statistical significance during treatment or in the 300 mg group. In T2DM, A1C decreased significantly more in the 600 mg group compared to placebo at day 90 (-0.94% versus -0.47%, respectively, p = 0.009) and day 120, 30 days after washout (-0.73% versus -0.24%, respectively, p = 0.013). This was accompanied by significant reductions in mean glucose. No difference from placebo was detected in the 300 mg group or in T1DM. Injection site reactions were the most common adverse event, occurring in 8 (36%) of placebo, 19 (90%) of 300 mg, and 15 (75%) of 600 mg groups (T1DM) and 14 (33%) of placebo, 27 (64%) of 300 mg, and 29 (69%) of 600 mg groups (T2DM).. INGAP peptide increases C-peptide secretion in T1DM and improves glycaemic control in T2DM. Longer-term exposure, more frequent dosing, better tolerated formulations or combination with other therapies may be necessary to achieve optimal clinical response.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antigens, Neoplasm; Area Under Curve; Arginine; Biomarkers, Tumor; Blood Glucose; Body Mass Index; C-Peptide; Cytokines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Insulin; Insulin-Secreting Cells; Lectins, C-Type; Male; Middle Aged; Pancreatitis-Associated Proteins; Peptide Fragments; Proinsulin; Receptor-Like Protein Tyrosine Phosphatases, Class 8; Regeneration; Treatment Outcome; Young Adult

To investigate the effect of glucagon on ghrelin secretion in type 2 diabetes mellitus (T2DM) patients.. Circulating ghrelin and C-peptide were measured during glucagon stimulation test in 38 cases with T2DM and 30 cases in normal controls (NC) at the 1st Affiliated Hospital of Shantou University from May 2006 to December 2007.. (1) There was no significant difference in the fasting C-peptide and fasting ghrelin levels of the NC group were (1.3 +/- 0.6) microg/L and (3.0 +/- 1.0) ng/ml respectively, both not significantly different from those of the T2DM group [(1.2 +/- 0.4) microg/L and (2.7 +/- 0.8) microg/L respectively, P > 0.05 and P > 0.05]; six minutes after the injection of glucagon, the C-peptide level of the T2DM group increased to (2.0 +/- 0.8) microg/L (P < 0.01), and that of the NC group increased to (3.0 +/- 0.8) microg/L (P < 0.01), and the C-peptide level 6 min after of the T2DM group was significantly lower than that of the NC group (P < 0.01). The ghrelin level 6 min after the injection of glucagon of the NC group was (2.3 +/- 0.7) microg/L, significantly lower than that before the injection (P < 0.01). But the ghrelin level 6 min after the injection of glucagon of the T2DM group was (2.9 +/- 0.9) microg/L, NOT significantly different from that before the injection (P > 0.05). (2) Fasting ghrelin level was significantly negatively correlated with the waist circumference (r = -0.343, P < 0.05).. In healthy subjects exogenous glucagon decreases the ghrelin level. Ghrelin may be associated with the beta-cell hypofunction and first-phase insulin secretion defects in T2DM. Insulin, glucagon, and ghrelin secreted influence each other to regulate glucose homeostasis.

Topics: Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucagon; Humans; Male; Middle Aged

Fatty acids (FA) can impair glucose metabolism to a varying degree depending on time of exposure and also of type of FA. Here we tested for acute effects of marine n-3 FA on insulin sensitivity, insulin secretion, energy metabolism, and oxidative stress. This was a randomized, double-blind, crossover study in 11 subjects with type 2 diabetes mellitus. A 4-hour lipid infusion (Intralipid [Fresenius Kabi, Halden, Norway], total of 384 mL) was compared with a similar lipid infusion partly replaced by Omegaven (Fresenius Kabi) that contributed a median of 0.1 g fish oil per kilogram body weight, amounting to 0.04 g/kg of marine n-3 FA. Insulin sensitivity was assessed by isoglycemic hyperinsulinemic clamps; insulin secretion (measured after the clamps), by C-peptide glucagon tests; and energy metabolism, by indirect calorimetry. Infusion of Omegaven increased the proportion of n-3 FA in plasma nonesterified fatty acids (NEFA) compared with Intralipid alone (20:5n-3: median, 1.5% [interquartile range, 0.6%] vs -0.2% [0.2%], P = .001; 22:6n-3: 0.8% [0.4%] vs -0.7% [0.2%], P = .001). However, glucose utilization was not affected; neither was insulin secretion or total energy production (P = .966, .210, and .423, respectively, for the differences between the lipid clamps). Omegaven tended to lower oxidation of fat (P = .062) compared with Intralipid only, correlating with the rise in individual n-3 NEFA (r = 0.627, P = .039). The effects of clamping on phospholipid FA composition, leptin, adiponectin, or F(2)-isoprostane concentrations were not affected by Omegaven. Enrichment of NEFA with n-3 FA during a 4-hour infusion of Intralipid failed to affect insulin sensitivity, insulin secretion, or markers of oxidative stress in subjects with type 2 diabetes mellitus.

Topics: Adult; Aged; Biomarkers; Body Composition; C-Peptide; Calorimetry, Indirect; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Dinoprost; Double-Blind Method; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Female; Glucagon; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin; Insulin Resistance; Isoprostanes; Male; Middle Aged; Oxidative Stress

Glucagon-like peptide-1 (GLP-1) is insulinotropic, but its effect on the alpha-cell is less clear. We investigated the dose-response relationship for GLP-1-induced glucagon suppression in patients with type 2 diabetes (T2DM) and healthy controls.. Ten patients with T2DM (duration of DM, 4 +/- 1 yr; glycosylated hemoglobin, 7.1 +/- 0.3%) were studied on 2 d, with stepwise increasing GLP-1 infusions (0.25, 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1)) (d 1) or saline (d 2) with plasma glucose (PG) clamped at fasting level. On d 3, patient PG was normalized overnight using a variable insulin infusion, followed by a 3-h GLP-1 infusion as on d 1. Ten healthy subjects were examined with the same protocol on d 1 and 2.. We observed similar dose-dependent stepwise suppression of glucagon secretion in both patients and controls. Significant suppression was observed at a GLP-1 infusion rate of 0.25 pmol x kg(-1) x min(-1) (resulting in physiological plasma concentrations) as early as time 15 min in healthy controls and time 30 min in patients (d 1 and d 3). AUC for glucagon was significantly reduced on d 1 and 3 (1096 +/- 109 and 1116 +/- 108 3h x pmol/liter; P = NS) as compared to d 2 (1733 +/- 193 3h x pmol/liter; P < 0.01) in patients with T2DM. A similar reduction in AUC for glucagon was observed in healthy controls [1122 +/- 186 (d 1) vs. 1733 +/- 312 3h x pmol/liter (d 2); P < 0.001].. The diabetic alpha-cell appears to be highly sensitive to the inhibitory action of GLP-1 both during high and near-normalized PG levels, but responds with a short, nevertheless significant delay.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Tolerance Test; Humans; Infusions, Intravenous; Insulin; Male; Middle Aged

Muraglitazar is a dual (alpha/gamma) PPAR activator. Dual receptor activation may improve glycaemic and lipid profiles in patients with type 2 diabetes mellitus.This randomised double-blind trial in 1,477 drug-naive patients with type 2 diabetes compared the efficacy and safety of muraglitazar (0.5, 1.5, 5, 10, and 20 mg) with pioglitazone (15 mg). Endpoints included changes in HbA(1C) and plasma lipids, last observation carried forward over 24 weeks. At week 24, mean changes from baseline in HbA(1C) ranged from -0.25% to -1.76% with muraglitazar (p

Topics: Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Edema; Female; Glycated Hemoglobin; Glycine; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Oxazoles; Pioglitazone; PPAR alpha; PPAR gamma; Thiazolidinediones; Time Factors; Treatment Outcome; Weight Gain

Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes.. Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging.. Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 +/- 1.0 vs. 12.2 +/- 0.7 micromol . kg(-1) . min(-1), P = 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 +/- 0.25 vs. 1.26 +/- 0.30 micromol . kg(-1) . min(-1), P < 0.001). Hepatic triglyceride content decreased by approximately 50% (P = 0.03), and muscle (anterior tibialis) triglyceride content decreased by approximately 55% (P = 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r = 0.64, P = 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r = -0.63, P = 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP. CONCLUSIONS Reduction in hepatic triglyceride by pioglitazone is very closely related to improvement in fasting and postprandial EGP in type 2 diabetes.

Topics: Abdominal Fat; Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Pioglitazone; Postprandial Period; Sulfonylurea Compounds; Thiazolidinediones; Triglycerides

This trial evaluated the effects of 16 weeks of consumption of 1000mg rebaudioside A (n=60) a steviol glycoside with potential use as a sweetener, compared to placebo (n=62) in men and women (33-75 years of age) with type 2 diabetes mellitus. Mean+/-standard error changes in glycosylated hemoglobin levels did not differ significantly between the rebaudioside A (0.11+/-0.06%) and placebo (0.09+/-0.05%; p=0.355) groups. Changes from baseline for rebaudioside A and placebo, respectively, in fasting glucose (7.5+/-3.7mg/dL and 11.2+/-4.5mg/dL), insulin (1.0+/-0.64microU/mL and 3.3+/-1.5microU/mL), and C-peptide (0.13+/-0.09ng/mL and 0.42+/-0.14ng/mL) did not differ significantly (p>0.05 for all). Assessments of changes in blood pressure, body weight, and fasting lipids indicated no differences by treatment. Rebaudioside A was well-tolerated, and records of hypoglycemic episodes showed no excess vs. placebo. These results suggest that chronic use of 1000mg rebaudioside A does not alter glucose homeostasis or blood pressure in individuals with type 2 diabetes mellitus.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Diterpenes, Kaurane; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Lipids; Male; Middle Aged; Placebos; Sweetening Agents

This prospective, randomized, controlled study was designed to investigate the effects of a diabetes specific formula (Diason low energy: 313.8 kJ/100 ml), compared with a standard formula, on insulin sensitivity, serum C peptide, serum lipids and free fatty acid (FFA) in type 2 diabetics.. In total of 71 type 2 diabetics completed the study. Enteral formulas were given orally as the sole source of nutrition to the subjects for 6 days. Venous blood samples (0.5, 1, 2, 3 hours) were collected at day-7 after a 75 g oral glucose tolerance test (OGTT), day 1 after a standard test meal (1673.6 kJ) and after 6 days of either the test diabetes specific formula or a standard formula. Plasma glucose, serum insulin, C peptide and lipids were measured.. After the intervention period, the diabetes specific formula resulted in a significantly lower postprandial rise in blood glucose concentrations at 0.5 hour (P < 0.05) and 1 hour (P < 0.01); significantly lower peak height of plasma glucose (P = 0.05); significantly lower plasma insulin concentrations at 0.5 hour (P < 0.01), 1 hour (P < 0.01) and 2 hours (P < 0.01); and a significantly lower plasma insulin peak compared to controls; both OGTT and a standard test meal (P < 0.05). The glucose and insulin area under the curve after the diabetes specific formula compared to the standard formula were significantly lower. The C peptide level was lower after 6 days of both nutrition formulas compare to 75 g OGTT, but not different from the standard mixed meal. Both formulas were well tolerated.. In summary the diabetes specific formula with a relatively high monounsaturated fatty acid and high multi fiber proportion significantly improved glycemic control. On top of this, the insulin sensitivity (HOMA-IS) was significantly improved and may therefore directly improve the impact on long term complications. The disease specific formula should therefore be the preferred option to be used by diabetic and hyperglycemic patients in need of nutritional support.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Fatty Acids, Nonesterified; Humans; Insulin; Insulin Secretion; Lipids; Middle Aged; Prospective Studies

This study was designed to compare effectiveness and remission rate between gliclazide and insulin as initial treatment in newly diagnosed, drug-naive patients with type 2 diabetes.. Newly diagnosed, drug-naive subjects with type 2 diabetes having mean fasting blood glucose >200 mg/dL were enrolled into either of two groups (gliclazide or insulin). The former received gliclazide modified-release 60 mg daily, while the insulin group received 16 units of premixed insulin as two divided doses along with medical nutrition therapy. Premeal blood glucose was monitored, and the dose was adjusted accordingly. Glycosylated hemoglobin (HbA1c), lipid profile, and postmeal C-peptide were estimated at baseline and 6 months. Remission was defined as euglycemia off drug for a minimum duration of 1 month.. Baseline and 6-month blood glucose, HbA1c, and lipid profile were comparable between groups. Blood glucose levels normalized in 2-6 weeks in both groups. At 6 months, one of 30 (3.33%) in the gliclazide group and 24 of 30 (80%) in the insulin group were in remission. Ten of 16 (62.5%) in the insulin group and one of 20 (.5%) in the gliclazide group continued to maintain euglycemia off all pharmacological treatment at 12 months. At 6 months, C-peptide increased in the insulin group (3.21+/-1.61 ng/mL at baseline vs. 5.82+/-2.23 ng/mL at 6 months), while it remained unchanged in the gliclazide group (3.4+/-1.87 ng/mL at baseline vs. 3.82+/-1.78 ng/mL at 6 months) (P=0.0003).. Comparable glycemic control could be achieved with both insulin and oral hypoglycemic agent in newly diagnosed type 2 diabetes subjects. Insulin treatment exceeded gliclazide in the remission (drug-free) rate.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Treatment Outcome

Changes in plasma immunoreactive insulin (IRI) and connecting-peptide immunoreactivity (CPR) concentrations during hemodialysis (HD) were evaluated in diabetic HD patients with 3 different high-flux membranes. The removal properties of the membranes were compared.. In this prospective controlled study, 15 stable diabetic patients on HD were randomly selected for 6 HD sessions with 3 different membranes: polysulfone (PS), cellulose triacetate (CTA), and polymethylmethacrylate (PMMA). Blood samples were obtained from the blood tubing at the arterial (A) site at the beginning and end of the sixth HD session. At 60 minutes after dialysis initiation, blood samples were obtained from both the A and venous (V) sites of the dialyzer to investigate the clearance and removal properties of the membranes.. The plasma IRI and CPR levels decreased significantly at each time point with all 3 membranes. IRI clearance with the PS membrane was significantly higher than that with the CTA and PMMA membranes. No difference was observed in the IRI reduction rate between the 3 membranes. CPR clearance and reduction rate with the PMMA membrane were lower than with the PS and CTA membranes. No significant difference was observed in serum creatinine clearance and reduction rates between the 3 membranes; however, serum urea nitrogen clearance was significantly lower with the PMMA membrane compared with the PS and CTA membranes. A significantly high beta2-microglobulin clearance and reduction rate was achieved in the order PS > CTA > PMMA.. Plasma IRI and CPR are cleared by HD; their clearance rates differ with the dialyzer membranes. Plasma IRI clearance with the PS membrane is higher than that with the CTA and PMMA membranes.

Topics: Blood Glucose; C-Peptide; Cellulose; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Equipment Design; Hemoglobins; Humans; Insulin; Membranes, Artificial; Polymers; Polymethyl Methacrylate; Renal Dialysis; Serum Albumin; Sulfones; Urea; Uremia

The objective of this study was to determine whether the combination therapy of intrapancreatic autologous stem cell infusion (ASC) and hyperbaric oxygen treatment (HBO) before and after ASC can improve islet function and metabolic control in patients with type 2 diabetes mellitus (T2DM). This prospective phase 1 study enrolled 25 patients with T2DM who received a combination therapy of intrapancreatic ASC and peri-infusion HBO between March 2004 and October 2006 at Stem Cells Argentina Medical Center Buenos Aires, Argentina. Clinical variables (body mass index, oral hypoglycemic drugs, insulin requirement) and metabolic variables (fasting plasma glucose, C-peptide, HbA1c, and calculation of C-peptide/glucose ratio) were assessed over quartile periods starting at baseline and up to 1 year follow-up after intervention. Means were calculated in each quartile period and compared to baseline. Seventeen male and eight female patients were enrolled. Baseline variables expressed as means +/- SEs were: age 55 +/- 2.14 years, diabetes duration 13.2 +/- 1.62 years, insulin dose 34.8 +/- 2.96 U/day, and BMI 27.11 +/- 0.51. All metabolic variables showed significant improvement when comparing baseline to 12 months follow-up, respectively: fasting glucose 205.6 +/- 5.9 versus 105.2 +/- 14.2 mg/dl, HbAlc 8.8 +/- 0.2 versus 6.0 +/- 0.4%, fasting C-peptide 1.5 +/- 0.2 versus 3.3 +/- 0.3 ng/ml, C-peptide/glucose ratio 0.7 +/- 0.2 versus 3.5 +/- 0.3, and insulin requirements 34.8 +/- 2.9 versus 2.5 +/- 6.7 U/day. BMI remained constant over the 1-year follow-up. Combined therapy of intrapancreatic ASC infusion and HBO can improve metabolic control and reduce insulin requirements in patients with T2DM. Further randomized controlled clinical trials will be required to confirm these findings.

Topics: Adult; Animals; Blood Glucose; Bone Marrow Cells; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hyperbaric Oxygenation; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Stem Cell Transplantation; Transplantation, Autologous

To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes.. Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment.. Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered.. In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Female; Follow-Up Studies; Glucagon; Glyburide; Glycated Hemoglobin; Health Status Indicators; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Insulin, Long-Acting; Lipids; Male; Middle Aged; Proinsulin; Quality of Life

This study evaluates the effects of glucagon 30 mug/kg (maximal 1 mg) on beta-cell function in children by C-peptide determined before and 6 min after intravenous administration. From 1990 to 2005, 118 Taiwanese children with newly diagnosed diabetes mellitus (98 children with type 1 and 20 children with type 2) and 29 normal Taiwanese children were enrolled in this study. Fasting and 6-min post-glucagon C-peptide levels were analyzed. In the pre-pubertal group, the median fasting serum C-peptide levels were 0.2 and 0.8 nmol/l in type 1 diabetes and normal children, respectively. These levels rose to 0.3 and 1.9 nmol/l after glucagon stimulation. In the pubertal group, the median fasting serum C-peptide levels were 0.3, 1.0 and 0.9 nmol/l in type 1 diabetes, type 2 diabetes and normal children, respectively. They rose to 0.4, 2.5 and 2.7 nmol/l after glucagon stimulation. Both fasting and post-glucagon C-peptide levels in type 1 diabetes patients were significantly lower than those of normal children and children with type 2 diabetes. The optimal cut-off values to distinguish type 1 diabetes patients from those with type 2 as determined by the receiving operating characteristic curve were 0.7 and 1.1 nmol/l, respectively. The sensitivities of both C-peptide values were 93%. The post-glucagon C-peptide level was more powerful in distinguishing type 1 diabetes from type 2 diabetes with higher specificity (95% vs. 85%). The 6-min glucagon test is valuable in assessing beta-cell function in children and can help pediatricians in the differential diagnoses of diabetes mellitus in children.

Topics: Adolescent; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Evaluation Studies as Topic; Female; Glucagon; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Infant; Islets of Langerhans; Male; ROC Curve; Taiwan

To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action.. Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 mg) for 4 months.. Glucose was clamped before and after therapy at approximately 5 mmol/l, insulin raised to approximately 180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at approximately 75 pg/ml, and glycerol maintained at approximately 200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 +/- 3 vs. 24 +/- 2 micromol x kg(-1) x min(-1)) or metformin (22 +/- 2 vs. 24 +/- 3 micromol x kg(-1) x min(-1)). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 +/- 1.0 vs. 0.2 +/- 1.6 micromol x kg(-1) x min(-1)) and gluconeogenesis (n = 11; 4.5 +/- 0.9 vs. 0.8 +/- 1.2 micromol x kg(-1) x min(-1)). Metformin did not alter either suppression of glucose production (5.8 +/- 1.0 vs. 5.0 +/- 0.8 micromol x kg(-1) x min(-1)) or gluconeogenesis (n = 9; 3.7 +/- 0.8 vs. 2.6 +/- 0.7 micromol x kg(-1) x min(-1)). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 +/- 0.03 vs. 0.06 +/- 0.01 mmol/l) but unchanged with metformin (0.12 +/- 0.03 vs. 0.15 +/- 0.07 mmol/l).. Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Drug Administration Schedule; Fatty Acids, Nonesterified; Female; Glucagon; Gluconeogenesis; Glucose Clamp Technique; Glycerol; Glycogenolysis; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Kinetics; Liver; Male; Metformin; Middle Aged; Pioglitazone; Placebos; Thiazolidinediones

To evaluate the efficacy and safety of glimepiride plus insulin glargine in ethnic Japanese patients with type 2 diabetes mellitus (T2DM).. This 24-week, open-label, single-arm study was conducted in eight centers in Brazil. One hundred ethnic Japanese T2DM patients with inadequate glycemic control [HbA(1c): 8.0-11.0% and fasting plasma glucose (FPG)>or=140 mg/dL] on oral antidiabetic drugs (OADs) were enrolled. Patients were treated once daily with glimepiride 3mg (morning) and glargine (bedtime) with dose titration to achieve FPG 72-100mg/dL.. At Week 24, the mean dose of glargine was 37.6 IU/day. There were significant decreases (p<0.0001) compared with baseline, for mean HbA(1c) (1.5%), mean FPG (88.3mg/dL) (p<0.0001), mean PPG (112.0mg/dL), and mean fasting C-peptide (1.14 ng/mL). Peptide index (peak-basal/basal) in carbohydrate challenge test increased by 2.24 units. No severe adverse events, including severe hypoglycemia were reported.. Our study suggests that combined therapy of insulin glargine and glimepiride should be considered for T2DM patients who have unsatisfactory response to previous OAD treatment.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Japan; Male; Middle Aged; Sulfonylurea Compounds

A comparison of the plasma glucose and insulin day profiles between two prandial rapid-acting insulin analogues, insulin glulisine (glulisine) and insulin lispro (lispro), in 18 obese subjects with Type 2 diabetes. Subjects (body mass index: males, 36.7 [33.2-43.8] kg/m(2); females, 40.0 [35.7-46.5] kg/m(2)) received subcutaneous glulisine or lispro (0.15 U/kg) at 4-h intervals immediately (within 2 min) before three standard test meals during each of two 12-h, randomised, open-label, crossover studies (7+/-2-day interval between each). Overall, preprandial-subtracted glucose concentrations (area under the curve) were similar on the glulisine and lispro study days. However, the mean of the three maximal preprandial subtracted plasma glucose concentrations (DeltaGLU(max)) were lower with glulisine versus lispro (12%; p<0.01). Mean concentrations of insulin analogue were significantly higher post-meal with glulisine (p<0.01 for all). Post hoc analysis showed a significantly faster absorption rate for glulisine versus lispro in the first 30 min post-meal (estimated difference 0.48 microU/min; p<0.0001). Only two cases of hypoglycaemia were reported; both from one subject during the lispro day. When glulisine is injected immediately before a meal in obese patients with Type 2 diabetes, glulisine achieves significantly lower glucose excursions over lispro. Significantly faster absorption with higher and sustained post-meal levels of insulin analogue was achieved at every meal with glulisine versus lispro.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Lispro; Male; Middle Aged; Obesity

Women with former gestational diabetes mellitus (fGDM) often show defects in both insulin sensitivity and beta-cell function but it is not clear which defect plays the major role or which appears first. This might be because fGDM women are often studied as a unique group and not divided according to their glucose tolerance. Different findings might also be the result of using different tests. Our aim was to study insulin sensitivity and beta-cell function with two independent glucose tolerance tests in fGDM women divided according to their glucose tolerance.. A total of 108 fGDM women divided into normal glucose tolerance (IGT; N = 82), impaired glucose metabolism (IGM; N = 20) and overt type 2 diabetes (T2DM; N = 6) groups, and 38 healthy control women (CNT) underwent intravenous (IVGTT) and oral glucose tolerance tests (OGTT). Measurements Insulin sensitivity and beta-cell function were assessed by both the IVGTT and the OGTT.. Both tests revealed impaired insulin sensitivity in the normotolerant group compared to controls (IVGTT: 4.2 +/- 0.3 vs. 5.4 +/- 0.4 10(-4) min(-1) (microU/ml)(-1); OGTT: 440 +/- 7 vs. 472 +/- 9 ml min(-1) m(-2)). Conversely, no difference was found in beta-cell function from the IVGTT. However, some parameters of beta-cell function by OGTT modelling analysis were found to be impaired: glucose sensitivity (106 +/- 5 vs. 124 +/- 7 pmol min(-1) m(-2) mm(-1), P = 0.0407) and insulin secretion at 5 mm glucose (168 +/- 9 vs. 206 +/- 10 pmol min(-1) m(-2), P = 0.003).. Both insulin sensitivity and beta-cell function are impaired in normotolerant fGDM but the subtle defect in beta-cell function is disclosed only by OGTT modelling analysis.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Pregnancy; Prognosis; Recovery of Function; Sensitivity and Specificity

To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test.. The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity.. Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Islets of Langerhans; Liraglutide; Male; Middle Aged; Receptors, Glucagon; Treatment Outcome

To assess the optimal dose and timing of subcutaneous injection of insulin Aspart (IAsp) in relation to meal to mimic first phase insulin response in patients with recently diagnosed type 2 diabetes.. Twenty patients were randomised in a double blind, double dummy design to four standard meal tests with pre-meal injection of insulin Aspart 0.08 IU/kg BW 30 min before the meal, insulin Aspart 0.04 IU/kg BW 30 or 15 min before the meal and placebo.. All three insulin regimes significantly reduced postprandial glucose increment (area under the curve AUC(-30 to 240 min)) and peak plasma glucose increment (DeltaC(max)) compared with placebo. Postprandial glucose increment AUC(-30 to 240 min) but not DeltaC(max) was significantly lower with IAsp 0.08 IU/kg BW as compared to IAsp 0.04IU/kg BW, (p<0.03 and p=0.18). One patient experienced hypoglycaemia after injection of IAsp 0.08 IU/kg BW. No difference in postprandial glucose profile was demonstrated whether IAsp 0.04 IU/kg BW was administrated 15 or 30 min before mealtime.. IAsp 0.04IU/kg BW injected subcutaneously 15 or 30 min before meal reduced the postprandial blood glucose increment without risk of hypoglycaemia in patients with recently diagnosed type 2 diabetes. Doubling of the IAsp dose significantly reduced the postprandial glucose increment but increased the risk of hypoglycaemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Aspart; Middle Aged; Placebos; Postprandial Period

The aim of this study was to determine the effect of diabetic autonomic neuropathy (AN) on the incretin effect in patients with type 2 diabetes mellitus (DM2).. Forty patients with DM2 (20 with and 20 without AN) and 10 healthy controls were studied. The subjects underwent an oral glucose tolerance test (OGTT) and 7-14 days later an intravenous infusion of 25 g glucose. Blood samples were drawn for glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) determination during the tests. The incretin effect was calculated from the total integrated amount of insulin or C-peptide during OGTT (A) and intravenous glucose infusion (B) according to the formula (A-B)/Ax100.. Total insulin and C-peptide responses during OGTT were significantly higher than those after IV glucose infusion in the group of normal subjects, but not in the groups of diabetic patients. After the oral glucose load, GIP levels presented a significant increase in normal subjects and patients without AN, whereas GLP-1 levels increased only in normal subjects. Calculated either with the insulin or C-peptide responses, the incretin effect presented no significant difference between the two diabetic groups. However, using insulin responses, only the patients with AN had significantly lower incretin effect than controls, whereas when using C-peptide responses, both diabetic groups did.. The incretin effect was impaired in both groups of diabetic patients. Autonomic neuropathy may further impair the incretin effect in DM2 through interference with GIP secretion or hepatic insulin extraction.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Health; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male

Obesity and aging increase the risk of type 2 diabetes (T2D). We evaluated whether weight loss therapy improves pancreatic endocrine function and insulin sensitivity in obese older adults.. Twenty-four obese (BMI: 38 +/- 2 kg/m(2)) older (age: 70 +/- 2 years) adults completed a 6-month randomized, controlled trial. Participants were randomized to diet and exercise (treatment group) or no therapy (control group). beta-Cell function (assessed using the C-peptide minimal model), alpha-cell function (assessed by the glucagon response to an oral glucose load), insulin sensitivity (assessed using the glucose minimal model), and insulin clearance rate were evaluated using a 5-h modified oral glucose tolerance test.. Body weight decreased in the treatment group, but did not change in the control group (-9 +/- 1% vs. 0 +/- 1%; P < 0.001). Insulin sensitivity doubled in the treatment group and did not change in the control group (116 +/- 49% vs. -11 +/- 13%; P < 0.05). Even though indices of beta-cell responsivity to glucose did not change (P > 0.05), the disposition index (DI), which adjusts beta-cell insulin response to changes in insulin sensitivity, improved in the treatment group compared with the control group (100 +/- 47% vs. -22 +/- 9%; P < 0.05). The glucagon response decreased in the treatment but not in the control group (-5 +/- 2% vs. 4 +/- 4%; P < 0.05). Insulin secretion rate did not change (P > 0.05), but insulin clearance rate increased (51 +/- 25%; P < 0.05), resulting in lower plasma insulin concentrations.. Weight loss therapy concomitantly improves beta-cell function, lowers plasma glucagon concentrations, and improves insulin action in obese older adults. These metabolic effects are likely to reduce the risk of developing T2D in this population.

Topics: Aged; Aging; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise; Female; Glucagon; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Obesity; Risk Factors; Weight Loss

Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D).. This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D.. In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA(1c)), C-peptide, and fructosamine values.. Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose.. In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fructosamine; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Piperidines; Placebos; Time Factors; Treatment Outcome; Uracil

The aim of the present study was to investigate whether the use of pedometer increases walking and/or enhances beneficial outcomes in a physical intervention study in type 2 diabetes mellitus. Seventy persons with type 2 diabetes mellitus were randomized to a pedometer and a nonpedometer group (P and non-P groups). All participants were seen by a nurse at a baseline visit (V1), after 1 month, after 3 months, and after 6 months and were then encouraged to increase walking. Subjects in the P group additionally registered pedometer steps 3 days twice per month for 6 months. After V1 and the visit at 6 months, aerobic capacity (VO2peak) was measured; and subjects reported perceived physical fitness and activity. Twenty-two subjects did not complete the study (dropouts). The VO2peak at V1 was lower in dropouts than in subjects who completed the study (completers) (P=.003). In the P group, the number of steps per day did not increase from month 1 to month 6 (P=.65). In completers, taken together, there was a decrease in body weight (P=.005), hemoglobin A1c (P=.034), fasting blood glucose (P=.033), triglycerides (P=.002), and diastolic blood pressure (P=.048) and an increase in high-density lipoprotein cholesterol (P<.001), with no difference between the P group and non-P group for these variables (all P values>.38). Perceived improvement in physical and mental state correlated with improvement in VO2peak (r=0.45, P=.008 and r=0.38, P=.03, respectively; n=34). We conclude that the use of pedometer did not increase walking or enhance beneficial metabolic outcomes. The low aerobic capacity in dropouts indicates that persons most needy of physical exercise are the least compliant in exercise programs.

Topics: Adult; Aged; C-Peptide; Data Collection; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Oxygen Consumption; Walking

We have previously demonstrated that type 2 diabetes resolves after bariatric surgery. To study the role of NEFA in the prompt normalisation of beta cell glucose sensitivity, insulin secretion and beta cell glucose and lipid metabolism were investigated by a model of nutrient-stimulated insulin secretion using a multiple-meal test.. Hourly glucose, C-peptide and NEFA were measured in nine morbidly obese, type 2 diabetic patients before and 1 week after bariatric surgery and in six matched healthy volunteers over 24 h. A mathematical model of glucose-NEFA comodulation of insulin secretion rate (ISR) was used to compute ISR and beta-oxidation. Insulin sensitivity was measured by an OGTT minimal model.. Beta cell sensitivity to glucose and NEFA was doubled after surgery, while the 24 h insulin secretion decreased from 277.1 +/- 144.4 to 198.0 +/- 107.6 nmol/m(2) (p < 0.02). Insulin sensitivity was restored. The beta-oxidation rate of beta cells was completely normalised (from 0.032 +/- 0.012 x 10(-12) to 0.103 +/- 0.031 x 10(-12) mmol/min per cell, p < 0.005). The best predictor of beta cell function improvement was the duration of diabetes.. Bariatric surgery in type 2 diabetes restores beta-oxidation in beta cells, doubles glucose-NEFA sensitivity and reverses diabetes. It is likely that ISR is reduced to match insulin-sensitivity normalisation, in spite of no significant reduction in NEFA levels. We hypothesise that insulin sensitivity normalisation might appear as a consequence of nutrient exclusion from proximal intestinal transit, and that secondarily the need for insulin secretion diminishes. The insulin sensitivity increase is much higher than usually obtained by insulin-sensitising agents and is independent of weight changes.

Topics: Bariatric Surgery; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Models, Biological; Obesity, Morbid; Oxidation-Reduction; Postoperative Care; Preoperative Care

This study investigated whether strict control of plasma glucose levels with mealtime dosing of a rapid-acting insulin analog improves early morning fasting plasma glucose (FPG) levels in patients with type 2 diabetes. A rapid-acting insulin analog was administered at each mealtime to 40 Japanese patients with type 2 diabetes whose existing antidiabetic medication was discontinued. Approximately one-half (52.5%) of the patients achieved a minimum early morning FPG levels achievable (nadir FPG) of <120mg/dL with mealtime dosing of a rapid-acting insulin analog alone; no basal insulin replacement was needed in these patients. Nadir FPG levels were independent of duration of diabetes, baseline body mass index (BMI) or glycemic control. All patients who had been treated with sulfonylureas needed basal insulin replacement. Low responses of insulin to glucagon and to arginine, and high response of glucagon to arginine may explain the failure to improve FPG levels with postprandial insulin replacement alone. In conclusion, approximately one-half of the patients with type 2 diabetes achieved appropriate control of FPG by rapid-acting insulin analog monotherapy. Basal insulin secretory defects in type 2 diabetes may be estimated by the responses of insulin to glucagon and to arginine and the response of glucagon to arginine. This study contributes to a better understanding of the pathophysiology contributing to the heterogeneity in the characteristics of insulin secretion in type 2 diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Eating; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin, Regular, Pork; Male; Middle Aged

The abnormal glucose tolerance of Type 2 diabetes is characterized by post-prandial hyperglycaemia. We aimed to examine whether the restoration of a more physiological insulin profile using rapid-acting insulin analogues might, through effects on glucose toxicity, improve endogenous insulin secretion rate (ISR) and secondly improve markers of vascular risk. Eighteen people with insulin-treated Type 2 diabetes were recruited into a single centre, cross-over, open-labeled study. The order of pre-meal unmodified human insulin or insulin aspart was randomized: treatment periods lasted at least 8-12 weeks after which ISR was assessed by stepped low-dose glucose infusion and fasting markers of vascular risk measured. Glucose control was good (HbA(1c) 6.94+/-0.12 (+/-S.E.)% versus 7.07+/-0.13%, NS) with insulin aspart and human insulin. Mean post-prandial self-monitored blood glucose concentration was also good particularly with insulin aspart (7.5+/-0.41 mmol/l versus 8.19+/-0.34 mmol/l) but the difference did not reach statistical significance. Over 160 min ISR did not differ between insulin aspart and human insulin and there was also no change in various markers of vascular risk. In conclusion a meal-time+basal insulin regimen gave close to normal post-prandial blood glucose control with both the insulin aspart and human insulin regimens, such that no difference in ISR or markers of vascular risk could be demonstrated.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin Secretion; Male; Middle Aged; Postprandial Period

Topics: Adamantane; Adult; Analysis of Variance; Blood Glucose; C-Peptide; Chromatography, Liquid; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nitriles; Pyrrolidines; Radioimmunoassay; Tandem Mass Spectrometry; Time Factors; Vildagliptin

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

Topics: Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Genetic Predisposition to Disease; Glucose Clamp Technique; Hormones; Humans; Hyperglycemia; Hypolipidemic Agents; Insulin; Insulin Secretion; Male; Osmolar Concentration; Pyrazines; Time Factors

A growing body of evidence supports the concept that treatment with the newer angiotensin type-1 receptor blockers (ARBs) improves glucose homeostasis under conditions wherein it is impaired. Controversy exists, however, regarding the ability of losartan, an older ARB, to exert comparable improvement. The present study was undertaken to evaluate the effects of losartan on glucose homeostasis in subjects with type 2 diabetes and nephropathy.. Twenty-seven subjects with type 2 diabetic nephropathy were enrolled in this prospective, randomized, controlled study. Losartan (100 mg daily) or the calcium channel blocker amlodipine (10 mg daily) was administered for a period of 3 months. Fasting blood glucose, serum insulin and C-peptide concentrations were measured at baseline and at the end of the study. Oral glucose tolerance tests were performed to evaluate insulin sensitivity and beta-cell responsiveness. Insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA-IR).. Fasting blood glucose, HbA1c, AUC glucose, and urinary protein values were significantly decreased in the losartan group as compared with the amlodipine group (P<0.05). Furthermore, C-peptide concentrations, the insulin sensitivity index, and the insulin-to-glucose ratio were significantly increased after 3 months of therapy with losartan as compared to amlodipine (P<0.05). Reductions of fasting insulin concentrations and HOMA-IR were also observed for the losartan group; however, reductions were not significant when compared with the amlodipine group.. In addition to reducing urinary protein excretion, losartan at 100 mg daily increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetic nephropathy.

Topics: Adult; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Blood Glucose; C-Peptide; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Female; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Losartan; Male; Middle Aged; Proteinuria; Time Factors; Treatment Outcome

This study compared the time-action profiles of the novel albumin-bound basal insulin analogue NN344 with those of insulin detemir and insulin glargine in individuals with type 2 diabetes.. Twenty-seven insulin-treated men with type 2 diabetes [body mass index 30.8 +/- 2.6 kg/m(2) (mean +/- s.d.), haemoglobin A(1c) 7.6 +/- 1.1%] were enrolled in this randomized, double-blind trial and participated in six euglycaemic glucose clamp experiments [target blood glucose (BG) 5 mmol/l] each. Participants received NN344 in three experiments at a dose of 0.8, 1.6 and 2.8 dosing units (DU) (1 DU corresponds to 6 nmol NN344) per kilogram of body weight. In the other three experiments, the participants received 0.4, 0.8 and 1.4 U/kg of either insulin detemir or insulin glargine. The insulin preparations were characterized with regards to their effects on glucose infusion rates (GIRs) (in particular duration of action and within-subject and between-subject variabilities), BG, C-peptide, free fatty acids (FFA), endogenous glucose production (EGP) and peripheral glucose uptake (PGU) over 24 h post-dose.. The mean GIR profiles for all three preparations were similar in shape/flatness and showed increasing effect (area under the curve for GIR: AUC-GIR(total)) with increasing dose [low dose: 647 +/- 580, 882 +/- 634, 571 +/- 647 mg/kg (insulin detemir vs. NN344 vs. insulin glargine]; medium dose: 1203 +/- 816, 1720 +/- 1109, 1393 +/- 1203 mg/kg and high dose: 2171 +/- 1344, 3119 +/- 1549, 2952 +/- 2028 mg/kg; p = 0.48]. The duration of action increased with rising doses of all insulin preparations, without major differences between treatments. BG remained below 7 mmol/l in nearly all the experiments. Within-subject variability was lower for the albumin-bound insulin analogues, insulin detemir and NN344, than for insulin glargine (p < 0.0001). Between-subject variability did not differ between treatments, nor did the effects on BG, C-peptide, FFA, EGP or PGU.. In individuals with type 2 diabetes, the time-action profiles and the duration of action of the albumin-bound insulin analogues, insulin detemir and NN344, were comparable with those of insulin glargine, whereas within-subject variability in the metabolic effect was significantly lower. Therefore, insulin detemir and NN344 seem to be as well suited as insulin glargine for once-daily administration in type 2 diabetes. The better predictability may be an important characteristic of the albumin-bound analogues as insulin detemir has already been shown to improve hypoglycaemia.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

Metformin is the 'drug-of-first-choice' in obese patients with type 2 diabetes mellitus (T2DM) due to its antihyperglycaemic and cardiovascular protective potentials. In non-obese patients with T2DM, insulin secretagogues are empirically used as first choice. In this investigator-initiated trial, we evaluated the effect of metformin vs. an insulin secretagogue, repaglinide on glycaemic regulation and markers of inflammation and insulin sensitivity in non-obese patients with T2DM.. A single-centre, double-masked, double-dummy, crossover study during 2 x 4 months involved 96 non-obese (body mass index < or = 27 kg/m(2)) insulin-naïve patients with T2DM. At enrolment, previous oral hypoglycaemic agents (OHA) were stopped and patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either repaglinide 2 mg thrice daily followed by metformin 1 g twice daily or vice versa each during 4 months with 1-month washout between interventions.. End-of-treatment levels of haemoglobin A(1c) (HbA(1c)), fasting plasma glucose, mean of seven-point home-monitored plasma glucose and fasting levels of high-sensitivity C-reactive protein and adiponectin were not significantly different between treatments. However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs. repaglinide. Both drugs were well tolerated.. In non-obese patients with T2DM, overall glycaemic regulation was equivalent with less hypoglycaemia during metformin vs. repaglinide treatment for 2 x 4 months. Metformin was more effective targeting non-glycaemic cardiovascular risk markers related to total and abdominal body fat stores as well as fasting insulinaemia. These findings may suggest the use of metformin as the preferred OHA also in non-obese patients with T2DM.

Topics: Adiponectin; Biomarkers; Blood Glucose; Body Weight; C-Peptide; C-Reactive Protein; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Patient Compliance; Piperidines; Prospective Studies; Waist-Hip Ratio

Children with new onset diabetes (n = 175) were evaluated over 12-months. Patients were presumptively diagnosed with type 2 diabetes mellitus (T2DM) (n = 26) based on obesity, a relative with T2DM, the ability to wean from insulin, and absence of glutamic acid decarboxylase-65 (GAD-65) antibodies. We hypothesized that markers of insulinization at diagnosis, including fasting C-peptide and insulin-like growth factor-binding protein (IGFBP)-1, in addition to initial CO(2) levels and urine ketones, would help in distinguishing type 1 diabetes mellitus (T1DM) from T2DM.. Children with T1DM (84 male, 65 female) had a mean age of 8.7 +/- 4.3 yr and a racial background of 78% white, 19% black, and 3% other. In contrast, children with T2DM (13 female, 13 male) had a mean age of 14.2 +/- 3.1 yr with a racial background of 58% black, 27% white, and 15% other. Fasting C-peptide level was 0.38 +/- 0.37 ng/mL in T1DM vs. 2.66 +/- 2.14 ng/mL in T2DM; a C-peptide of 0.85 ng/mL had 83% sensitivity in distinguishing T1DM from T2DM. Fasting IGFBP-1 level was 38.1 +/- 39.1 ng/mL (T1DM) vs. 3.6 +/- 4.5 ng/mL (T2DM); a value of 3.6 ng/dL could distinguish the two types of diabetes with 93% sensitivity. Urinary ketones were found in 79% of children with T1DM compared with 56% of those with T2DM, and the magnitude was associated with type of diabetes. Initial CO(2) level for T1DM was 17.9 +/- 6.9 mmol/L vs. 22.7 +/- 5.7 mmol/L for T2DM; a value of 21.5 mmol/L could distinguish the two types of diabetes with 83% sensitivity.. In addition to obesity, family history of T2DM, and absence of GAD-65 antibodies, children with new-onset T2DM may be distinguished from those with T1DM by a combination of biochemical parameters (C-peptide, IGFBP-1, CO(2), and urine ketones).

Topics: Adolescent; Biomarkers; C-Peptide; Carbon Dioxide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Ketones; Male; Obesity

Absorption rates of the phosphate-buffered insulin analogs aspart, lispro, and glulisine prevail over that of regular human insulin. The aim of this prospective observational open-label controlled study was to compare the effects of aspart and human regular insulin resulting from their sequential long-lasting routine administration in small preprandial boluses to individuals with type 2 diabetes according to identical algorithms.. Fifty-seven individuals with type 2 diabetes 64.0 +/- 1.29 (mean +/- SE) years old with diabetes' duration of 12.4 +/- 1.06 years, treated with human regular insulin for 5.2 +/- 0.44 years, and a serum C-peptide level of 1.1 +/- 0.10 nmol/L were enrolled into the study. Following two checkups performed in the course of the 364 +/- 17.9-day baseline period, human regular insulin was replaced with aspart in equivalent boluses, and two checkups in the course of 330 +/- 11.1-day sequential period were performed. The control group consisted of 17 individuals with type 2 diabetes 68.4 +/- 2.36 years old with diabetes' duration of 9.9 +/- 1.57 years, treated with insulin for 4.2 +/- 0.57 years, and a C-peptide level of 1.1 +/- 0.11 nmol/L. Data were analyzed using the statistical program SPSS version 10.1. (SPSS, Inc., Chicago, IL).. Following the switch from human regular insulin to aspart, hemoglobin A1c (HbA1c) decreased from 8.4 +/- 0.23% at baseline to 7.9 +/- 0.17% (P = 0.031), and thereafter to 7.5 +/- 0.20% (P < 0.001), while plasma glucose concentrations in 10-point profiles, daily insulin dose (37.1 +/- 1.39 IU/day), body mass index (BMI) (30.5 +/- 0.82 kg/m(2)), and frequency of hypo- and hyperglycemic episodes did not change (P > 0.05). Patients quote satisfaction was good. No adverse events were recorded. In the control group, no significant change of baseline HbA1c (8.4 +/- 0.54%), insulin dose (33.1 +/- 3.17 IU/day), and BMI (32.1 +/- 1.12 kg/m(2)) was found.. Aspart appears to be more effective than human regular insulin for complementary insulin treatment in individuals with type 2 diabetes.

Topics: Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Lipids; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Treatment Outcome

To compare the pharmacokinetic and pharmacodynamic effects of glimepiride between once- and twice-daily dosing in type 2 diabetic patients. Eight Japanese type 2 diabetic patients, who had been treated with 2 mg glimepiride alone over 4 weeks (age 40-70, body mass index

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds

This study was designed to compare the effectiveness of co-administration of pioglitazone with metformin or a sulfonylurea (SU), with a fixed-dose combination of metformin and glibenclamide on glycemic control and beta-cell function in patients with type 2 diabetes.. Patients (n = 250) treated with metformin (3 months and with glycosylated hemoglobin (HbA(1c)) between 7.5% and 11% inclusive were randomized to receive either pioglitazone (15-30 mg/day) as add-on therapy to metformin or an SU or a fixed-dose combination of metformin (400 mg) and glibenclamide (2.5 mg) (up to three tablets per day) for 6 months. HbA(1c) and fasting plasma glucose (FPG) were measured at baseline and 2, 4, and 6 months. C-peptide levels were measured at baseline and 6 months, and post-challenge glucose and insulin responses were measured.. After 6 months, pioglitazone-based and fixed-dose metformin + glibenclamide resulted in similar reductions in HbA(1c) (-1.11% vs. -1.29%, respectively; P = 0.192) and FPG (-2.13 vs. -1.81 mmol/L, respectively; P = 0.370). Patients treated with pioglitazone for 6 months had significantly reduced C-peptide levels compared with baseline (-0.09 nmol/L, P = 0.001), while patients receiving fixed-dose metformin + glibenclamide combination had slightly increased C-peptide levels (+0.04 nmol/L, P = 0.08). Pioglitazone treatment also improved post-challenge insulin responses.. Co-administration of pioglitazone with metformin or an SU is an effective alternative to fixed-dose metformin + glibenclamide combination for patients with type 2 diabetes. The complementary effects of pioglitazone with either metformin or an SU may also have the potential to preserve beta-cell function and delay the progression of type 2 diabetes.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Metformin; Pioglitazone; Safety; Thiazolidinediones

We evaluated and compared the effects on glycaemic control of two different exercise protocols in elderly men with type 2 diabetes mellitus.. Eighteen patients with type 2 diabetes mellitus carried out home-based bicycle training for 5 weeks. Patients were randomly assigned to one of two training programmes at 60% of maximal oxygen uptake: three 10 min sessions per day (3 x 10) or one 30 min session per day (1 x 30). Plasma insulin, C-peptide and glucose concentrations were measured during a 3 h oral glucose tolerance test (OGTT). Insulin sensitivity index (ISI(composite)), pre-hepatic insulin secretion rates (ISR) and change in insulin secretion per unit change in glucose concentrations (B(total)) were calculated.. Cardiorespiratory fitness increased in response to training in both groups. In group 3 x 10 (n = 9) fasting plasma glucose (p = 0.01), 120 min glucose OGTT (p = 0.04) and plasma glucose concentration areas under the curve at 120 min (p < 0.04) and 180 min (p = 0.07) decreased. These parameters remained unchanged in group 1 x 30 (n = 9). No significant changes were found in ISI(composite), ISR and B(total) in either of the exercise groups. In a matched time-control group (n = 10), glycaemic control did not change.. Moderate to high-intensity training performed at 3 x 10 min/day is preferable to 1 x 30 min/day with regard to effects on glycaemic control. This is in spite of the fact that cardiorespiratory fitness increased similarly in both exercise groups. A possible explanation is that the energy expenditure associated with multiple short daily sessions may be greater than that in a single daily session.

Topics: Age of Onset; Aged; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Exercise; Exercise Test; Humans; Insulin; Lipoproteins; Male; Middle Aged; Oxygen Consumption; Patient Compliance; Time Factors

The aim of this study was to evaluate the contribution of insulin processing to the improved meal-related B-cell function previously shown with the DPP-4 inhibitor vildagliptin. Fifty-five patients with type 2 diabetes (56.5+/-1.5 years; BMI=29.6+/-0.5 kg/m(2); FPG=9.9+/-0.2 mmol/l; HbA1c=7.7+/-0.1 %) were studied: 29 patients were treated with vildagliptin and 26 patients with placebo, both added to an ongoing metformin regimen (1.5-3.0 g/day). A standardized breakfast was given at baseline and after 52 weeks of treatment, and proinsulin related to insulin secretion was measured with C-peptide in the fasting and postprandial (over 4 h post-meal) states to evaluate B-cell function. The between-treatment difference (vildagliptin-placebo) in mean change from baseline in fasting proinsulin to C-peptide ratio (fastP/C) was -0.007+/-0.009 (p=0.052). Following the standard breakfast, 52 weeks of treatment with vildagliptin significantly decreased the dynamic proinsulin to C-peptide ratio (dynP/C) relative to placebo by 0.010+/-0.008 (p=0.037). Importantly, when the P/C was expressed in relation to the glucose stimulus (i.e., the fasting glucose and glucose AUC(0-240 min), respectively), the P/C relative to glucose was significantly reduced with vildagliptin vs. placebo, both in the fasting state (p=0.023) and postprandially (p=0.004). In conclusion, a more efficient B-cell insulin processing provides further evidence that vildagliptin treatment ameliorates abnormal B-cell function in patients with type 2 diabetes.

Topics: Adamantane; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Nitriles; Postprandial Period; Proinsulin; Pyrrolidines; Treatment Outcome; Vildagliptin

Diabetes is associated with increased oxidative stress and atherosclerosis development. In the present study, we investigated the effects of pomegranate juice (PJ; which contains sugars and potent anti-oxidants) consumption by diabetic patients on blood diabetic parameters, and on oxidative stress in their serum and macrophages. Ten healthy subjects (controls) and 10 non-insulin dependent diabetes mellitus (NIDDM) patients who consumed PJ (50ml per day for 3 months) participated in the study. In the patients versus controls serum levels of lipid peroxides and thiobarbituric acid reactive substances (TBARS) were both increased, by 350% and 51%, respectively, whereas serum SH groups content and paraoxonase 1 (PON1) activity, were both decreased (by 23%). PJ consumption did not affect serum glucose, cholesterol and triglyceride levels, but it resulted in a significant reduction in serum lipid peroxides and TBARS levels by 56% and 28%, whereas serum SH groups and PON1 activity significantly increased by 12% and 24%, respectively. In the patients versus controls monocytes-derived macrophages (HMDM), we observed increased level of cellular peroxides (by 36%), and decreased glutathione content (by 64%). PJ consumption significantly reduced cellular peroxides (by 71%), and increased glutathione levels (by 141%) in the patients' HMDM. The patients' versus control HMDM took up oxidized LDL (Ox-LDL) at enhanced rate (by 37%) and PJ consumption significantly decreased the extent of Ox-LDL cellular uptake (by 39%). We thus conclude that PJ consumption by diabetic patients did not worsen the diabetic parameters, but rather resulted in anti-oxidative effects on serum and macrophages, which could contribute to attenuation of atherosclerosis development in these patients.

Topics: Adult; Aged; Antioxidants; Atherosclerosis; C-Peptide; Carbohydrates; Cells, Cultured; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Flavonoids; Humans; Lipid Peroxidation; Lipoproteins, LDL; Lythraceae; Macrophages; Male; Middle Aged; Monocytes; Oxidative Stress; Phenols; Plant Extracts; Polyphenols; Triglycerides

First-degree relatives of type 2 diabetic patients (offspring) are often characterized by insulin resistance and reduced physical fitness (VO2 max). We determined the response of healthy first-degree relatives to a standardized 10-wk exercise program compared with an age-, sex-, and body mass index-matched control group. Improvements in VO2 max (14.1 +/- 11.3 and 16.1 +/- 14.2%; both P < 0.001) and insulin sensitivity (0.6 +/- 1.4 and 1.0 +/- 2.1 mg x kg(-1) x min(-1); both P < 0.05) were comparable in offspring and control subjects. However, VO2 max and insulin sensitivity in offspring were not related at baseline as in the controls (r = 0.009, P = 0.96 vs. r = 0.67, P = 0.002). Likewise, in offspring, exercise-induced changes in VO2 max did not correlate with changes in insulin sensitivity as opposed to controls (r = 0.06, P = 0.76 vs. r = 0.57, P = 0.01). Skeletal muscle oxidative capacity tended to be lower in offspring at baseline but improved equally in both offspring and controls in response to exercise training (delta citrate synthase enzyme activity 26 vs. 20%, and delta cyclooxygenase enzyme activity 25 vs. 23%. Skeletal muscle fiber morphology and capillary density were comparable between groups at baseline and did not change significantly with exercise training. In conclusion, this study shows that first-degree relatives of type 2 diabetic patients respond normally to endurance exercise in terms of changes in VO2 max and insulin sensitivity. However, the lack of a correlation between the VO2 max and insulin sensitivity in the first-degree relatives of type 2 diabetic patients indicates that skeletal muscle adaptations are dissociated from the improvement in VO2 max. This could indicate that, in first-degree relatives, improvement of insulin sensitivity is dissociated from muscle mitochondrial functions.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Citrate (si)-Synthase; Diabetes Mellitus, Type 2; Electron Transport Complex IV; Exercise; Exercise Test; Family Health; Female; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Muscle, Skeletal; Oxidation-Reduction; Oxygen; Physical Fitness; Regression Analysis

Glucagon-like peptide-1 (GLP-1) is metabolised by the enzyme dipeptidyl-peptidase 4 (DPP-4), generating a metabolite with potential antagonistic properties. This study was conducted to evaluate the effect of that metabolite on plasma glucose levels in patients with type 2 diabetes.. The randomised crossover study consisted of five regimens: (1) i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1); IV); (2 and 3) s.c. infusion of GLP-1 (2.4 and 9.6 pmol kg(-1) min(-1); LSC, HSC); (4) s.c. infusion of GLP-1 (2.4 pmol kg(-1) min(-1)) in combination with a DPP-4 inhibitor (IB); and (5) s.c. infusion of saline (154 mmol NaCl/l; SAL). Seven patients with type 2 diabetes participated in all protocols.. Plasma levels of intact GLP-1 increased from 7+/-1 (SAL) to 17+/-3 (LSC), 61+/-7 (IB), 62+/-5 (IV) and 94+/-10 (9.6 s.c.) pmol/l, p<0.0001. Plasma concentrations of the metabolite increased from 1+/-3 (SAL) and 2+/-6 (IB) pmol/l to 42+/-4 (LSC), 64+/-8 (IV) and 327+/-16 (HSC) pmol/l, p<0.0001. Mean plasma glucose levels at 6 h decreased from 12.4+/-1.1 (SAL) mmol/l to 10.4+/-1.1 (LSC), 8.6+/-0.6 (IB), 8.8+/-0.8 (IV) and 9.1+/-0.9 (HSC) mmol/l, p<0.0001.. At approximately similar concentrations of intact GLP-1 (IV, IB, HSC), but with widely ranging metabolite concentrations, the effect on plasma glucose levels was equal, indicating that the presence of the metabolite does not antagonise the glucose-lowering effect of GLP-1.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Enzyme Activation; Enzyme Inhibitors; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Nitriles; Peptides; Pyrrolidines

Hyperproinsulinemia in type 2 diabetic subjects has recently been accepted as an independent cardiovascular risk factor. Moreover, it has been confirmed that high proinsulin concentrations stimulate amylin secretion by pancreatic beta-cells and amyloid accumulation within pancreatic islets leading to impairment of pancreatic islets secretory function. The association between sulfonylureas administration and secretory function of pancreatic beta-cells, especially concerning insulin precursor peptides, is not sufficiently elucidated. Preliminary studies by our research group revealed that the fasting proinsulin serum concentration is significantly higher in type 2 diabetic patients treated with sulfonylureas than in a well-matched group treated with insulin only.. A total of 101 subjects with type 2 diabetes were treated either with sulfonylureas (n = 32), with insulin (n = 40), with sulfonylureas + insulin (n = 17) or with diet alone (n = 12).. The basal secretory function in the four groups were comparable (C-peptide fasting serum level > 0.5 ng/l). An effect of fasting glycemia, long-term metabolic control (HbA1c), postprandial hyperglycemia (1,5-anhydro-D-glucitol), insulin resistance (HOMA(IR)score) and diabetes duration on the fasting proinsulin serum level in the subjects treated could be excluded.. The disproportionately high proinsulin levels are due to sulfonylureas therapy. The effect is independent of fasting glycemia, long-term metabolic control, postprandial hyperglycemia, diabetes duration and peripheral insulin resistance.

Topics: Aged; Blood Glucose; Body Mass Index; C-Peptide; Caloric Restriction; Deoxyglucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Multivariate Analysis; Patient Selection; Proinsulin; Sulfonylurea Compounds

To study the effect of the short-acting insulin secretagogue nateglinide in patients with maturity-onset diabetes of the young type 3 (MODY3), which is characterized by a defective insulin response to glucose and hypersensitivity to sulfonylureas.. We compared the acute effect of nateglinide, glibenclamide, and placebo on prandial plasma glucose and serum insulin, C-peptide, and glucagon excursions in 15 patients with MODY3. After an overnight fast, they received on three randomized occasions placebo, 1.25 mg glibenclamide, or 30 mg nateglinide before a standard 450-kcal test meal and light bicycle exercise for 30 min starting 140 min after the ingestion of the first test drug.. Insulin peaked earlier after nateglinide than after glibenclamide or placebo (median [interquartile range] time 70 [50] vs. 110 [20] vs. 110 [30] min, P = 0.0002 and P = 0.0025, respectively). Consequently, compared with glibenclamide and placebo, the peak plasma glucose (P = 0.031 and P < 0.0001) and incremental glucose areas under curve during the first 140 min of the test (P = 0.041 and P < 0.0001) remained lower after nateglinide. The improved prandial glucose control with nateglinide was achieved with a lower peak insulin concentration than after glibenclamide (47.0 [26.0] vs. 80.4 [71.7] mU/l; P = 0.023). Exercise did not induce hypoglycemia after nateglinide or placebo, but after glibenclamide six patients experienced symptomatic hypoglycemia and three had to interrupt the test.. A low dose of nateglinide prevents the acute postprandial rise in glucose more efficiently than glibenclamide and with less stimulation of peak insulin concentrations and less hypoglycemic symptoms.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise Test; Female; Glucagon; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

We have previously demonstrated abnormalities in insulin secretion in adolescents with type 2 diabetes mellitus (DM2) in response to the mixed meal test and to glucagon. In order to further assess beta-cell function in DM2, we measured insulin and C-peptide responses to oral glucose in adolescents with DM2 in comparison to non-diabetic obese and lean adolescents. We studied 20 patients with DM2, 25 obese adolescents with matching body mass index (BMI) (33.8 +/- 1.4 vs 34.3 +/- 1.0 kg/m2), and 12 non-obese control adolescents (BMI 22.6 +/- 0.6 kg/m2). Mean age, sex and sexual maturation did not differ between the three groups. All adolescents with DM2 had negative islet cell antibodies (ICA); five patients were on diet and 15 on insulin treatment. Fasting lipid profiles were determined in all participants. Plasma glucose and serum C-peptide and insulin levels were measured at 0, 30, 60, 90, and 120 min after an oral glucose load. The C-peptide increment (deltaCP) was calculated as peak minus fasting C-peptide. Area under the curve (AUC) was estimated using the trapezoid method. Insulin resistance was estimated using the HOMA model (HOMA-IR). The first phase of insulin secretion (PH1) was computed using a previously published formula. Serum triglyceride levels were significantly higher in the patients with DM2 compared to the non-obese controls (1.4 +/- 0.1 vs 0.9 +/- 0.1 mmol/l; p = 0.02). Plasma glucose AUC was greater in the patients with DM2 compared to the obese and non-obese control groups (1,660 +/- 130 vs 717 +/- 17 vs 647 +/- 14 mmol/l x min; p < 0.0001). ACP was lower in adolescents with DM2 than in obese and non-obese adolescents (761 +/- 132 vs 1,721 +/- 165 vs 1,225 +/- 165 pmol/l; p < 0.001). Insulin AUC was lower in the patients with DM2 compared to obese controls (888 +/- 206 vs 1,606 +/- 166 pmol/l x h; p = 0.009), but comparable to that of the non-obese controls (888 +/- 206 vs 852 +/- 222 pmol/l x h; p = 0.9). Insulin AUC was also higher in the obese than in the non-obese group (p = 0.05). PH1 was significantly higher in the obese group compared to the patients with DM2 as well as to the non-obese controls (2,614 +/- 2,47.9 vs 929.6 +/- 403.5 vs 1,946 +/- 300.6 pmol/l, respectively; p = 0.001). PH1 was also higher in the non-obese controls than in the patients with DM2 (p = 0.05). HOMA-IR was three-fold higher in the patients with DM2 than in the BMI-matched obese group, and five-fold higher than in the lean controls (14.3 +/- 1.2 vs 5.4

Topics: Adolescent; Black or African American; Blood Glucose; C-Peptide; Child; Cholesterol; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Obesity; Reference Values; Triglycerides

The pharmacokinetic and pharmacodynamic properties of biphasic insulin aspart (BIAsp 30) (30% soluble, 70% protaminated insulin aspart [IAsp]) and insulin glargine (IGlarg) were compared.. Twelve people with type 2 diabetes took part in two 24-h isoglycaemic clamp studies, 1 week apart. Patients were randomised to treatment with 0.5 U/kg of BIAsp 30 (0.25 U/kg at 08.30 h and 0.25 U/kg at 20.30 h) or 0.50 U/kg IGlarg at 08.30 h. Both insulins were given by subcutaneous injection into the anterior abdominal wall. The plasma glucose, glucose infusion rates, plasma insulin and C-peptide concentrations were measured.. All 12 patients were men; mean (+/-SD) age was 58.8 (8.9) years, BMI 31.0 (3.0) kg/m2 and HbA(1c) 7.1 (0.6)%. Plasma glucose was constant throughout the 24-h clamp period. After each injection of BIAsp 30, glucose infusion rates increased, reaching a distinct peak approximately 3-5 h after injection. A much flatter postinjection profile was observed following IGlarg administration. Plasma insulin concentrations rose rapidly after each injection of BIAsp 30, reaching a distinct peak after approximately 2-3 h. A flatter plasma insulin profile reached a plateau approximately 6-16 h after IGlarg administration. Plasma C-peptide fell below baseline after both injections of BIAsp 30 but remained unaltered after IGlarg injection.. The pharmacodynamic and pharmacokinetic profiles were 34 and 28%, respectively, higher following equivalent doses (0.5 U/kg) of BIAsp 30 given as two split doses than following IGlarg given as a single daily dose.

Topics: Aged; Area Under Curve; Biphasic Insulins; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Insulin; Insulin Aspart; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Kinetics; Male; Middle Aged

Large interventional studies have shown that statins may reduce the incidence of type 2 diabetes mellitus. However, it is uncertain whether short-term statin therapy can affect insulin sensitivity in patients with the metabolic syndrome. We evaluated the effect of atorvastatin (10 mg/day) in 10 insulin-resistant subjects (age 40 +/- 12 years, body mass index 33.6 +/- 5.2 kg/m(2), triglycerides 2.84 +/- 1.99 mmol/L [249 +/- 175 mg/dl], glucose 6.06 +/- 0.67 mmol/L [109 +/- 12 mg/dl)] using the homeostasis model assessment (HOMA) index (parameter of insulin resistance derived from fasting glucose and fasting insulin concentrations; 5.7 +/- 2.6) in a randomized placebo-controlled, double-blind, crossover study. Subjects were randomized to receive placebo or atorvastatin, each given for 6 weeks separated by a 6-week wash-out period. At the beginning and end of each treatment phase, the patients underwent an oral glucose tolerance test, a 72-hour continuous glucose measurement, and a detailed lipid determination, including a standardized fat tolerance test. Compared with placebo, atorvastatin resulted in a significant (p = 0.05) reduction in the HOMA index (-21%), fasting C-peptides (-18%), glucose (area under the curve during the oral glucose tolerance test, -7%), and a borderline (p = 0.08) reduction of insulin (-18%). The parameters derived from the continuous 72-hour glucose monitoring did not change. A significant reduction also occurred in the total and low-density lipoprotein cholesterol concentrations, although the fasting and postprandial triglyceride concentrations did not change significantly. However, we found a significant correlation between atorvastatin-induced changes in the HOMA and baseline HOMA and between the atorvastatin-induced changes in triglycerides and insulin concentrations. The free-fatty acid, interleukin-6, and high sensitivity C-reactive protein concentrations did not change. Our data indicated that in insulin-resistant, nondiabetic subjects, 6 weeks of atorvastatin (10 mg/day) resulted in significant improvement in insulin sensitivity.

Topics: Adult; Atorvastatin; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Pyrroles; Treatment Outcome

Supplementary insulin therapy provides assistance to meal-time insulin secretion in patients with type 2 diabetes and may have protective effects on beta-cell function.. This study explored the immediate effect of supplementary insulin therapy on beta- cell function in patients with glimepiride monotherapy (five women, 15 men; 61.8 +/- 6.4 years old; body mass index, 31.1 +/- 4.4 kg/m(2); hemoglobin A1c, 7.0 +/- 1.3%). After 1 week of continued glimiperide therapy, the patients were randomized either to continue with their oral treatment or to switch to a fixed-dose supplementary insulin therapy (8 U of insulin aspart subcutaneously before each meal) for another week. Oral glucose tolerance tests (OGTTs) after drug uptake were performed at days 7 and 14, with measurement of glucose, insulin, C-peptide, intact and total proinsulin, glucagon, lactate, free fatty acids, and adiponectin.. Significant reductions from baseline were seen in the supplementary insulin therapy group for the fasting values of insulin (from 13.1 +/- 5.1 microU/mL to 10.6 +/- 5.2 microU/mL, P < 0.01), intact proinsulin (from 18.3 +/- 11.2 pmol/L to 10.3 +/- 4.6 pmol/L, P micro 0.05), total proinsulin (from 43.3 +/- 22.7 pmol/L to 29.7 +/- 14.5 pmol/L, P < 0.01), split proinsulin (from 24.9 +/- 13.8 pmol/L to 19.4 +/- 10.8 pmol/L, P micro 0.01), and the degree of beta-cell dysfunction (P < 0.05). Also, lower values for intact and total proinsulin and split proinsulin in the OGTT were observed in this group during the OGTT at the end point, while no changes at all occurred in the glimepiride group.. A fixed low-dose preprandial insulin aspart therapy resulted in an overall beta-cell protection with an improved fasting beta-cell secretion profile already within 1 week. Our study indicates that supplementary insulin therapy might be a reasonable alternative to bedtime basal insulin injections for initiation of insulin therapy in patients with type 2 diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Oxidase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin-Secreting Cells; Male; Middle Aged; Proinsulin; Sulfonylurea Compounds

This study was designed to assess the usefulness of a model-based index of insulin sensitivity during an oral glucose tolerance test (OGTT) in the identification of possible changes in this metabolic parameter produced by pharmacological agents known to be potent insulin sensitizers, that is metformin (M) and thiazolidinedione (T). The association of these agents with several other factors related to glucose metabolism was also investigated, as well as the relation of insulin sensitivity and secretion with markers of endothelial function such as different adhesion molecules (cAMs), that is vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-Selectin.. Twenty type 2 diabetic patients treated with diet only underwent a 3-h OGTT for measurement of plasma glucose, insulin, proinsulin, C-peptide and cAMs before and after administration of randomly given M (n = 9; 1700 mg/day) or T (n = 11; 600 mg/day). After 16 weeks of treatment, a second OGTT was performed. Insulin sensitivity was calculated with homeostasis model assessment and with oral glucose insulin sensitivity (OGIS), which quantifies dynamic glucose clearance per unit change of insulin. Insulin secretion was assessed by modelling technique. Differences in these parameters before and after treatment, as well as possible relationships with cAMs, were assessed.. Basal and stimulated plasma glucose decreased after therapy in both the groups by approximately 20%. Basal insulin resistance also decreased. Insulin sensitivity in dynamic conditions (OGIS: ml/min/m(2)) increased with M (289.3 +/- 18.8 vs. 234.7 +/- 18.1, p < 0.02) and tended to improve with T (323.5 +/- 18.1 vs. 286.8 +/- 22.1, p = 0.09). Total insulin secretion over the OGTT [TIS: nmol/l(3 h)] tended to decrease with M (17.1 +/- 2.5 vs. 27.3 +/- 0.3, p = 0.08) but not with T (23.6 +/- 3.5 vs. 22.5 +/- 2.7). Plasma concentrations of E-Selectin decreased in T (38.0 +/- 2.3 vs. 51.2 +/- 6.1 ng/ml, p < 0.05). No correlation was found between insulin sensitivity and cAMs.. Model-based indices of insulin sensitivity and secretion during an OGTT can be able to detect changes observed in patients under treatment with pharmacological agents such as M or T. Both the drugs improved glucose control similarly. Decreased plasma E-Selectin concentrations were seen in patients on T therapy only.

Topics: Blood Glucose; Body Weight; C-Peptide; Cell Adhesion Molecules; Chromans; Diabetes Mellitus, Type 2; Drug Monitoring; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metformin; Middle Aged; Proinsulin; Thiazolidinediones; Troglitazone

To compare the effect of an experimental viscous fiber (VF) crispy bar on the postprandial glucose, insulin, and C-peptide response in adult subjects with type 2 diabetes to two commercially available control crispy bars.. The study was a randomized, double-blinded, three period, crossover study.. The study was conducted at two sites: Park Nicollet Institute, International Diabetes Center, Minneapolis, MN, and Radiant Research, Inc., Minneapolis, MN.. A total of 60 adults with type 2 diabetes taking oral antihyperglycemic medication participated in the study.. After an overnight fast, subjects consumed a test meal containing an equicaloric amount (300 kcal) of an experimental VF crispy bar or one of two commercially available crispy bars at each of three test visits, followed by a four hour meal tolerance test. Subjects also completed gastrointestinal (GI) response records for the 24 hours following each test visit.. The VF crispy bars produced significantly lower glucose (p < 0.0001), insulin (p < 0.0001), and C-peptide (p < 0.0001) responses (as measured by positive area under the curve) in subjects with type 2 diabetes, as compared with the two commercially available bars. Intensity (p < 0.05) and frequency (p < 0.05) of flatulence were significantly higher with the VF bar as compared with the 2 commercial bars. While the VF bar produced significant subjective GI tolerance scoring values, the mean value was below 3 on a scale of 0 (no effect) to 10 (most severe effect) for all tested materials.. The incorporation of VF into a crispy bar provided a means to improve blood glucose levels by reducing postprandial glucose, insulin, and C-peptide responses in subjects with type 2 diabetes. Though associated with some GI symptoms, VF may have application in improving the postprandial glycemic response in people with diabetes attempting intensive glucose control.

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Fiber; Double-Blind Method; Female; Flatulence; Humans; Insulin; Intestinal Absorption; Male; Middle Aged; Postprandial Period; Viscosity

This study evaluated the efficacy of rosiglitazone in non-obese and obese Korean type 2 diabetic patients of long duration. A total of 125 patients (M:F=44:81, mean age: 58.4+/-9.1 years, BMI: 24.2+/-2.7 kg/m2, duration of diabetes: 11.0+/-6.4 years) were randomly allocated to 12 weeks of rosiglitazone treatment (4 mg per day) or a control group. Responders were defined as patients who experienced fasting plasma glucose (FPG) reduction of >20% or HbA1c reduction of >1 (%). Rosiglitazone significantly improved glycemic control by reducing FPG and HbA1c (-3.4 mmol/l and -1.1%, P<0.001, respectively). It also significantly increased HOMA(beta-cell function) (+9.7, P<0.01) and QUICKI (+0.029, P<0.001), and decreased HOMA(IR) (-1.73, P<0.001). Females and those with higher waist-hip ratio made up a greater portion of rosiglitazone-responders. Responders (45 patients, 75%) also showed significantly higher FPG, HbA1c, systolic blood pressures, fasting insulin levels and HOMA(IR), and lower QUICKI than nonresponders. Among these parameters of responders, waist-hip ratio of non-obese subgroup, initial glycemic control of obese subgroup, and systolic blood pressure of both subgroups lost their significance after subdivision analysis. However, the baseline HOMA(IR) and QUICKI were significantly correlated with the response rate to rosiglitazone. Moreover, in multiple logistic regression analysis, HOMA(IR) and QUICKI retained their significance as the independent predictors. Even in Korean type 2 diabetic patients of long duration but with relatively preserved beta-cell function, rosiglitazone improved glycemic control, insulin sensitivity, and beta-cell function. In this ethnic group, female gender, central obesity, and especially severe insulin resistance were identified as predictive clinical parameters of rosiglitazone-responders.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Korea; Male; Middle Aged; Patient Selection; Rosiglitazone; Thiazolidinediones

This study compared the effects of pioglitazone and gliclazide on metabolic control in drug-naive patients with Type 2 diabetes mellitus.. A total of 1270 patients with Type 2 diabetes were randomized in a parallel-group, double-dummy, double-blind study. Patients with poorly controlled Type 2 diabetes (HbA1c 7.5-11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C-peptide and pro-insulin levels were measured.. Mean HbA1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: -1.4%; gliclazide: -1.4%; (90% CI: -0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference -0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: -0.7 to -0.1)]. Improvements in high-density lipoprotein cholesterol (HDL-C) and total cholesterol/HDL-C were greater with pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide.. Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Gliclazide; Humans; Hypoglycemic Agents; Insulin; Lipids; Middle Aged; Pioglitazone; Proinsulin; Thiazolidinediones; Treatment Outcome

Acarbose is able to enhance GLP-1 release and delay gastric emptying in normal subjects. The effect of alpha-glucosidase inhibition on GLP-1 has been less evident in Type 2 diabetic patients. The aim of this study was to investigate the possible influence of acarbose on GLP-1 release and gastric emptying in Type 2 diabetic patients after a mixed test meal.. Ten Type 2 diabetic patients were tested with 100 mg acarbose or placebo served with a mixed meal that was labelled with 100 mg 13C-octanoic acid. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1 and GIP were determined over 6 h. Gastric emptying was measured by determining breath 13CO2 using infrared absorptiometry. Statistics repeated-measures anova.. Gastric emptying rates (t1/2: 162 +/- 45 vs. 163 +/- 62 min, P = 0.65) and plasma concentrations (increasing from approximately 12 to approximately 25 pmol/l, P = 0.37) and integrated responses of GLP-1 (P = 0.37) were not changed significantly by acarbose treatment. Postprandial plasma glucose concentrations (P < 0.0001) and their integrated responses were lowered by acarbose (by 64%; P = 0.016). The plasma concentrations of insulin and C-peptide were reduced (P = 0.007 and 0.057, respectively) by acarbose, while glucagon was not changed (P = 0.96). GIP plasma concentrations (increasing with placebo from approximately 10 to approximately 85 pmol/l and with acarbose to approximately 55 pmol/l (P < 0.0001) and their integrated responses were significantly lowered (by 43%) by acarbose (P = 0.021). After 2 weeks of acarbose treatment (50 mg t.i.d. for the first and 100 mg t.i.d. for the second week, n = 6), similar results were found.. In hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a mixed test meal failed to enhance GLP-1 release and did not influence gastric emptying.

Topics: Acarbose; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptide Fragments; Postprandial Period; Protein Precursors

The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined. A euglycemic-hyperinsulinemic clamp, combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle, was performed before and after 26 weeks of metformin (n = 9), rosiglitazone (n = 10), or placebo (n = 11) treatment. Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32%, respectively, after rosiglitazone (P < 0.01) but not after metformin or placebo treatment. Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, approximately 2.3 fold before treatment. These insulin signaling parameters were unaltered after metformin, rosiglitazone, or placebo treatment. Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups. Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling. In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Gene Expression Regulation; Glucose; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Metformin; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rosiglitazone; Thiazolidinediones

To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal.. Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart.. The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses.. Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Piperidines; Postprandial Period

The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function.. This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors.. Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P < 0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P < 0.0001) relative to placebo.. Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

Topics: Adamantane; Adenosine Deaminase Inhibitors; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Enzyme Inhibitors; Female; Glycoproteins; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Models, Biological; Nitriles; Pyrrolidines; Treatment Outcome; Vildagliptin

The aim of this analysis was to examine the long-term effects of pioglitazone or gliclazide addition to failing metformin monotherapy and pioglitazone or metformin addition to failing sulphonylurea monotherapy in patients with type 2 diabetes.. Two 2-year, randomised, multicentre trials were performed in patients with inadequately controlled type 2 diabetes (HbA1c 7.5-11% inclusive), who were receiving either metformin or a sulphonylurea at > or = 50% of the maximum recommended dose or at the maximum tolerated dose. In the first study, patients on metformin received add-on therapy with pioglitazone (15-45 mg/day, n = 317) or gliclazide (80-320 mg/day, n = 313). In the second study, patients on sulphonylurea therapy were randomised to receive add-on therapy with either pioglitazone (15-45 mg/day, n = 319) or metformin (850-2,550 mg/day, n = 320). HbA(1)c, fasting plasma glucose, insulin and lipids were investigated.. At week 104, the mean reduction from baseline in HbA(1)c was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin (p = 0.200). There was a statistically significant between-group difference for the change in mean fasting plasma glucose at week 104 (-1.8 mmol/l for pioglitazone vs -1.1 mmol/l for gliclazide, p < 0.001). There were no significant differences in changes from baseline in glycaemic parameters for pioglitazone compared with metformin addition to sulphonylurea therapy. Whether added to metformin or sulphonylurea, pioglitazone caused significantly greater decreases in triglycerides and significantly greater increases in HDL cholesterol than the comparator regimens (p < or = 0.001). There were decreases in LDL cholesterol in the comparator groups and these were significantly different from the small changes observed with pioglitazone (p < 0.001). All treatment regimens were well tolerated. There were weight increases of 2.5 kg and 3.7 kg in the pioglitazone and 1.2 kg in the gliclazide add-on groups, and there was a mean decrease of 1.7 kg in the metformin add-on group.. As add-on therapy to existing sulphonylurea or metformin therapy, pioglitazone improved glycaemic control and this improvement was sustained over 2 years. Furthermore, there were potential benefits in terms of improvements in specific lipid abnormalities. This could offer an advantage over the addition of other oral agents in the long-term treatment of diabetes.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Pioglitazone; Reproducibility of Results; Safety; Thiazolidinediones; Treatment Failure; Treatment Outcome

The aim of this study was to determine whether the influence of insulin therapy on fasting and stimulated C-peptide levels in type 2 diabetic subjects is due to plasma glucose reduction or a direct effect of exogenous insulin.. Plasma glucose and serum C-peptide levels were determined before and after IV injection of 1mg glucagon on three separate days in 21 type 2 diabetic subjects. Day 1: without pharmacological treatment and fasting plasma glucose > 11.1 mmol/L; day 2: fasting plasma glucose 4.4-7.8 mmol/L, 1h after withdrawing intravenous regular insulin infusion; day 3: fasting plasma glucose 4.4-7.8 mmol/L with bed-time NPH insulin.. Fasting and glucagon stimulated C-peptide levels were higher on day 1 than days 2 and 3. Fasting, but not stimulated C-peptide levels, were lower on day 3 than day 2. These differences were not appeared when the percentage of C-peptide increment or the C-peptide/glucose ratio were compared in the three days.. Blood glucose reduction instead of exogenous insulin is responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged

Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone.. We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals.. Triglyceride levels were reduced by 51.9 +/- 7.8 mg/dl with pioglitazone, but were increased by 13.1 +/- 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 +/- 0.5 vs. 2.4 +/- 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 +/- 1.6 vs. 21.3 +/- 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005).. Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.

Topics: Aged; Apolipoproteins B; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipidemias; Hypoglycemic Agents; Lipids; Male; Middle Aged; Pioglitazone; Placebos; Rosiglitazone; Thiazolidinediones; Triglycerides

An autoregulatory mechanism involving a reciprocal relationship between gluconeogenesis and glycogenolysis regulates endogenous glucose production (EGP) in healthy individuals. In type 2 diabetes, fasting hyperglycemia may be due to increased EGP.. To examine gluconeogenesis and autoregulation of EGP in type 2 diabetes, 9 type 2 diabetics and 8 healthy controls were studied during a 3-h infusion of 30 micromol/kg/min Na-lactate. The diabetics were also studied during a control infusion of Na-bicarbonate. To standardize levels of glucoregulatory hormones, plasma insulin, growth hormone, and glucagon were clamped at identical levels during the three experiments. Glucagon levels were elevated from basal levels to approximately 330 ng/l when the lactate or bicarbonate infusions were started, in order to mimic the hyperglucagonemia often seen in diabetes. Lactate gluconeogenesis and total EGP were measured by infusions of [6-(3)H] glucose and [U-14C] lactate.. In the bicarbonate experiments, hyperglugagonemia increased lactate gluconeogenesis in the diabetic patients from 4.3+/-1.8 to 6.1+/-2.4 micromol/kg/min (p=0.04). EGP did not change significantly (basal EGP: 15.3+/-3.9, EGP at the end of the study: 14.2+/-3.9 micromol/kg/min, p=0.14). During both lactate experiments, plasma lactate increased more than 4-fold. The increase in lactate gluconeogenesis was significantly higher in diabetics than in controls (values obtained at the end of experiments minus basal values: 10.8+/-3.6 versus 6.4+/-3.6 micromol/kg/min, p=0.03). Compared with normal subjects, the diabetic patients had higher EGP values both at basal conditions (p=0.001) and during lactate infusion (p=0.005). Despite augmented gluconeogenesis, EGP did not change during lactate and glucagon infusion in any of the groups (diabetics, basal EGP: 15.4+/-2.7 versus EGP at the end of experiments: 15.6+/-3.6 micromol/kg/min, p>0.30. Controls, basal EGP: 11.8+/-0.8 versus EGP at the end of experiments: 11.6+/-1.9 micromol/kg/min, p>0.30).. Although type 2 diabetics have increased EGP and increased lactate gluconeogenesis, the hepatic autoregulation of EGP during increased substrate-induced gluconeogenesis seems to be intact.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon; Gluconeogenesis; Glucose; Glucose Clamp Technique; Homeostasis; Human Growth Hormone; Humans; Insulin; Liver; Male; Middle Aged; Sodium Bicarbonate; Sodium Lactate

This study evaluated the efficacy and tolerability of glimepiride in patients with type 2 diabetes mellitus that was inadequately controlled with a combination of immediate- or extended-release metformin and a thiazolidinedione.. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 2-arm study consisting of a 4-week stabilization and eligibility period and a 26-week treatment period. Patients with a diagnosis of type 2 diabetes for a minimum of 1 year received glimepiride (titrated sequentially from 2 to 4 to 8 mg/d over 6 weeks, followed by 20 weeks of maintenance therapy) or placebo in combination with an established regimen of immediate- or extended release metformin and rosiglitazone or pioglitazone. The primary efficacy outcome was the change in glycosylated hemoglobin (HbA(1c)) from baseline. The safety analysis was based on the incidence of hypo glycemia, adverse events, and laboratory abnormalities. Changes in lipid levels (high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglycerides) were evaluated, and health-related quality of life was assessed based on scores on the Diabetes Care Profile (DCP) and Health Utilities Index Mark 3 (HU13).. Of 170 randomized patients, 159 were included in the efficacy analysis and 168 were included in the safety analysis. Demographic variables were similar at baseline between the glimepiride and placebo groups (mean age, 56.5 and 56.4 years, respectively; percent men/women, 61.0%/39.0% and 62.3%/37.7%; weight, 100.9 and 96.3 kg). HbA(1c) was significantly improved at end point with glimepiride combination therapy compared with placebo (mean [SE], -1.31% [0.08] vs -0.33% [0.08], respectively; P < 0.001). The majority of patients (62.2%) who received glimepiride achieved an HbA(1c) value of < or =7%, compared with 26.0% of patients receiving placebo (P < 0.001 between groups). At end point, the adjusted mean differences between treatments significantly favored the glimepiride combination in terms of fasting plasma glucose (-37.4 [4.0] mg/dL; P < 0.001), fasting insulin (4.06 [1.69] microIU/mL; P < 0.03), and C-peptide (124.5 [35.9] pmol/L; P < 0.001). The adjusted mean changes in body mass index from baseline to end point were 1.26 (0.16) kg/m(2) with glimepiride and 0.17 (0.16) kg/m(2) with placebo (P < 0.001). Similarly, the mean change in weight was greater with glimepiride than with placebo (3.76 [0.54] vs 0.45 [0.52] kg; P < 0.001). There were no significant differences in lipid levels between groups. Clinically significant adverse events, laboratory abnormalities, and rates of severe hypoglycemia were similar between treatment groups. The overall incidence of hypoglycemia, however, was 51.2% in the glimepiride group and 8.3% in the placebo group (P < 0.001). In general, there was no significant difference between treatment groups with respect to scores on the DCP or HUI3 over the study period.. In these patients with type 2 diabetes that was not adequately controlled by dual combination therapy with metformin and a thiazolidinedione, the addition of glimepiride improved glycemic control compared with placebo with an acceptable tolerability profile. Although there were significantly more episodes of hypoglycemia with triple therapy than with dual therapy and placebo, the risk for severe hypoglycemia was low.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metformin; Middle Aged; Pioglitazone; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Time Factors

This was a randomized, double blind, three period crossover study. The objective was to compare glucose, insulin and C-peptide 24 h profiles in patients with type 2 diabetes mellitus after dosing with nateglinide (given preprandially before three test meals), glibenclamide (administered once before breakfast) or placebo (given before three test meals).. Fourteen patients underwent screening followed within 3 weeks by three treatment periods of 1 day, each separated by 7 days. Dosing followed a six-sequence balanced, two 3 x 3-replicated Latin square.. Mean peak serum insulin levels were lower after nateglinide (115 mU/l) than after glibenclamide (145 mU/l.h; p = 0.017) but higher than after placebo (79 mU/l; p = 0.001). However, peak insulin levels were reached earlier after nateglinide [mean time to peak (tmax) 1.7 h] compared to glibenclamide (mean tmax 2.1 h, p = 0.06). Total insulin exposure over the day was higher after glibenclamide compared with that following nateglinide (1216 vs. 1067 mU/l.h; p = 0.009). Similar findings were seen with serum C-peptide. Despite this, mean peak plasma glucose concentrations were lower following nateglinide (11.4 mmol/l from a baseline of 8.3 mmol/l) compared with glibenclamide (13.2 mmol/l from a baseline of 8.5 mmol/l; p = 0.001) and placebo (14.0 mmol/l from a baseline of 8.0 mmol/L; p < 0.001).. Nateglinide improves early prandial measures of insulin and glucose response to a standard meal, more so than glibenclamide, in people with type 2 diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

To compare the efficacy of combination therapy using rosiglitazone (8 mg per day) and glibenclamide (7.5 mg per day) with upward titration of glibenclamide as monotherapy (maximum dose=15 mg per day) in reducing HbA(1c) levels over 26 weeks in patients with type 2 diabetes mellitus (T2DM).. Three hundred and forty patients with T2DM inadequately controlled (FPG > or =7.0 and < or =15.0 mmol/l) on glibenclamide 7.5 mg per day were randomised to either additional treatment with rosiglitazone 8 mg per day or up-titration of the glibenclamide dose (maximum dose=15 mg per day).. After 26 weeks, treatment with rosiglitazone combination reduced HbA(1c) by 0.81% (P<0.0001) and FPG by 2.4 mmol/l (P<0.0001) compared with glibenclamide monotherapy. HOMA-S and HOMA-B increased by 12 and 28%, respectively (P<0.0001 for both) with combination compared with glibenclamide monotherapy. With rosiglitazone combination and glibenclamide monotherapy, total cholesterol: HDL ratio reduced by 5 and 13%, triglycerides reduced by 6 and 2%, and FFAs reduced by 15 and 8%, respectively. Both treatments were well tolerated and had predictable safety profiles.. For patients inadequately controlled on glibenclamide, addition of rosiglitazone provides significantly improved glycaemic control compared with uptitration of glibenclamide. This may be preferable to continued monotherapy with higher doses of glibenclamide.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Fatty Acids, Nonesterified; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Placebos; Rosiglitazone; Thiazolidinediones; Triglycerides

The aim of this study was to determine the metabolic effect and the safety of a novel oral insulin spray (Oralin) formulation at breakfast-time in subjects with type 2 diabetes with suboptimal glucose control and maintained on a combination therapy of oral hypoglycemic agents (OHAs). This was an open-label, crossover, randomized study design in subjects (n = 21) with type 2 diabetes (glycated hemoglobin A1c >8.0%). Subjects received each of the following treatments, in random order: metformin + glyburide and placebo puffs at time 0 min; or metformin + glyburide and Oralin spray (100 U) at time 0 min. Fifteen minutes later, subjects were given a standard breakfast containing 360 calories [Sustacal (Mead Johnson, Evansville, IN) liquid meal]. Blood samples were taken at regular intervals to measure serum glucose, insulin, and C-peptide. Time-averaged postprandial glucose increments (PPGIs) between 0 and 240 min were calculated for each treatment. Group mean PPGIs to OHAs versus Oralin in combination with OHAs were compared to determine the mean efficacy of the active treatment. The Oralin spray lowered the 2-h postprandial glucose rise significantly in comparison with the OHAs alone. The serum insulin levels were significantly higher with faster onset of action in the Oralin spray treatment when compared with the OHAs treatment. The reductions in C-peptides were also significantly greater in the Oralin arm than in the OHAs treatment. This study results demonstrated that Oralin could be used as meal insulin as an add-on therapy in combination with failing OHAs treatment in subjects with type 2 diabetes to regulate postprandial glucose levels.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Metformin; Middle Aged; Prospective Studies; Statistics, Nonparametric

The effect of short- (2 h) and long-term (24 h) low-grade Intralipid infusion on whole-body insulin action, cellular glucose metabolism, and proximal components of the insulin signal transduction cascade was studied in seven obese male glucose intolerant first degree relatives of type 2 diabetic patients [impaired glucose tolerance (IGT) relatives] and eight matched control subjects. Indirect calorimetry and excision of vastus lateralis skeletal muscle biopsies were performed before and during hyperinsulinemic euglycemic clamps combined with 3[(3)H]glucose. Clamps were performed after 0, 2, or 24 h Intralipid infusion (0.4 ml.kg(-1).min(-1)). Insulin-stimulated glucose disposal decreased approximately 25% after short- and long-term fat infusion in both IGT relatives and controls. Glucose oxidation decreased and lipid oxidation increased after both short- and long-term fat infusion in both groups. Insulin-stimulated glucose oxidation was higher after long-term as compared with short-term fat infusion in control subjects. Short- or long-term infusion did not affect the absolute values of basal or insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation, tyrosine-associated phosphoinositide 3-kinase (PI 3-kinase) activity, insulin receptor substrate-1-associated PI 3-kinase activity, or Akt serine phosphorylation in IGT relatives or matched controls. In fact, a paradoxical increase in both basal and insulin-stimulated PI 3-kinase activity was noted in the total study population after both short- and long-term fat infusion. Short- and long-term low-grade Intralipid infusion-induced (or enhanced) whole-body insulin resistance and impaired glucose metabolism in IGT relatives and matched control subjects. The fat-induced metabolic changes were not explained by impairment of the proximal insulin signaling transduction in skeletal muscle.

Topics: Blood Glucose; C-Peptide; Calorimetry, Indirect; Diabetes Mellitus, Type 2; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Glucose Clamp Technique; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Risk Factors; Signal Transduction; Triglycerides

To compare the effect of Repaglinide vs Glimepiride on glucose- and meal-induced insulin secretion and on meal-test induced postprandial glucose excursions.. After 2 weeks washout period, a 3-Month randomised, cross-over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with type 2 diabetes "naive" in diet treatment was made.. Both R and G significantly but similarly lowered fasting glucose levels and improved fasting plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/- 34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120'; p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/- 0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G administration. In the meal test, R therapy produced a more rapId induction of insulin secretion during the first part. In fact, the mean rise in insulin secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R). Consequently, glucose spike at 60 min was higher in G group compared to glucose spike at 45 min in R group (p=0.002).. Our study demonstrates that R is more efficient that G on improving glucose- and meal- induced insulin secretion as well as on controlling for postprandial glucose excursion.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Middle Aged; Piperidines; Postprandial Period; Sulfonylurea Compounds; Time Factors; Triglycerides

We examined the long-term metabolic effects of glipizide gastrointestinal therapeutic system (GITS), a potent sulfonylurea (SU), in impaired glucose-tolerant (IGT), first-degree relatives of African American patients with type 2 diabetes. To this end, we assessed glucose homeostasis, beta-cell function, insulin sensitivity (Si), and glucose effectiveness (Sg) in patients with IGT before and at yearly intervals for 24 months of GITS or an identical placebo in a randomized, double-blind manner. Eighteen IGT patients were randomized to receive either glipizide GITS (GITS, 5 mg/d, n = 9; mean age, 43.3 +/- 8.7 years; mean body mass index [BMI], 32.9 +/- 6.3 kg/m(2)) or identical placebo (PLAC, n = 9; mean age, 41.5 +/- 5.7 years; mean BMI, 39 +/- 4.2 kg/m(2)) for 24 months. Each of the subjects underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and yearly intervals for 2 years. Si and Sg were determined by Bergman's minimal model method. The ability of beta cell to compensate for peripheral insulin resistance was calculated as the disposition index (DI). Chronic administration of glipizide GITS attenuated serum glucose responses to oral glucose challenge at 12 and 24 months when compared to baseline (0 months). In contrast, serum glucose levels at fasting and during OGTT tended to increase in the IGT/PLAC group at 12 and 24 months when compared to baseline. Serum insulin (P <.05 to 0.01) and serum C-peptide levels progressively increased in the GITS group at 12 and 24 months versus 0 months. In contrast, serum insulin and C-peptide responses remained unchanged in the IGT/PLAC group. During FSIGT, chronic GITS was associated with significant improvement in the blunted acute first insulin release in the IGT patients at 12 and 24 months. These parameters remained blunted in the IGT/PLAC group. We found that Si increased in the IGT/GITS group at 12 months (P <.01) and 24 months(P <.05) versus baseline, but deteriorated in the IGT/PLAC group. Similarly, the DIs significantly (P <.01) increased following GITS therapy at 12 and 24 months when compared to baseline. In contrast, DI did not change from baseline values in the IGT/PLAC group throughout the study period. Chronic GITS partially restored the ability of beta cells to compensate for peripheral insulin resistance (as assessed by DIs). GITS was well tolerated without any symptoms suggestive of either hypoglycemia or significant weight gain.

Topics: Adult; Black or African American; Blood Glucose; Body Composition; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Glipizide; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Models, Biological; Obesity; Risk Factors

To investigate the effect of treatment with pioglitazone on beta-cell function and insulin sensitivity in Type 2 diabetes.. Thirty subjects with diet-controlled Type 2 diabetes were randomized to 3 months treatment with pioglitazone (n = 19) or placebo (n = 11). All subjects underwent basal sampling for homeostatic model assessment (HOMA), followed by an intravenous glucose tolerance test and hyperglycaemic clamp, followed by an euglycaemic hyperinsulinaemic clamp; at baseline and after treatment.. All results are expressed as mean (sem). Pioglitazone increased basal insulin sensitivity by 24.7% (7.8) HOMA-%S vs. 2.1% (5.9) in the placebo group (P = 0.02). Stimulated insulin sensitivity, M/I, increased in the pioglitazone group compared with placebo: +15.1 (2.8) l kg(-1) min(-1) vs. +3.2 (2.9) l kg(-1) min(-1), respectively (P = 0.009). Pioglitazone increased adiponectin by 39.3 (6.3), ng/ml compared with a decrease of 0.8 (1.3) ng/ml with placebo (P = 0.00004). HOMA-%B increased with pioglitazone, +11.5% (4.8) vs. -2.0% (4.8) with placebo (P = 0.049), but there was no change in stimulated beta-cell function as determined by hyperglycaemic clamps. There was a significant reduction in the proinsulin/insulin ratio in the pioglitazone group, -0.057 (0.02) compared with placebo, +0.004 (0.02) (P = 0.03). There was a significant reduction in HbA(1c) of 0.6% (0.1) in the pioglitazone group compared with placebo (P = 0.003). There was no significant weight gain associated with pioglitazone therapy: +0.7 (sem 0.6) kg vs. +1.1 (sem 0.5) kg in placebo group (P = NS).. Basal beta-cell function and insulin sensitivity improved following pioglitazone therapy. The improvement in proinsulin to insulin ratio suggests that beta-cells are under less stress.

Topics: Aged; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Middle Aged; Pioglitazone; Thiazolidinediones

The effects of a combination of repaglinide and metformin on the insulin secretion pattern and insulin sensitivity were studied in a fixed-dose, open-label, placebo-controlled cross-over study. Eleven patients with T2 DM were allocated in random order to treatment with placebo or repaglinide (1 mg pre-meal 3 x/day) in combination with metformin (2550 mg/day) for one-week periods of each. At the end of each period a hyperglycaemic (HC) and a euglycaemic clamp (EC) were performed. Both early (0 - 10 min) and late (25 - 180 min) phases of insulin secretion were significantly increased during HC with repaglinide compared to placebo (263.3 +/- 133.1 vs. 443.6 +/- 138.5 pmol/l/10 min, p = 0.008 and 18 750.9 +/- 5936.4 vs. 34 508.65 +/- 9234.0 pmol/l/25 - 180 min; p = 0.008). The C-peptide concentrations under steady-state conditions were lower in EC with placebo than with repaglinide (p = 0.014). When euglycaemia was achieved in EC, the C-peptide concentrations decreased from hyperglycaemic to normoglycaemic values in the presence of repaglinide but remained higher than after placebo. The insulin sensitivity index (ISI) was increased by 35 % after 1 week of combination therapy with repaglinide plus metformin (1.11 +/- 0.03 x 10 (2) vs. 0.83 +/- 0.21 x 10 (2) mg x kg (-1) body weight x min (-1) x pmol (-1) x l, respectively; p = 0.033). Repaglinide increased early and late phases of insulin responses in HC, without markedly enhancing insulin secretion in euglycaemia. Repaglinide in combination with metformin produced a significant enhancement of ISI, suggesting a synergistic effect on insulin sensitivity.

Topics: Adult; Aged; C-Peptide; Carbamates; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Metformin; Middle Aged; Piperidines; Placebos; Time Factors

In healthy young subjects, training increases insulin sensitivity but decreases the capacity to secrete insulin. We studied whether training changes beta-cell function in type 2 diabetic patients. Patients, stratified into "moderate" and "low" secretors according to individual C-peptide responses to an intravenous glucagon test, were randomly assigned to a training program [ergometer cycling 30-40 min/day, including at least 20 min at 75% maximum oxygen consumption (Vo(2 max)), 5 days/wk for 3 mo] or a sedentary schedule. Before and after the intervention (16 h after last training bout), a sequential hyperglycemic (90 min at 11, 18, and 25 mM) clamp was performed. An intravenous bolus of 5 g of arginine was given at the end. Training increased Vo(2 max) 17 +/- 13% and decreased heart rate during submaximal exercise (P < 0.05). During the 3 mo of sedentary lifestyle, insulin and C-peptide responses to the clamp procedures were unchanged in both moderate and low secretors. Likewise, no change in beta-cell response was seen after training in the low secretors (n = 5). In contrast, moderate secretors (n = 9) showed significant increases in beta-cell responses to 18 and 25 mM hyperglycemia and to arginine stimulation. Glucagon responses to arginine as well as measures of insulin sensitivity and Hb A(1c) levels were not altered by training. In conclusion, in type 2 diabetic patients, training may enhance beta-cell function if the remaining secretory capacity is moderate but not if it is low. The improved beta-cell function does not require changes in insulin sensitivity and Hb A(1c) concentration.

Topics: Adaptation, Physiological; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Exercise; Glucose Clamp Technique; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Physical Exertion; Physical Fitness

We investigated effects of weight loss from diet and exercise regimen in obese subjects with normal fasting plasma glucose or impaired glucose tolerance (IGT) on insulin release capacity and insulin sensitivity. Eight subjects were recruited among visceral obesity patients (4 men, 4 women; age range, 24 to 57 years; body mass index [BMI], 32.8 to 60.3 kg/m(2)). All were admitted to Chiba University Hospital for 2 weeks, were treated with a tapering 5,023 to 2,930 kJ diet, and were given exercise equivalent to 628 kJ/d. For assessments, we used a combination of C-peptide secretion rate determination and minimal model analysis as previously reported. BMI and visceral fat area (V) significantly decreased (BMI on initiation v after intervention, 43.0 +/- 3.2 v 40.3 +/- 3.1 kg/m(2), P <.05; V, 224 +/- 22 v 188 +/- 22 cm(2); P <.05). Fasting immunoreactive insulin (F-IRI) and leptin concentrations decreased significantly. Capacity for insulin release in response to glucose increased in all subjects (first-phase insulin secretion [CS1], 4.66 +/- 4.05 v 6.81 +/- 4.57 ng/mL/5 min, P <.05), but the insulin sensitivity index (S(i)) did not change significantly. These data suggest that weight reduction early in development of type 2 diabetes can oppose progression of diabetes by improving capacity for insulin release.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Exercise Therapy; Female; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Models, Biological; Obesity; Weight Loss

This study was designed to compare the effects of repaglinide plus acarbose combination treatment to repaglinide alone on postprandial glucose, serum insulin, C-peptide and proinsulin concentrations. A total of 40 patients with Type 2 diabetes (T2DM) (fasting blood glucose: 120-180 mg/dl; postprandial blood glucose: 140-240 mg/dl) were included in this single-centre, controlled, randomised, single-dose, cross-over study. On two consecutive days, patients either received 2 mg repaglinide 15 min before breakfast followed by 100 mg acarbose with breakfast or repaglinide alone. Two fasting (7.30 h, 8.00 h) and five postprandial blood samples (from 8.30 h to 12.00 h) were taken for blood glucose, serum insulin, C-peptide and proinsulin determination. Repaglinide plus acarbose treatment significantly reduced the mean increase in postprandial blood glucose levels (24.2+/-18.2 mg/dl) compared to repaglinide alone (51.1+/-29.0 mg/dl; p<0.001). Serum insulin, C-peptide and proinsulin levels [mean area under the curve (AUC7.30-12.00h)] were significantly lower than those observed with repaglinide monotherapy (e.g. insulin: 1089.2+/-604.5 hr x pmol/l and 1596.8+/-1080.6 hr x pmol/l, resp., p<0.001), suggesting that acarbose modifies the rapid insulin release induced by repaglinide. Prandial treatment with a combination of acarbose and repaglinide results in an additive glucose lowering effect and modified insulin secretion compared to repaglinide alone. Postprandial hyperglycaemia is not abolished by rapid stimulation of insulin release induced by repaglinide. Additional reduction of postprandial blood glucose by acarbose modifies the stimulation of insulin release.

Topics: Acarbose; Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Food; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Middle Aged; Piperidines; Proinsulin

We examined the metabolic effects of rosiglitazone therapy on glucose control, insulin sensitivity, insulin secretion, and adiponectin in first-degree relatives of African Americans with type 2 diabetes (DM) with impaired glucose tolerance (IGT) and DM for 3 months. The study was comprised of 12 first-degree relatives with IGT, 17 newly diagnosed DM, and 19 healthy relatives with normal glucose tolerance (NGT). Oral glucose tolerance test (OGTT) was performed before and after 3 months of rosiglitazone therapy (4 to 8 mg/d) in patients with IGT and DM. Serum glucose, insulin, C-peptide, and adiponectin levels were measured before and 2 hours during OGTT in the NGT and patients with IGT and DM. Insulin resistance index (HOMA-IR) and beta-cell function (HOMA-%B) were calculated in each subject using homeostasis model assessment (HOMA). Rosglitazone improved the overall glycemic control in the IGT and DM groups. Following rosiglitazone, the beta-cell secretion remained unchanged, while HOMR-IR was reduced in DM by 30% (4.12 +/- 1.95 v 6.33 +/- 3.54, P < .05) and the IGT group (3.78 +/- 2.45 v 4.81 +/- 3.49, P = not significant [NS]). Mean plasma adiponectin levels were significantly (P < .05) lower in the DM (6.74 +/- 1.95 microg/mL) when compared with the NGT group(9.61 +/- 5.09). Rosiglitazone significantly (P < .001) increased adiponectin levels by 2-fold in patients with IGT (22.2 +/- 10.97 microg/mL) and 2.5-fold greater in DM (15.68 +/- 8.23 microg/mL) at 3 months when compared with the 0 month. We conclude that adiponectin could play a significant role (1) in the pathogenesis of IGT and DM and (2) the beneficial metabolic effects of thiazolidinediones (TZDs) in high-risk African American patients.

Topics: Adiponectin; Adult; Black or African American; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Lipids; Longitudinal Studies; Middle Aged; Risk Factors; Rosiglitazone; Thiazolidinediones

A double-blind, prospective, randomised, cross-over clinical trial was performed comparing a glibenclamide (G) 5.0 mg/metformin (M) 400 mg combination with a G 2.5 mg/M 400 mg formulation to evaluate whether a higher dose of glibenclamide was able to improve glycaemia in poorly controlled Type 2 diabetic patients. One hundred and ninety-eight patients with poorly controlled Type 2 diabetes mellitus were randomised to receive one of the two trial drugs for a first 3-month period, and were then assigned to the alternative combination for further 3 months. The starting dose (2 tablets/day, 30 min before breakfast and dinner) was to be up-titrated to 3 tablets/day when required. A standard dietary regimen was kept constant for the total trial duration. Fasting plasma glucose, HbA1c, C-peptide, insulin and lactate levels, haematology and blood chemistry were measured at the start/end of each cycle. Patients' self-assessment of the glycaemic profile (at fasting and 2 hr after the main meals) was performed weekly. Patients were constantly monitored for adverse events and episodes of hypoglycaemia, and all events were recorded. Decrease of mean fasting glucose levels measured in the first cycle was more pronounced in the group treated with G 5.0 mg/M 400 (p<0.01) compared to baseline, although the difference was not significant--no changes were observed in the second 3-month period. Results of patients' self-assessment of the glycaemic profile in the overall 6-month period show that the two trial drugs produced similar effects on fasting glucose, but the decrease of post-prandial glycaemic levels was markedly higher with G 5 mg/M 400 mg than with G 2.5 mg/M 400 mg at both main meals. A similar significant decrease (p<0.01) of HbA1c was observed in both sequence groups at the end of the first 3-month treatment period, and mean levels remained unchanged at 6 months. Drug-related adverse events were observed in 2 patients during treatment with G 2.5 mg/M 400 mg and in 5 with G 5 mg/M 400 mg, while 14 and 22 episodes of hypoglycaemia occurred with the two trial drugs, respectively (p=NS between treatments). Metformin-induced increases of lactate levels were similar in the two sequence groups. No differences between groups were found either in the number of up-titrated patients or in all the other laboratory parameters. In conclusion, the new combination containing 5-mg glibenclamide produced a greater improvement in post-prandial glycaemic control compared with the s

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Food; Glyburide; Glycated Hemoglobin; History, 18th Century; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Lactic Acid; Male; Metformin; Middle Aged; Prospective Studies

Congestive heart failure (CHF) is a serious disease with a poor prognosis. Diabetes is an independent risk factor for CHF, probably in part due to disturbances in myocardial metabolism. Glucagon-like peptide-1 (GLP-1) causes glucose-dependent secretion of insulin, improving glycaemic control. In turn, this may improve myocardial metabolism and myocardial function. The aim of the present study was to assess the feasibility and safety of three days' infusion of recombinant GLP-1 in an open observational study in six patients with type 2 diabetes and CHF. The study included assessment of myocardial function. There were no major complications of the infusion, and all patients completed the study protocol. Some improvement was observed in glycaemic state, and there was an insignificant trend towards improved myocardial function. It is concluded that GLP-1 deserves further evaluation in such patients.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Echocardiography, Doppler; Exercise Test; Glucagon; Glucagon-Like Peptide 1; Heart; Heart Failure; Humans; Infusions, Parenteral; Injections, Subcutaneous; Insulin; Male; Myocardial Contraction; Pilot Projects; Recombinant Proteins; Time Factors

A gut insulinotropic peptide, glucagon-like peptide-1 (GLP-1), when given continuously subcutaneously, has been shown to be an effective agent to treat type 2 diabetes. Because of inactivation by dipeptidyl peptidase IV (DPP IV), it has a very short half-life (90-120 s), hence the need for continuous administration. Exendin-4 is an agonist of the GLP-1 receptor. It is not a substrate for DPP IV, and we previously demonstrated that intravenous administration has potent insulinotropic properties in type 2 diabetic volunteers. We evaluated the efficacy of bolus subcutaneous exendin-4 in insulin-naive type 2 diabetic volunteers. Ten patients aged 44-72 yr with mean fasting glucose levels of 11.4 +/- 0.9 mmol/l were enrolled, and daily or twice-daily bolus subcutaneous exendin-4 was self-administered for 1 mo. Glycosylated hemoglobin, multiple daily capillary blood glucose, beta-cell sensitivity to glucose, and peripheral tissue sensitivity to insulin were compared before and after treatment. The greatest decline in capillary blood glucose was seen before bed, with a drop from 15.5 to 9.2 mmol/l (P < 0.0001). Glycosylated hemoglobin improved significantly with treatment, from 9.1 to 8.3% (P = 0.009). beta-Cell sensitivity to glucose was improved, as assessed by C-peptide levels during a hyperglycemic clamp. No significant adverse effects were noted or reported. Our data suggest that, even with this short duration of therapy, exendin-4 treatment had a significant effect on glucose homeostasis.

Topics: Aged; Blood Glucose; Body Composition; C-Peptide; Diabetes Mellitus, Type 2; Exenatide; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Resistance; Islets of Langerhans; Male; Middle Aged; Peptides; Venoms

Whether free fatty acid (FFA) rate of appearance (R(a)) is increased in type 2 diabetes is controversial. To characterize nocturnal and postprandial abnormalities in FFA kinetics and to determine the effects of treatment with insulin sensitizers on lipolysis, we measured palmitate R(a) in control subjects (n = 6) and individuals with poorly controlled, sulfonylurea-treated type 2 diabetes (HbA(1c) = 8.7 +/- 0.2%, n = 20), the latter before and at the end of 12 weeks of treatment with troglitazone (600 mg/day, n = 4), metformin ( approximately 2,000 mg/day, n = 8), or placebo (n = 8). Subjects consumed a standard breakfast at 0800 h. Results in control subjects and type 2 diabetic subjects were compared at baseline. Integrated nocturnal FFA R(a) (AUC(1:00-8:00 A.M.)) was approximately 50% higher in type 2 diabetic subjects than in control subjects (29.4 +/- 3.0 vs. 19.4 +/- 3.9 mmol. m(-2). 7 h(-1), respectively, P < 0.05), whereas postprandial palmitate R(a) (AUC(0-240 min)) was almost threefold higher in type 2 diabetic subjects than in control subjects (14.2 +/- 1.7 vs. 5.3 +/- 1.0 mmol. m(-2). 4 h(-1), respectively, P < 0.01). After troglitazone treatment, nocturnal palmitate R(a) did not change, but postprandial palmitate R(a) decreased by approximately 30% (P < 0.05). Palmitate kinetics did not change with metformin or placebo treatment. In summary, nocturnal and postprandial FFA R(a) is increased in type 2 diabetes. Postprandial lipolysis appears to be preferentially improved by thiazolidinediones compared with nocturnal lipolysis.

Topics: Adult; Blood Glucose; C-Peptide; Chromans; Circadian Rhythm; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Food; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Kinetics; Lipolysis; Male; Metformin; Middle Aged; Placebos; Thiazoles; Thiazolidinediones; Troglitazone

Impaired fasting glucose (IFG) is commonly seen in the US population. Approximately 20% of patients with IFG can progress to develop type 2 diabetes mellitus (DM-2) within 1 year. In the recent diabetes prevention study, lifestyle changes reduced the progression to only 8% per year, and metformin reduced the progression from IFG to DM-2 from 20% to 11% per year. Sulfonylurea therapy in DM-2 increases beta-cell function and fails to accelerate the 4% loss in function observed per year. Low-dose sulfonylurea therapy for IFG may be an effective treatment to delay the onset of type 2 diabetes if the treatment does not cause hypoglycemia. A very low dose of glyburide (20 microg/kg body weight) was given orally to 15 nondiabetic volunteers in an attempt to describe its effects on glucose production rates (GPR), blood glucose concentrations, and conterregulatory hormone profile. Six of the volunteers had IFG (mean +/- SEM, 115 +/- 1.8 mg/dL), and 9 had a normal fasting glucose (NFG) (94 +/- 2.3 mg/dL). Fasting blood glucose (FBG) decreased more in IFG after glyburide when compared with the NFG group (29% +/- 2.4% v 17% +/- 3.5%, P <.05). Patients with IFG had a larger insulin response to glyburide than those with NFG (17.7 +/-3 v 10.7 +/- 2.9 microU/mL; P <.05). The IFG patients also had a greater decrease in GPR (19% +/- 4%) than seen with the normals (12% +/- 3%, P <.05). The steeper decrease in GPR may have been due to a greater insulin response to oral glyburide in those with IFG. Low-dose glyburide increases insulin's effect on the liver.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Epinephrine; Fasting; Female; Glucose; Glucose Tolerance Test; Glyburide; Hormones; Humans; Hypoglycemic Agents; Lung Neoplasms; Male; Middle Aged; Oxidation-Reduction

We examined the long-term metabolic effects of a potent sulfonylurea (SU), glipizide gastrointestinal therapeutic system (glipizide GITS) in normal glucose-tolerant (NGT), first-degree relatives of African American patients with type 2 diabetes in a randomized, placebo-controlled, double-blind manner for 24 months and 6 months after discontinuation of glipizide GITS. Fifty NGT African American first-degree relatives (n = 50)) were randomized to receive either glipizide GITS (GITS, 5 mg/d) or identical placebo (PLAC). The NGT consisted of NGT/GITS (n = 16; mean age, 43.1 +/- 8.7years; body mass index [BMI], 34.8 +/- 10) and NGT/PLAC (n = 34; 45.5 +/- 9.7 years; BMI, 31.3 +/- 3.1years). Each of the subjects underwent an oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and at yearly intervals for 2 years. Insulin sensitivity (Si) and glucose effectiveness (Sg) were determined by Bergman's minimal model method. Hepatic insulin extraction (HIE) was calculated as the molar ratio of C-peptide and insulin. The mean fasting serum glucose, insulin, and C-peptide levels in the NGT/GITS were not different from that of the NGT/PLAC. After oral glucose challenge, mean serum glucose responses slightly increased (P = not significant [NS]) at 12 and 24 months in the NGT/GITS group when compared with the baseline, 0 month, but remained unchanged in the NGT/PLAC group. In addition, serum insulin and C-peptide responses significantly increased in the NGT/GITS group, but were unchanged in the NGT/PLAC group at 12 and 24 months versus 0 month. The HIE, during OGTT, decreased by 30% from the baseline (0 month) values in the NGT/ GITS, but remained unchanged in the NGT/PLAC group at 12 and 24 months. Mean Si decreased by 30% from the baseline in the NGT/GITS group by 12 and 24 months, but remained unchanged in the NGT/PLAC group. However, the disposition index (DI) remained normal in the NGT/GITS and the NGT/PLAC groups. The DI data in the NGT/GITS group suggested that beta cells maintained the ability to compensate for the lower Si during the chronic GITS administration in our high risk African Americans. Chronic GITS was well tolerated without any symptoms of either hypoglycemia or weight gain in the NGT/IGTS group. After discontinuation of GITS, the altered metabolic parameters significantly improved, returning to baseline values in the NGT/IGTS group in 6 months. In summary, chronic glipizide GITS administration

Topics: Adult; Black People; Blood Glucose; C-Peptide; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Glipizide; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Longitudinal Studies; Male; Middle Aged

We have previously reported the beneficial effects of Caiapo, the extract of white-skinned sweet potato (ipomoea batatas), on fasting plasma glucose, as well as on total and low-density lipoprotein (LDL) cholesterol in type 2 diabetic patients. The present study aimed to describe the underlying mechanism responsible for the improvement in metabolic control following administration of Caiapo in those type 2 subjects. A total of 18 male patients (age=58+/-8 years, body mass index [BMI]=27.7+/-2.7 kg/m2, mean +/- SEM) treated only by diet were randomized into 3 groups (placebo, low-dose Caiapo, 2 g/d, and high-dose, 4 g/d). Parameters related to glucose tolerance, glucose disappearance, and insulin secretion were obtained by performing both frequently sampled intravenous glucose tolerance test (FSIGT) and oral glucose tolerance test (OGTT) before and after 6 weeks of treatment with Caiapo. Following treatment with high dose Caiapo, insulin sensitivity significantly ameliorated when assessed both with OGTT (from 308+/-13 mg/min/m2 to 334+/-10, P=.048) and FSIGT (from 1.21+/-0.32 10(4) min(-1)/(microU/mL) to 1.73+/-0.40, P=.021). Improvement of insulin sensitivity with the low dose was observed only with the FSIGT (from 2.02+/-0.70 10(4) min(-1)/(microU/mL) to 2.76+/-0.89, P<.05). Glucose effectiveness did not change. While no changes in glucose tolerance were observed in the placebo and low-dose groups, it increased from 0.85+/-0.13 %min(-1) to 1.46+/-0.13 (P<.02) in patients on high dose. No significant changes were seen in any of the parameters related to insulin dynamics: insulin secretion (from C-peptide), distribution, clearance, and hepatic extraction remained virtually the same after the treatment. In conclusion, short-term treatment with 4 g/d of the nutraceutical Caiapo consistently improved metabolic control in type 2 diabetic patients by decreasing insulin resistance without affecting body weight, glucose effectiveness, or insulin dynamics. No side effects related to the treatment were observed. Thus these results indicate that Caiapo could potentially play a role in the treatment of type 2 diabetes.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Ipomoea batatas; Kinetics; Male; Middle Aged; Phytotherapy; Placebos; Plant Extracts; Prospective Studies

We studied the effect of a low-grade short- and long-term 20% Intralipid infusion (0.4 mL(-1) x kg(-1) x h(-1)) on insulin secretion and insulin action in 15 elderly obese men; 7 glucose intolerant first-degree relatives of type 2 diabetic patients (impaired glucose tolerance [IGT] relatives) and 8 healthy controls of similar age and body mass index (BMI). Intravenous glucose tolerance test (IVGTT) and a graded glucose infusion (dose-response test [DORE]) were performed to determine first phase insulin response and to explore the dose response relationship between glucose concentration and insulin secretion rates (ISR). ISR were calculated by deconvolution of plasma C-peptide concentrations. Insulin action was determined by performing a 120-minute hyperinsulinemic euglycemic clamp. All tests were performed 3 times, preceded by 0, 2, or 24 hours Intralipid infusion. Disposition indices (DI) were calculated for the IVGTT. Insulin action was reduced 25% after 2 and 24 hours Intralipid infusion in both groups. In IGT relatives, the beta-cell responsiveness to glucose (measured during DORE) decreased after 2 and 24 hours Intralipid infusion (P=.02), whereas first phase insulin response (measured during IVGTT) decreased after 24 hours Intralipid infusion. Insulin secretion measured during DORE and IVGTT was not affected by Intralipid infusion in controls. DI decreased after 2 and 24 hours Intralipid infusion in the total study population. In conclusion, insulin resistance induced by low-grade short- and long-term Intralipid infusion is not balanced by an adequate compensatory increase in insulin secretion in IGT relatives or in matched controls. IGT relatives appear to be more sensitive to the deleterious effects of low-grade fat infusion on insulin secretion than normal glucose tolerant control subjects.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity; Triglycerides

To evaluate whether treatment with insulin in recently diagnosed type 2 diabetes is advantageous compared with glibenclamide treatment.. Beta-cell function, glycemic control, and quality of life were monitored over 2 years in 39 patients with islet cell antibody-negative type 2 diabetes diagnosed 0-2 years before inclusion in a Swedish multicenter randomized clinical trial. Patients were randomized to either two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide (3.5-10.5 mg daily). C-peptide-glucagon tests were performed yearly in duplicate after 2-3 days of temporary withdrawal of treatment.. After 1 year the glucagon-stimulated C-peptide response was increased in the insulin-treated group by 0.14 +/- 0.08 nmol/l, whereas it was decreased by 0.12 +/- 0.08 nmol/l in the glibenclamide group, P < 0.02 for difference between groups. After 2 years, fasting insulin levels were higher after treatment withdrawal in the insulin-treated versus the glibenclamide-treated group (P = 0.02). HbA(1c) levels decreased significantly during the first year in both groups; however, at the end of the second year, HbA(1c) had deteriorated in the glibenclamide group (P < 0.01), but not in the insulin-treated group. The difference in evolution of HbA(1c) during the second year was significant between groups, P < 0.02. A questionnaire indicated no difference in well-being related to treatment.. Early insulin versus glibenclamide treatment in type 2 diabetes temporarily prolongs endogenous insulin secretion and promotes better metabolic control.

Topics: Adult; Aged; Amyloid; Blood Glucose; Body Weight; C-Peptide; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islet Amyloid Polypeptide; Islets of Langerhans; Male; Middle Aged; Proinsulin; Quality of Life

Safety and effect intrapulmonary administration (by inhalation) of 60 % honey solution, 10% dextrose or distill water on blood sugar, plasma insulin and C-peptide, blood pressure, heart rate, and peaked expiratory flow rate (PEFR) in normal or diabetic subjects were studied. - Twenty-four healthy subjects, 16 patients with type 11 diabetes mellitus and six patients with hypertension were entered for study. They were underwent complete physical examination and laboratory investigations. Twelve healthy subjects were subjected for distill water inhalation for 10 min, and after one week they received inhalation of honey solution (60% wt/v) for 10 min. Another 12 healthy subjects received inhalation of 10% dextrose for 10 min. Blood glucose level, plasma insulin and C-peptide, blood pressure, heart rate and PEFR were estimated before inhalation and during 2-3 hrs after inhalation, at 30 min intervals. Random blood glucose level was estimated in eight patients with poorly controlled diabetes mellitus, and repeated 30 min after honey inhalation. One week later, fasting blood glucose level was estimated in each patient and blood glucose level was re-estimated during three hrs after honey inhalation, at 30 min intervals. Glucose tolerance test was performed in another eight patients with type-2 diabetes mellitus, and after one week the procedure was repeated with inhalation of honey, which was started immediately after ingestion of glucose. Six hypertensive patients received honey inhalation for 10 min; supine blood pressure and heart rate were measured before and after inhalation. - Results showed that in normal subjects distill water caused mild elevation of blood glucose level, mild lowering of plasma insulin, and significant reduction of plasma C-peptide. 10% dextrose inhalation caused mild reduction of plasma insulin and C-peptide and unremarkable changes in blood glucose level. No significant changes were obtained in blood pressure, heart rate or PEFR after distill water or 10% dextrose inhalation. Honey inhalation caused lowering of blood glucose level and elevation of plasma insulin and C-peptide, mild reduction of blood pressure and up to 11 and 16 percent increase in PEFR. Honey inhalation significantly reduced random blood glucose level from 199 +/- 40.9 mg/dl to 156 +/- 52.3 mg/dl after 30 min (p = 0.0303). Fasting blood glucose level was reduced after honey inhalation during three hr post-inhalation, which was significant at hr three (p<0.05). Intensi

Topics: Administration, Inhalation; Adult; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Honey; Humans; Hypertension; Insulin; Male; Middle Aged; Osmolar Concentration; Peak Expiratory Flow Rate; Solutions; Water

Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous or subcutaneous administration of GLP-1 concomitant with intravenous glucose results in hypoglycemia in healthy subjects. Because GLP-1 is also effective in type 2 diabetic patients and is currently being evaluated as a therapeutic agent, it is important to investigate whether GLP-1 may cause hypoglycemia in such patients. We have previously shown that GLP-1 does not cause hypoglycemia in obese type 2 diabetic patients with insulin resistance amounting to 5.4 +/- 1.1 according to homeostasis model assessment (HOMA). In this study, we investigated diabetic patients with normal or close to normal insulin sensitivity.. Eight lean type 2 diabetic patients (group 1) aged 60 years (range 50-72) with BMI 23.1 kg/m(2) (20.3-25.5) and HbA(1c) 8.0% (6.9-11.4) and eight patients with type 2 diabetes secondary to chronic pancreatitis (group 2) aged 52 years (41-62) with BMI 21.9 kg/m(2) (17.6-27.3) and HbA(1c) 7.8% (6.2-12.4) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body wt. Then, 15 min later, at the time of peak GLP-1 concentration, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus. HOMA (mean +/- SEM) showed insulin resistance amounting to 1.9 +/- 0.3 and 1.7 +/- 0.5 in the two groups, respectively.. In both groups, PG decreased rapidly and stabilized at 7.5 mmol/l (range 3.9-10.1) and 7.2 mmol/l (3.1-10.9) in groups 1 and 2, respectively, after 90 min. Neither symptoms of hypoglycemia nor biochemical hypoglycemia were observed in any patient.. We conclude that a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycemia in insulin-sensitive type 2 diabetic patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Kinetics; Middle Aged; Pancreatitis; Peptide Fragments; Protein Precursors

Glycation of insulin has been demonstrated within pancreatic beta-cells and the resulting impaired bioactivity may contribute to insulin resistance in diabetes. We used a novel radioimmunoassay to evaluate the effect of nateglinide on plasma concentrations of glycated insulin and glucose tolerance in type 2 diabetes.. Ten patients (5 M/5 F, age 57.8+/-1.9 years, HbA(1c) 7.6+/-0.5%, fasting plasma glucose 9.4+/-1.2 mmol/l, creatinine 81.6+/-4.5 microM/l) received oral nateglinide 120 mg or placebo, 10 min prior to 75 g oral glucose in a random, single blind, crossover design, 1 week apart. Blood samples were taken for glycated insulin, glucose, insulin and C-peptide over 225 min.. Plasma glucose and glycated insulin responses were reduced by 9% (P=0.005) and 38% (P=0.047), respectively, following nateglinide compared with placebo. Corresponding AUC measures for insulin and C-peptide were enhanced by 36% (P=0.005) and 25% (P=0.007) by nateglinide.. Glycated insulin in type 2 diabetes is reduced in response to the insulin secretagogue nateglinide, resulting in preferential release of native insulin. Since glycated insulin exhibits impaired biological activity, reduced glycated insulin release may contribute to the antihyperglycaemic action of nateglinide.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycosylation; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Nateglinide; Phenylalanine; Single-Blind Method

The dynamic of glycemia, insulin, C-peptide, glycosylated hemoglobin, fructosamine, thyroid hormones, parameters of serum lipids, lipid peroxidation and system of antioxidant defense in 81 hospital patients and out-patients with obesity associated with diabetes mellitus type II was studied of influence of hypocaloric diet 9. Universal normalizing influence of hypocaloric diet 9 with vegetation tea was discovered on parameters of carbohydrate, lipid and oxidative metabolism and of patients clinical state of pateni. The additional criteria of evaluation of efficacy of food dietary supplements in complex treatment of patients with obesity associated with diabetes mellitus type II was offered on basis of study of influence vegetation tea on mechanisms of metabolic disorders in these patients.

Topics: Adult; Aged; Beverages; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diet Therapy; Female; Fructosamine; Glycated Hemoglobin; Humans; Insulin; Male; Medicine, Chinese Traditional; Middle Aged; Obesity; Plants, Medicinal; Thyroid Gland; Thyroid Hormones; Ultrasonography

African Americans (AA) have greater prevalence of type 2 diabetes mellitus (DM), and nondiabetic AA have demonstrated increased insulin resistance when compared with Caucasian Americans (CA). The objective of this study was to examine the impact of chronic use of an insulin sensitizer on glucose metabolism in normal glucose tolerant AA at risk for DM (previous gestational diabetes mellitus [GDM] or first-degree relative with DM). Forty-nine high-risk AA received 200 mg/d troglitazone (TRO) versus 81 age-, weight-, and body mass index (BMI)-matched high-risk AA who received placebo (PLA) for 24 months. Yearly anthropometric measurements, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Biochemical parameters were monitored quarterly. There was no significant change in anthropometric measurements over 24 months in TRO versus PLA. There were no significant differences in serum glucose, insulin, or C-peptide incremental area under the curve (AUC) in TRO versus PLA at baseline or 24 months for OGTT and FSIVGTT. The insulin sensitivity (S(I)) for TRO and PLA increased from baseline to 24 months by 17% and 16%, respectively. The TRO demonstrated a 26% increase in insulin/glucose ratio versus 1% increase in the PLA at 24 months. The disposition index (DI) increased 33% from baseline in TRO versus 21% increase in PLA. Modest improvement in glucose metabolism was seen in TRO when compared with PLA. TRO was well tolerated without significant reported adverse events. Based on our current data, the treatment of normal glucose tolerant high-risk AA with thiazolidinedione (TZD) may be beneficial to "reset" and protect glucose metabolism by improving insulin responses. Because of the potential drug-related risks associated with use of TZD and the proven positive impact of diet and exercise in prevention of DM, studies of longer duration with examination of other potentially beneficial parameters, such as cardiovascular indices and inflammatory markers will be necessary to justify the cost in the nondiabetic population.

Topics: Adult; Black People; Blood Glucose; Body Constitution; Body Mass Index; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Genetic Predisposition to Disease; Glucose Intolerance; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Placebos; Skinfold Thickness; Thiazoles; Thiazolidinediones; Troglitazone

Glucagon-like peptide 1 (GLP-1) is an insulinotropic gut hormone that, when given exogenously, may be a useful agent in the treatment of type 2 diabetes. We conducted a 3-month trial to determine the efficacy and safety of GLP-1 in elderly diabetic patients.. A total of 16 patients with type 2 diabetes who were being treated with oral hypoglycemic agents were enrolled. Eight patients (aged 75 +/- 2 years, BMI 27 +/- 1 kg/m(2)) remained on usual glucose-lowering therapy and eight patients (aged 73 +/- 1 years, BMI 27 +/- 1 kg/m(2)), after discontinuing hypoglycemic medications, received GLP-1 delivered by continuous subcutaneous infusion for 12 weeks. The maximum dose was 120 pmol x kg(-1). h(-1). Patients recorded their capillary blood glucose (CBG) levels (four times per day, 3 days per week) and whenever they perceived hypoglycemic symptoms. The primary end points were HbA(1c) and CBG determinations. Additionally, changes in beta-cell sensitivity to glucose, peripheral tissue sensitivity to insulin, and changes in plasma ghrelin levels were examined.. HbA(1c) levels (7.1%) and body weight were equally maintained in both groups. The usual treatment group had a total of 87 CBG measurements of

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Implants; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Insulin; Male; Peptide Fragments; Protein Precursors; Treatment Outcome

The effect of acute repaglinide administration (2 mg) on postprandial glycaemia and lipaemia has been examined in 20 subjects with type 2 diabetes mellitus. Each subject received in the morning, after a 12 to 14 h fast, a standard mixed meal (total energy 783 kcal), preceded by one tablet of 2 mg repaglinide or placebo. Chylomicrons and chylomicron-deficient plasma were prepared by ultracentrifugation. Triglyceride levels in CM fraction (CM-triglycerides) in total plasma as well as in CM-deficient plasma (non-CM-triglycerides) were determined. A significant reduction in postprandial glycaemia was observed after repaglinide administration compared to placebo ( p < 0.001). Plasma concentrations of total triglycerides, CM-triglycerides, non-CM-triglycerides, free fatty acids and the other plasma lipids measured, were not significantly different between the two phases of the study. It is concluded that, in contrast to sulphonylureas, acute repaglinide administration does not improve postprandial lipaemia in patients with type 2 diabetes.

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Kinetics; Piperidines; Postprandial Period; Triglycerides

In single-meal studies, dietary protein does not result in an increase in glucose concentrations in persons with or without type 2 diabetes, even though the resulting amino acids can be used for gluconeogenesis.. The metabolic effects of a high-protein diet were compared with those of the prototypical healthy (control) diet, which is currently recommended by several scientific organizations.. The metabolic effects of both diets, consumed for 5 wk each (separated by a 2-5-wk washout period), were studied in 12 subjects with untreated type 2 diabetes. The ratio of protein to carbohydrate to fat was 30:40:30 in the high-protein diet and 15:55:30 in the control diet. The subjects remained weight-stable during the study.. With the fasting glucose concentration used as a baseline from which to determine the area under the curve, the high-protein diet resulted in a 40% decrease in the mean 24-h integrated glucose area response. Glycated hemoglobin decreased 0.8% and 0.3% after 5 wk of the high-protein and control diets, respectively; the difference was significant (P < 0.05). The rate of change over time was also significantly greater after the high-protein diet than after the control diet (P < 0.001). Fasting triacylglycerol was significantly lower after the high-protein diet than after the control diet. Insulin, C-peptide, and free fatty acid concentrations were not significantly different after the 2 diets.. A high-protein diet lowers blood glucose postprandially in persons with type 2 diabetes and improves overall glucose control. However, longer-term studies are necessary to determine the total magnitude of response, possible adverse effects, and the long-term acceptability of the diet.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Dietary Proteins; Female; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Middle Aged; Postprandial Period

The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Male; Middle Aged; Neurotransmitter Agents; Nuclear Proteins; Pancreatitis; Peptide Fragments; Phenotype; Protein Precursors; Transcription Factors

This study was designed to compare the efficacy of three insulinotropic agents in the control of postprandial hyperglycemia in type 2 diabetes. Fifteen subjects with noninsulin-requiring type 2 diabetes were admitted to the General Clinical Research Center on four separate occasions. During the control study and following 7-10 d on each study medication, daylong glucose profiles were performed to investigate the effects of the assigned medication on postprandial hyperglycemia. During each admission, placebo or study medications were administered before three isocaloric meals as follows: immediate-release glipizide 30 min before breakfast and 30 min before supper, glipizide gastrointestinal therapeutic system (GITS) 30 min before breakfast, or nateglinide 120 mg 10 min before breakfast, before lunch, and before supper. Blood was drawn for analysis of glucose, insulin, and C-peptide at -0.05, 0, 0.25, 0.5, 1, 2, 3, and 4 h relative to each test meal. Immediate-release glipizide, nateglinide, or glipizide GITS administration resulted in significantly lower integrated daylong (glucose area under the curve) and peak glucose levels, compared with placebo. There were no significant differences in the daylong integrated glucose levels among the three study medications. The peak postbreakfast glucose level (but not glucose area under the curve) was lower with nateglinide, compared with either immediate-release glipizide or glipizide GITS. Postlunch and postdinner integrated glucose levels were significantly lower with immediate-release glipizide or glipizide GITS, compared with nateglinide. C-peptide levels were significantly higher with immediate-release glipizide, compared with glipizide GITS. Insulin levels did not differ among the three study medications. Once-daily glipizide GITS, twice-daily immediate-release glipizide, or three-times-a-day administration of nateglinide results in equivalent control of postmeal hyperglycemia in type 2 diabetes. The decision to prescribe one of these three insulinotropic agents should be based on factors such as the patient's ability to comply with complex dosing regimens, the need to control fasting hyperglycemia, the risk of interprandial hypoglycemia, and pharmacoeconomic considerations, rather than postprandial glucose-lowering efficacy.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

The glycaemic control of thrice daily treatment with premixed biphasic insulin aspart (BIAsp) without other antidiabetic therapy was tested in type 2 diabetic patients, in order to compare the glucose control of a 'high' mixture (BIAsp 70) or a 'medium' mixture (BIAsp 50) (70 or 50% soluble IAsp and 30 or 50% protamine-crystallized IAsp, respectively) administered just before dinner.. To compare these regimens to conventional 30 : 70 premixture on a twice a day basis.. This randomized, double-blind, two-period crossover study included 16 patients with type 2 diabetes. Twenty four-hour serum glucose and insulin profiles were obtained thrice: (1) after a one-week run-in period with biphasic human insulin (BHI) 30/70 twice daily (run-in), (2) after 4 weeks of treatment with thrice daily BIAsp 70 before breakfast, lunch and dinner (Dinner70 regimen) and (3) after 4 weeks of BIAsp 70 before breakfast and lunch and BIAsp 50 before dinner (Dinner50).. Daytime average serum glucose was lower with Dinner70 compared to run-in (9.6 +/- 0.39 mmol/l vs. 11.2 +/- 0.61 mmol/l, p < 0.05). Postprandial glucose excursions after breakfast and lunch were lower, but fasting morning glucose was higher during the treatment periods than in the run-in period. Twenty four-hour C-peptide AUC was considerably lower during both treatment periods than in the run-in period (run-in/Dinner50 ratio 1.29 [1.08; 1.54] p < 0.01; run-in/Dinner70 ratio 1.31 [1.08;1.58], p < 0.01).. Switching the dinner dose to BIAsp 50 did not alter overall glucose control significantly from that provided with BIAsp 70. Exploratory analyses between the two active treatment regimens and run-in/BHI indicate that thrice daily BIAsp 70 administration: (1) for optimization of the night-time control, the dinner dose needs adjustment or replacement by a premixed insulin with a larger proportion of basal insulin than BIAsp 50 and (2) none of the premixtures adequately provide for both the evening meal and overnight requirements.

Topics: Aged; Blood Glucose; C-Peptide; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Male; Middle Aged; Postprandial Period

Type 2 diabetes is caused by reduced insulin secretion and insulin resistance in skeletal muscle and liver. We tested the combination therapy with insulin aspart, rosiglitazone, and metformin with the purpose of treating all three defects in order to test the hypothesis that this "triple therapy" will normalize glucose metabolism.. Sixteen obese type 2 diabetic outpatients on human NPH or MIX (regular + NPH insulin) insulin twice daily were randomized to either triple therapy, i.e., insulin aspart (a rapid-acting insulin analog) at meals, metformin (which improves hepatic insulin sensitivity), and rosiglitazone (which improves peripheral insulin sensitivity), or to continue their NPH or MIX insulin twice daily for 6 months. Insulin doses were adjusted in both groups based on algorithms. HbA(1c), insulin dose, hypoglycemic episodes, insulin sensitivity (clamp), hepatic glucose production (tracer), and diurnal profiles of plasma glucose and insulin were used in evaluating treatment.. In the triple therapy group, HbA(1c) declined from 8.8 to 6.8% (P < 0.01) without inducing severe hypoglycemic events. Postprandial hyperglycemia was generally avoided, and the diurnal profile of serum insulin showed fast and high peaks without any need to increase insulin dose. In the control group, the insulin dose was increased by 50%, but nevertheless both HbA(1c) and 24-h blood glucose profiles remained unchanged. Insulin sensitivity improved in both skeletal muscle and the liver in the triple therapy group, whereas no change was observed in the control group.. We conclude that treatment of the three major pathophysiological defects in type 2 diabetic subjects by triple therapy significantly improved glucose metabolism in obese type 2 diabetic subjects.

Topics: Aged; Blood Glucose; Blood Pressure; C-Peptide; Circadian Rhythm; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucose Clamp Technique; Glycated Hemoglobin; Glycolysis; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Male; Metformin; Middle Aged; Obesity; Rosiglitazone; Thiazolidinediones

To investigate the effect of 3-months' daily administration of high doses of sucralose, a non-nutritive sweetener, on glycemic control in subjects with type 2 diabetes.. A multicenter, double-blind, placebo-controlled, randomized study, consisting of a 6-week screening phase, a 13-week test phase, and a 4-week follow-up phase.. Subjects with type 2 diabetes (age range 31 to 70 years) entered the test phase of this study; 128 subjects completed the study. The subjects were recruited from 5 medical centers across the United States and were, on average, obese.. Subjects were randomly assigned to receive either placebo (cellulose) capsules (n=69) or 667 mg encapsulated sucralose (n=67) daily for the 13-week test phase. All subjects blindly received placebo capsules during the last 4 weeks of the screening phase and for the entire 4-week follow-up phase.. Glycated hemoglobin (HbA1c), fasting plasma glucose, and fasting serum C-peptide were measured approximately every 2 weeks to evaluate blood glucose homeostasis. Data were analyzed by analysis of variance using repeated measures.. There were no significant differences between the sucralose and placebo groups in HbA1c, fasting plasma glucose, or fasting serum C-peptide changes from baseline. There were no clinically meaningful differences between the groups in any safety measure.. This study demonstrated that, similar to cellulose, sucralose consumption for 3 months at doses of 7.5 mg/kg/day, which is approximately three times the estimated maximum intake, had no effect on glucose homeostasis in individuals with type 2 diabetes. Additionally, this study showed that sucralose was as well-tolerated by the study subjects as was the placebo.

Topics: Administration, Oral; Adult; Aged; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Homeostasis; Humans; Male; Middle Aged; Patient Compliance; Sucrose; Sweetening Agents

Insulin secretion following the intravenous infusion of gastric inhibitory polypeptide (GIP) is diminished in patients with type 2 diabetes and at least a subgroup of their first-degree relatives at hyperglycemic clamp conditions. Therefore, we studied the effects of an intravenous bolus administration of GIP at normoglycemic conditions in the fasting state. Ten healthy control subjects were studied with an intravenous bolus administration of placebo, and of 7, 20, and 60 pmol GIP/kg body weight (BW), respectively. Forty-five first-degree relatives of patients with type 2 diabetes and 33 matched control subjects were studied with (1) a 75-g oral glucose tolerance test (OGTT) and (2) an intravenous bolus injection of 20 pmol GIP/kg BW with blood samples drawn over 30 minutes for determination of plasma glucose, insulin, C-peptide, and GIP. Statistical analysis applied repeated-measures analysis of variance (ANOVA) and Duncan's post hoc tests. Insulin secretion was stimulated after the administration of 20 and of 60 pmol GIP/kg BW in the dose-response experiments (P <.0001). GIP administration (20 pmol/kg BW) led to a significant rise of insulin and C-peptide concentrations in the first-degree relatives and control subjects (P <.0001), but there was difference between groups (P =.64 and P =.87, respectively). Also expressed as increments over baseline, no differences were apparent (Delta(insulin), 7.6 +/- 1.2 and 7.6 +/- 1.6 mU/L, P =.99; Delta(C-peptide), 0.35 +/- 0.06 and 0.38 +/- 0.08 ng/mL, P =.75). Integrated insulin and C-peptide responses after GIP administration significantly correlated with the respective insulin and C-peptide responses after glucose ingestion (insulin, r = 0.78, P <.0001; C-peptide, r = 0.35, P =.0015). We conclude that a reduced insulinotropic effect of GIP in first-degree relatives of patients with type 2 diabetes cannot be observed at euglycemia. Therefore, a reduced GIP-induced insulin secretion in patients with type 2 diabetes and their first-degree relatives at hyperglycemia is more likely due to a general defect of B-cell function than to a specific defect of the GIP action.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gastric Inhibitory Polypeptide; Glucose Tolerance Test; Humans; Injections, Intravenous; Insulin; Male; Middle Aged

To determine the efficacy of, and compliance with, glimepiride or acarbose in patients with Type 2 diabetes.. Two hundred and nineteen patients with Type 2 diabetes uncontrolled by diet alone were randomized to receive either glimepiride (1, 2, 3, 4 or 6 mg once daily, n = 111) or acarbose (50, 100, 150 or 200 mg 3 times daily, n = 108). Both drugs were titrated in a 6-week dose-finding phase to achieve a fasting blood glucose (FBG) concentration < or = 7.8 mmol/ (140 mg/dl). Patients achieving this target entered a 20-week treatment period. Efficacy was assessed by responder rate, number of patients achieving a FBG of < or = 7.8 mmol/l, HbA1c, blood glucose concentrations in response to a standard breakfast, body weight and compliance.. Glimepiride was associated with a significantly greater responder rate than acarbose (61 vs 34%, p < 0.001), significantly greater decreases in HbA1c (2.5 +/- 2.2% vs 1.8 +/- 2.2%, p = 0.014) and FBG (2.6 +/- 2.6 mmol/l vs 1.4 +/- 2.8 mmo/l, p = 0.004), a decreased glucose response to breakfast compared with acarbose [area under curve (AUC) end: 8.9 +/- 2.7 mmol/l vs 11.3 +/- 3.9 mmol/l, p = 0.0001], and was accompanied by significantly greater compliance (91 < or = 12% vs 66 +/- 26%, p = 0.0001). Weight loss during the study was observed in both the acarbose group (1.9 +/- 3.9 kg, p = 0.001) and glimepiride group [0.4 +/- 5.2 kg, p = 0.8 (NS)].. Improved efficacy and greater compliance were observed in response to treatment with glimepiride compared with acarbose, in patients with Type 2 diabetes.

Topics: Acarbose; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Patient Compliance; Sulfonylurea Compounds

Acarbose is an oral antidiabetic mainly acting on postprandial blood glucose, inhibiting alphaglucosidase. Through this mechanism, it could improve the peripheral insulin sensitivity and/or increase the insulin secretion. The aim of the present study is to assess the therapeutic efficacy of Acarbose in obese type 2 diabetic patients on both insulin resistance and insulin secretion.. 17 obese non insulin-dependent diabetic patients, well controlled with diet alone were randomized into 2 groups: acarbose (2 x 50 mg) or placebo during 16 weeks. A glucagon test allowed to evaluate insulin secretion before and after treatment as well as a triple test (glucose-insulin-somatostatin) with indirect calorimetry allowed to evaluate insulin sensitivity.. A significant improvement in post-prandial plasma glucose was detected only in the Acarbose group (8.0 +/- 0.5 mmol/l before vs 6.5 0.5 mmol/l after, p<0.05). Basal C-peptide secretion was similar between groups and remained unchanged after treatment. However, stimulated insulin secretion was significantly increased by 30%, p<0.05, in the Acarbose group while no change was detected in the placebo group. Interestingly, the group receiving Acarbose disclosed a 15% reduction in insulin resistance (15.0 +/- 1.8 mmol/l before vs 12.8 +/- 1.4 mmol/l after).. Our results show that a treatment with Acarbose is efficient even in diabetic patients presenting a good glucose control without any other associated treatment. By decreasing post-prandial blood glucose, acarbose improves both insulin sensitivity and secretion.

Topics: Acarbose; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Obesity; Placebos; Research Design

Recent studies have demonstrated that C-peptide exerts beneficial effects on the diabetic state, including improvements in kidney and nerve function. Thus, we investigated the effect of residual pancreatic C-peptide secretion on the cardiac autonomic nervous system in well- and poorly controlled type II diabetic patients.. Randomised cross-sectional study.. Forty type II diabetic patients free from diabetic neuropathy, with similar anthropometric parameters, volunteered for our study.. Insulin action, residual pancreatic C-peptide secretion and the cardiac autonomic nervous system were investigated by euglycaemic hyperinsulinaemic clamp, glucagon bolus test and heart rate variability, respectively. M-values were used as an index of insulin sensitivity. High frequency (HF) and low frequency (LF) oscillations in heart rate were analysed.. The patients were categorized into those with good (HbA1c < or = 7.0) and poor (HbA1c > or = 8.0) metabolic control. The patients with good metabolic control had fasting plasma glucose and C-peptide levels, plasma area under the curve (auc) insulin and C-peptide levels, M-values, LF values and LF/HF ratio significantly lower than patients with poor metabolic control. In contrast, RR interval, total power and HF values had an opposite trend. Basal plasma C-peptide correlated with LF/HF in patients with good (r = -0.42; P < 0.05) and poor metabolic control (r = -0.45; P < 0.05). An even stronger correlation between auc C-peptide and LF/HF in patients with good (r = -0.53, P < 0.002) and poor metabolic control (r = -0.49; P < 0.03), as well as in the whole group (r = -0.83; P < 0.001) was found. By multiple regression analyses performed in all patients, LF/HF were independently associated with auc C-peptide (t = -8.618; P < 0.001) but not basal C-peptide levels (t = -0.137; P < 0.88).. Our study demonstrated that preserved C-peptide secretion is associated with a well balanced cardiac autonomic activity in type II diabetic patients.

Topics: Area Under Curve; Autonomic Nervous System; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Electrocardiography, Ambulatory; Female; Heart Conduction System; Humans; Islets of Langerhans; Male; Middle Aged

The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is being examined as a potential new agent for treatment in type 2 diabetic patients. Whereas the insulinotropic properties of this peptide are well established, another property of the hormone, an insulinomimetic effect per se, is controversial. In the normal glucose-tolerant lean state, it is difficult to demonstrate an insulinomimetic effect. The current study was conducted to examine whether GLP-1 has insulinomimetic effect in the obese state. Ten obese volunteers (body mass index, 34.6 +/- 0.8 kg/m(2)), whose ages were 32.5 +/- 3.0 yr, participated in two euglycemic clamp studies (n = 20 clamps) for 120 min. Five of the volunteers were females. The initial clamp was performed with a primed (0-10)-constant (10-60) infusion of GLP-1 at a final rate of 1.5 pmol x kg(-1) x min(-1). At 60 min, the GLP-1 infusion was terminated, and euglycemic was maintained from 60-120 min. After the GLP-1 study, each individual's plasma insulin level was measured. A second study was performed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were regulated in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Fasting plasma insulin levels were similar between studies. In response to the GLP-1 infusion, with maintenance of plasma glucose level clamped at fasting level, significant increases in plasma insulin occurred in all subjects (P < 0.001). The insulin levels during the insulin infusion study were similar to that induced by GLP-1. The rate of disappearance of glucose (insulin-mediated glucose uptake) progressively increased in response to both the GLP-1 and insulin infusion. However, the rate of disappearance of glucose during the GLP-1 study was significantly higher (P = 0.033) than during the insulin study. We conclude that in insulin-resistant states, GLP-1 has insulinomimetic properties per se.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Obesity; Peptide Fragments; Protein Precursors

This study compared the effects of acarbose plus glibenclamide combination therapy with acarbose or glibenclamide treatment alone on postprandial blood glucose, serum insulin and C-peptide levels, and the tendency to develop hypoglycaemia. A total of 84 patients with Type 2 diabetes (fasting blood glucose: 120-180 mg/dl; postprandial blood glucose: 140-240 mg/dl) was included in this two-centre, double-blind, double-dummy, placebo-controlled study. Patients were randomised to one of 4 treatment groups: acarbose (100 mg); glibenclamide (3.5 mg); acarbose plus glibenclamide; or placebo. Treatment was administered before a standard breakfast, and fasting (07.30 h, 08.00 h) and postprandial (09.00, 10.00, 11.00, 12.00 h) blood glucose, serum insulin and C-peptide levels were determined. Acarbose plus glibenclamide treatment significantly reduced the mean increase in postprandial blood glucose levels (23.7+/-17.3 mg/dl) compared with either acarbose (58.4+/-31.6 mg/dl), glibenclamide (56.9+/-42.8 mg/dl) or placebo (101.6+/-49.2 mg/dl) (p<0.05 for all). Serum insulin levels (mean AUC(7.30-12 h)) observed with acarbose plus glibenclamide combination therapy were significantly lower than those observed with glibenclamide monotherapy (243.5+/-161.1 vs 383.4+/-215.8 hr x microU/ml; p=0.02), and comparable with the values seen with placebo (226.0+/-166.6 hr x microU/ml), suggesting that acarbose modifies the insulin secretion induced by glibenclamide. Glibenclamide monotherapy resulted in a significantly higher rate of decrease in blood glucose level than with acarbose plus glibenclamide (71.8+/-29.9 vs 46.2+/-18.0 mg/dl x h(-1); p=0.0003), and blood glucose levels at 11.00 h were also markedly lower with glibenclamide (84.4+/-29 mg/dl) than acarbose plus glibenclamide (102.0+/-41 mg/dl), suggesting a reduced tendency for hypoglycaemic episodes with acarbose plus glibenclamide than with glibenclamide alone. In all, 6 (29%) hypoglycaemic episodes occurred with glibenclamide, 2 (10%) with acarbose plus glibenclamide and none with acarbose. Acarbose plus glibenclamide combination therapy results in an additive glucose lowering effect and reduced risk for hypoglycaemia. Acarbose modifies the insulin secretion induced by glibenclamide, which explains the lower risk of hypoglycaemia compared with glibenclamide monotherapy.

Topics: Acarbose; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Food; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kinetics; Male; Placebos

The purpose of this study was to assess the effect of glimepiride on insulin sensitivity and secretion in subjects with type 2 diabetes.. After a 2-week washout from prior sulfonylurea therapy, 11 obese subjects with type 2 diabetes underwent euglycemic and hyperglycemic clamp studies before and during glimepiride therapy.. Glimepiride resulted in a 2.4-mmol/l decrease in fasting plasma glucose (P = 0.04) that was correlated with reductions in postabsorptive endogenous glucose production (EGP) (16.4 +/- 0.6 vs. 13.5 +/- 0.5 micro mol. kg(-1). min(-1), P = 0.01) (r = 0.21, P = 0.01). Postabsorptive EGP on glimepiride was similar to that of control subjects (12.8 +/- 0.9 micro mol. kg(-1). min(-1), NS). Fasting plasma insulin (66 +/- 18 vs. 84 +/- 48 pmol/l, P = 0.05), and first-phase (19 +/- 8 vs. 32 +/- 11 pmol/l, P = 0.04) and second-phase incremental insulin responses to glucose (48 +/- 23 vs. 72 +/- 32 pmol/l, P = 0.02) improved with glimepiride therapy. Insulin sensitivity did not change with treatment (4.6 +/- 0.7 vs. 4.3 +/- 0.7 micro mol. kg(-1). min(-1). pmol(-1)) and remained below that of control subjects (8.1 +/- 1.8 micro mol. kg(-1). min(-1). pmol(-1), P = 0.04).. The current study demonstrates that glimepiride improves both first and second phases of insulin secretion, but not insulin sensitivity, in individuals with type 2 diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Sulfonylurea Compounds

Splanchnic glucose uptake (SGU) plays a major role in the disposal of an oral glucose load (OGL). To investigate the effect of an elevated plasma free fatty acid (FFA) concentration on SGU in patients with type 2 diabetes, we measured SGU in eight diabetic patients (mean age 51 +/- 4 years, BMI 29.3 +/- 1.4 kg/m(2), fasting plasma glucose 9.3 +/- 0.7 mmol/l) during an intravenous Intralipid/heparin infusion and 7-10 days later during a saline infusion. SGU was estimated by the OGL insulin clamp method: subjects received a 7-h euglycemic-hyperinsulinemic clamp (insulin infusion rate = 100 mU x m(-2) x min(-1)), and a 75-g OGL was ingested 3 h after starting the insulin clamp. After glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4-h period after glucose ingestion from the ingested glucose load (75 g). 3-[(3)H]glucose was infused during the 3-h insulin clamp before glucose ingestion to determine the rates of endogenous glucose production and glucose disappearance (R(d)). Intralipid/heparin or saline infusion was initiated 2 h before the start of the OGL clamp. Plasma FFA concentrations were significantly higher during the OGL clamp with the intralipid/heparin infusion than with the saline infusion (2.5 +/- 0.3 vs. 0.11 +/- 0.02 mmol/l, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, Intralipid/heparin infusion reduced R(d) (4.4 +/- 0.3 vs. 5.3 +/- 0.3 mg x kg(-1) x min(-1), P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly decreased during the intralipid/heparin versus saline infusion (30 +/- 2 vs. 37 +/- 2%, P < 0.01). In conclusion, an elevation in plasma FFA concentration impairs both peripheral and SGU in patients with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Splanchnic Circulation

To evaluate the safety and efficacy of treatment with insulin alone, insulin plus metformin, or insulin plus troglitazone in individuals with type 2 diabetes.. A total of 88 type 2 diabetic subjects using insulin monotherapy (baseline HbA(lc) 8.7%) were randomly assigned to insulin alone (n = 31), insulin plus metformin (n = 27), or insulin plus troglitazone (n = 30) for 4 months. The insulin dose was increased only in the insulin group. Metformin was titrated to a maximum dose of 2,000 mg and troglitazone to 600 mg.. HbA(lc) levels decreased in all groups, the lowest level occurring in the insulin plus troglitazone group (insulin alone to 7.0%, insulin plus metformin to 7.1%, and insulin plus troglitazone to 6.4%, P < 0.0001). The dose of insulin increased by 55 units/day in the insulin alone group (P < 0.0001) and decreased by 1.4 units/day in the insulin plus metformin group and 12.8 units/day in the insulin plus troglitazone group (insulin plus metformin versus insulin plus troglitazone, P = 0.004). Body weight increased by 0.5 kg in the insulin plus metformin group, whereas the other two groups gained 4.4 kg (P < 0.0001 vs. baseline). Triglyceride and VLDL triglyceride levels significantly improved only in the insulin plus troglitazone group. Subjects taking metformin experienced significantly more gastrointestinal side effects and less hypoglycemia.. Aggressive insulin therapy significantly improved glycemic control in type 2 diabetic subjects to levels comparable with those achieved by adding metformin to insulin therapy. Troglitazone was the most effective in lowering HbA(lc), total daily insulin dose, and triglyceride levels. However, treatment with insulin plus metformin was advantageous in avoiding weight gain and hypoglycemia.

Topics: Adult; Age of Onset; Aged; Body Mass Index; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins; Male; Metformin; Middle Aged; Racial Groups; Texas; Thiazoles; Thiazolidinediones; Troglitazone

Arginine is converted in the endothelial cells to nitric oxide (NO) and citrulline. NO is a potent vasodilator in humans, but diabetics may have a reduced generation of NO which results in endothelial dysfunction. The aim of this study was to evaluate the effects of oral arginine on nitric oxide production, counter-regulatory hormones and blood pressure in mildly hypertensive type 2 diabetic patients.. A prospective, crossover clinical trial was performed over a three-day stay in the General Clinical Research Center. Six patients with type 2 diabetes mellitus and mild hypertension consented and were given orally three grams of arginine per hour for 10 hours on either day 2 or day 3. On both days 2 and 3, blood pressure was monitored between 5 AM and 4 PM and mean pressure determined.. Oral arginine increased plasma citrulline from 31.3 +/- 6.0 to 41.5 +/- 6.0 micro mol/L (mean +/- SEM; p < 0.05) which may reflect an increased conversion of arginine into NO and citrulline. Arginine reduced systolic BP from 135 +/- 7 to 123 +/- 8 mmHg; p < 0.05. Diastolic BP fell from 86.9 +/- 1.7 to 80.7 +/- 2.4 mmHg; p < 0.05). The reduction in BP was noted to occur two hours after starting oral arginine, and BP returned to normal within one hour of stopping the arginine. The oral arginine had no effect on C-peptide, insulin or other hormone concentrations.. These data suggest that oral arginine may increase endothelial nitric oxide synthase (NOS) to increase vascular NO and temporally reduce blood pressure in mildly hypertensive type 2 diabetic patients.

Topics: Adult; Arginine; Blood Pressure; C-Peptide; Citrulline; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Hypertension; Insulin; Kinetics; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Prospective Studies

In patients with non-insulin dependent diabetes mellitus (T2DM) and associated chronic liver disease, plasma levels of glucose, insulin and triglycerides are high, lipid peroxidation is increased and natural antioxidant reserves are reduced. Thus, we hypothesised that the re-balancing of cell redox levels and amelioration of liver function could result in a better glucose and lipid metabolism. To study this, we assessed the effect of a new oral formulation of an antioxidant agent - silybin-beta-cyclodextrin (named IBI/S) - in patients with chronic alcoholic liver disease and concomitant T2DM.. Sixty outpatients were enrolled in a three-centre, double blind, randomised, IBI/S vs placebo study. Forty-two (21 in the group IBI/S - 135 mg/d silybin per os - and 21 in the placebo group) concluded the 6-month treatment period. The efficacy parameters included fasting and mean daily plasma glucose levels, glycosylated hemoglobin (HbA1c), basal, stimulated C-peptide and insulin levels, total-, HDL-cholesterol and triglycerides levels in addition to conventional liver function tests. Insulin sensitivity was estimated by HOMA-IR. Malondialdehyde (MDA) was also measured before and after treatment as an index of oxidative stress.. Fasting blood glucose levels, which were similar at baseline in IBI/S group and in the placebo group (173.9 mg/dl and 177.1 mg/dl, respectively), decreased to 148.4 mg/dl (-14.7% vs baseline; p = 0.03) in the IBI/S group while they were virtually unchanged in the placebo group. The comparison between the groups at mo 6 (T6) also showed a significant reduction of glucose levels in the IBI/S group (p = 0.03). The same trend was observed in mean daily blood glucose levels, HbA1c and HOMA-IR, although differences were not significant. Basal and stimulated C-peptide values showed that only a few changes had occured in both groups. Such results indicate that insulin secretion was virtually unaffected, as confirmed also by the insulinemia data. Plasma triglycerides concentrations dropped from a baseline value of 186 mg/dl to 111 mg/dl (T6) in the IBI/S group, with significant differences at all instances with respect to baseline values. By contrast, triglycerides increased from 159 mg/dl at entry to 185 mg/dl (T6) in the placebo group. The difference between the groups at T6 was highly significant (p < 0.01). Total and HDL cholesterol as well as liver function tests did not change significantly during the study in both groups. MDA decreased significantly only in the group receiving IBI/S. No clinically relevant side effects were observed in either group.. Oral administration silybin-beta-cyclodextrin in patients with T2DM and compensated chronic alcoholic liver disease causes a significant decrease in both glucose and triglyceride plasma levels. These effects may be due to the recovery of energy substrates, consistent with a reduced lipid peroxidation and an improved insulin activity.

Topics: Antioxidants; beta-Cyclodextrins; Blood Glucose; C-Peptide; Cholesterol, HDL; Cyclodextrins; Diabetes Mellitus, Type 2; Double-Blind Method; Female; gamma-Glutamyltransferase; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Liver Diseases, Alcoholic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Placebos; Silybin; Silymarin; Triglycerides

To study the effect on body weight and glycaemic control of two insulin treatment regimens in patients with Type 2 diabetes and moderate failure to oral hypoglycaemic agents.. Sixteen patients treated with oral hypoglycaemic agents (6 men and 10 women) were included in this open-label, randomized, parallel group study. Their age was 62 +/- 2 (mean +/- SEM) years (range 44-79 years), body weight 71.3 +/- 2.9 kg, body mass index (BMI) 24.6 +/- 0.8 kg/m(2). The patients were switched to insulin treatment with bedtime NPH insulin combined with daytime sulphonylurea (combination group) or twice daily injections of a premixed combination of regular human and NPH insulin (insulin twice daily group) with measurements as given below before and after 12 and 24 weeks of treatment.. HbA(1c) was lowered from 8.3 +/- 0.3% to 7.0 +/- 0.2% in the insulin twice daily group (p<0.05) and from 8.3 +/- 0.3% to 6.8 +/- 0.5% in the combination group (p<0.03; ns between treatment groups). Body weight increased from 71.7 +/- 4.0 kg to 77.6 +/- 4.4 kg in the insulin twice daily group (p<0.001) and from 70.8 +/- 4.6 kg to 72.7 +/- 5.1 kg in the combination group (ns; p<0.02 between groups). The dose of insulin at 24 weeks in the insulin twice daily group was 45.8 +/- 4.2 U and 29.4 +/- 5.4 U in the combination group (p=0.03). Combination treatment reduced fasting and stimulated C-peptide levels.. Both treatments improved glycaemic control to the same extent but the combination of bedtime NPH insulin and daytime sulphonylurea gave a very small increase of body weight over a 6 months period. We conclude that combination therapy is an attractive alternative when starting insulin treatment in patients with Type 2 diabetes as this is a critical period for weight gain in such patients.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin, Isophane; Middle Aged; Sulfonylurea Compounds; Weight Gain

This study was designed to compare the efficacy of acute premeal administration of glipizide versus nateglinide in controlling postprandial hyperglycemia in subjects with non-insulin-requiring type 2 diabetes.. A total of 20 subjects (10 female, 10 male) with non-insulin-requiring type 2 diabetes were admitted overnight to the General Clinical Research Center on four occasions. In random order, 10 mg glipizide (30 min premeal), 120 mg nateglinide (15 min premeal), 10 mg glipizide plus nateglinide (30 and 15 min premeal, respectively), or placebo pills (30 and 15 min premeal) were administered in a double-blind fashion before a standardized breakfast. Blood was drawn for analysis of glucose, insulin, and C-peptide at -0.05, 0, 0.5, 1, 2, 3, and 4 h relative to the meal.. The subjects were aged 56 +/- 2 years and were moderately obese (BMI 31 +/- 1 kg/m(2)), with a mean HbA(1c) of 7.4 +/- 0.4%. The peak postprandial glucose excursion above baseline was higher with placebo (6.1 +/- 0.5 mmol/l) than glipizide (4.3 +/- 0.6 mmol/l, P = 0.002), nateglinide (4.2 +/- 0.4 mmol/l, P = 0.001), or glipizide plus nateglinide (4.1 +/- 0.5 mmol/l, P = 0.001). The area under the curve for the glucose excursion above baseline was also higher with placebo (14.1 +/- 1.8 mmol/h. l) compared with glipizide (6.9 +/- 2.4 mmol/h. l, P = 0.002), nateglinide (9.7 +/- 2 mmol/h. l, P = 0.004), or glipizide plus nateglinide (5.6 +/- 2.2 mmol/h. l, P < 0.001). Peak and integrated glucose excursions did not differ significantly between glipizide and nateglinide. However, by 4 h postmeal, plasma glucose levels were significantly higher with nateglinide (9 +/- 0.9 mmol/l) compared with the premeal baseline (7.8 +/- 0.6 mmol/l, P = 0.04) and compared with the 4-h postprandial glucose level after administration of glipizide (7.6 +/- 0.6 mmol/l, P = 0.02). Integrated postprandial insulin levels were higher with glipizide (1,556 +/- 349 pmol/h. l) than nateglinide (1,364 +/- 231 pmol/h. l; P = 0.03). Early insulin secretion, as measured by insulin levels at 30 min postmeal, did not differ between glipizide and nateglinide.. Acute premeal administration of nateglinide or glipizide has equal efficacy in controlling postbreakfast hyperglycemia in type 2 diabetes when each drug is administered at the optimum time before the meal. Glipizide causes a more pronounced and sustained postmeal insulin secretory response compared with nateglinide. Glipizide facilitates the return to near-fasting glucose levels at 4 h postmeal, but with the possible risk of increased frequency of postmeal hypoglycemia in drug-naive patients. The clinical decision to use glipizide versus nateglinide should be based on factors other than the control of postprandial hyperglycemia in type 2 diabetes.

Topics: C-Peptide; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Obesity; Postprandial Period

Our aim was to distinguish beneficial effects of B-cell rest from other effects of correction of hyperglycaemia. For this purpose we used diazoxide which reversibly blocks insulin secretion.. Eight obese (age 53 +/- 1 yr: BMI 33 +/- 2 kg/m2: 4 females) type 2 diabetic patients with poor metabolic control (HbA1c 8.7 +/- 0.9% ref.<5.2%) were studied twice after a randomly ordered treatment period of five days of intensive i.v. insulin treatment alone or i.v. insulin with peroral diazoxide (300 mg/day, divided into 3 doses). The glycaemic control was not altered between the two treatment periods. Insulin secretion was measured in response to i.v. glucose and arginine.. Insulin infusion was used to achieve close to identical degrees of glycaemia during the two treatment periods. Previous treatment with diazoxide was associated with a moderate 1.9 +/- 0.6 fold rise in insulin response to intravenous glucose (p=0.04) and 1.6 +/- 0.4 fold increased glucose potentiation of arginine-induced insulin secretion (GPAIS) (p=0.04). Conversely, after insulin alone there was no response to i.v. glucose and no change in GPAIS.. Short-term diazoxide treatment improved important parameters of B-cell function and these effects could be dissociated from confounding effects of changes in glycaemia. Consequently, the results indicate beneficial effects of B-cell rest.

Topics: Antihypertensive Agents; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, LDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diazoxide; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged; Obesity; Proinsulin; Regression Analysis; Triglycerides

Several experimental studies in rats have demonstrated that sulfonylurea treatment increases autoantigen expression in B-cells. This phenomenon may be deleterious for the preservation of residual beta cell function in patients with slowly progressing type 1 diabetes or latent autoimmune diabetes of adult (LADA).. The aim of the present study was to evaluate whether the exclusion of glibenclamide in the treatment of ICA positive type 2 diabetic patients may diminish or halt the humoral autoimmune response against B-cells as well as improve metabolic control and insulin secretion.. Fourteen type 2 diabetic patients with pancreatic autoimmunity (ICA+ and GABA+) and treated with insulin and glibenclamide (duration of disease 2.0 +/- 2.2, range 0.1-7 years and age 53 +/- 12.5, range 36-75 years) were studied. Patients were randomly assigned to two treatment groups, Group 1: insulin monotherapy (n = 8, age 53 +/- 6.4 years) (Exclusion of glibenclamide) and, Group 2: insulin plus glibenclamide (n = 6, age 53.5 +/- 16.9) (Unmodified treatment). Both groups were investigated at the beginning of the study and after one year for the following parameters: ICA and anti-GAD65 antibodies, fasting glucose and fasting C-peptide.. In group 1, six out of eight patients became ICA negative while all patients in group 2 remained ICA positive (p = 0.0097). Fasting glucose concentrations improved in group 1 (4.6 +/- 2.8) in relation to group 2 (11.5 +/- 5.5, p = 0.0023) after one year of treatment. No differences were found for anti-GAD antibodies and fasting C-Peptide between the groups.. These data show that exclusion of glibenclamide in the treatment of ICA+ type 2 diabetic patients partially decreases specific autoimmunity against endocrine pancreatic cells and improves metabolic control. This may reflect decreased expression of B-cell autoantigens suggesting that insulin monotherapy is a better choice for the treatment of LADA.

Topics: Autoantibodies; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Glyburide; Humans; Hypoglycemic Agents; Islets of Langerhans; Isoenzymes

Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes.. This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10-16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels > or =7.0 and < or =13.3 mmol/l (> or =126 and < or =240 mg/dl), HbA(1c) > or =7.0%, stimulated C-peptide > or =0.5 nmol/l (> or =1.5 ng/ml), and a BMI > 50th percentile for age.. Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was -2.4 mmol/l (-42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P < 0.001). Mean HbA(1c) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P < 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin.. Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients.

Topics: Adolescent; Blood Glucose; Body Mass Index; C-Peptide; Child; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Placebos; Racial Groups

Topics: Adolescent; Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Exercise Therapy; Glycated Hemoglobin; Humans; Middle Aged; Relaxation Therapy

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.

Topics: Acute Disease; Adult; Aged; Arginine; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged

The incidence of type 2 diabetes mellitus (DM) in children and adolescents has substantially increased over the past decade. The present study was conducted to evaluate the beta-cell response to intravenous glucagon (a non-glucose secretagogue) in children with type 2 DM. Twenty pediatric patients with type 2 DM were compared to 15 control subjects matched for body mass index and sexual maturation. The patients' ages ranged between 10 and 19 years. The duration of DM ranged from 1 to 5 years. Nine patients were on insulin treatment and 11 were on diet alone (3 patients) or metformin (8 patients). The criteria for type 2 DM were absent islet cell (IA-2) and glutamic acid decarboxylase (GAD65) antibodies and a fasting serum C-peptide level of > or = 0.23 nmol/l. Plasma glucose and serum C-peptide levels were determined in the fasting state and six minutes after an intravenous injection of 1 mg of glucagon. The fasting and stimulated plasma glucose levels and the fasting serum C-peptide levels (1.02 +/- 0.43 vs 0.79 +/- 0.26 nmol/l, p < 0.05) were higher in the patients with DM compared to weight-matched control subjects. While the absolute C-peptide responses to glucagon were not different between the two groups, the stimulated C-peptide to glucose ratios were significantly lower in the patients with DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p < 0.05). Patients with DM treated with diet or oral therapy had significantly greater basal and stimulated C-peptide concentrations, incremental C-peptide, and C-peptide to glucose ratios than patients on insulin treatment. Both the fasting and the stimulated C-peptide levels were inversely correlated with the duration of DM (r = -0.53, p < 0.05). HbA1c at one year follow-up was inversely correlated with glucagon-stimulated C-peptide levels at the time of the study (r = -0.658, p < 0.01) and positively correlated with the duration of diabetes (r = 0.671, p = 0.002). The apparently normal serum C-peptide levels measured after glucagon challenge in these children with type 2 DM reflect their higher glucose levels. The lower stimulated C-peptide to glucose ratios in these children with type 2 DM compared to normal controls demonstrate their diminished beta-cell response to intravenous glucagon, a non-glucose secretagogue. Among the patients with DM, a higher glucagon-stimulated serum C-peptide response was associated with diet/metformin treatment, a shorter duration of DM and predicted improved glycemi

Topics: Adolescent; Adult; Black or African American; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Glycated Hemoglobin; Hispanic or Latino; Humans; Hypoglycemic Agents; Injections, Intravenous; Insulin; Islets of Langerhans; Male; Metformin; Pancreatic Function Tests

Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo.. Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured.. There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin.. Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment.

Topics: Acetylcholine; Adult; Aged; Blood Flow Velocity; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diazoxide; Dipyridamole; Double-Blind Method; Female; Forearm; Glyburide; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sulfonylurea Compounds; Vasodilation

There is growing evidence in animal and in vitro studies showing that thiazolidinediones (TZDs) improve pancreatic beta cell (beta-cell) function. The aim of this study was to evaluate the effect of thiazolidinediones on the beta-cell function of patients with Type 2 diabetes mellitus (T2DM) in clinical practice.. This is an observational, nested case-control study. We identified 28 patients (TZD group), with T2DM, who had had a meal-stimulated C-peptide level documented before the addition of troglitazone to a failing double-therapy regimen with metformin (MET) and sulphonylurea (SU). As a control group (CTRL), we identified 26 patients, with T2DM, who also had had a meal-stimulated C-peptide documented before adding MET to a failing SU monotherapy regimen. We then proceeded to prospectively remeasure their meal-stimulated C-peptide levels and compared the changes over time between the two groups.. Both groups were well matched for age, body mass index (BMI), and HgbA1c before and after treatment. The C-peptide in the TZD group increased significantly during therapy (from 3.2 +/- 0.5 to 4.2 +/- 0.5, p = 0.01), whereas it remained unchanged in the CTRL group (from 4.8 +/- 0.6 to 5.0 +/- 0.5, p = 0.74). The C-peptide/glucose ratio also increased significantly in the TZD group (from 1.9 +/- 0.3 to 3.1 +/- 0.3, p = 0.0003) whereas it remained unchanged in the CTRL group (from 3.4 +/- 0.7 to 3.4 +/- 0.3, p = 0.97). Furthermore, the C-peptide/glucose ratio of the TZD group, which was significantly lower at baseline compared with the CTRL group (1.9 +/- 0.3 vs. 3.4 +/- 0.7, p = 0.04), caught up to its level during treatment (3.1 +/- 0.3 vs. 3.4 +/- 0.3, p = 0.48).. Thiazolidinediones seem to induce recovery of pancreatic beta cell function, independently of the correction of glucose toxicity.

Topics: Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Eating; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Middle Aged; Postprandial Period; Thiazoles; Thiazolidinediones

Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects of continuous administration of this peptide hormone in a 6-week pilot study.. 20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent beta-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A(1c), and fructosamine. The primary endpoints were haemoglobin A(1c) concentration, 8-h profile of glucose concentration in plasma, and beta-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol.. One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in fructosamine concentration (p=0.0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4.3 mmol/L and 5.5 mmol/L (p<0.0001). Haemoglobin A(1c) decreased by 1.3% (p=0.003) and fructosamine fell to normal values (p=0.0002). Fasting and 8 h mean concentrations of free fatty acids decreased by 30% and 23% (p=0.0005 and 0.01, respectively). Gastric emptying was inhibited, bodyweight decreased by 1.9 kg, and appetite was reduced. Both insulin sensitivity and beta-cell function improved (p=0.003 and p=0.003, respectively). No important side-effects were seen.. GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term effects of GLP-1 is needed.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Peptide Fragments; Pilot Projects; Protein Precursors

Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had high-ferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 +/- 0.9% vs. 6.39 +/- 1.2%), insulin sensitivity (2.75 +/- 1.8 vs. 3.2 +/- 2.1 mg.dl(-1).min(-1)), and area under the curve for C-peptide (AUC(C-peptide); 38.7 +/- 11.6 vs. 37.6 +/- 14.1 ng.ml(-1).min(-1)) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA(1c) decreased significantly only in group 1 subjects (mean differences, -0.61; 95% CI, -0.17 to -1.048; P = 0.01). AUC(C-peptide) decreased by -10.2 +/- 6.3% after blood letting. In contrast, a 10.4 +/- 6.4% increase in AUC(C-peptide) was noted in group 2 subjects at 4 months (P = 0.032). At 12 months, AUC(C-peptide) returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 +/- 43.2% vs. -8.6 +/- 9.9% in groups 1 and 2, respectively, P = 0.049). At 12 months, the differences between the two groups were even more marked (55.5 +/- 24.8% vs. -26.8 +/- 9.9%; P = 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 +/- 1.81 to 3.08 +/- 2.55 mg.dl(-1).min(-1) at 4 months, to 3.16 +/- 1.85 mg.dl(-1).min(-1) at 12 months; P = 0,045) in contrast with group 2 subjects (from 3.24 +/-

Topics: Analysis of Variance; Area Under Curve; Blood Glucose; Blood Pressure; C-Peptide; C-Reactive Protein; Diabetes Mellitus, Type 2; Ferritins; Glucagon; Glycated Hemoglobin; Hematocrit; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Phlebotomy; Smoking; Transferrin

Aim of this study was to investigate whether octreotide, a synthetic somatostatin analogue that inhibits growth hormone, insulin and glucagon secretion and improves glycaemic control in insulin dependent diabetic patients was able to exert similar effects in insulin treated type 2 diabetic patients with chronic renal failure who have high plasma glucagon levels. For this purpose saline or octreotide was randomly administered by continuous subcutaneous infusion (100 mcg/daily) in addition to usual insulin treatment for 5 days to six type 2 insulin treated diabetic patients with chronic renal failure and to six type 2 patients with normal renal function, as a control group. At day 3 of insulin plus saline or insulin plus octreotide treatment, total glucose uptake and hepatic glucose production (HGP) were investigated during an euglycemic clamp; at day 5 GH, glucagon and C-peptide plasma levels were evaluated. Octreotide treatment lowered endogenous insulin secretion (evaluated by C-Peptide levels assay), GH and glucagon in all patients, but caused a significant reduction of daily insulin requirement (32 +/- 14 I.U. vs 41 +/- 19 I.U., P<0.02) only in patients with renal failure. HGP was significantly (P<0.05) lowered in patients with renal failure but glucose uptake remained unchanged. The lowering effect of octreotide on insulin requirement in diabetic patients with renal failure in spite of the contemporaneous inhibition on insulin secretion could be explained on the basis of the greater reduction of glucagon levels which are very elevated in these patients as compared to patients with normal renal function. The lowering of glucagon could decrease HGP and, consequently, insulin requirement.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gluconeogenesis; Glucose Clamp Technique; Human Growth Hormone; Humans; Infusions, Parenteral; Insulin; Insulin Secretion; Kidney Failure, Chronic; Kidney Function Tests; Liver; Male; Middle Aged; Octreotide

To determine the effects of combined therapy of gliclazide and bedtime insulin on glycemic control and C-peptide secretion, we studied 25 patients with type 2 diabetes and sulfonylurea secondary failure, aged 56.8 +/- 8.3 years, with a duration of diabetes of 10.6 +/- 6.6 years, fasting plasma glucose of 277.3 +/- 64.6 mg/dl and a body mass index of 27.4 +/- 4.8 kg/m2. Patients were submitted to three therapeutic regimens lasting 2 months each: 320 mg gliclazide (phase 1), 320 mg gliclazide and bedtime NPH insulin (phase 2), and insulin (phase 3). At the end of each period, glycemic and C-peptide curves in response to a mixed meal were determined. During combined therapy, there was a decrease in all glycemic curve values (P<0.01). Twelve patients (48%) reached fasting plasma glucose <140 mg/dl with a significant weight gain of 64.8 kg (43.1-98.8) vs 66.7 kg (42.8-101.4) (P<0.05), with no increase in C-peptide secretion or decrease in HbA1. C-Peptide glucose score (C-peptide/glucose x 100) increased from 0.9 (0.2-2.1) to 1.3 (0.2-4.7) during combined therapy (P<0.01). Despite a 50% increase in insulin doses in phase 3 (12 U (9-30) vs 18 U (11-60); P<0.01) only 3 patients who responded to combined therapy maintained fasting plasma glucose <140 mg/dl (P<0.02). A tendency to a higher absolute increase in C-peptide (0.99 (0.15-2.5) vs 0.6 (0-2.15); P = 0.08) and C-peptide incremental area (2.47 (0.22-6.2) vs 1.2 (0-3.35); P = 0.07) was observed among responders. We conclude that combined therapy resulted in a better glucose response to a mixed meal than insulin alone and should be tried in type 2 diabetic patients before starting insulin monotherapy, despite difficulties in predicting the response.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Gliclazide; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds; Treatment Failure

Non-insulin-dependent diabetes mellitus (type 2 diabetes) not responding to dietary treatment alone in patients with non-alcoholic liver cirrhosis is characterized by high postprandial hyperglycaemia. The control of postprandial hyperglycaemia in such patients, is generally achieved by the means of progressively higher doses of insulin, with an increasing risk of hypoglycaemia in the late postprandial period. The aim of this study was to evaluate the use of acarbose for the control of postprandial hyperglycaemia in 100 patients with well-compensated liver cirrhosis and type 2 diabetes treated with insulin.. The study was double blind with randomization of treatments into acarbose (52 patients) vs. placebo (48 patients) with parallel branches over a period of 28 weeks.. All patients tolerated the treatments well and no significant variations in liver function tests were observed (< 5% vs. pretreatment). A significant reduction of several parameters was observed only after acarbose treatment: fasting glycaemia (173 +/- 28 vs. 146 +/- 19 mg/dl; p < 0.01), postprandial glycaemia (230 +/- 24 vs. 148 +/- 20 mg/dl; p < 0.01), mean glycaemia (206 +/- 20 vs. 136 +/- 13 mg/dl; p < 0.01), mean variation (180 +/- 14 vs. 51 +/- 10 mg/dl; p < 0.01), HbA1c (8.9 +/- 0.8 vs. 7.2 +/- 0.5; p < 0.05), C-peptide 2 h after a standard meal (4.5 +/- 1.9 vs. 2.8 +/- 1.7 ng/ml; p < 0.05), whereas the parameters did not change significantly after the placebo. After acarbose treatment a significant increase of intestinal voiding/week (+116% vs. +10%; p < 0.01) and a parallel reduction of blood ammonia levels (-52 +/- 9% vs. -9 +/- 5%; P < 0.01) were observed.. The results clearly document the good tolerability and the absence of toxic effects of acarbose on liver, due to the lack of both intestinal absorption and hepatic metabolism of the drug at doses in the therapeutic range. In fact, acarbose increases the peristalsis movements of the gut, stimulates the proliferation of the saccarolytic bacteria and simultaneously reduces the proliferation of proteolytic bacteria, thus resulting active in the reduction of blood ammonia levels. These effects of acarbose may be advantageously exploited in the treatment of type 2 diabetic patients with well-compensated non-alcholic liver cirrhosis.

Topics: Acarbose; Ammonia; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Food; Glycated Hemoglobin; Humans; Insulin; Liver Cirrhosis; Male; Placebos

To determine the efficacy of rosiglitazone compared with placebo in reducing hyperglycemia.. After a 4-week placebo run-in period, 959 patients were randomized to placebo or rosiglitazone (total daily dose 4 or 8 mg) for 26 weeks. The primary measure of efficacy was change in the HbA1c concentration.. Rosiglitazone produced dosage-dependent reductions in HbA1c of 0.8, 0.9, 1.1, and 1.5% in the 4 mg o.d., 2 mg b.i.d., 8 mg o.d., and 4 mg b.i.d. groups, respectively, compared with placebo. Clinically significant decreases from baseline in HbA1c were observed in drug-naive patients at all rosiglitazone doses and in patients previously treated with oral monotherapy at rosiglitazone 8 mg o.d. and 4 mg b.i.d. Clinically significant decreases from baseline in HbA1c were also observed with rosiglitazone 4 mg b.i.d. in patients previously treated with combination oral therapy. Approximately 33% of drug-naive patients treated with rosiglitazone achieved HbA1c < or =7% at study end. The proportions of patients with at least one adverse event were comparable among the rosiglitazone and placebo groups. There was no evidence of hepatotoxicity in any treatment group. There were statistically significant increases in weight and serum lipids in all rosiglitazone treatment groups compared with placebo. For LDL and HDL cholesterol, the observed increase appeared to be dose related.. Rosiglitazone at total daily doses of 4 and 8 mg significantly improved glycemic control in patients with type 2 diabetes and was well tolerated.

Topics: Aged; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Middle Aged; Placebos; Rosiglitazone; Thiazoles; Thiazolidinediones; Triglycerides

Amino acids derived from ingested protein are potential substrates for gluconeogenesis. However, several laboratories have reported that protein ingestion does not result in an increase in the circulating glucose concentration in people with or without type 2 diabetes. The reason for this has remained unclear. In people without diabetes it seems to be due to less glucose being produced and entering the circulation than the calculated theoretical amount. Therefore, we were interested in determining whether this also was the case in people with type 2 diabetes. Ten male subjects with untreated type 2 diabetes were given, in random sequence, 50 g protein in the form of very lean beef or only water at 0800 h and studied over the subsequent 8 h. Protein ingestion resulted in an increase in circulating insulin, C-peptide, glucagon, alpha amino and urea nitrogen, and triglycerides; a decrease in nonesterified fatty acids; and a modest increase in respiratory quotient. The total amount of protein deaminated and the amino groups incorporated into urea was calculated to be approximately 20-23 g. The net amount of glucose estimated to be produced, based on the quantity of amino acids deaminated, was approximately 11-13 g. However, the amount of glucose appearing in the circulation was only approximately 2 g. The peripheral plasma glucose concentration decreased by approximately 1 mM after ingestion of either protein or water, confirming that ingested protein does not result in a net increase in glucose concentration, and results in only a modest increase in the rate of glucose disappearance.

Topics: Adult; Aged; Animals; Blood Glucose; C-Peptide; Cattle; Circadian Rhythm; Diabetes Mellitus, Type 2; Dietary Proteins; Drinking; Fatty Acids, Nonesterified; Glucagon; Humans; Insulin; Male; Meat; Middle Aged; Triglycerides; Uric Acid

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Sulfonylurea Compounds; Thailand; Thiazoles; Thiazolidinediones; Time Factors; Troglitazone

We studied the significance of BsmI restriction enzyme polymorphism of the vitamin D receptor (VDR) gene and the XbaI and PvuII polymorphisms of the estrogen receptor (ER) gene in patients with type 2 diabetes (n=49), android type obesity with normal carbohydrate metabolism (n=29) and healthy controls (n=138).. The distribution of genotypes in the study groups, as well as their relationship to fasting and 1 h postprandial serum C-peptide levels were analyzed.. Postprandial serum C-peptide levels of BB genotypes were significantly higher in the diabetes and obese groups (6.18+/-5.09 ng/ml) compared with other genotypes (2.71+/-2.45 vs. 1.72+/-1.97 ng/ml, respectively, P=0.05). Among patients with type 2 diabetes and obese subjects, the XX allelic variant of the ER gene was more frequent (P=0.00015). Postprandial C-peptide levels of subjects exhibiting XX genotype were significantly lower compared with those with Xx genotype (1.67+/-2.16 vs. 3.8+/-3.72 ng/ml, P=0.021). The BBXx allelic combination of the VDR/ER receptor genes was less frequent in diabetic patients than in healthy subjects or in obese patients. The BBXx genotype was associated with significantly elevated postprandial C-peptide levels in all subjects compared with other combinations (9.65+/-3.14 vs. 1.35+/-2.82 ng/ml, P=0.003). No difference was found in the distribution of the PvuII polymorphism of the ER gene or in the association with the C-peptide levels among study groups.. Polymorphisms of the VDR/ER receptor genes might play a role in the pathogenesis of type 2 diabetes by influencing the secretory capacity of beta-cells.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Obesity; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; Vitamin D

To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes.. A total of 23 diabetic patients (age 30-70 years BMI < 36 kg/m2) who being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n = 11) or pioglitazone (45 mg/day) (n = 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT) and hepatic peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU x min(-1) x m(-2) clamp performed with 3-[3H]glucose and indirect calorimetry HbA1c measured monthly throughout the study period.. After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 +/- 15 to 135 +/- 11 mg/dl, P < 0.01), mean plasma glucose during OGTT(293 +/- 12 to 225 +/- 14 mg/dl, P < 0.01), and HbA1c (8.9 +/- 0.3 to 7.2 +/- 0.5%, P < 0.01 ) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 +/- 39 to 478 +/- 49) microEq/l, P < 0.01) and mean plasma FFA during OGTT (485 +/- 30 to 347 +/- 33 microEq/l, P < 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose prodution (EGP) and FPG were strongly correlated (r = 0.67, P < 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P < 0.05) whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P < 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGGTT was strongly related to the change in total body glucose disposl during the second insulin clamp step.. These results suggest that pioglitazone therapy in type 2 diabetic patients decreases lasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin.

Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Middle Aged; Pioglitazone; Placebos; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Triglycerides

The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients.. In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite.. Fasting plasma glucose (day 2) decreased from 13.9 +/- 1 (no treatment) to 11.2 +/- 0.4 (metformin) and 11.5 +/- 0.5 (GLP-1) and further decreased to 9.4 +/- 0.7 (combination therapy) (P = 0.0005, no difference between monotherapy with GLP-1 and metformin). The 24-h mean plasma glucose (day 2) decreased from 11.8 +/- 0.5 (metformin) and 11.7 +/- 0.8 (GLP-1) to 9.8 +/- 0.5 (combination) (P = 0.02, no difference between GLP-1 and metformin). Insulin levels were similar between the three regimens, but glucagon levels were significantly reduced with GLP-1 compared with metformin (P = 0.0003). Combination therapy had no additional effect on appetite scores.. Monotherapy with GLP-1 and metformin have equal effects on plasma glucose and additive effects upon combination.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Infusions, Parenteral; Insulin; Insulin Secretion; Kinetics; Male; Metformin; Middle Aged; Peptide Fragments; Placebos; Research Design

The minimal model of Bergman et al has been used to yield estimates of insulin sensitivity (Si) and glucose effectiveness (Sg) in type 2 diabetes by incorporating exogenous insulin protocols into the regular intravenous glucose tolerance test (IVGTT). These estimates, however, are influenced by the degree to which the dose of exogenous insulin is greater than the physiologic response to a glucose load. Moreover, most studies have related to type 2 diabetes subjects whose diabetes was relatively mild in terms of therapeutic requirements. To develop a "minimal disturbance" approach in estimating Si and Sg in type 2 diabetes, we have used a reduced glucose load (200 mg/kg) and a "physiologic" insulin infusion throughout the IVGTT in a series of 8 patients, 5 of whom were insulin-requiring. Data from this approach were analyzed using the modelling program CONSAM to apply the Bergman model, either unmodified (BMM), or incorporating an additional delay element between the plasma and "remote" insulin compartments (MMD). Application of the MMD and extension of the IVGTT from 3 to 5 hours improved successful resolution of Si and Sg from 37.5% (BMM, 3-hour IVGTT) to 100% (MMD, 5-hour IVGTT). Si was reduced in these type 2 diabetes patients compared with normal subjects (1.86 +/- 0.60 v. 8.65 +/- 2.27 min(-1) x microU(-1) x mL x 10(4) P <.01). The results were validated in the type 2 diabetes group using a 2-stage euglycemic clamp ((Si)CLAMP = 2.02 +/- 0.42 min(-1) x microU(-1) x mL x 10(4) P >.4). Sg was not significantly reduced (2.00 +/- 0.25 type 2 diabetes v. 1.55 +/- 0.26 normal min(-1) x 10(2)). Data from a group of normal nondiabetic subjects was then analyzed using the MMD, but this approach did not enhance the fit of the model compared with the BMM. This result indicates that the delay in insulin action in type 2 diabetes represents an abnormality whereby the onset of insulin action cannot be described as a single phase in the transfer of insulin from plasma to the remote compartment. It is postulated that the physiologic basis for this delayed action may relate to transcapillary endothelial transfer of insulin, this process limiting the rate of onset of insulin action.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Infusions, Intravenous; Insulin; Insulin Resistance; Kinetics; Male; Middle Aged; Models, Biological

This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes.. This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks -1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured.. During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide ( = -4.94 vs. -2.71 mmol. h/l, P < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide ( = -2.9 vs. -1.0 mmol/l, respectively, P < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide ( = +1.83 vs. +0.95 nmol. h/l, P < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control ( 12-h incremental AUC = -13.2 vs. -15.3 mmol. h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide ( 12-h AUC = +866 vs. +1,702 pmol. h/l, P = 0.01).. This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide.

Topics: Aged; Area Under Curve; Blood Glucose; C-Peptide; Cyclohexanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos; Postprandial Period; Proinsulin; Single-Blind Method; Time Factors

In the first report (Journal of Clinical Pharmacology 2000; 40:647-654), it was shown that ingestion of 120 mg of Ginkgo biloba extract (EGb 761) daily for 3 months by normal glucose-tolerant individuals caused a significant increase in pancreatic beta-cell insulin and C-peptide response, measured as the area under the curve (AUC0-->120) during a 2-hour standard (75 g) oral glucose tolerance test (OGTT). This follow-up study was designed to determine the effect of the same Ginkgo biloba treatment on glucose-stimulated pancreatic beta-cell function in non-insulin-dependent diabetes mellitus (NIDDM) subjects. In diet-controlled subjects (fasting plasma glucose [FPG], 117 +/- 16 mg/dl; fasting plasma insulin [FPI], 29 +/- 8 microU/ml; n = 6), ingestion of Ginkgo biloba produced no significant effect on the insulin AUC0-->120 (193 +/- 53 vs. 182 +/- 58 microU/ml/h, before and after ingesting Ginkgo biloba, respectively). In hyperinsulinemic NIDDM subjects taking oral hypoglycemic medications (n = 6) (FPG 143 +/- 48 mg/dl; FPI 46 +/- 13 microU/ml), ingestion of Ginkgo biloba caused blunted plasma insulin levels from 30 to 120 minutes during the OGTT, leading to a reduction of the insulin AUC0-->120 (199 +/- 33 vs. 147 +/- 58 microU/ml/h, before and after Ginkgo biloba, respectively). The C-peptide levels increased, and so the AUC0-->120 did not parallel the insulin AUC0-->120, creating a dissimilar insulin/C-peptide ratio indicative of an enhanced hepatic extraction of insulin relative to C-peptide. Thus, in pancreatic beta-cells that are already maximally stimulated, ingestion of Ginkgo biloba may cause a reduction in plasma insulin levels. Only in NIDDM subjects with pancreatic exhaustion (FPG 152 +/- 46 mg/dl; FPI 16 +/- 8 microU/ml; n = 8), who also took oral hypoglycemic agents, did Ginkgo biloba ingestion significantly increase pancreatic beta-cell function in response to glucose loading (insulin AUC0-->120 increased from 51 +/- 29 to 98 +/- 20 microU/ml/h, p < 0.0001), paralleled by a C-peptide AUC0-->120 increase from 7.2 +/- 2.8 to 13.7 +/- 6.8 (p < 0.0001). Whether this increase is due to "resuscitation" of previously exhausted islets or increased activity of only the remaining functional islets is unclear. However, not even in this group did increased pancreatic beta-cell activity cause a reduction of blood glucose during the OGTT. It is concluded that ingestion of Ginkgo biloba extract by an NIDDM subject may increase the hepatic metabolic clearanc

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet; Female; Ginkgo biloba; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Middle Aged; Phytotherapy; Plant Extracts; Vasodilator Agents

To evaluate the efficacy and tolerability of pioglitazone in combination with a sulfonylurea in the treatment of type 2 diabetes mellitus.. This 16-week, double-blind study included patients on a stable regimen of a sulfonylurea for > or = 30 days and with a glycosylated hemoglobin (HbA1C) level > or = 8.0%. Patients were randomly assigned to receive once daily pioglitazone 15 mg (n = 184), pioglitazone 30 mg (n = 189), or placebo plus sulfonylurea (n = 187).. Patients receiving pioglitazone + sulfonylurea had significant (P < 0.05) decreases from baseline in HbA1C and fasting plasma glucose levels compared with patients treated with placebo + sulfonylurea. As compared with placebo, HbA1C decreased by 0.9% (95% confidence interval [CI]: 0.06% to 1.2%) with pioglitazone 15 mg and 1.3% (CI: 1% to 1.6%) with 30 mg pioglitazone; fasting plasma glucose levels decreased by 39 mg/dL (95% CI: 27 to 52 mg/dL) with pioglitazone 15 mg and by 58 mg/dL (95% CI: 46-70 mg/dL) with 30 mg pioglitazone. Both pioglitazone + sulfonylurea groups had significant (P < 0.05) mean percent decreases in triglyceride levels (17%, 95% CI: 6% to 27% for 15 mg; 26%, 95% CI: 16% to 36% for 30 mg) and increases in high-density lipoprotein cholesterol levels (6%, 95% CI: 1% to 11% for 15 mg; 13%, CI: 8% to 18% for 30 mg) compared with placebo + sulfonylurea. There were small but statistically significant mean percent increases in low-density lipoprotein cholesterol levels in all groups. Pioglitazone was well tolerated, and the rates of adverse events were similar in all groups.. In patients with type 2 diabetes, pioglitazone plus sulfonylurea significantly improves HbA1C and fasting plasma glucose levels with beneficial effects on serum triglyceride and HDL-cholesterol levels.

Topics: Adult; Aged; Analysis of Variance; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Pioglitazone; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Time Factors; Treatment Outcome; Triglycerides; United States

We studied the effect of the acute administration of gliclazide at 160 mg on insulin release during hyperglycaemic clamps in 12 type 2 diabetes patients, age 50 +/- 9.0 years, diabetes duration 5.5 +/- 4.8 years, fasting blood glucose 9.6 +/- 2.1 mmol/L (means +/- SD). After a 210 min of hyperinsulinaemic euglycaemic clamp (blood glucose 4.6 +/- 0.14mmol/L), gliclazide or placebo (randomised, double-blind, cross-over) was administered; 60 minutes later, a hyperglycaemic clamp (4hr) at 8mmol/L was started. Plasma C-peptide levels increased significantly after the administration of gliclazide (increment 0.17 +/- 0.15 vs. 0.04 +/- 0.07 nmol/L, p = 0.024) before the clamp. After the start of the hyperglycaemic clamp, the areas under the curve (AUC) for insulin and C-peptide did not differ from 0-10 min (first phase) with gliclazide. However, second-phase insulin release (30-240 min) was markedly enhanced by gliclazide. AUC plasma insulin (30 to 240 min) was statistically significantly higher after gliclazide (12.3 +/- 13.9 vs. -0.56 +/- 9.4 nmol/L x 210 min, p = 0.022); similarly, AUC plasma C-peptide (30 to 240 min) was also higher: 128 +/- 62 vs. 63 +/- 50 nmol/L x 210 min, p = 0.002). In conclusion, in long-standing type 2 diabetes the acute administration of gliclazide significantly enhances second phase insulin release at a moderately elevated blood glucose level. In contrast to previous findings in mildly diabetic subjects, these 12 type 2 diabetes patients who had an inconsiderable first phase insulin release on the placebo day, only showed an insignificant increase in first phase with gliclazide.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gliclazide; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged

To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.. Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily.. Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively).. Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Fasting; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between ind

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Entropy; Fatty Acids, Nonesterified; Gliclazide; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Middle Aged; Placebos; Prospective Studies; Time Factors

To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus.. Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded.. Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity.. Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.

Topics: Adult; Aged; Arteriosclerosis; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Lipids; Lipoproteins; Male; Middle Aged; Pioglitazone; Single-Blind Method; Thiazoles; Thiazolidinediones; Treatment Outcome; United States

In healthy subjects, paracrine factors partly regulate insulin secretion and basal endogenous glucose production. Administration of pentoxifylline, an adenosine receptor antagonist, inhibits transiently endogenous glucose production in healthy humans without any changes in glucoregulatory hormone concentrations. To evaluate the modulatory role of adenosine on endogenous glucose production and basal insulin secretion in type 2 diabetes, aminophylline, a potent adenosine receptor antagonist, was administered intravenously to 5 patients with type 2 diabetes mellitus in a saline-controlled study. Endogenous glucose production was measured before and during 6 hours after administration of aminophylline/saline by primed, continuous infusion of [6,6-(2)H(2)]glucose. During both experiments, the decrease in plasma glucose concentration was similar (16% v 18% from basal, not significant [NS]). After aminophylline administration, basal endogenous glucose production was transiently inhibited within 15 minutes to 70% from basal, whereas it did not change significantly in the control experiment (P =.02). The inhibition of glucose production coincided with stimulation of insulin secretion to 144% from basal 90 minutes after the administration of aminophylline (P =.008). In the control experiment insulin secretion decreased gradually by 29% during 6 hours. We conclude that aminophylline inhibits endogenous glucose production in type 2 diabetes by stimulation of insulin secretion. Paracrine factors, such as adenosine, may be involved in the regulation of basal insulin secretion in type 2 diabetes mellitus.

Topics: Aged; Aminophylline; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Humans; Hydrocortisone; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Norepinephrine; Purinergic P1 Receptor Antagonists

These studies examined the influence of timing of administration of nateglinide on the glucose profile and beta-cell secretory response to a standardized test meal and the effect of meal composition on the pharmacokinetic and pharmacodynamic profile. In study 1, nateglinide (60 mg) or placebo was given orally at -10, -1, or +10 min to healthy subjects (n = 12), in relation to a standardized test meal (500 kcal) that commenced at 0 min. In study 2, also in healthy subjects (n = 12), a single oral dose (60 mg) of nateglinide was given either 10 min before or 10 min after the start of each of three different test meals (i.e. high in carbohydrate, fat, or protein). In both studies, the postmeal observation period was a minimum of 240 min. In the first study premeal (-10,-1 min), administration of nateglinide led to earlier and higher peak plasma nateglinide concentrations, compared with postprandial dosing (+10 min). A significantly lower maximum postprandial glucose concentration was seen with preprandial dosing compared with either placebo (P < 0.01) or nateglinide given postprandially (P < 0.01). The impact on the glucose profile was consistent with the enhanced insulin profiles after nateglinide, resulting in higher peak plasma insulin concentrations compared with placebo (P < 0.01). Study 2 confirmed the greater impact of pre- vs. postprandial dosing on the glucose and insulin profiles, irrespective of meal type. Nateglinide administration, before a meal, resulted in a more rapid rise and higher peak nateglinide plasma concentrations, irrespective of meal composition. Preprandial administration of nateglinide was more effective in reducing prandial glucose excursions, compared with postmeal dosing (+10 min), a consequence of the earlier insulin response.

Topics: Area Under Curve; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Double-Blind Method; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Time Factors

There are scarce data dealing with the degree of postprandial lipaemia after sulphonylurea administration. The aim of this study was to examine the effect of acute glibenclamide administration on postprandial lipaemia in Type 2 diabetic patients.. Eight randomly selected Type 2 diabetic individuals, aged 43-65 years (mean, 54 years), who had never received any anti-diabetic drug, were included in the study. Each patient was given a 485 kcal mixed meal (45% fat, 40% carbohydrate and 15% protein) twice on separate days after an overnight fast: once with placebo and once with 5 mg glibenclamide, per os, in a random order. The two tests were performed with an interval of 7 days. Venous blood samples were drawn just before and 2 h, 4 h and 6 h after meal consumption. Total triglyceride levels in plasma, in chylomicrons (CM), in CM-deficient plasma, in very low-density lipoprotein (VLDL) subfractions (VLDL-1, VLDL-2) and in intermediate-density lipoprotein (IDL) were determined. Free fatty acid (FFA) and total cholesterol levels in plasma, as well as high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels in CM-deficient plasma, were also measured. Finally, serum glucose, insulin and C-peptide concentrations were measured in each sample.. As expected there was a significant decrease in postprandial glycaemia after glibenclamide administration compared to placebo (mean area under the curve values: AUC = 53.3 +/- 18.2 and 69.1 +/- 21.6 mm/h, P = 0.00009). In addition, the mean AUC values of insulin and C-peptide were significantly greater after drug administration. The AUC values of total plasma triglyceride and of CM triglyceride following glibenclamide administration were significantly lower compared to placebo, while the AUC values of postprandial triglyceride in CM-deficient plasma and of postprandial triglyceride in VLDL-1, VLDL-2 and IDL were not different after drug administration compared to placebo. Finally, no significant differences were noted in the AUC values of total cholesterol, LDL cholesterol, HDL cholesterol and plasma FFA levels after glibenclamide administration.. These results demonstrate that glibenclamide administration improves postprandial hypertriglyceridaemia acutely by reducing postprandial triglycerides of intestinal origin.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Cholesterol; Chylomicrons; Coronary Disease; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glyburide; Humans; Hypertriglyceridemia; Hypoglycemic Agents; Insulin; Lipoproteins, VLDL; Middle Aged; Postprandial Period; Triglycerides

Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose-induced insulin secretion in patients with type 2 diabetes. It has also been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs because this hormone enhances insulin-mediated glucose disposal. However, interpretations of the studies have been controversial. This study determines the effect of GLP-1 on insulin-mediated glucose disposal in elderly patients with type 2 diabetes.. Studies were conducted on 8 elderly patients with type 2 diabetes (age range, 76 +/- 1 years; body mass index, 28 +/- 1 kg/m(2)). Each subject underwent two 180-minute euglycemic (insulin infusion rate, 40 mU/m(2)/min) insulin clamps in random order. Glucose production (Ra) and disposal (Rd) rates were measured using tritiated glucose methodology. In one study, glucose and insulin alone were infused. In the other study, a primed-continuous infusion of GLP-1 was administered at a final rate of 1.5 pmol x kg(-1) x min(-1) from 30 to 180 minutes.. Glucose values were similar between the control and GLP-1 infusion studies. 120- to 180-minute insulin values appeared to be higher during the GLP-1 infusion study (control, 795 +/- 63 pmol/l; GLP-1, 1140 +/- 275 pmol/l; p = not significant [NS]). The higher insulin values were largely due to 2 subjects who had substantial insulin responses to GLP-1 despite euglycemia and hyperinsulinemia. The 120- to 180-minute insulin values were similar in the other 6 subjects (control, 746 +/- 35 pmol/l; GLP-1, 781 +/- 41 pmol/l; p = NS). Basal (control, 2.08 +/- 0.05 mg/kg/min; GLP-1, 2.13 +/- 0.04 mg/kg/min; p = NS) and 120- to 180-minute (control, 0.50 +/- 0.18 mg/kg/min; GLP-1, 0.45 +/- 0.14 mg/kg/min; p = NS) Ra was similar between studies. The 120- to 180-minute Rd values were higher during the GLP-1 infusion studies (control, 4.73 +/- 0.39 mg/kg/min; GLP-1, 5.52 +/- 0.43 mg/kg/min; p <.01). When the 2 subjects who had significant insulin responses to GLP-1 during the euglycemic clamp were excluded, the 120- to 180-minute Rd values were still higher in the GLP-1 infusion study (control, 5.22 +/- 0.32 mg/kg/min; GLP-1, 6.05 +/- 0.37 mg/kg/min; p <.05).. We conclude that GLP-1 may enhance insulin sensitivity in elderly patients with diabetes.

Topics: Aged; Biological Transport, Active; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Clamp Technique; Humans; Insulin; Peptide Fragments; Peptides

To examine the effects of improved glycaemic control over 20 weeks on the type and distribution of weight change in patients with type 2 diabetes who at baseline have poor glycaemic control.. Forty-three patients with type 2 diabetes and HbA1c > 8.9% were randomised to either intensive glycaemic control (IC) n = 21 or usual glycaemic control (UC) n = 22 for 20 weeks. Dual energy X-ray absorptiometry was used to assess the type and distribution of weight change during the study.. After 20 weeks HbA1c was significantly lower in patients randomised to IC than UC (HbA1c IC 8.02 +/- 0.25% vs. UC 10.23 +/- 0.23%, p < 0.0001). In the IC group weight increased by 3.2 +/- 0.8 kg after 20 weeks (fat-free mass increased by 1.8 +/- 0.3 kg) compared to 0.02 +/- 0.70 kg in UC (p = 0.003). The gain in total body fat mass comprised trunk fat mass (IC 0.94 +/- 0.5 kg vs. UC 0.04 +/- 0.4 kg, p = 0.18) and peripheral fat mass (total body fat - trunk fat) (IC 0.71 +/- 0.32 kg vs. UC -0.21 +/- 0.28 kg, p = 0.04). Blood pressure and serum lipid concentrations did not change over time in either group.. Intensive glycaemic control was associated with weight gain which was distributed in similar proportions between the central and peripheral regions and consisted of similar proportions of fat and fat-free mass. Blood pressure and serum lipid concentrations were not adversely affected.

Topics: Absorptiometry, Photon; Adipose Tissue; Blood Glucose; Body Composition; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Electrocardiography; Ethnicity; Female; Humans; Lipids; Male; Middle Aged; New Zealand; Weight Gain

To metabolically characterize patients with slowly progressing autoimmune diabetes (LADA) of short duration we measured insulin, C peptide, and glucagon responses to glucose and arginine at three blood glucose levels (fasting and 14 and 28 mmol/L) in 11 patients with LADA, 11 patients with type 2 diabetes, and 14 healthy control subjects matched for age and body mass index. The acute insulin response to arginine was impaired in LADA vs. type 2 diabetes at all glucose levels, with the greatest impairment in the maximally stimulated insulin concentrations (P<0.04). In contrast, beta-cell sensitivity to glucose was unaltered in LADA and type 2 diabetes. The glucagon concentrations were elevated in both LADA and type 2 diabetic patients compared with healthy control subjects (P<0.02), but did not differ between the diabetic groups. In conclusion, patients with LADA share insulin resistance with type 2 diabetic patients, but display a more severe defect in maximally stimulated beta-cell capacity than patients with type 2 diabetes.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose; Humans; Insulin; Male

Recent studies indicate that endogenous epinephrine provides protection against hypoglycemia in fasted elderly patients with type 2 diabetes treated with sulfonylureas. To establish a dose-response relationship and further characterize this hormonal action, 10 subjects with type 2 diabetes aged 67 +/- 1.3 years and receiving glyburide 20 mg daily were studied on 3 separate occasions. Saline placebo, half dose epinephrine ([Epi] 0.375 microg/min), and full dose Epi (0.75 microg/min) were infused during the final 10 hours of a 28-hour fast in a paired, randomized single-blind study to simulate physiologic epinephrine levels. Substrate and hormonal parameters and glucose production (Rd), disposal (Rd), and metabolic clearance rates were determined every 30 minutes. In the placebo study, the mean decline in plasma glucose during the final 10 hours of fasting was -2.7 +/- 0.6 mmol/L, compared with -0.3 +/- 0.3 mmol/L in the half dose Epi study and an actual increase in glucose of 1.0 +/- 0.8 mmol/L in the full dose Epi study (P < .001). There was a similar decline in the glucose Ra in all 3 studies, and the glucose Rd was not significantly different among the 3 study conditions. The baseline-adjusted metabolic clearance rate of glucose was significantly decreased during the epinephrine studies compared with the placebo study (P = .01). The concentration of other counterregulatory hormones did not differ between the studies. We conclude that low physiologic concentrations of epinephrine prevent the progressive decline in plasma glucose observed during fasting in elderly sulfonylurea-treated patients with type 2 diabetes. This finding may be attributable to a relative insulin resistance induced by epinephrine, resulting in a decreased rate of glucose clearance by cells.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Female; Hemodynamics; Humans; Insulin; Male; Receptors, Adrenergic; Single-Blind Method

This study was designed to test the efficacy and safety of low-dose rosiglitazone, a potent, insulin-sensitizing thiazolidinedione, in combination with sulphonylurea in Type 2 diabetic patients.. For the intention-to-treat analysis, 574 patients (59% male, mean age 61 years) were available, randomized to receive 26 weeks of twice-daily placebo (n = 192), rosiglitazone 1 mg (n = 199) or rosiglitazone 2 mg (n = 183) in addition to existing sulphonylurea treatment with gliclazide (47.6% of patients), glibenclamide (41.8%) or glipizide (9.4%) (two patients were taking carbutamide or glimepiride). Change in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), fructosamine, insulin, C-peptide, albumin, and lipids were measured, and safety was evaluated.. Mean baseline HbA1c was 9.2% and FPG was 11.4 mmol/l. Rosiglitazone at doses of 1 and 2 mg b.d. plus sulphonylurea produced significant decreases, compared with sulphonylurea plus placebo, in HbA1c (-0.59% and -1.03%, respectively; both P<0.0001) and FPG (1.35 mmol/l and 2.44 mmol/l, respectively; both P<0.0001). Both HDL-cholesterol and LDL-cholesterol increased and potentially beneficial decreases in non-esterified fatty acids and gamma glutamyl transpeptidase levels were seen in both rosiglitazone groups. The overall incidence of adverse experiences was similar in all three treatment groups, with no significant cardiac events, hypoglycaemia or hepatotoxicity.. Overall, the combination of rosiglitazone and a sulphonylurea was safe, well tolerated and effective in patients with Type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Europe; Female; Fructosamine; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Rosiglitazone; Safety; Thiazoles; Thiazolidinediones; Triglycerides

The aims of this study were to examine the effects of trandolapril, a long acting angiotensin converting enzyme (ACE) inhibitor with high tissue uptake, on insulin sensitivity and lipid concentrations in hypertensive patients with Type 2 diabetes mellitus.. Insulin sensitivity was assessed after an acute dose (day 3) and 19 days continuous treatment (days 3-21) using the isoglycaemic, hyperinsulinaemic glucose clamp with D[3-3H] labelled glucose, a variable D[3-3H] priming dose and a 'hot' glucose infusion. Rates of glucose appearance (Ra) and glucose disappearance (Rd) were isotopically determined during the basal and insulin stimulated periods of the clamp. Twenty-four (5 female) hypertensive (blood pressure >75th centile for age and sex) patients with Type 2 diabetes mellitus were studied. Patients were randomized, in a double-blind manner, to either trandolapril 4 mg daily (T) or placebo (P).. Baseline (day 1) systolic (mean +/- SD; P 164+/-14 and T 168+/-13 mm Hg) and diastolic (P 93+/-6, and T 98+/-10 mm Hg) blood pressures were comparable. On days 3 and 21, significant reductions were observed in both groups (P<0.001). In the trandolapril-treated group, serum trandolapril concentrations were >200 pg/ml on days 3 and 21, in all patients apart from one subject at a single visit, while trandolapril was undetectable in the placebo group. Body mass index (BMI) was greater in T compared with P (32.2+/-5.4 v. 28.3+/-4.6, P = 0.07). After correcting for BMI, basal hepatic glucose output (HGO) P 2.6 (95% CI 2.23-3.13) and T 1.91 (1.33-2.51) mg x kg(-1) x min(-1) and clamped HGO P 0.32 (-0.44-1.09) and T 0.87 (0.40-1.34) mg x kg(-1) x min(-1) were similar in both groups. The insulin sensitivity index was comparable in both groups on all days. Total cholesterol concentrations were similar in both groups throughout the study. Triglyceride concentrations were significantly lower in group P 1.38 (1.07-1.68); T 2.14 (1.70-2.58) mmol/l, P<0.01), no significant treatment effect being observed.. An acute dose and 19 days' continuous treatment with trandolapril resulted in no change in insulin sensitivity or plasma lipid profiles in patients with Type 2 diabetes mellitus and hypertension. These data support the metabolic neutrality of trandolapril in patients with Type 2 diabetes mellitus and hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Clamp Technique; Humans; Hypertension; Indoles; Insulin; Lipids; Male; Middle Aged; Placebos

The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been shown to enhance insulin secretion in animals and in healthy human volunteers and thus offers a potential advance in the treatment of Type 2 diabetes mellitus. This study examined whether nateglinide can enhance insulin secretion, and particularly the first phase insulin response, in patients with Type 2 diabetes.. A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months).. Insulin secretion (both overall and first phase) was significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001) and proinsulin (P < 0.001) secretion. Overall glucose concentrations following glucose challenge were lower after nateglinide than after placebo (P = 0.05).. Nateglinide significantly increases insulin secretion in Type 2 diabetic patients, in particular restoring the first phase insulin response. Further study is necessary to determine the effects of chronic administration on insulin secretion and blood glucose concentration.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos; Proinsulin

Bedtime ingestion of slow-release carbohydrates leads to sustained nocturnal fatty acid suppression and improved glucose tolerance in type 2 diabetic patients.. This study assessed the effects of 2 different doses of bedtime carbohydrate supplement (BCS) on morning glycemic control and glycated hemoglobin (Hb A(1c)) in type 2 diabetic patients. In addition, the effects of the high-dose BCS on insulin sensitivity and postprandial glucose and triacylglycerol concentrations were assessed.. Two BCS doses were studied separately in 7-wk randomized, placebo-controlled, double-blind studies with either a parallel (low-dose BCS; n = 24 patients) or crossover (high-dose BCS; n = 14 patients) design. The effects of the low and high doses (0.30 and 0.55 g uncooked cornstarch/kg body wt, respectively) were compared with those of a starch-free placebo.. Compared with the starch-free placebo, the high-dose BCS ( approximately 45 g) produced enhanced nocturnal glucose (P < 0.01) and insulin (P < 0.01) concentrations as well as a 32% suppression of fatty acid concentrations (P < 0.01). Moreover, glucose tolerance (P < 0.05) and C-peptide response (P < 0.05) improved after breakfast the next morning. The low-dose BCS ( approximately 25 g) improved fasting blood glucose concentrations (P < 0.05). However, there were no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or Hb A(1c) after 7 wk.. Nocturnal fatty acid suppression by BCS improved fasting and postprandial blood glucose concentrations in type 2 diabetic patients the next morning. In contrast, no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or long-term glycemic control assessed by Hb A(1c) were seen after BCS supplementation.

Topics: Blood Glucose; Body Weight; C-Peptide; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lactic Acid; Male; Middle Aged; Starch; Triglycerides

Characterization of beta-cell function in humans is essential for identifying genetic defects involved in abnormal insulin secretion and the pathogenesis of type 2 diabetes.. We designed a novel test assessing plasma insulin and C-peptide in response to 3 different secretagogues. Seven lean, healthy volunteers twice underwent a 200 min hyperglycaemic clamp (10 mmol L-1) with administration of GLP-1 (1.5 pmol. kg-1. min-1) starting at 120 min and an arginine bolus at 180 min. We determined glucose-induced first and second-phase insulin secretion, GLP-1-stimulated insulin secretion, arginine-stimulated insulin response (increase above prestimulus, DeltaIarg) and the maximal, i. e. highest absolute, insulin concentration (Imax). Insulin sensitivity was assessed during second-phase hyperglycaemia. On a third occasion 6 subjects additionally received an arginine bolus at > 25 mM blood glucose, a test hitherto claimed to provoke maximal insulin secretion.. Insulin levels increased from 46 +/- 11 pM to 566 +/- 202 pM at 120 min, to 5104 +/- 1179 pM at 180 min and to maximally 8361 +/- 1368 pM after arginine (all P < 0.001). The within subject coefficients of variation of the different secretion parameters ranged from 10 +/- 3% to 16 +/- 6%. Except for second-phase which failed to correlate significantly with DeltaIarg (r = 0.52, P = 0.23) and Imax (r = 0.75, P = 0.053) all phases of insulin secretion correlated with one another. The insulin concentration after the arginine bolus at > 25 mM glucose (n = 6) was 2773 +/- 855 pM vs. 7562 +/- 1168 pM for Imax (P = 0.003).. This novel insulin secretion test elicits a distinct pattern of plasma insulin concentrations in response to the secretagogues glucose, GLP-1 and arginine and is highly reproducible and can be used for differential characterization of islet function.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Peptide Fragments; Protein Precursors; Reproducibility of Results

To evaluate the clinical efficacy and safety of rosiglitazone as a once daily treatment for Type 2 diabetes mellitus (DM).. Three hundred and sixty-nine patients with Type 2 DM (mean age 63 years; mean body mass index (BMI) 29.4 kg/m2) were enrolled in a double-blind, parallel group, placebo-controlled, dose-ranging study. Patients were randomly assigned to receive placebo or rosiglitazone at doses of 4, 8, or 12 mg daily for 8 weeks.. At 8 weeks, fasting plasma glucose (FPG) decreased significantly in the rosiglitazone 4 mg, 8 mg, and 12 mg groups (-0.9, -2.0 and -1.7 mmol/l; P = 0.0003, < 0.0001, and < 0.0001, respectively) compared with placebo (+0.4 mmol/l). The improvements in FPG were dose ordered for 4 and 8 mg/ day. The 12 mg/day dose produced no additional improvement. There were small decreases in haemoglobin and haematocrit in the rosiglitazone treatment groups. The overall incidence of adverse experiences was similar in all treatment groups, including placebo with no evidence of hypoglycaemia or hepatotoxicity.. Rosiglitazone improves glycaemic control when given once daily to treat Type 2 diabetes mellitus and is well tolerated at doses up to and including 12 mg.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Europe; Female; Fructosamine; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Placebos; Rosiglitazone; Thiazoles; Thiazolidinediones; Time Factors

The enteric incretin hormone, glucagon-like peptide-1 (GLP-1), is a potent insulin secretagogue in healthy humans and patients with Type II (non-insulin-dependent) diabetes mellitus. In this study we assessed the impact of short-term GLP-1 infusion on pulsatile insulin secretion in Type II diabetic patients.. Type II diabetic patients (n = 8) were studied in a randomised cross-over design. Plasma insulin concentration time series were obtained during basal conditions and during infusion with saline or GLP-1 (1.2 pmol/l x kg(-1) x min(-1)) on 2 separate days. Plasma glucose was clamped at the initial concentration by a variable glucose infusion. Serum insulin concentration time series were evaluated by deconvolution analysis, autocorrelation analysis, spectral analysis and approximate entropy.. Serum insulin concentrations increased by approximately 100% during GLP-1 infusion. Pulsatile insulin secretion was increased as measured by secretory burst mass (19.3 +/- 3.8 vs 53.0 +/- 10.7 pmol/l/ pulse, p = 0.02) and secretory burst amplitude (7.7 +/- 1.5 vs 21.1 +/- 4.3 pmol/l/min, p = 0.02). A similar increase in basal insulin secretion was observed (3.6 +/- 0.9 vs 10.2 +/- 2.2 pmol/l/min, p = 0.004) with no changes in the fraction of insulin delivered in pulses (0.50 +/- 0.06 vs 0.49 +/- 0.02, p = 0.84). Regularity of secretion was unchanged as measured by spectral analysis (normalised spectral power: 5.9 +/- 0.6 vs 6.3 +/- 0.8, p = 0.86), autocorrelation analysis (autocorrelation coefficient: 0.19 +/- 0.04 vs 0.18 +/- 0.05, p = 0.66) and the approximate entropy statistic (1.48 +/- 0.02 vs 1.51 +/- 0.02, p = 0.86).. Short-term stimulation with GLP-1 jointly increases pulsatile and basal insulin secretion, maintaining but not improving system regularity in Type II diabetic patients.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Middle Aged; Peptide Fragments; Periodicity; Protein Precursors

To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes.. A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations.. During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate.. A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast.

Topics: Administration, Oral; Area Under Curve; Blood Glucose; C-Peptide; Carbamates; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Eating; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines

To characterize metabolic effects of troglitazone in type 2 diabetic, obese, and lean subjects, and examine the effects of troglitazone 2-3 weeks after discontinuation.. Nine type 2 diabetic, nine obese, and nine lean subjects underwent baseline metabolic studies including an 8-h meal-tolerance test (MTT) and a 5-h glucose clamp. Subjects then received troglitazone (600 mg/day) for 12 weeks and subsequently had repeat metabolic studies. Diabetic subjects remained off hypoglycemic agents for 2-3 weeks and then underwent a 5-h glucose clamp.. In diabetic subjects, fasting plasma glucose was reduced (P<0.05) and insulin-stimulated glucose disposal (Rd) was enhanced by treatment (P<0.02). The area under the MTT 8-h plasma glucose curve declined with therapy (P<0.001), and its change was positively correlated with the improvement in Rd (r = 0.75, P<0.05). There was also a positive correlation between the change in fasting hepatic glucose output (HGO) and the change in fasting plasma glucose with treatment (r = 0.92, P<0.001). Discontinuation of therapy for 2-3 weeks did not significantly affect fasting plasma glucose or insulin-stimulated glucose Rd. In obese subjects, insulin-stimulated glucose Rd improved with therapy (P<0.001), allowing for maintenance of euglycemia by lower plasma insulin concentrations (P<0.05). In lean subjects, an increase in fasting HGO (P<0.001) and glucose clearance (P<0.01) was observed.. Troglitazone lowers fasting and postprandial plasma glucose in type 2 diabetes by affecting both fasting HGO and peripheral insulin sensitivity. Its effects are evident 2-3 weeks after discontinuation. In obese subjects, its insulin sensitizing effects suggest a role for its use in the primary prevention of type 2 diabetes.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Chromans; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Thiazoles; Thiazolidinediones; Troglitazone

To determine the long-term effects of troglitazone as monotherapy or in combination with sulfonylureas or insulin regarding glycemic and lipid measures.. Patients who completed one of three double-blind studies (a 6-month troglitazone monotherapy study, a 52-week study of troglitazone in combination with micronized glyburide, or a 6-month study of troglitazone in combination with insulin) were allowed to enter open-label extensions of their respective double-blind studies. Troglitazone dose titrations were allowed to a maximum of 600 mg in response to inadequate glycemic control during the open-label phases of troglitazone monotherapy or sulfonylurea combination therapy but not with insulin combination therapy. This article focuses on the effectiveness of the highest dose of troglitazone used in these studies (600 mg daily). Safety data from all patients studied at all doses are also presented.. For patients who received a fixed dose of 600 mg troglitazone, mean changes in fasting serum glucose and HbA1c levels from baseline to the end of the open-label phase were -57 mg/dl and -0.4%, respectively (monotherapy); -49 mg/dl and -1.8%, respectively (sulfonylurea combination); and -31 mg/dl and -1.0%, respectively (insulin combination). The proportion of patients achieving an HbA1c level of < or =8% from the combined cohort of all three studies was 54% versus only 19% at baseline. The mean decrease in triglycerides from baseline to the end of the open-label phase was 18% among all patients in the three studies who received a fixed dose of 600 mg troglitazone. Troglitazone was well tolerated in these three open-label studies; a total of 758 patients completed a total exposure of 16,264 patient-months to troglitazone in these three studies with minimal adverse events.. Long-term use of troglitazone alone or in combination with sulfonylureas or insulin is safe and effective in sustaining glycemic control and in reducing hypertriglyceridemia in type 2 diabetic patients.

Topics: Blood Glucose; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins, HDL; Thiazoles; Thiazolidinediones; Troglitazone

To detect and understand the changes in beta-cell function in the pathogenesis of type 2 diabetes, an accurate and precise estimation of prehepatic insulin secretion rate (ISR) is essential. There are two common methods to assess ISR, the deconvolution method (by Eaton and Polonsky)-considered the "gold standard"-and the combined model (by Vølund et al.). The deconvolution method is a 2-day method, which generally requires separate assessment of C-peptide kinetics, whereas the combined model is a single-day method that uses insulin and C-peptide data from a single test of interest. The validity of these mathematical techniques for quantification of insulin secretion have been tested in dogs, but not in humans. In the present studies, we examined the validity of both methods to recover the known infusion rates of insulin and C-peptide mimicking ISR during an oral glucose tolerance test. ISR from both the combined model and the deconvolution method were accurate, i.e., recovery of true ISR was not significantly different from 100%. Furthermore, both maximal and total ISRs from the combined model were strongly correlated to those obtained by the deconvolution method (r = 0.89 and r = 0.82, respectively). These results indicate that both approaches provide accurate assessment of prehepatic ISRs in type 2 diabetic patients and control subjects. A simplified version of the deconvolution method based on standard kinetic parameters for C-peptide (Van Cauter et al.) was compared with the 2-day deconvolution method, and a close agreement was found for the results of an oral glucose tolerance test. We also studied whether C-peptide kinetics are influenced by somatostatin infusion. The decay curves after bolus injection of exogenous biosynthetic human C-peptide, the kinetic parameters, and the metabolic clearance rate were similar whether measured during constant peripheral somatostatin infusion or without somatostatin infusion. Assessment of C-peptide kinetics can be performed without infusion of somatostatin, because the endogenous insulin concentration remains constant. Assessment of C-peptide kinetics with and without infusion of somatostatin results in nearly identical secretion rates for insulin during an oral glucose tolerance test.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Somatostatin

Although it is well established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulator of insulin secretion, its effects on insulin action and glucose effectiveness are less clear. To determine whether GLP-1 increases insulin action and glucose effectiveness, subjects with type 2 diabetes were studied on two occasions. Insulin was infused during the night on both occasions to ensure that baseline glucose concentrations were comparable. On the morning of study, either GLP-1 (1.2 pmol x kg(-1) x min(-1)) or saline were infused along with somatostatin and replacement amounts of glucagon. Glucose also was infused in a pattern mimicking that typically observed after a carbohydrate meal. Insulin concentrations were either kept constant at basal levels (n = 6) or varied so as to create a prandial insulin profile (n = 6). The increase in glucose concentration was virtually identical on the GLP-1 and saline study days during both the basal (1.21 +/- 0.15 vs. 1.32 +/- 0.19 mol/l per 6 h) and prandial (0.56 +/- 0.14 vs. 0.56 +/- 0.10 mol/l per 6 h) insulin infusions. During both the basal and prandial insulin infusions, glucose disappearance promptly increased after initiation of the glucose infusion to rates that did not differ on the GLP-1 and saline study days. Suppression of endogenous glucose production also was comparable on the GLP-1 and saline study days during both the basal (-2.7 +/- 0.3 vs. -3.1 +/- 0.2 micromol/kg) and prandial (-3.1 +/- 0.4 vs. -3.0 +/- 0.6 pmol/kg) insulin infusions. We conclude that when insulin and glucagon concentrations are matched, GLP-1 has negligible effects on either insulin action or glucose effectiveness in people with type 2 diabetes. These data strongly support the concept that GLP-1 improves glycemic control in people with type 2 diabetes by increasing insulin secretion, by inhibiting glucagon secretion, and by delaying gastric emptying rather than by altering extrapancreatic glucose metabolism.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Food; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Human Growth Hormone; Humans; Hydrocortisone; Insulin; Kinetics; Peptide Fragments; Somatostatin

Insulin is released in high-frequency pulsatile bursts at intervals of 6-13 min. Intrapancreatic mechanisms are assumed to coordinate pulsatile insulin release, but small oscillations in plasma glucose concentrations may contribute further. To gain additional insight into beta-cell (patho)physiology, we explored the ability of repetitive small glucose infusions (6 mg/kg over 1 min every 10 min) to modify rapid pulsatile insulin secretion in 10 type 2 diabetic individuals (plasma glucose 9.3 +/- 1.0 mmol/l, HbA1c 7.9 +/- 0.5%, mean +/- SE) and 10 healthy subjects. All subjects were investigated twice in randomly assigned order: during saline and during glucose exposure. Blood was collected every minute for 90 min to create a plasma insulin concentration time-series for analysis using 3 complementary algorithms: namely, spectral analysis, autocorrelation analysis, and approximate entropy (ApEn). During saline infusion, none of the algorithms were able to discriminate between diabetic and control subjects (P > 0.20). During glucose entrainment, spectral density peaks (SP) and autocorrelation coefficients (AC) increased significantly (P < 0.001), and ApEn decreased (P < 0.01), indicating more regular insulin time-series in the healthy volunteers. However, no differences were observed in the diabetic individuals between the glucose and saline conditions. Furthermore, in spite of identical absolute glucose excursions (approximately 0.3 mmol/l) glucose pulse entrainment led to a complete (SP: 4.76 +/- 0.62 [range 2.08-7.60] vs. 17.24 +/- 0.93 [11.70-20.58], P < 0.001; AC: 0.01 +/- 0.05 [0.33-0.24] vs. 0.64 +/- 0.05 [0.35-0.83], P < 0.001) or almost complete (ApEn: 1.59 +/- 0.02 [1.48-1.67] vs. 1.42 +/- 0.05 [1.26-1.74], P < 0.005) separation of the insulin time-series in diabetic and control subjects. Even elevating the glucose infusion rate in the diabetic subjects to achieve comparable relative (and hence higher absolute) glucose excursions (approximately 4.9%) failed to entrain pulsatile insulin secretion in this group. In conclusion, the present study demonstrates that failure to respond adequately with regular oscillatory insulin secretion to recurrent high-frequency and (near)-physiological glucose excursion is a manifest feature of beta-cell malfunction in type 2 diabetes. Whether the model will be useful in unmasking subtle (possible prediabetic) defects in beta-cell sensitivity to glucose drive remains to be determined.

Topics: Algorithms; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Glycated Hemoglobin; Humans; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Reference Values; Time Factors

Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy.

Topics: Body Mass Index; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipoproteins; Male; Metformin; Middle Aged; Obesity; Placebos; Triglycerides

The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic patients with residual beta-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU/kg) immediately (Act0) or 30 minutes before (Act-30) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43-71), body mass index 28.3 kg/m2 (range, 21.9-35.0), HbA1c 8.5% (range, 6.8-10.0), glucagon-stimulated C-peptide 1.0 nmol/l (range, 0.3-2.5) and diabetes duration 12.5 years (range, 3.0-26.0). Twenty-two patients completed the study. A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act0, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899 +/- 609 (SD) mmol/l.min versus Act0, 1102 +/- 497 mmol/l min, p < 0.01) and supported by a significantly lower maximum serum glucose concentration (Cmax) up to 360 min after dosing (IAsp, 10.8 +/- 2.2 mmol/l vs. Act0, 12.0 +/- 2.4 mmol/l, p < 0.02). No difference was demonstrated in glucose endpoints between IAsp, administered with a meal and Actrapid injected 30 minutes before the meal (AUCglucose IAsp, 899 +/- 609 mmol/l min vs. Act-30, 868 +/- 374 mmol/l min; Cmax IAsp, 10.8 +/- 2.2 mmol/l vs. Act-30, 11.1 +/- 1.8 mmol/l). No concerns about the safety of IAsp were raised. Immediate pre-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Aspart; Insulin, Regular, Pork; Male; Middle Aged; Postprandial Period

The insulin-sensitizing action of troglitazone may be mediated through the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the promotion of preadipocyte differentiation in adipose tissue on which troglitazone has depot-specific effects. We investigated the relationship between efficacy of the drug and body fat distribution. Changes in body fat distribution were also investigated by long-term administration of the drug.. Troglitazone was given at a dose of 400 mg/day to 20 patients with type 2 diabetes whose diet and sulfonylurea therapy produced unsatisfactory glycemic control (HbA(1c) >7.8%) and whose insulin secretory capacity was found to be preserved (postprandial C-peptide >3 ng/ml). HbA(1c) values, serum lipid levels, and body weight were measured monthly Body fat distribution was evaluated in subcutaneous (SC) and visceral fat using a computed tomography scan at umbilical levels before and after troglitazone therapy. During the 1-year troglitazone treatment, HbA(1c) was significantly decreased (from 9.2 +/- 0.2 to 7.1 +/- 0.2%, P < 0.01), showing lowest values at 4-6 months, whereas body weight was significantly increased (BMI 24.6 +/- 0.6 to 25.7 +/- 0.6 kg/m2, P < 0.01). Reduction of HbA(1c) (deltaHbA(1c)) from the baseline value during treatment was significantly greater in obese patients (BMI >26 kg/m2) than in nonobese patients (-3.2 +/- 0.4 vs. -2.1 +/- 0.3%, P < 0.05) and was more significant in women than in men (-3.2 +/- 0.2 vs. - 1.4 +/- 0.2%, P < 0.01). The level of deltaHbA(1c) during treatment showed a significant negative correlation with SC fat area (r = -0.742, P < 0.01) but not with visceral fat area. Weight gain during troglitazone treatment resulted in increased accumulation of SC fat without a change in visceral fat area and, consequently. in a significant decrease in the visceral-to-SC fat ratio.. Predominant accumulation of SC fat for the visceral fat tissue was an important predictor of the efficacy of troglitazone therapy in patients with type 2 diabetes. Greater efficacy of troglitazone was observed in women who were characterized by more accumulation of SC adipose tissue than men. Long-term administration of the drug resulted in weight gain with increased accumulation of SC adipose tissue, probably because of the activation of PPAR-gamma in the region.

Topics: Adipose Tissue; Body Mass Index; C-Peptide; Chromans; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Sex Characteristics; Thiazoles; Thiazolidinediones; Tomography, X-Ray Computed; Troglitazone; Viscera; Weight Gain

Available basal insulin formulations do not provide a constant and reliable 24-h insulin supply. We compared the efficacy and safety of glargine (a long-acting insulin analog) and NPH insulins in insulin-naive type 2 diabetic patients treated with oral antidiabetic agents.. There were 426 type 2 diabetic patients (age 59 +/- 9 years, BMI 28.9 +/- 4.3 kg/m2, mean +/- SD) with poor glycemic control on oral antidiabetic agents randomized to treatment for 1 year with bedtime insulin glargine or bedtime NPH insulin. Oral agents were continued unchanged. The fasting blood glucose (FBG) target was 6.7 mmol/l (120 mg/dl).. Average glycemic control improved similarly with both insulins (HbA(1c), [reference range <6.5%] 8.3 +/- 0.1 vs. 8.2 +/- 0.1% at 1 year, glargine vs. NPH, mean +/- SEM, P < 0.001 vs. baseline for both). However, there was less nocturnal hypoglycemia (9.9 vs. 24.0% of all patients, glargine vs. NPH, P < 0.001) and lower post-dinner glucose concentrations (9.9 +/- 0.2 vs. 10.7 +/- 0.3 mmol/l, P < 0.02) with insulin glargine than with NPH. Insulin doses and weight gain were comparable. In patients reaching target FBG, HbA(1c) averaged 7.7 and 7.6% in the glargine and NPH groups at 1 year.. Use of insulin glargine compared with NPH is associated with less nocturnal hypoglycemia and lower post-dinner glucose levels. These data are consistent with peakless and longer duration of action of insulin glargine compared with NPH. Achievement of acceptable average glucose control requires titration of the insulin dose to an FBG target < or =6.7 mmol/l. These data support use of insulin glargine instead of NPH in insulin combination regimens in type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Circadian Rhythm; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Antibodies; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged; Postprandial Period; Triglycerides

Impaired insulin secretion in type 2 diabetes is characterized by decreased first-phase insulin secretion, an increased proinsulin-to-insulin molar ratio in plasma, abnormal pulsatile insulin release, and heightened disorderliness of insulin concentration profiles. In the present study, we tested the hypothesis that these abnormalities are at least partly reversed by a period of overnight suspension of beta-cell secretory activity achieved by somatostatin infusion. Eleven patients with type 2 diabetes were studied twice after a randomly ordered overnight infusion of either somatostatin or saline with the plasma glucose concentration clamped at approximately 8 mmol/l. Controls were studied twice after overnight saline infusions and then at a plasma glucose concentration of either 4 or 8 mmol/l. We report that in patients with type 2 diabetes, 1) as in nondiabetic humans, insulin is secreted in discrete insulin secretory bursts; 2) the frequency of pulsatile insulin secretion is normal; 3) the insulin pulse mass is diminished, leading to decreased insulin secretion, but this defect can be overcome acutely by beta-cell rest with somatostatin; 4) the reported loss of orderliness of insulin secretion, attenuated first-phase insulin secretion, and elevated proinsulin-to-insulin molar ratio also respond favorably to overnight inhibition by somatostatin. The results of these clinical experiments suggest the conclusion that multiple parameters of abnormal insulin secretion in patients with type 2 diabetes mechanistically reflect cellular depletion of immediately secretable insulin that can be overcome by beta-cell rest.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Insulin; Islets of Langerhans; Middle Aged; Proinsulin; Somatostatin

A homogeneous patient population is necessary to identify genetic factors that regulate complex disease pathogenesis. In this study, we evaluated clinical and biochemical phenotyping criteria for type 2 diabetes in end-stage renal disease (ESRD) probands of families in which nephropathy is clustered. C-peptide concentrations accurately discriminate type 1 from type 2 diabetic patients with normal renal function, but have not been extensively evaluated in ESRD patients. We hypothesized that C-peptide concentrations may not accurately reflect insulin synthesis in ESRD subjects, since the kidney is the major site of C-peptide catabolism and would poorly correlate with accepted clinical criteria used to classify diabetics as types 1 and 2.. Consenting diabetic ESRD patients (N = 341) from northeastern Ohio were enrolled. Clinical history was obtained by questionnaire, and predialysis blood samples were collected for C-peptide levels from subjects with at least one living diabetic sibling (N = 127, 48% males, 59% African Americans).. Using clinical criteria, 79% of the study population were categorized as type 1 (10%) or type 2 diabetics (69%), while 21% of diabetic ESRD patients could not be classified. In contrast, 98% of the patients were classified as type 2 diabetics when stratified by C-peptide concentrations using criteria derived from the Diabetes Control and Complications Trial Research Group (DCCT) and UREMIDIAB studies. Categorization was concordant in only 70% of ESRD probands when C-peptide concentration and clinical classification algorithms were compared. Using clinical phenotyping criteria as the standard for comparison, C-peptide concentrations classified diabetic ESRD patients with 100% sensitivity, but only 5% specificity. The mean C-peptide concentrations were similar in diabetic ESRD patients (3.2 +/- 1.9 nmol/L) and nondiabetic ESRD subjects (3.5 +/- 1.7 nmol/L, N = 30, P = NS), but were 2.5-fold higher compared with diabetic siblings (1.3 +/- 0.7 nmol/L, N = 30, P < 0.05) with normal renal function and were indistinguishable between type 1 and type 2 diabetics. Although 10% of the diabetic ESRD study population was classified as type 1 diabetics using clinical criteria, only 1.5% of these patients had C-peptide levels less than 0.20 nmol/L, the standard cut-off used to discriminate type 1 from type 2 diabetes in patients with normal renal function. However, the criteria of C-peptide concentrations> 0.50 nmol/L and diabetes onset in patients who are more than 38 years old identify type 2 diabetes with a 97% positive predictive value in our ESRD population.. Accepted clinical criteria, used to discriminate type 1 and type 2 diabetes, failed to classify a significant proportion of diabetic ESRD patients. In contrast to previous reports, C-peptide levels were elevated in the majority of type 1 ESRD diabetic patients and did not improve the power of clinical parameters to separate them from type 2 diabetic or nondiabetic ESRD subjects. Accurate classification of diabetic ESRD patients for genetic epidemiological studies requires both clinical and biochemical criteria, which may differ from norms used in diabetic populations with normal renal function.

Topics: Adult; Age of Onset; Algorithms; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Predisposition to Disease; Humans; Insulin; Insulin Secretion; Kidney Failure, Chronic; Male; Middle Aged; Phenotype; Predictive Value of Tests; Sensitivity and Specificity

Sulfonylureas are used to treat patients with type 2 diabetes mellitus when diet and exercise fail. Glimepiride, a new sulfonylurea, can be administered in one daily dose, thanks to its pharmacokinetic properties. We attempted to establish the optimal time of day for the administration of Glimepiride in a group of patients from the Mediterranean area by clinical trial. No relationship was found between the time of administration and fasting blood glucose values, or HbA1c, or the frequency or severity of hypoglycemic episodes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Middle Aged; Placebos; Prospective Studies; Sulfonylurea Compounds; Time Factors

Non-obese type 2 diabetic subjects in good metabolic control (n=6, HbA1c 7.0 +/- 0.3%, mean diabetes duration: 5.7 +/- 1 years) and matched non-diabetic subjects (control; n = 6) were studied during hyperinsulinemic (approximately 3 nmol/l)-hypoglycemic (approximately 3.1 mmol/l) clamp tests (0-120 min) and the subsequent recovery period (120-240 min). Plasma glucagon rose gradually but not significantly, whereas norepinephrine and epinephrine similarly increased approximately 2 and approximately 25-fold in both groups. Islet amyloid polypeptide (IAPP) decreased to approximately 41% and approximately 24% of basal values during hypoglycemia and rapidly rose approximately 4.7-fold during the recovery period, while plasma C-peptide remained suppressed in both groups. Within 140 min, plasma free fatty acids similarly decreased to approximately 70 micromol/l (p < 0.05), but then rose to values being approximately 50% higher in diabetic than in control subjects (240 min: 907 +/- 93 vs. 602 +/- 90 micromol/l; p < 0.05). Glucose infusion rates were comparable during hypoglycemia, but approximately 40% lower during recovery in diabetic patients (1.88 +/- 0.27 vs. 3.44 +/- 0.27 mg x kg(-1) x min(-1), p < 0.001). These results demonstrate that (i) hypoglycemia induced by high-dose insulin largely abolishes the counterregulatory response of glucagon, but not of catecholamines in nondiabetic and well-controlled type 2 diabetic subjects, (ii) the rapid posthypoglycemic increase of plasma IAPP occurs independently of plasma insulin, and (iii) the superior rise in plasma free fatty acids may account at least in part for the posthypoglycemic insulin resistance of type 2 diabetic patients.

Topics: Adult; Amyloid; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Glucose Clamp Technique; Hormones; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Male; Norepinephrine

To evaluate the efficacy and safety of four doses of pioglitazone monotherapy in the treatment of patients with type 2 diabetes.. There were 408 patients randomized in this multicenter double-blind placebo-controlled clinical trial. Patients who had HbA1c > or = 7.0%, fasting plasma glucose (FPG) > or = 140 mg/dl, and C-peptide > 1 ng/ml were randomized to receive placebo or 7.5, 15, 30, or 45 mg pioglitazone administered once a day for 26 weeks.. Patients treated with 15, 30, or 45 mg pioglitazone had significant mean decreases in HbA1c (range -1.00 to -1.60% difference from placebo) and FPG (-39.1 to -65.3 mg/dl difference from placebo). The decreases in FPG were observed as early as the second week of therapy; maximal decreases occurred after 10-14 weeks and were maintained until the end of therapy (week 26). In the 15-, 30-, or 45-mg pioglitazone groups, there were significant mean percent decreases in triglycerides, significant mean percent increases in HDL cholesterol, and only small percent changes in total cholesterol and LDL. The subset of patients naive to therapy had greater improvements in HbA1c and FPG (difference from placebo of -2.55% and -79.9 mg/dl for the 45-mg group) compared with previously treated patients. The overall adverse event profile of pioglitazone was similar to that of placebo. There was no evidence of drug-induced hepatotoxicity or drug-induced elevations of alanine aminotransferase levels in this study. Pioglitazone monotherapy significantly improves HbA1c and FPG while producing beneficial effects on serum lipids in patients with type 2 diabetes with no evidence of drug-induced hepatotoxicity.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Ethnicity; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Placebos; Racial Groups; Thiazoles; Thiazolidinediones; United States

Their complimentary mechanisms of action suggest that a combination of pioglitazone hydrochloride and metformin may have clinically beneficial effects in the treatment of patients with type 2 diabetes.. This study was undertaken to assess the efficacy and tolerability of pioglitazone in combination with metformin in patients with type 2 diabetes mellitus.. This was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled diabetes mellitus (glycated hemoglobin [HbA1c] > or =8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for > or =30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded. Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the open-label extension received pioglitazone 30 mg (with optional titration to 45 mg) + metformin.. Three hundred twenty-eight patients were randomized to treatment (168 pioglitazone + metformin, 160 placebo + metformin), and 249 completed the study. Of these, 154 elected to enter the open-label extension study. Patients' mean age was 56 years; most (84%) were white and slightly more than half (57%) were male. Patients receiving piogli- tazone 30 mg + metformin had statistically significant mean decreases in HbA1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P < or = 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (-18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin (P < or = 0.05). Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of -1.36% in HbA1c and -63.0 mg/dL in FPG. The incidence of adverse events was similar in both groups. Throughout the study, no patient in either treatment group had an alanine aminotransferase (ALT) value > or =3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-induced hepatotoxicity or drug-induced elevations in serum ALT was observed.. In this study in patients with type 2 diabetes mellitus, pioglitazone + metformin significantly improved HbA1c and FPG levels, with positive effects on serum lipid levels and no evidence of drug-induced hepatotoxicity. These effects were maintained for >1.5 years, including the open-label extension.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Pioglitazone; Placebos; Thiazoles; Thiazolidinediones

An extrapancreatic effect of sulfonylureas has been postulated. However, in vivo results have been disputed because the amelioration of insulin action that follows sulfonylurea may represent the relief from glucose toxicity rather than a direct effect of the drug. Therefore, we studied the hypoglycemic action of gliclazide acutely and after 2 months of therapy in seven type 2 diabetic patients. All patients received a 240-minute i.v. glucose infusion with [3-3H]glucose. In a random order, 160 mg gliclazide (study 1) or placebo (study 2) was given orally before glucose infusion. Finally, the effect of 160 mg gliclazide was reassessed after a two-month treatment with the same sulfonylurea (80 mg t.i.d.). Basal plasma glucose, insulin, C-peptide and endogenous glucose production (EGP) were similar before the two initial studies. During glucose infusion, EGP was more suppressed after gliclazide in spite of comparable increase in plasma insulin and C-peptide. After the two-month therapy, basal plasma glucose levels and HbA1c were lower while plasma insulin and C-peptide were higher with respect to baseline (p < 0.05). Gliclazide further reduced plasma glucose, the incremental area above baseline, and EGP during glucose infusion, while plasma insulin and C-peptide achieved higher plateaus (p < 0.05). When data were pooled, plasma glucose concentration and EGP correlated both in the basal state (r = 0.71) and during the last hour of glucose infusion (r = 0.84; both p < 0.05). These data suggest that gliclazide enhances the suppression of EGP induced by insulin and that this effect is greater with chronic treatment because of concomitant improvement of insulin secretion.

Topics: Acute Disease; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus, Type 2; Gliclazide; Gluconeogenesis; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kinetics; Middle Aged; Placebos; Regression Analysis; Time Factors; Tritium

Compared with other insulin regimens, combination therapy with oral hypoglycemic agents and bedtime insulin produces similar improvement in glycemic control but induces less weight gain.. To determine whether bedtime insulin regimens differ with respect to their effects on weight gain in patients with type 2 diabetes.. Randomized, controlled trial.. Four outpatient clinics at central hospitals.. 96 patients (mean age, 58 +/- 1 years; mean body mass index, 29 +/- 1 kg/m2) whose type 2 diabetes was poorly controlled with sulfonylurea therapy (mean glycosylated hemoglobin value, 9.9% +/- 0.2%; mean fasting plasma glucose level, 11.9 +/- 0.3 mmol/L [214 +/- 5 mg/dL]).. Random assignment to 1 year of treatment with bedtime intermediate-acting insulin plus glyburide (10.5 mg) and placebo, metformin (2 g) and placebo, glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements.. Body weight, biochemical and symptomatic hypoglycemias, and indices of glycemic control.. At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change, 0.9 +/- 1.2 kg; P < 0.001 compared with all other groups) but increased by 3.9 +/- 0.7 kg, 3.6 +/- 1.2 kg, and 4.6 +/- 1.0 kg in patients receiving bedtime insulin plus glyburide, those receiving bedtime insulin plus both oral drugs, and those receiving bedtime and morning insulin, respectively. The greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7% +/- 0.4% to 7.2% +/- 0.2% [difference, -2.5 +/- 0.4 percentage points] at 1 year; P < 0.001 compared with 0 months and P < 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P < 0.05) than the other groups.. Combination therapy with bedtime insulin plus metformin prevents weight gain. This regimen also seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia.

Topics: Albuminuria; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Metformin; Middle Aged; Weight Gain

We investigated the influence of treatment with nicorandil, a K-channel opener currently used for angina, on glucose homeostasis in patients with non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD). Adenosine triphosphate (ATP)-sensitive K (K-ATP) channels are present in various tissues, including pancreatic B cells and skeletal muscle, and are the putative targets of this agent. Nine NIDDM patients with CAD and five healthy subjects participated in the study. Fasting plasma levels (mean+/-SEM) of glucose (144+/-11 to 180+/-22 mg/dL, P<.05) and insulin (5.8+/-1.6 to 7.0+/-1.8 microU/mL, P<.05) and hemoglobin A1c (7.54+/-0.47 to 8.11+/-0.55%, P<.01) increased significantly in nine NIDDM patients after treatment with nicorandil at a dose of 5 mg three times daily for 2 to 8 months. Glucose tolerance as examined by an identical meal test deteriorated (P<.001), but the insulin response did not change significantly. A washout of nicorandil for 1 to 4 months restored glucose tolerance almost to pretreatment levels in four patients. A 5- to 7-day trial of nicorandil (5 mg three times daily) in five healthy subjects resulted in a marginal to twofold increase in fasting plasma insulin, reflecting the progression of insulin resistance. In addition, three healthy subjects showed a substantial reduction in the glucose infusion rate (GIR) required in the euglycemic-hyperinsulinemic clamp study. Since the therapeutic dose of nicorandil did not affect pancreatic B-cell function but caused insulin resistance in both healthy and NIDDM subjects, we conclude that K-ATP channels play a regulatory role in insulin-mediated glucose transport in humans.

Topics: Adenosine Triphosphate; Aged; ATP-Binding Cassette Transporters; Blood Glucose; C-Peptide; Coronary Disease; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; KATP Channels; Male; Middle Aged; Nicorandil; Potassium Channels; Potassium Channels, Inwardly Rectifying

To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes.. A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period.. In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05).. Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.

Topics: Australia; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Triglycerides

The purpose of the study was the comparison of the effect of the oral therapy of non-insulin-dependent diabetes mellitus (NIDDM) with either a sulphonylurea or biguanide derivative on plasma amylin level. In 10 healthy individuals the fasting plasma amylin level was 1.56 +/- 0.27 pmol/l (mean +/- SEM) and 6 min after i.v. injection of 1 mg glucagon a fourfold increase was observed. In 10 patients with NIDDM receiving glibenclamide (CAS 10238-21-8) the fasting plasma amylin level was twofold higher than in healthy control (2.72 +/- 0.38 pmol/l; p < 0.025) but following glucagon administration it increased only twofold. In 15 patients treated with metformin (CAS 657-24-9) the fasting plasma amylin level was similar to that in healthy individuals (1.64 +/- 0.25 pmol/l), but after glucagon stimulation the increment of plasma amylin was minimal and the relevant mean value was significantly lower when compared with those in healthy individuals and with NIDDM patients treated with glibenclamide. In 10 untreated obese patients with newly diagnosed NIDDM the administration of glibenclamide (14 days) resulted in the increase of basal (2.47 +/- 0.23 and 3.16 +/- 0.29 pmol/l; p < 0.1), and glucagon stimulated (3.34 +/- 0.39 and 4.56 +/- 0.38; p < 0.05) plasma amylin concentrations, whereas other 10 patients receiving metformin showed a decrease in fasting plasma level of this peptide before (2.64 +/- 0.59 and 1.28 +/- 0.38 pmol/l; p < 0.1), and after glucagon injection (5.02 +/- 0.55 and 2.83 +/- 0.65 pmol/l; p < 0.02). With the respect to the trophic effect of amyloid deposits in the pancreatic islets and to a hypothetic effect of amylin increasing insulin resistance, the present results emphasize the particular usefulness of metformin in the pharmacological treatment of NIDDM. All contraindications and side effects of metformin should be taken into account before drug administration.

Topics: Adult; Amyloid; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Male; Metformin

This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naïve patients suggest that patients given repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiv

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fibrinogen; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Prospective Studies; Triglycerides; United States; United States Food and Drug Administration

The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore sought to evaluate the effect of infusion of GLP-1 for 48 h in patients with type 2 diabetes.. We infused GLP-1 (2.4 pmol.kg-1.min-1) or saline subcutaneously for 48 h in randomized order in six patients with type 2 diabetes to evaluate the effect on appetite during fixed energy intake and on plasma glucose, insulin, glucagon, postprandial lipidemia, blood pressure, heart rate, and basal metabolic rate.. The infusion resulted in elevations of the plasma concentrations of intact GLP-1 similar to those observed after intravenous infusion of 1.2 pmol.kg-1.min-1, previously shown to lower blood glucose effectively in type 2 diabetic patients. Fasting plasma glucose (day 2) decreased from 14.1 +/- 0.9 (saline) to 12.2 +/- 0.7 mmol/l (GLP-1), P = 0.009, and 24-h mean plasma glucose decreased from 15.4 +/- 1.0 to 13.0 +/- 1.0 mmol/l, P = 0.0009. Fasting and total area under the curve for insulin and C-peptide levels were significantly higher during the GLP-1 administration, whereas glucagon levels were unchanged. Neither triglycerides nor free fatty acids were affected. GLP-1 administration decreased hunger and prospective food intake and increased satiety, whereas fullness was unaffected. No side effects during GLP-1 infusion were recorded except for a brief cutaneous reaction. Basal metabolic rate and heart rate did not change significantly during GLP-1 administration. Both systolic and diastolic blood pressure tended to be lower during the GLP-1 infusion.. We conclude that 48-h continuous subcutaneous infusion of GLP-1 in type 2 diabetic patients 1) lowers fasting as well as meal-related plasma glucose, 2) reduces appetite, 3) has no gastrointestinal side effects, and 4) has no negative effect on blood pressure.

Topics: Adult; Aged; Appetite; Appetite Depressants; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Drug Delivery Systems; Energy Intake; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Infusion Pumps; Insulin; Lipids; Middle Aged; Peptide Fragments; Peptides; Pilot Projects; Postprandial Period; Protein Precursors

Patients with type 2 diabetes are often obese and require large doses of insulin to achieve glycemic control. Weight gain often accompanies insulin therapy and results in increasing insulin requirements.. To evaluate the efficacy of metformin in combination with insulin in patients with type 2 diabetes poorly controlled with insulin therapy alone.. Randomized, double-blind, placebo-controlled trial.. Outpatient diabetes clinic at a university medical center.. 43 patients with poorly controlled type 2 diabetes who were receiving insulin therapy.. Patients were randomly assigned to receive placebo or metformin in combination with insulin for 24 weeks.. Hemoglobin A1c levels decreased by 2.5 percentage points (95% CI, 1.8 to 3.1 percentage points) in the metformin group, a significantly greater change (P = 0.04) than the decrease of 1.6 percentage points in the placebo group. Average final hemoglobin A1c levels were 6.5% in the metformin group and 7.6% in the placebo group (difference, 11%). For patients who received placebo, the insulin dose increased 22.8 units (CI, 11 to 44 units) or 29% more than did the dose for patients who received metformin (P = 0.002); for these patients, the insulin dose decreased slightly. Patients in the placebo group gained an average of 3.2 kg of body weight (CI, 1.2 to 5.1 kg); patients in the metformin group gained an average of 0.5 kg of body weight (P = 0.07). Total cholesterol and low-density lipoprotein cholesterol levels decreased in both groups. High-density lipoprotein cholesterol and triglyceride levels did not change.. The addition of metformin to insulin therapy resulted in hemoglobin A1c concentrations that were 10% lower than those achieved by insulin therapy alone. This improvement in glycemic control occurred with the use of 29% less insulin and without significant weight gain. Metformin is an effective adjunct to insulin therapy in patients with type 2 diabetes.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Energy Intake; Hemoglobin A; Humans; Hypoglycemic Agents; Insulin; Lipids; Metformin; Obesity; Statistics, Nonparametric

In the present study we assessed and compared the effectiveness and safety of preconstituted, fixed, combinations of low-dose glyburide plus metformin with higher-dose glyburide monotherapy in patients with type 2 diabetes. This randomized, double-blind, cross-over study comprised 40 patients. After a 30-day run-in period of dietary treatment, patients received combined glyburide (5, 7.5 or 10 mg/day) and metformin (800, 1,200 or 1,600 mg/day) as preconstitued, fixed combinations, or glyburide alone (5, 10 or 15 mg/day). The dose was increased stepwise so as to have 1 (T1), 2 (T2) and 3 (T3) months of treatment for any given regimen (6 months in total). After 2 weeks of washout (T4), the groups were then crossed over (T5, T6, T7 periods). Body weight, fasting plasma glucose, HbA(1c), blood lactate, total cholesterol and HDL-cholesterol, and triglycerides were measured at the beginning and end of T1 and T5, and end of T2, T3, T6 and T7; postprandial plasma glucose, fasting and postprandial plasma insulin and C-peptide were evaluated at the beginning of T1 and T5, and end of T3 and T7. At these latter time points additional assessments included routine clinical chemistry measurements, ECG, and ophthalmoscopic examination. Statistical analysis was performed by the paired Student's t-test and analysis of variance for cross-over studies. Thirty-three patients completed the study. Fasting plasma glucose, postprandial plasma glucose and HbA(1c) levels improved significantly during combined treatment with glyburide at lower doses plus metformin. This effect was achieved without any major change of insulin and C-peptide concentrations. Circulating lactate concentrations increased during the regimen including metformin, but they remained well within the reference values for normal subjects. Plasma total cholesterol and triglycerides levels remained substantielly unchanged throughout the study, whereas HDL-cholesterol concentrations increased slightly, but significantly, with glyburide plus metformin therapy. Routine clinical chemistry measurements, ECG and ophthalmoscopic examinations did not change during the study. These results demonstrate that improved metabolic control can be achieved with preconstituted, fixed combinations of low-dose glyburide plus metformin in patients with type 2 diabetes, compared to higher doses of the sulphonylurea alone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Postprandial Period; Time Factors

In this prospective study we aimed to compare insulin plus acarbose with insulin plus gliclazide with respect to their effect on insulin requirement, lipid profiles and body mass index (BMI) while achieving good glycemic control. Forty patients with type 2 diabetes mellitus who were on conventional insulin therapy (subcutaneous insulin therapy consisting of regular and NPH insulin, two times a day) were included in the study. They were randomized to double blind treatment with insulin in combination with gliclazide or acarbose for 6 months. For both groups, acceptable glycemic control was achieved at the end of study period. The mean HbA(1c) levels decreased from 8.32+/-0.26 to 7.13+/-0.18% in acarbose group and 8. 6+/-0.15 to 7.48+/-0.21% in the gliclazide group. The difference between groups was not significant (P 0.29). In the acarbose group, total cholesterol and LDL concentration decreased significantly while other parameters did not change. In the gliclazide group, HDL levels decreased significantly from 46.6+/-2.48 mg/dl to 41.3+/-2.09 mg/dl (P 0.001) BMI increased significantly from 27.60+/-1.21 kg/m(2) to 28.69+/-1.26 kg/m(2). (P 0.003) Total daily insulin dose was not changed in the acarbose group significantly, but increased from 42.6+/-2.73 to 49.27+/-3.58 U/day, which was significant in gliclazide group of (P 0.016). In the acarbose group, there were no significant differences between responders and nonresponders with respect to fasting and stimulated C-peptide, HbA(1c) levels and baseline BMI values. But in the gliclazide group, baseline BMI values were significantly higher in the nonresponding group compared to responders (P 0.02). In conclusion, combination of insulin with acarbose can be a good alternative for type 2 diabetic patients on insulin therapy; seems more beneficial than combination with gliclazide; may have advantage of achieving good glycemic control without increasing insulin dose and BMI; also may have the advantage of providing a decrease in LDL level, which are all important to prevent atherosclerosis.

Topics: Acarbose; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Prospective Studies; Triglycerides

To evaluate the effects of cilnidipine (CNP), L- and N-type calcium channel blocker and nilvadipine (NVP) on 24-h urinary epinephrine (U-EP), norepinephrine (U-NE), dopamine (U-DA) and C-peptide (U-CPR) in patients associated with hypertension and non-insulin-dependent diabetes mellitus (HT-NIDDM), a randomized crossover study was performed with 35 HT-NIDDM patients. The patients were given CNP (10 mg/day) and NVP (8 mg/day), separately, for 4 weeks each. After CNP treatment, U-NE, U-DA and U-CPR levels were significantly reduced compared with pre-treatment levels: 160.4 +/- 12.7 to 111.7 +/- 8.9 microg/day (mean +/- S.E., P < 0.005); 934.8 +/- 163.4 to 590.3 +/- 33.4 microg/day (P < 0.05); 86.7 +/- 9.9 to 57.6 +/- 7.4 microg/day (P < 0.05), respectively. Although no significant differences were observed in U-EP, U-NE, U-DA and U-CPR levels by NVP treatment, U-NE, U-DA and U-CPR levels after CNP treatment were significantly lower than those after NVP treatment: 111.7 +/- 8.9 versus 155.0 +/- 13.7 microg/day (P < 0.02); 590.3 + 33.4 versus 822.2 +/- 104.3 microg/day (P < 0.05); 57.6 +/- 7.4 versus 80.6 +/- 8.1 microg/day (P < 0.05), respectively. In conclusion, it was demonstrated that CNP treatment significantly reduced U-NE, U-DA and U-CPR excretion compared with NVP treatment in HT-NIDDM patients.

Topics: Aged; C-Peptide; Calcium Channel Blockers; Catecholamines; Chromatography, High Pressure Liquid; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Dopamine; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Norepinephrine

To study whether changes in endogenous insulin secretion at the same glycaemic control affect the plasma concentrations of lipoproteins in patients with Type 2 diabetes mellitus.. Fifteen patients, age 59+/-2 years (mean +/- SEM), body weight 86.3+/-3.0kg, body mass index 29.6+/-0.9 kg/m2 were treated with sulphonylurea and insulin in combination or with insulin alone in a randomized, double-blind, crossover study. All patients were treated with a multiple daily injection regimen with the addition of glibenclamide 10.5 mg daily or placebo tablets.. During combination therapy, the dose of insulin was 25% less (P < 0.002) and there was a 29% increase in plasma C-peptide concentration (P = 0.01). Plasma levels of free insulin were not changed. Plasma levels of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein (IGFBP)-1 were lowered. There were no differences in the 24-h blood glucose profiles or HbA1c (6.0+/-0.2 vs. 6.3+/-0.2%; P = 0.16). Body weight was similar. There was a significant decrease in plasma LDL cholesterol (3.04+/-0.24 vs. 3.41+/-0.21 mmol/l; P = 0.04), apolipoprotein A1 and of lipoprotein(a) but an increase in VLDL-triglycerides (1.36+/-0.31 vs. 0.96+/-0.16 mmol/l; P = 0.02) during combination therapy. The ratio between LDL cholesterol and apolipoprotein B concentrations was significantly lower during combination therapy (P < 0.01).. Combination therapy with insulin and sulphonylureas increases portal insulin supply and thereby alters liver lipoprotein metabolism when compared with insulin therapy alone.

Topics: Aged; C-Peptide; Cholesterol, LDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Lipoproteins; Lipoproteins, VLDL; Male; Middle Aged; Sex Hormone-Binding Globulin; Sulfonylurea Compounds; Triglycerides

Troglitazone and metformin lower glucose levels in diabetic patients without increasing plasma insulin levels. We compared the insulin sparing actions of these two agents and their effects on insulin sensitivity and insulin secretion in 20 type 2 diabetic patients. To avoid the confounding effect of improved glycemic control on insulin action and secretion, patients were first rendered euglycemic with 4 weeks of continuous subcutaneous insulin infusion (CSII) before randomization to CSII plus troglitazone (n = 10) or CSII plus metformin (n = 10); euglycemia was maintained for another 6-7 weeks. Insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp 1) at baseline, 2) after 4 weeks of CSII, and 3) after CSII plus either troglitazone or metformin. The 24-h glucose, insulin, and C-peptide profiles were performed on the day before the second and third glucose clamps. Good glycemic control was achieved with CSII alone and was maintained with CSII plus an oral agent (mean 24-h glucose: troglitazone, 6.2+/-0.6 mmol/l; metformin, 6.2 +/-0.3 mmol/l). Insulin requirements decreased 53% with troglitazone compared with CSII alone (48+/-4 vs. 102+/-13 U/day, P < 0.001), but only 31% with metformin (76+/-13 vs. 110+/-18 U/day, P < 0.005). The 24-h C-peptide profiles were similar. Normal fasting hepatic glucose output was maintained with both agents despite lower insulin levels than on CSII alone. Insulin sensitivity did not change significantly with CSII alone or with CSII plus metformin, but improved 29% with CSII plus troglitazone (P < 0.005 vs. CSII alone) and was then 45% higher than in the CSII plus metformin patients (P < 0.005). In conclusion, metformin has no effect on insulin-stimulated glucose disposal independent of glycemic control in type 2 diabetes. Troglitazone (600 mg/day) has greater insulin-sparing effects than metformin (1,700 mg/day) in CSII-treated euglycemic patients. This is probably explained by the peripheral tissue insulin-sensitizing effects of troglitazone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Chromans; Circadian Rhythm; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Fructosamine; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Male; Metformin; Middle Aged; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone

The fundamental role of insulin resistance for metabolic changes linked to cardiovascular disease and type 2 diabetes is increasingly recognized. Oral contraceptives (OC) may affect insulin sensitivity, and a detailed characterization hereof, as well as the secondary effects on related metabolic systems, are relevant in the evaluation of the risk of developing vascular disorders or diabetes in OC users. We studied insulin sensitivity index (S(I)), glucose effectiveness (S(g)), and insulin response in young, healthy women by frequently sampled intravenous glucose tolerance tests before and after randomization to 6 months of treatment with ethinyl estradiol in triphasic combination with norgestimate (n = 17) or gestodene (n = 20). Measurements of fasting triglycerides and antigen concentrations of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were also included. Both compounds increased fasting plasma insulin and reduced S(i) but did not affect S(g). The relationships between S(i) and insulin response were unchanged. No consistent correlation between insulin sensitivity and triglycerides, t-PA, or PAI-1 were demonstrated before or during treatment. We conclude that the treatments were followed by a compensated decrease in insulin sensitivity that was unrelated to changes in triglycerides, t-PA, or PAI-1 antigen.

Topics: Adult; Antibodies, Monoclonal; Blood Glucose; C-Peptide; Cardiovascular Diseases; Contraceptives, Oral, Synthetic; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Ethinyl Estradiol; Female; Fibrinolysis; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Norgestrel; Plasminogen Activator Inhibitor 1; Prospective Studies; Tissue Plasminogen Activator; Triglycerides

Rosiglitazone is the most potent of the thiazolidinediones, a novel class of oral antidiabetic agents that reduce blood glucose levels by sensitizing peripheral tissues to insulin. This study was designed to identify doses of rosiglitazone that would lower fasting plasma glucose (FPG) in patients with type 2 diabetes.. In this 12-week, double-blind, multicentre study, 380 patients with FPG values > or =7.8 mmol/L (140 mg/dL) and < or =13.3 mmol/L (240 mg/dL) were randomly assigned to receive treatment with placebo or rosiglitazone, 0.05, 0.25, 1.0, or 2.0 mg twice daily. The primary efficacy parameter was changed in FPG from baseline after 12 weeks of treatment. Secondary endpoints were changes in HbA1c, fructosamine, C peptide, insulin, lipid levels, and body weight (b.w.). Safety monitoring included clinical laboratory evaluations, electrocardiography, and echocardiography.. Rosiglitazone 1.0 and 2.0 mg b.i.d. produced significant decreases in FPG (p=0.0001). Fructosamine also decreased in patients treated with these two dosages (p=0.003 in the 2.0 mg b.i.d. group). Rosiglitazone 2.0 mg b.i.d. significantly reduced plasma insulin levels (p=0.0044) and free fatty acids (p=0.0014) compared with placebo. Total cholesterol (p=0.0001), HDL (p=0.0009), and LDL (p=0.0001) increased in the rosiglitazone 2.0 mg b.i.d. group, but there was no significant change in the total cholesterol/HDL ratio or triglyceride levels in any rosiglitazone treatment group. Clinically insignificant dose-dependent increases in b.w. were observed in the rosiglitazone 1.0 and 2.0 mg b.i.d. treatment groups.. Twelve weeks of treatment with rosiglitazone 2.0 mg b.i.d. significantly decreases fasting plasma glucose, fructosamine, plasma insulin, and free fatty acids in patients with type 2 diabetes. Longer studies using higher doses will be needed to assess the efficacy and safety of rosiglitazone in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fructosamine; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Middle Aged; Placebos; Rosiglitazone; Thiazoles; Thiazolidinediones

Troglitazone is a new insulin-sensitizing agent used to treat type 2 diabetes mellitus. The mechanism by which troglitazone exerts its effect on systemic glucose metabolism is unknown.. To determine the effects of 6 months of troglitazone monotherapy on glucose metabolism in patients with type 2 diabetes mellitus.. Randomized, double-blind, placebo-controlled trial.. Six general clinical research centers at university hospitals.. 93 patients (mean age, 52 years) with type 2 diabetes mellitus (mean fasting plasma glucose level, 11.2 mmol/L) who were being treated with diet alone or who had discontinued oral antidiabetic medication therapy.. Patients were randomly assigned to one of five treatment groups (100, 200, 400, or 600 mg of troglitazone daily or placebo) and had metabolic assessment before and after 6 months of treatment.. Plasma glucose and insulin profiles during a meal tolerance test; basal hepatic glucose production and insulin-stimulated glucose disposal rate during a hyperinsulinemic-euglycemic clamp procedure.. Troglitazone at 400 and 600 mg/d decreased both fasting (P < 0.001) and postprandial (P = 0.016) plasma glucose levels by approximately 20%. All four troglitazone dosages also decreased fasting (P = 0.012) and postprandial (P < 0.001) triglyceride levels; 600 mg of the drug per day decreased fasting free fatty acid levels (P = 0.018). Plasma insulin levels decreased in the 200-, 400-, and 600-mg/d groups (P < 0.001), and C-peptide levels decreased in all five study groups (P < 0.001). Basal hepatic glucose production was suppressed in the 600-mg/d group compared with the placebo group (P = 0.02). Troglitazone at 400 and 600 mg/d increased glucose disposal rate by approximately 45% above pretreatment levels (P = 0.003). Stepwise regression analysis showed that troglitazone therapy was the strongest predictor of a decrease in fasting (P < 0.001) or postprandial (P = 0.01) glucose levels. Fasting C-peptide level was the next strongest predictor (higher C-peptide level equaled greater glucose-lowering effect).. Troglitazone monotherapy decreased fasting and postprandial glucose levels in patients with type 2 diabetes, primarily by augmenting insulin-mediated glucose disposal.

Topics: Adult; Aged; Analysis of Variance; Blood Glucose; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Middle Aged; Placebos; Regression Analysis; Thiazoles; Thiazolidinediones; Troglitazone

To determine the effect of benfluorex on glycaemic control in obese insulin-requiring Type 2 diabetes, 76 patients (aged 53.8 +/- 12.8 years) receiving insulin (> or = 0.5 IU/kg) and an appropriate low-calorie diet were evaluated after a 1-month run-in followed by a 3-month double-blind treatment period (3 tablets daily) with benfluorex (B; n = 37) vs placebo (P; n = 39). At inclusion, the B and P groups respectively did not differ in body weight (80.9 +/- 10.3 vs 77.2 +/- 9.1 kg), body mass index (BMI) (30.1 +/- 4.6 vs 29.0 +/- 2.3 kg/m2) or fasting blood glucose (11.22 +/- 4.33 vs 10.35 +/- 4.42 mmol/l). However, daily insulin dose and HbA1c levels were higher in the B group (59.9 +/- 18.6 vs 50.4 +/- 12.8 IU, p = 0.012; and 7.72 +/- 1.60 vs 6.96 +/- 1.27%, p = 0.025, respectively). After 3 months of treatment, the decrease in daily insulin dose was greater in the B group (8.7 +/- 10.1 vs 2.7 +/- 8.1 IU; p = 0.032), with a decrease in HbA1c (-0.73 +/- 1.74%, p = 0.026), vs no change in the P group (+0.01 +/- 1.65%, NS) and a tendency towards a greater decrease in fasting blood glucose (-1.43 +/- 5.41 vs +0.42 +/- 3.78 mmol/l respectively). Body weight and BMI were also lower in the B group (1.77 ñ 2.27 vs 0.21 ñ 2.68 kg, p = 0.013; and 0.64 +/- 0.84 vs 0.07 +/- 1.07 kg/m2, p = 0.019, respectively) in parallel with the decrease in insulin dose. Triglycerides decreased in the B group vs an increase in the P group (-0.54 +/- 2.04 vs +0.21 +/- 0.70 mmol/l p = 0.06). Total cholesterol decreased within the B group (-0.47 +/- 1.01 mmol/l; p = 0.013) and vs the P group (intergroup p = 0.006). Adverse events were reported in 11 patients in the B group vs 5 in the P group (NS), causing dropout in only one case (intercurrent illness, P group). Addition of benfluorex in obese insulin-requiring Type 2 diabetes thus enhances glycaemic control and lowers both daily insulin requirement and body weight. Benfluorex + insulin is a valid alternative for obese patients who remain poorly controlled despite insulin or who require high doses of insulin.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Fenfluramine; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Monitoring, Physiologic; Obesity; Postprandial Period

To determine whether the lipoprotein response to weight loss in obese patients with type 2 diabetes can be improved by modifying the macronutrient composition of the commonly prescribed low-fat, high-carbohydrate (CHO) hypocaloric diet.. Nine obese patients with type 2 diabetes were treated with a monounsaturated fatty acid (MUFA)-enriched weight-reducing formula diet and compared with eight obese patients with type 2 diabetes treated with a low-fat, high-CHO weight-reducing formula diet. Weight loss ensued for 6 weeks, followed by 4 weeks of refeeding using isocaloric formulas enriched with MUFA or CHO, respectively. Fasting blood samples were obtained to measure plasma lipoproteins and LDL susceptibility to oxidation (measured as lag time: time required to induce in vitro formation of conjugated dienes).. At baseline, there were no differences between the groups in plasma lipids, lipoproteins, or LDL susceptibility to oxidation. Weight loss was similar between the groups. Dieting resulted in decreases in total plasma cholesterol, LDL, HDL, triglycerides, and apolipoproteins A and B (P < 0.05), but the MUFA group manifested a greater decrease in total cholesterol, triglycerides, and apolipoprotein B and a smaller decrease in HDL and apolipoprotein A than the CHO group (P < 0.05). Improvements in these parameters were sustained during refeeding. After dieting, lag time was prolonged in the MUFA group (208 +/- 10 min) compared with the CHO group (146 +/- 11 min; P < 0.05). Lag time was prolonged further during refeeding in the MUFA group (221 +/- 13 min, P = 0.10), while the CHO group remained unchanged (152 +/- 9 min, P < 0.05). Lag time correlated strongly with the oleic acid content of LDL after dieting and refeeding (r = 0.74 and r = 0.93, respectively; both P < 0.001).. Macronutrient content is an important determinant of the lipoprotein response to weight loss in obese patients with type 2 diabetes. MUFA-enriched hypocaloric diets potentiate the beneficial effects of weight loss to ameliorate cardiovascular risk factors in obese patients with type 2 diabetes.

Topics: Apolipoproteins; Blood Glucose; C-Peptide; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Dietary Carbohydrates; Dietary Fats, Unsaturated; Energy Intake; Fatty Acids, Monounsaturated; Female; Humans; Insulin; Lipids; Lipoproteins; Male; Middle Aged; Obesity; Regression Analysis; Risk Factors; Triglycerides; Weight Loss

Physical exercise is associated with a fall in serum insulin levels, whereas sulphonylurea administration increases insulin release. To date, the opposing effects of exercise and sulphonylurea administration have not been systematically studied in Type 2 diabetic patients, who are not infrequently treated with sulphonylureas. In this study nine patients with Type 2 diabetes mellitus were subjected to four treatments in random order on separate days: (A) endurance exercise after the administration of 3.5 mg glibenclamide; (B) as A but given only 1.75 mg glibenclamide; (C) as A but with placebo; (D) rest and administration of 1.75 mg glibenclamide. Exercise and placebo resulted in only a small decrease in glycaemia. Rest and administration of 1.75 mg glibenclamide led to a moderate but steady fall in blood glucose concentrations. If glibenclamide administration and exercise were combined, blood glucose concentrations declined more markedly. Serum insulin concentrations showed a physiological decrease during exercise and placebo administration. If patients rested after administration of glibenclamide serum insulin levels rose and remained elevated. When exercise and glibenclamide were combined the rise in serum insulin levels was blunted and insulin levels fell once exercise was begun. Thus, exercise attenuates the glibenclamide induced increase in serum insulin in moderately hyperglycaemic Type 2 diabetic patients. Nevertheless, exercise has a substantial hypoglycaemic effect in glibenclamide treated Type 2 diabetic patients.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Exercise; Glucagon; Glyburide; Humans; Hypoglycemic Agents; Insulin; Lactic Acid; Middle Aged

The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving standard and intensive treatment. We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients. Therefore, we assessed the variations of response and correlated factors that might explain such differences.. One hundred fifty-three men aged 40-69 years with NIDDM for < or = 15 years were randomized to either the standard therapy (n = 78) or the intensive therapy (n = 75) arm. Of the 75 patients in the intensive therapy group, 57 completed the study on insulin therapy alone. Of these, 18 were African-Americans and 39 were non-African-Americans. We conducted an analysis of the data collected to determine differences in baseline characteristics, glycemic response, insulin requirement, body weight, exercise, and basal C-peptide level, factors that may explain a difference in response to insulin therapy.. Glycemic control improved in all patients with intensive insulin therapy. African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin. This difference could not be explained by differences in body weight, activity, concomitant use of other medicines, or insulin-secretory capacity of the pancreas.. We conclude that ethnic differences may exist in the response to insulin therapy. A knowledge of such differences may aid in achieving good glycemic control, especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes.

Topics: Adult; Aged; Black People; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Ethnicity; Glycated Hemoglobin; Hospitals, Veterans; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds; United States; White People

Amylin, a secretory peptide of beta-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid.. In a randomized crossover design, eight subjects with NIDDM underwent three 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in beta-cell function (% beta) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp.. Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal % beta, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0-11.8] vs. 3.0 [1.4-6.2] pmol/l, P = 0.003; for ALP, 16.4 [8.5-31.7] vs. 10.1 [4.9-20.8] pmol/l, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5-5.6] vs. 6.0 [2.6-13.6] pmol/l, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3-6.5] pmol/l) or ALP (10.0 [5.5-18.1] pmol/l).. By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of % beta in NIDDM, compared with diet therapy alone.

Topics: Aged; Amyloid; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Islets of Langerhans; Male; Middle Aged; Sulfonylurea Compounds

Eighteen patients with non-insulin-dependent (type 2) diabetes mellitus of normal body weight [body mass index (BMI) <25 kg/m2] without signs of autoimmunity [negative for islet cell antibodies (ICA)], with secondary failure of sulphonylureas, defined as persistent hyperglycaemia in spite of maximal doses of sulphonylureas, were evaluated for C-peptide release under basal conditions and 6 min after i.v. glucagon, for glycosylated haemoglobin (HbA1C), and for fasting and mean daily blood glucose levels. They entered a 6-month, single-blind study in which they were randomly assigned to one of three treatments: (1) insulin plus nicotinamide (group 1, 0.5 g, three tablets/day); (2) insulin plus placebo (group 2, 3 tablets/day); (3) current sulphonylureas plus nicotinamide (group 3, 0.5 g, three tablets/day). They were re-evaluated for C-peptide, HbA1C, and fasting and mean daily blood glucose levels after 6 months. Compared with group 2, C-peptide release increased in both groups 1 and 3, while HbA1C, fasting and mean daily blood glucose levels improved in the three groups to the same extent. With multiple regression analysis, nicotinamide administration was the only significant factor for the improvement of C-peptide release. These data indicate that nicotinamide improves C-peptide release in type 2 diabetic patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Niacinamide; Retreatment; Single-Blind Method; Sulfonylurea Compounds; Treatment Failure; Treatment Outcome

GLP-1 (7-36 amide) normalizes fasting plasma glucose in NIDDM patients. It was the aim to study the effect of overnight intravenous GLP-1 (7-36 amide) on the following 24 h-glucose profiles. Ten NIDDM patients (7 female, 3 male; age 62 +/- 4 y., BMI (Body-Mass-Index) 29.6 +/- 3.9 kg/m2, duration 10 +/- 7 y., HbA1c 10.9 +/- 1.3% (normal 4.0-6.1%), treated with glibenclamide and/or metformin) were studied on two occasions in random order: Either GLP-1 (7-36 amide) (Saxon Biochemicals, Hannover, FRG, 1 pmol x kg(-1) x min(-1)) or placebo (0.9% NaCl with 1% human serum albumin, Behringwerke, Marburg, FRG) were infused intravenously from 22:00 to 7:00 (9 h) and plasma glucose profiles were obtained during the GLP-1 infusion and the following 24 hours. GLP-1 (7-36 amide) (plasma concentration 110 +/- 12 pmol/l) raised plasma C-peptide concentrations (p = 0.0005), suppressed glucagon (p = 0.01) and lowered plasma glucose to 5.5 +/- 0.6 and 6.3 +/- 0.4 mmol/l at 3:00 and 7:00 a.m. (vs. 10.3 +/- 0.9 and 11.3 +/- 0.6 mmol/l, p = 0.0003 and p < 0.0001, respectively, with placebo). Thereafter, starting 1 h after breakfast, no significant differences in plasma glucose, insulin, C-peptide or glucagon profiles were found between experiments with GLP-1 (7-36 amide) and placebo. Average plasma glucose concentrations over the whole 24 h period were reduced by 18% by GLP-1 administered overnight. In conclusion, (1) overnight GLP-1 (7-36 amide) normalizes fasting plasma glucose, but (2) has no sustained effect on meal-induced glucose, insulin or glucagon concentrations once its administration has been stopped. (3) Normalization of fasting plasma glucose alone does not improve daytime metabolic control in NIDDM patients on oral agents.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Peptide Fragments; Postprandial Period; Protein Precursors; Single-Blind Method; Time Factors; Treatment Outcome

GLP-1, an incretin hormone of the enteroinsular axis with insulinotropic and glucagonostatic activity, is secreted after nutrient ingestion. GLP-1 is mainly produced by intestinal L-cells in the lower gastrointestinal tract (GIT); simple carbohydrates are absorbed in the upper GIT and alpha-glucosidase inhibition leads to augmented and prolonged GLP-1 release in normal subjects. In a cross-over study, 100 mg acarbose or placebo was administered simultaneously with 100 g sucrose to 11 hyperglycaemic Type 2 diabetic patients poorly controlled with diet and sulphonylureas. Plasma levels of GLP-1, insulin, C-peptide, glugacon, GIP, glucose and H2-exhalation were measured over 6 h. Differences in the integrated responses over the observation period were evaluated by repeated measurement analysis of variance with fasting values used as covariates. With acarbose, sucrose reached the colon 60-90 min after ingestion as indicated by a significant increment in breath hydrogen exhalation (p = 0.005). After an early GLP-1 increment 15 min after sucrose under both conditions, GLP-1 release was prolonged in the acarbose group (p = 0.001; significant from 210 to 360 min.). Initially (0-150 min), glucose (p = 0.001), insulin (p = 0.001), and GIP (p < 0.001) were suppressed by acarbose, whereas later there were no significant differences. Glucagon levels were higher with acarbose in the last 3 h of the 6 h observation period (p = 0.02). We conclude that in hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a sucrose load leads to elevated and prolonged GLP-1 release.

Topics: Acarbose; Administration, Oral; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptide Fragments; Sucrose; Time Factors; Trisaccharides

This study tested a simple algorithm for beginning insulin for obese patients with type 2 diabetes after sulfonylurea failure, comparing suppertime 70/30 insulin plus continued glimepiride with insulin alone.. This was a multicenter ambulatory randomized double-masked parallel comparison. There were 208 subjects with secondary failure to sulfonylureas who took glimepiride titrated to 8 mg b.i.d. for 8 weeks; 145 subjects with fasting plasma glucose (FPG) 180-300 mg/dl (10-16.7 mmol/l) on this treatment were randomized to placebo plus insulin (PI) or glimepiride plus insulin (GI) for 24 weeks. A dosage of 70/30 insulin before supper was titrated, seeking fasting capillary blood glucose (FBG) 120 mg/dl (6.7 mmol/l), equivalent to FPG 140 mg/dl (7.8 mmol/l). Outcome measures included FPG, HbA1c, insulin dosage, weight, serum insulin and lipids, and adverse events.. FPG and HbA1c were equivalent at baseline: 261 vs. 250 mg/dl (14.5 vs. 13.9 mmol/l), and 9.9 vs. 9.7%. At 24 weeks, the FPG target was achieved in both groups (136 vs. 138 mg/dl, 7.6 vs. 7.6 mmol/l), and HbA1c values were equal (7.7 vs. 7.6%). However, with GI, control improved faster and fewer subjects dropped out (3 vs. 15%, P < 0.01), and less insulin was needed (49 vs. 78 U/d, P < 0.001). The outcomes were alike in other respects. No subject had severe hypoglycemia.. Injection of 70/30 insulin before supper safely restored glycemic control of type 2 diabetes not controlled by glimepiride alone. Control was restored more rapidly and with less injected insulin when glimepiride was continued.

Topics: Aged; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Patient Dropouts; Sulfonylurea Compounds; Treatment Outcome; Triglycerides

Subjects with poorly controlled type 2 diabetes are both hyperglycemic and insulin resistant. To determine whether short term restoration of normoglycemia improves insulin action, hyperinsulinemic (approximately 300 pmol/L) euglycemic clamps were performed in diabetic subjects after either overnight infusion of saline or overnight infusion of insulin in amounts sufficient to maintain euglycemia throughout the night. Fasting glucose concentrations (5.2 +/- 0.2 vs. 11.9 +/- 1.4 mmol/L; P < 0.01) and rates of endogenous glucose production (13.0 +/- 1.1 vs. 18.6 +/- 1.6 mumol/kg.min; P < 0.05) were both lower after overnight insulin than overnight saline. Insulin-induced stimulation of glucose uptake (to 34.9 +/- 6.8 vs. 28.8 +/- 3.4 mumol/kg.min; P = 0.2) and inhibition of free fatty acids (to 0.13 +/- 0.03 vs. 0.12 +/- 0.04 mmol/L; P = 0.6) did not differ after overnight saline and overnight insulin. In contrast, endogenous glucose production during the final hour of the hyperinsulinemic clamps (i.e. when glucose concentrations were the same) remained higher (P = 0.05) after overnight saline than after overnight insulin (5.5 +/- 1.5 vs. 0.02 +/- 1.4 mumol/kg.min). Thus, acute restoration of euglycemia by means of an overnight insulin infusion improves hepatic (and perhaps renal) but not extrahepatic insulin action.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Humans; Hypoglycemic Agents; Insulin; Liver; Male; Norepinephrine; Oxidation-Reduction

The study of insulin blood spectrum, capillary morphology (by evidence of skin biopsies), antithrombogenic activity of the vascular wall in patients with non-insulin-dependent diabetes mellitus; assessment of possible corrective therapy.. 65 patients with type II diabetes mellitus (DM) entered the trial. Concentrations of free, bound, immunoreactive insulin (IRI) and C peptide were measured before and 10, 30, 60, 120 min after intravenous injection of glucose. Microcirculatory bed condition was evaluated by the data from skin biopsies. Antithrombogenic characteristics of the vascular wall were investigated at-test.. The tests discovered that DM patients had high IRI and low free insulin in high glucose levels; disorders of hemostasis, active proliferation in the microvessels. In patients with microangiopathy tiklid therapy given for 45 days reduced the speed and degree of platelet aggregation, improved fibrinolysis and clinical course of the disease.. High level of IRI may be due to emergence of insulin-like substances dissociation of which produces peptides enhancing proliferative processes.

Topics: Aged; Biopsy; Blood Glucose; C-Peptide; Capillaries; Cell Division; Diabetes Mellitus, Type 2; Hemostasis; Humans; Insulin; Insulin Secretion; Microcirculation; Middle Aged; Platelet Aggregation Inhibitors; Skin; Ticlopidine

It has been proposed that high plasma free fatty acid (FFA) levels observed in patients with non-insulin dependent diabetes mellitus (NIDDM) contribute to the development of their insulin resistance. We examined patients with NIDDM to find whether maintaining plasma FFA levels in the fasting range with a euglycemic hyperinsulinemic clamp combined with an oral glucose load (clamp OGL) would affect insulin-mediated peripheral glucose uptake (PGU) and splanchnic glucose uptake (SGU). Nine NIDDM subjects (age, 55 +/- 3 years; duration of diabetes, 11 +/- 2 years; body mass index, 21.0 +/- 0.4 kg/m2; hemoglobin A1c, 9.0 +/- 0.3%; fasting plasma glucose, 9.4 +/- 3.0 mmol/l, means +/- SEM) were hospitalized and treated with diet, oral hypoglycemic agents or insulin for at least 2 weeks to maintain fasting plasma glucose < 8 mmol/l. All the patients were subjected to two different protocols in a random order. On one protocol, under the hyperinsulinemic condition, FFAs were maintained at the their fasting levels (1.19 +/- 0.08) by triglyceride emulsion infusion (Lipid infusion study, L), and on the other protocol, FFAs were made to fall (0.26 +/- 0.06 mmol/l) with saline instead of triglyceride emulsion infusion (Saline infusion study, S). During euglycemic (L, 5.4 +/- 0.2; S, 5.1 +/- 0.2 mmol/l) hyperinsulinemic (L, 1377 +/- 108; S, 1328 +/- 67 pmol/l) clamp, high FFA levels significantly reduced PGU (L, 26.7 +/- 3.6; S, 32.1 +/- 3.4 mumol.kg-1.min-1, P < 0.05) and SGU (L, 12.1 +/- 4.2; S, 27.5 +/- 5.6%, P < 0.05). In conclusion, high FFA levels in patients with NIDDM impaired insulin-mediated glucose uptake in the splanchnic as well as peripheral tissues.

Topics: 3-Hydroxybutyric Acid; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Humans; Hydroxybutyrates; Insulin; Male; Middle Aged; Splanchnic Circulation; Triglycerides

In a double-blind, randomized study, miglitol (BAY m 1099), an alpha-glucosidase inhibitor, 100 mg tds or placebo was given orally with meals for a period of 24 weeks in 117 patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) treated with insulin. Fasting and 1 h postprandial plasma glucose and C-peptide were measured at the beginning and at the end of each 4-week interval and glycosylated haemoglobin was determined at day 0 and at the end of the 12th and 24th week. One hour postprandial plasma glucose was significantly lower in the miglitol group at the end of the 24th week (placebo: 11.6 +/- 1.5 vs miglitol: 8.2 +/- 1.5 mmol l-1, mean +/- SD, p = 0.001). Diabetes control improved in the same group as the HbA1 was lowered by 16% (p = < 0.0001) at the end of the treatment. Mild reversible adverse effects were observed in 37 patients of the miglitol group (mainly flatulence and mild hypoglycaemia) and 2 of the placebo group. Urinary glucose was rendered negative in 41 patients in the miglitol group only. Thus miglitol appears to be a safe and effective adjunct in the management of Type 2 DM, in association with insulin.

Topics: 1-Deoxynojirimycin; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Enzyme Inhibitors; Fasting; Female; Follow-Up Studies; Glucosamine; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Imino Pyranoses; Insulin; Male; Middle Aged; Postprandial Period; Time Factors

This multicenter, randomized, placebo-controlled study of glimepiride, a new oral sulfonylurea, was conducted in patients with type 2 diabetes for whom dietary treatment was unsuccessful (fasting plasma glucose [FPG] = 151-300 mg/dL) during a 1-week screening period. Patients were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10-week dose-titration period, then maintained on an individually determined optimal dose (1-8 mg of glimepiride or placebo) for 12 weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin A1C (HbA1C) by 1.4%, and 2-hour postprandial glucose by 72 mg/dL more than placebo. Glimepiride improved postprandial insulin and C-peptide responses without producing clinically meaningful increases in fasting insulin or C-peptide levels. Good glycemic control (HbA1C < or = 7.2%) was achieved by 69% of the patients taking glimepiride versus 32% of those taking placebo. The overall incidence of adverse events was similar in both groups. No clinically noteworthy abnormal laboratory values or hypoglycemia (blood glucose < 60 mg/dL) occurred. Glimepiride is safe and effective for treatment of patients with type 2 diabetes for whom diet therapy is unsuccessful.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet Therapy; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Postprandial Period; Sulfonylurea Compounds

To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone.. There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed.. Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy. Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.

Topics: Blood Glucose; Body Weight; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Treatment Outcome; Troglitazone

To assess the effects of troglitazone monotherapy on glycemic control in patients with type 2 diabetes mellitus, we carried out a 6-month, randomized, double-blind, placebo-controlled study in 24 hospital and outpatient clinics in the United States and Canada. Troglitazone 100, 200, 400, or 600 mg or placebo once daily with breakfast was administered to 402 patients with type 2 diabetes with fasting serum glucose (FSG) > 140 mg/dL, glycosylated hemoglobin (HbA1c) > 6.5%, and fasting C-peptide > or = 1.5 ng/mL. Prior oral hypoglycemic therapy was withdrawn in patients who received it before the study. FSG, HbA1c, C-peptide, and serum insulin were evaluated at baseline and the end of the study. Analysis was performed on two subsets of patients based on prestudy therapy: Patients treated with diet and exercise only before the study (22% of patients), and those who had been receiving sulfonylurea therapy (78% of patients). Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG and HbA1c at month 6 compared with placebo-treated patients (FSG: -51 and -60 mg/dL, respectively; HbA1c: -0.7 and -1.1%, respectively). In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P < 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P < 0.05) decreases in mean FSG with 200-600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). Significant (P < 0.05) decreases in mean HbA1c occurred with 400 and 600 mg troglitazone therapy at month 6 (-0.8 and -1.2%, respectively) compared with placebo in this same subset. Significant (P < 0.05) decreases in triglycerides and free fatty acids occurred with troglitazone 400 and 600 mg, and increased high-density lipoprotein occurred with 600 mg troglitazone. We conclude that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with type 2 diabetes. Troglitazone 600 mg monotherapy is efficacious for patients who are newly diagnosed and have never received pharmacological intervention for diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Placebos; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Troglitazone

Glucagon-like peptide 1 (GLP-1) has glucose-dependent insulinotropic and glucagonostatic actions in type 2 diabetic patients on diet and on oral agents. It is not known, however, whether after secondary sulfonylurea failure, GLP-1 is still effective.. Therefore, 10 type 2 diabetic patients (6 women, 4 men; age 65+/-10 years, BMI 30.4+/-5.1 kg/m2, HbA1c 8.2+/-1.5%, 6+/-3 [2-13] years after starting insulin treatment) were examined in the fasting state after discontinuing NPH insulin on the evening before the two study days. GLP-1 (1.2 pmol x kg(-1) x min(-1) or placebo (NaCl with 1% human serum albumin) were infused over 6 h. Plasma glucose (glucose oxidase) insulin (IMx), and C-peptide (enzyme-linked immunosorbent assay) were measured. Statistical analysis was performed using repeated measures analysis of variance.. Fasting plasma glucose was 9.4+/-0.5 mmol/l and was reduced by GLP-1 to 5.3+/-0.3 (3.9-7.3) mmol/l (placebo: 8.2+/-0.7 mmol/l; P < 0.0001). GLP-1 transiently increased insulin (from 115+/-31 to 222+/-64 pmol/l at 150 min; P < 0.0001) and C-peptide (from 1.00+/-0.12 to 1.90+/-0.23 nmol/l at 120 min; P < 0.0001) with no effect of placebo. Glucagon and free fatty acids were lowered transiently. After normalization of plasma glucose, insulin and C-peptide concentrations became lower again during the ongoing administration of exogenous GLP-1, and no hypoglycemia occurred.. It is concluded that exogenous GLP-1 effectively lowers plasma glucose concentrations in advanced type 2 diabetes long after sulfonylurea secondary failure. These findings may broaden the applicability of GLP-1-derived drugs as a new treatment to nearly all type 2 diabetic patients.

Topics: Aged; Blood Glucose; C-Peptide; Calorimetry, Indirect; Cholesterol; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptide Fragments; Postprandial Period; Proinsulin; Protein Precursors; Sulfonylurea Compounds; Triglycerides

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65+/-6 years; BMI 34.3+/-7.9 kg m(-2); HbA1c 9.6+/-1.2%; treatment with diet alone (n=2), sulphonylurea (n=5), metformin (n=1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg(-1)min(-1) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7+/-0.9 [7-36 amide] and 11.3+/-0.9 mmol l(-1) [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168+/-32 and 156+/-47 pmol l(-1), p<0.0001 vs basal; C-peptide peak 2.32+/-0.28 and 2.34+/-0.43 nmol l(-1), p<0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8+/-0.4 and 4.6+/-0.3 mmol l(-1), p<0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1+/-0.4 and 5.3+/-0.4 mmol l(-1), for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p=0.99; insulin, p=0.99; C-peptide, p=0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism.

Topics: Age of Onset; Aged; Blood Glucose; C-Peptide; Calorimetry, Indirect; Cholesterol; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Peptide Fragments; Peptides; Triglycerides

Although some studies have suggested a direct action of troglitazone on vascular cells, its effects on diabetic vascular diseases have not been reported. We therefore investigated the effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy.. A total of 30 patients with type 2 diabetes associated with microalbuminuria (urinary albumin-to-creatinine ratio [ACR] [milligrams per gram creatinine] ranging from 30 to 300 mg/g creatinine) were studied. They were randomly divided into two groups: patients treated with metformin (500 mg/day, n = 13) or with troglitazone (400 mg/day, n = 17) for 12 weeks. ACR, lipid profile, blood pressure, glycated hemoglobin, and plasma glucose during meal-load tests were measured every 4 weeks.. Anthropometric indices (BMI and percent fat), lipid profile, and blood pressure did not change with either treatment. Fasting and postmeal glucose levels decreased similarly in the two groups. Decrements in glycated hemoglobin were greater in the metformin group at 4 and 8 weeks after the initiation of treatment (P < 0.05). Troglitazone reduced ACR (median [25-75th percentiles]) from 70 (49-195) to 40 (31-90) mg/g creatinine at 4 weeks (P = 0.021) and maintained these reduced levels throughout the treatment period (8 weeks: 35 [26-68], P = 0.007; 12 weeks: 43 [26-103], P = 0.047). Metformin did not change ACR throughout the 12 weeks.. Troglitazone ameliorated microalbuminuria in diabetic nephropathy. Furthermore, our findings suggest that troglitazone has some effects on vascular cells other than lowering plasma glucose levels. Troglitazone might be useful for diabetic angiopathy, including nephropathy and coronary artery disease.

Topics: Aged; Albuminuria; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Chromans; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone

To compare the long-term effects of the angiotensin-converting enzyme (ACE)-inhibitor quinapril and the cardioselective beta-adrenergic blocking agent metoprolol on glycaemic control, with glycosylated haemoglobin (HbA1c) as the principal variable, in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension.. A randomized, double-blind, double-dummy, multicentre study during 6 months preceded by a 4 week wash-out and a 3 week run-in placebo period. Quinapril (20 mg) and metoprolol (100 mg, conventional tablets) were given once daily. No change was made in the treatment of diabetes (diet and hypoglycaemic agents).. Seventy-two patients fulfilling the criteria were randomized and entered the double-blind period. Twelve patients did not complete the study. Sixty patients, 26 on quinapril and 34 on metoprolol, were available for the final analysis.. The effect was assessed by changes in HbA1c, the fasting serum glucose and the post-load serum glucose, C-peptide and insulin levels during the oral glucose tolerance test.. In the quinapril group, the fasting serum glucose, oral glucose tolerance and the C-peptide and insulin responses, determined as the incremental area under the curves (AUC), showed no change, but the mean HbA1c level increased from 6.2 +/- 1.1% to 6.5 +/- 1.3% (P < 0.05). In the metoprolol group, the rise in the mean level of HbA1c, from 6.3 +/- 1.0% to 6.8 +/- 1.3% (P < 0.01), tended to be more marked than after quinapril, although there was no significant difference between the increments. The mean fasting serum glucose showed an increase from 9.1 +/- 1.9 mM to 10.1 +/- 2.8 mM (P < 0.01) which correlated significantly with the duration of diabetes (P < 0.01) and the increase in fasting serum triglycerides (P < 0.001). Moreover, in the metoprolol group we found significant decreases in the oral glucose tolerance as well as C-peptide and insulin responses to the glucose load.. Treatment with quinapril for 6 months appears to have advantages over metoprolol in NIDDM patients with hypertension. Although treatment with quinapril or metoprolol over 6 months was concomitant with a rise in the HbA1c, increased fasting blood glucose, decreased oral glucose tolerance and decreased C-peptide and insulin responses to a glucose challenge were observed only in patients treated with metoprolol.

Topics: Adrenergic beta-Antagonists; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Tolerance Test; Hemoglobin A; Humans; Hypertension; Insulin; Isoquinolines; Lipids; Male; Metoprolol; Middle Aged; Quality of Life; Quinapril; Sweden; Tetrahydroisoquinolines

Glucosamine has a major influence on the impairment of some metabolic mechanisms in the human body. As shown in vitro experiments, it takes part in inducing mechanisms of insulin resistance. Therefore, the purpose of our study was to evaluate glucosamine levels in the serum of patients who suffered myocardial infarction (MI) and who either had or didn't have diagnosed type II diabetes in relation to healthy people. The levels of glucosamine, immunoreactive insulin, C-peptide, glucose and lipid indexes were measured in venous blood in investigated patients. In patients with MI without diabetes the highest concentrations of glucosamine, insulin and C-peptide were noted as compared to the results obtained from other groups of patients. In patients with diabetes, on the other hand, the highest glucose levels were noted as compared to the results of other patients. There were no statistically differences of lipid indexes between two groups of patients following MI. A negative correlation between glucosamine levels and glucose concentrations in patients without diabetes may suggest that glucose does not directly determine glucosamine levels. The returning of insulin levels to normal in patients with hyperinsulinemia (antidiabetic drugs) may play a role in the lowering of glucosamine induced peripheral insulin resistance.

Topics: Adult; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Glucosamine; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Myocardial Infarction; Statistics, Nonparametric; Triglycerides

Troglitazone is a thiazolidinedione under development for the treatment of NIDDM and potentially other insulin-resistant disease states. Treatment with troglitazone is associated with an improvement in hyperglycemia, hyperinsulinemia, and insulin-mediated glucose disposal. No significant side effects have been observed in humans. Because of reported cardiac changes in animals treated with drugs of this class, this multicenter 48-week study was conducted to evaluate whether NIDDM patients treated with troglitazone develop any cardiac mass increase or functional impairment. A total of 154 NIDDM patients were randomized to receive troglitazone 800 mg q.d. or glyburide titrated to achieve glycemic control (< or =20 mg b.i.d. or q.d.). Two-dimensional echocardiography and pulsed Doppler were used to measure left ventricular mass index (LVMI), cardiac index (CI), and stroke volume index (SVI). All echocardiograms were performed at each center (baseline, 12, 24, 36, and 48 weeks), recorded on videotape, and forwarded to a blinded central echocardiographic interpreter for analysis. The results showed that LVMI of patients treated with troglitazone was not statistically or clinically different from baseline after 24 or 48 weeks. Statistically significant increases in SVI and CI and a statistically significant decrease in diastolic pressure and estimated peripheral resistance were observed in troglitazone-treated patients. These results were not sex-specific. Glycemic benefits of troglitazone treatment were observed as evidenced by long-term improvement of HbA1c and C-peptide levels. Furthermore, triglycerides were significantly lower, and HDL was significantly higher at weeks 24 and 48. In conclusion, NIDDM patients treated with troglitazone do not show any cardiac mass increase or cardiac function impairment. Conversely, patients on troglitazone benefited from enhanced cardiac output and stroke volume, possibly as a result of decreased peripheral resistance. Treatment with troglitazone appears to have a favorable impact on known cardiovascular risk factors and could potentially lower cardiovascular morbidity in NIDDM patients.

Topics: Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Chromans; Confidence Intervals; Diabetes Mellitus, Type 2; Echocardiography; Female; Glyburide; Glycated Hemoglobin; Heart; Heart Function Tests; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Stroke Volume; Thiazoles; Thiazolidinediones; Time Factors; Triglycerides; Troglitazone

It is difficult to treat obese non-insulin-dependent diabetic patients (NIDDs) whose glycaemic control remains poor despite maximal oral antidiabetic therapy. We studied the effect of a continuous subcutaneous insulin infusion (CSII) associated with a low-calorie diet and metformin 1,700 mg/day on glycaemic control and basal and stimulated insulin secretion in a series of 82 overweight NIDD before (T1), during CSII (T2), and after CSII withdrawal (T3). Patients were treated for 8 to 23 days with a mean amount of 0.50 +/- 0.02 IU/kg/day. Glycaemic control was very good after 3-5 days of CSII and remained good at T3. At T2, fasting and postprandial plasma C peptide levels decreased significantly. At T3, fasting C peptide was very similar to T1, and postprandial C peptide was significantly higher than at T1. The molar fasting and postprandial plasma C peptide/glycaemia ratios increased significantly at T3. After glucagon injection, the molar delta C peptide/glycaemia ratio was significantly increased at T2 and even higher at T3. At T2, as at T1 and T3, there were significant correlations between fasting and postprandial C peptide levels and between the glucagon-induced C peptide peak and fasting and postprandial C peptide levels. Between T1 and T3 weight changes correlated significantly with the molar fasting C peptide/glycaemia ratio at T1. Twenty-nine of the 30 patients for whom this ratio was > 6.6 x 10(-8) lost weight. The length of CSII treatment did not correlate with weight changes or other biological parameters. This study shows that CSII with moderate amounts of insulin associated with a low-calorie diet and metformin provided rapid glycaemic control, led to weight loss, maintained regulation of insulin secretion and seemed to improve insulin secretion and sensitivity. These results were obtained in only 8 to 10 days.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Infusions, Parenteral; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Secretory Rate; Time Factors

Many newly diagnosed obese African-American patients with history of severe hyperglycemia or diabetic ketoacidosis (DKA) are able to discontinue pharmacological treatment with continued good metabolic control. However, many of these individuals relapse into hyperglycemia within 1 year. In such patients, we compared the effect of low-dose sulfonylurea and dietary therapy in the prevention of recurrence of hyperglycemia.. We conducted an intention-to-treat study in 35 obese newly diagnosed diabetic patients (17 with DKA and 18 with severe hyperglycemia). After discontinuation of insulin, seven of 17 patients with DKA and seven of 18 patients with hyperglycemia were managed with diet and glyburide (1.25-2.5 mg/day), whereas other patients were followed with diet alone. In all patients, pancreatic insulin reserve was documented 1 day after resolution of hyperglycemic crises and within 1 week of discontinuation of insulin. Recurrence of hyperglycemia was defined as fasting blood glucose > 7.8 mmol/l (140 mg/dl) or random blood glucose > 10 mmol/l (180 mg/dl) on two or more consecutive determinations, or HbA1c > 7.5%.. Both treatment groups were comparable in age, sex, duration of diabetes, months of insulin therapy, BMI, glucose, and HbA1c. At presentation, the acute C-peptide response to glucagon in obese DKA patients was lower than in patients with hyperglycemia (P < 0.01), but responses were comparable after discontinuation of insulin. Sulfonylurea treatment significantly reduced recurrence of hyperglycemia in both obese DKA and obese hyperglycemic patients (P = 0.03). With a median follow-up of 16 months, hyperglycemia recurred in six of 10 DKA patients and in five of 11 hyperglycemia patients treated with diet alone, compared with one of seven DKA and one of seven hyperglycemia patients treated with glyburide. Readmission with metabolic decompensation occurred in four patients treated with diet but in none of the patients treated with diet and glyburide.. Low-dose sulfonylurea therapy prevents recurrence of hyperglycemia in newly diagnosed obese African-American patients with a history of hyperglycemic crises.

Topics: Adult; Black or African American; Black People; Blood Glucose; C-Peptide; Combined Modality Therapy; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Diet, Diabetic; Female; Georgia; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Middle Aged; Obesity; Recurrence

To determine the effect over a 4-week period of varying doses of BTS 67,582, a novel nonsulfonylurea insulinotropic agent, on fasting plasma glucose (FPG) levels in sulfonylurea-responsive NIDDM patients.. This was a 12-week multicenter, double-masked, placebo-controlled trial. Patients entered a 4-week stabilization period during which they received their previously prescribed sulfonylurea. Qualified patients (FPG < or = 10 mmol/l) then entered a 4-week sulfonylurea withdrawal single-masked placebo run-in period. Qualified patients (FPG 8.9-16.7 mmol/l) were randomized to either placebo (n = 14), 50 mg b.i.d. BTS 67,582 (n = 18), 250 mg b.i.d. BTS 67,582 (n = 18), 500 mg b.i.d. BTS 67,582 (n = 15), 100 mg q.d. BTS 67,582 (n = 17), or 500 mg q.d. BTS 67,582 (n = 16). The primary efficacy variables were mean changes from baseline in FPG and fructosamine (FRUC). Additional variables included mean changes from baseline in HbA1c, fasting serum insulin (FSI), and fasting serum C-peptide.. After 4 weeks of treatment, all BTS 67,582 dose groups showed a decrease from baseline in FPG and FRUC compared with the placebo group. The treatment groups of 250 mg b.i.d. (-3.1 +/- 0.7 mmol/l), 500 mg b.i.d. (-2.3 +/- 0.6 mmol/l), and 500 mg q.d. (-1.2 +/- 0.7 mmol/l) had statistically significant (P < 0.05) decreases in FPG compared with placebo (0.7 +/- 0.6 mmol/l). Similarly, there were statistically significant (P < 0.05) decreases from baseline in FRUC for the 250 mg b.i.d (-55 +/- 10 mumol/l), 500 mg b.i.d. (-40 +/- 12 mumol/l), and 500 mg q.d. (-13 +/- 9 mumol/l) treatment groups compared with placebo (15 +/- 11 mumol/l). Although the treatment period was only 4 weeks in duration, there were also significant differences (P < 0.05) in the HbA1c changes from baseline for the 250 mg b.i.d. (0.0 +/- 0.1%) and 500 mg b.i.d. (-0.2 +/- 0.1%) treatment groups compared with placebo (0.6 +/- 0.2%). There were no significant differences among the treatment groups in the changes from baseline for FSI or C-peptide levels. The most frequently reported side effects were headache, asthenia, infection, and thirst, and the incidence of these events as well as the incidence of study drug discontinuation was comparable in all treatment groups including placebo.. Four weeks of treatment with BTS 67,582 at doses of 250 mg b.i.d. and 500 mg b.i.d. in NIDDM patients was effective in reducing FPG and FRUC, with significant results also seen for HbA1c. The drug was well tolerated with an incidence of discontinuations and laboratory side-effect safety profiles comparable to placebo. BTS 67,582 is a safe and effective oral treatment for NIDDM patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fasting; Female; Fructosamine; Glycated Hemoglobin; Guanidines; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Patient Selection; Placebos; Postmenopause

To investigate the efficacy, safety, and dose-response characteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosylated hemoglobin (HbA1c), and insulin secretion to a liquid-mixed meal in NIDDM patients.. Two prospective, randomized, double-blind, placebo-controlled, multicenter clinical trials were performed in 22 sites and 347 patients with NIDDM (aged 59 +/- 0.6 years; BMI, 29 +/- 0.3 kg/m2; known diabetes duration, 8 +/- 0.4 years) were studied. Each clinical trial had a duration of 16 weeks with a 1-week washout, 3-week single-blind placebo phase, 4-week titration to a fixed dose, and 8-week maintenance phase at the assigned dose. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizide GITS were compared with placebo in 143 patients. In the second trial, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with placebo in 204 patients. HbA1c, fasting plasma glucose (FPG), insulin, C-peptide, and glipizide levels were determined at regular intervals throughout the study. Postprandial plasma glucose (PPG), insulin, and C-peptide also were determined at 1 and 2 h after a mixed meal (Sustacal).. All doses of glipizide GITS in both trials produced significant reductions from placebo in FPG (range -57 to -74 mg/dl) and HbA1c (range -1.50 to -1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and reduction in FPG and HbA1c over a dose range of 5-60 mg, with maximal efficacy achieved at a dose of 20 mg for FPG and at 5 mg for HbA1c. PPG levels were significantly lower, and both postprandial insulin and C-peptide levels significantly higher in patients treated with glipizide GITS compared with placebo. The percent reduction in FPG was comparable across patients with diverse demographic and clinical characteristics, including those with entry FPG > or = 250 mg/dl, resulting in greater absolute decreases in FPG and HbA1c in patients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only 11 patients in both studies discontinued therapy because of hypoglycemia. Glipizide GITS did not alter lipids levels or produce weight gain.. The once-daily glipizide GITS 1) lowered HbA1c, FPG, and PPG over a dose range of 5-60 mg, 2) was maximally effective at 5 mg (using HbA1c) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) maintained its effectiveness in poorly controlled patients (those with entry FPG > or = 250 mg/dl), 4) was safe and well tolerated in a wide variety of patients with NIDDM, and 5) did not produce weight gain or adversely affect lipids.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Digestive System; Dose-Response Relationship, Drug; Fasting; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Placebos; Single-Blind Method; Time Factors

Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis.. A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels.. There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group.. These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Topics: Aged; Antioxidants; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycosuria; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis, Alcoholic; Male; Malondialdehyde; Middle Aged; Silymarin; Time Factors

High intake of trans fatty acids and saturated fatty acids (SFAs) is known to increase the risk of coronary heart disease. We studied the effects of diets enriched in various fatty acids on postprandial insulinemia and fasting serum levels of lipids and lipoproteins in obese patients with NIDDM.. Sixteen obese NIDDM patients were studied in a free-living outpatient regimen. After a run-in period, the patients received three different isocaloric diets for 6 weeks using a randomized crossover design. The patients were instructed to keep the energy intake from carbohydrate and protein constant at 50 and 20 E% (percent of energy intake), respectively, on all three diets. The fat composition of the diets differed: saturated fat (SAT) diet (20 E% SFAs, 5 E% polyunsaturated fatty acids [PUFAs], and 5 E% monounsaturated fatty acids [MUFAs]) versus cis monounsaturated fatty acid (CMUFA) diet (20 E% cis-MUFAs, 5 E% PUFAs, and 5 E% SFAs) versus trans monounsaturated fatty acid (TMUFA) diet (20 E% trans-MUFAs, 5 E% PUFAs, and 5 E% SFAs). Fasting serum levels of lipids and lipoproteins were measured at baseline and in the fasting state before meal tolerance tests at the end of each study period. Insulin secretion was assessed from incremental serum insulin and C-peptide responses during the meal tests.. BMI, waist-to-hip ratio, and glycemic control remained stable throughout the study. After meal stimulation, postprandial glycemic responses were similar on all diets; however, serum insulin and C-peptide responses were greater following the TMUFA and SAT diets than following the baseline or CMUFA diets (P < 0.05). No statistical difference was found in fasting levels of serum lipids (total cholesterol, triglyceride, phospholipid, and nonesterified fatty acids) or lipoproteins of HDL cholesterol, VLDL cholesterol, LDL cholesterol, and apolipoprotein B between diets.. In the presence of unchanged glycemia, both dietary trans fatty acids and SFAs induce an increase in postprandial insulinemia in obese patients with NIDDM.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Humans; Insulin; Insulin Secretion; Lipids; Lipoproteins; Male; Middle Aged; Obesity; Postmenopause; Random Allocation; Time Factors

This study compared the effect of mild exercise while fasting on plasma glucose concentrations in subjects with NIDDM treated with extended-release glipizide and subjects not taking an oral hypoglycemic agent.. Twenty-five moderately obese subjects with NIDDM were randomized to treatment with extended-release glipizide or placebo. After 9 weeks of treatment, they fasted overnight, took their study drug, omitted breakfast, and exercised on a treadmill for 90 min. Glucose, insulin, and C-peptide concentrations were measured before, during, and after exercise.. On the fasting-exercise day, fasting glucose concentrations were lower (153 vs. 241 mg/dl, P < 0.01) and insulin and C-peptide concentrations higher in the extended-release glipizide group. The decrement of glucose from the fasting baseline was modest and equivalent in the two groups: 17 vs. 21 mg/dl at the end of exercise and 28 vs. 27 mg/dl after 2 h of recovery. No subject had hypoglycemic symptoms.. Chronic use of extended-release glipizide does not enhance the hypoglycemic effect of fasting plus mild exercise for people with NIDDM. Routine lifestyle treatments for NIDDM may be continued during ongoing use of this agent.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise; Exercise Test; Female; Glipizide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Time Factors

To investigate the metabolic effects and frequency of adverse events with 6 mg of glimepiride, a new oral sulfonylurea, given both in once- and twice-daily dosages to patients with non-insulin-dependent diabetes mellitus (NIDDM).. This 15-week study involved 161 subjects with NIDDM. Subjects were randomized into two groups. For 4 weeks, group 1 received glimepiride 3 mg twice daily, and group 2 received glimepiride 6 mg once daily. After a 3-week placebo-washout period, twice- and once-daily regimens were crossed over for a second 4-week treatment period. Subjects were hospitalized at the end of each placebo or active-treatment phase. Their glucose concentrations were recorded at 20 time points over a 24-hour period, and their insulin and C-peptide concentrations were recorded at 16 time points over the same period. Parameters that were calculated included fasting, 24-hour, and postprandial concentrations of glucose, insulin, and C-peptide.. One hundred six patients were randomized to receive treatment; 94 completed the entire study. Existing physiologic mechanisms of glucose control were apparently unimpaired by glimepiride treatment. Insulin concentrations increased more during the postprandial glucose peaks than when subjects were fasting. Both twice- and once-daily regimens proved equally effective in reducing concentrations of fasting, postbreakfast, postlunch, and postdinner plasma glucose. Twenty-four-hour mean glucose concentrations showed a slightly greater decrease from baseline for the twice-daily regimen; the difference between the regimens was statistically significant but not clinically meaningful. The incidence of adverse events with glimepiride approximated that obtained with placebo, with both groups reporting only one adverse event, headache, in more than 5% of the subjects.. Glimepiride is equally effective whether administered once or twice daily. Glimepiride seems to stimulate insulin production primarily after meals, when plasma glucose concentrations are highest, but controls blood glucose throughout the day.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Postprandial Period; Sulfonylurea Compounds

In order to determine the influence of a 5 h infusion of pramlintide compared to placebo on postprandial glucose, lactate, insulin, and C-peptide concentrations in patients with Type 2 diabetes, a single-blind, randomized, cross-over study was conducted in 24 patients; 12 treated with exogenous insulin and 12 managed with diet and/or oral hypoglycaemic agents. One hour after initiation of infusion, patients consumed a Sustacal test meal. The protocol was repeated on the following day with each patient receiving the alternate study medication. Pramlintide infusion in the insulin-treated patients resulted in statistically significant reductions in mean glucose, insulin, C-peptide, and lactate concentrations during the 4-h period after the Sustacal test meal. Pramlintide infusion also resulted in significant reductions of mean insulin, C-peptide, and lactate concentrations, but not glucose concentrations, in the patients treated with diet and/or oral hypoglycaemic agents. Within this latter group, reduction in postprandial glucose concentrations in individual patients correlated with glycated haemoglobin values. These results suggest that administration of pramlintide may improve glycaemic control in patients with Type 2 diabetes treated with insulin or poorly controlled on diet and/or oral hypoglycaemic agents.

Topics: Adult; Amyloid; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastrointestinal Diseases; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Lactic Acid; Male; Middle Aged; Postprandial Period; Single-Blind Method

The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia.

Topics: Administration, Oral; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Middle Aged; Pharmaceutical Preparations; Proinsulin; Sulfonylurea Compounds

We have studied the impact of liquid diets formulated for complete or supplemental enteral nutrition of type II, non insulin-dependent (NIDDM) diabetics on carbohydrate homeostasis. To achieve this, liquid formula tolerance tests were performed in NIDDM patients under an oral treatment regimen with a combination of diet plus glibenclamide (7 men, 3 women, age: 56 +/- 11 years; mean body mass index of 26.2 +/- 3.6 kg/m2). After an overnight fast, each patient received the usual morning medication and, thereafter, ingested formula diet in randomized order with 10 day intervals between tests. 500 ml were administered of either a standard liquid diet (Biosorb Sonde), a fibre containing diet (Biosorb Plus Sonde), or a carbohydrate modified, fructose containing "diabetes" diet (Fresubin Diabetes) (carbohydrate contents of approximately equal to 60 g, respectively). Blood samples were collected over 180 min. Considering minor variations in the nutritional values of the diets, IR-insulin, IR-C-peptide, IR-glucose-dependent insulinotropic polypeptide (GIP), and IR-glucagon-like peptide. 1 (GLP-1) in plasma did not significantly differ between the study groups. After ingestion of Biosorb Sonde area under the curve glucose was greater than that seen after uptake of fibre containing or carbohydrate modified, i.e. fructose containing "liquid diabetes diets". All diets challenged the entero-insular axis in non-insulin dependent diabetics to a comparable extent. This data does not support the contention to employ special "diabetes" formulas for enteral nutrition of patients with NIDDM.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Enteral Nutrition; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Peptides; Postprandial Period

We investigated how fasting or postprandial insulin levels were altered by treatment with acarbose or sulfonylureas. Plasma glucose and serum insulin, C-peptide, and proinsulin levels were measured before as well as 1 and 2 h after breakfast in 23 patients with non-insulin-dependent diabetes mellitus and 17 patients with impaired glucose tolerance. In the diabetic patients, 12 weeks of acarbose therapy decreased the postprandial levels of glucose (1 h: -60.0%; 2 h: -67.6%), insulin (1 h: -67.5%; 2 h: -72.2%) and proinsulin (1 h: -55.2%; 2 h: -46.7%), and proinsulin (1 h: -20.9%; 2 h: -57.5%). In contrast, sulfonylurea treatment increased postprandial insulin and proinsulin levels. Since increased in the serum insulin or proinsulin levels are associated with a higher risk of cardiovascular disease, the present findings suggest that the acarbose-induced reduction of the postprandial serum insulin or proinsulin responses to food intake might be useful for preventing vascular complications in patients with diabetes.

Topics: Acarbose; Aged; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Gliclazide; Glucose Intolerance; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Middle Aged; Postprandial Period; Proinsulin; Time Factors; Tolbutamide; Triglycerides; Trisaccharides

Oestrogen replacement therapy is associated with a decreased risk of cardiovascular disease in postmenopausal women. Patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased cardiovascular risk. However, oestrogen replacement therapy is only reluctantly prescribed for patients with NIDDM. In a double blind randomized placebo controlled trial we assessed the effect of oral 17 beta-estradiol during 6 weeks in 40 postmenopausal women with NIDDM. Glycated haemoglobin (HbA1c), insulin sensitivity, suppressibility of hepatic glucose production, lipoprotein profile and parameters of fibrinolysis were determined. The oestrogen treated group demonstrated a significant decrease of HbA1c and in the normotriglyceridaemic group a significantly increased suppression of hepatic glucose production by insulin. Whole body glucose uptake and concentrations of non-esterified fatty acids did not change. LDL-cholesterol- and apolipoprotein B levels decreased, and HDL-cholesterol, its subfraction HDL2-cholesterol and apolipotrotein A1 increased. The plasma triglyceride level remained similar in both groups. Both the concentration of plasminogen activator inhibitor-1 antigen and its active subfraction decreased. Tissue type plasminogen activator activity increased significantly only in the normotriglyceridaemic group. Oestrogen replacement therapy improves insulin sensitivity in liver, glycaemic control, lipoprotein profile and fibrinolysis in postmenopausal women with NIDDM. For a definite answer as to whether oestrogens can be more liberally used in NIDDM patients, long term studies including the effect of progestogens are necessary.

Topics: C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Estradiol; Estrogen Replacement Therapy; Fatty Acids, Nonesterified; Female; Fibrinolysis; Glycated Hemoglobin; Humans; Insulin Resistance; Lipids; Lipoproteins; Middle Aged; Plasminogen Activator Inhibitor 1; Postmenopause; Tissue Plasminogen Activator; Triglycerides

Abnormalities in free fatty acid (FFA) metabolism are an intrinsic feature of type II diabetes mellitus and may even play a role in the development of glycaemic imbalance. This study investigated whether the anti-diabetic drug metformin can reduce FFA levels in clinical practice and whether this correlates with its anti-diabetic effect. For 6 months metformin was added to sulfonylurea therapy in 68 type II diabetic outpatients with poor glycaemic control, being administered before meals and at bed-time. Basal and daily area-under-the-curve (AUC) glucose levels dropped (both P < 0.0005) like basal and daily AUC FFA levels (P < 0.004 and P < 0.001 respectively) reductions were all correlated (P < 0.001 and P < 0.003 respectively). Reductions in fasting and daily AUC glucose correlated more closely with body fat distribution, expressed by waist-hip ratio (WHR) (P < 0.006 and P < 0.004 respectively), than with the body mass index (BMI) (P < 0.02 and P < 0.04 respectively). Similarly fasting and daily AUC FFA correlated with WHR (P < 0.007 and P < 0.01 respectively) but not with BMI (both P = ns). Subdividing male and female diabetic patients into groups with low and high WHRs, fasting and daily AUC glucose were reduced in men (P < 0.01 and P < 0.02) and in women (P < 0.02 and P < 0.04 respectively) with low WHRs less than in men and in women with higher WHRs (for each gender P < 0.0001 and P < 0.0002, respectively). Decreases in fasting and daily AUC FFA, which did not reach significance in either men or women with low WHRs, were statistically significant in men (P < 0.03 and P < 0.01 respectively) and in women (P < 0.02 and P < 0.005 respectively) with high WHRs. These findings suggest that an improvement in FFA plasma levels might contribute to metformin's anti-diabetic activity which appears to be more marked in patients with high WHRs. Moreover adding a bed-time dosage to the standard administration at meal times seems to be an effective therapeutical strategy.

Topics: Blood Glucose; Body Constitution; Body Mass Index; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Fatty Acids, Nonesterified; Female; Gliclazide; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipoprotein(a); Male; Metformin; Middle Aged; Regression Analysis; Sex Characteristics

The present study was carried out to evaluate the effect of a low-dose intravenous supplementation of L-arginine on insulin-mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects (n = 7) and patients with obesity (n = 9) and non-insulin-dependent diabetes mellitus (NIDDM) (n = 9). Insulin-mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of L-arginine (0.52 mg kg-1 min-1). L-Arginine restored the imparied insulin-mediated vasodilatation observed in obesity (22.4 +/- 4.1%, P < 0.01 vs. without L-arginine) and NIDDM (20.3 +/- 3.2%, P < 0.01 vs. without L-arginine). In healthy subjects, no effect on insulin mediated-vasodilatation was observed (24.8 +/- 3.1% vs. 21.4 +/- 3.1%). Insulin sensitivity was improved significantly (P < 0.001) in all three groups by infusion of L-arginine. No effect of L-arginine was observed on insulin, insulin-like growth factor I (IGF-I), free fatty acids (FFAs) or C-peptide levels during the insulin suppression test. Our data indicate that defective insulin-mediated vasodilatation in obesity and NIDDM can be normalized by intravenous L-arginine. Furthermore, L-arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin-mediated vasodilatation.

Topics: Adult; Arginine; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids; Female; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Male; Middle Aged; Obesity; Vasodilation

1. The specific role of physical activity in the treatment of type 2 diabetes is still subject to discussion. A randomized prospective study was performed, investigating both the influence of physical training on metabolic control and the feasibility of physical training in the elderly. 2. A total of 58 patients (mean age: 62 +/- 5 years; range: 55-75 years) with type 2 diabetes were randomized to either a physical training or a control programme. The training programme consisted of three sessions a week, aiming at 60-80% of the maximal oxygen uptake (VO2max). The 12 week supervised period was followed by a 14 week non-supervised one. The control group followed an educational programme. VO2max was assessed during exercise on a cycle ergometer. Glycosylated haemoglobin (HbA1c) was used as a measure for glucose control, and an insulin tolerance test was performed to test insulin sensitivity. Multivariate analysis of variance, with repeated measures design, was used to test differences between groups. 3. Fifty-one patients completed the study. VO2max was higher in the training group than in the control group both after 6 weeks (P < or = 0.01 between groups) and after 26 weeks [training group: 1796 +/- 419 ml/min (prestudy), 1880 +/- 458 ml/min (6 weeks), 1786 +/- 591 ml/min (26 weeks); control group: 1859 +/- 455 ml/min (prestudy), 1742 +/- 467 ml/min (6 weeks), 1629 +/- 504 ml/min (26 weeks)]. Blood glucose control and insulin sensitivity did not change during the study. Levels of total triacylglycerols, very-low-density lipoprotein-triacylglycerols and apolipoprotein B were significantly lower after 6 weeks (P < or = 0.01, P < or = 0.05, P < or = 0.05 between groups respectively), and so was the level of total cholesterol after 12 weeks of training (P < or = 0.05 between groups). 4. Physical training in obese type 2 diabetic patients over 55 years of age does not change glycaemic control or insulin sensitivity in the short-term. Regular physical activity may lower triacylglycerol and cholesterol levels in this group of patients. 5. Finally, physical training in motivated elderly type 2 diabetic patients without major cardiovascular or musculoskeletal disorders is feasible, but only under supervision.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Exercise Therapy; Feasibility Studies; Female; Glycated Hemoglobin; Humans; Insulin; Lipid Metabolism; Male; Middle Aged; Oxygen Consumption

We student basal, glucose- and glucagon-induced insulin secretion in non-insulin diabetes mellitus (NIDDM) patients in relation to body mass index (BMI) and fasting serum glucose (FBS) level. A total of 46 NIDDM patients and 22 control subjects with varying degrees of BMI and FBS were given 100 g of oral glucose and 1 mg of intravenous glucagon on separate days. C-peptide response to glucose, but not basal serum C-peptide and C-peptide response to glucagon, was significantly lower in NIDDM than in controls (P < 0.001). FBS was inversely correlated with C-peptide response to glucose in NIDDM patients (r = -0.67, P < 0.001), but not with basal C-peptide level and C-peptide response to glucagon. On the other hand, BMI was positively correlated with basal serum C-peptide level both in NIDDM (r = 0.60, P < 0.001) and in control subjects (r = 0.74, P < 0.001). In 15 poorly controlled NIDDM patients, the tests were repeated after insulin treatment for 10-14 days. C-peptide response to glucose significantly increase, but not to a level in control subjects, after glycemic control. Basal serum C-peptide level and the C-peptide response to glucagon decreased after glycemic control to significantly lower levels than those in the baseline and those in control subjects. These results suggest that beta cell secretory reserve is reduced in moderate to severe NIDDM patients.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Cohort Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Glucose; Glucose Tolerance Test; Humans; Injections, Intravenous; Injections, Subcutaneous; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Reference Values

Subjects with NIDDM have increased plasma proinsulin concentrations, compared with nondiabetic subjects, both in absolute terms and as a proportion of circulating insulin-like molecules. It remains uncertain whether this reflects a primary beta-cell defect in proinsulin processing or is secondary to hyperglycemia. We addressed this question by assessing the effects of reducing hyperglycemia on relative hyperproinsulinemia in subjects with NIDDM. Eight subjects with NIDDM underwent three 8-week periods in a randomized crossover design of therapy with diet alone, sulfonylurea (gliclazide), or insulin (ultralente). The effects on beta-cell peptide concentrations were assessed 1) fasting, 2) in response to hyperglycemic clamping, and 3) in response to an injection of the nonglucose secretogogue arginine and compared with measurements in seven nondiabetic control subjects. Both sulfonylurea and insulin therapy substantially reduced fasting plasma glucose and glycosylated hemoglobin (HbA1e) concentrations, compared with diet therapy alone. The diabetic subjects on diet therapy had relative hyperproinsulinemia, assessed relative to C-peptide concentrations, fasting and in response to hyperglycemic clamping and arginine, compared with control subjects. Neither sulfonylurea nor insulin therapy altered the relative hyperproinsulinemia. Insulin therapy reduced fasting proinsulin concentrations from geometric mean 29.4 (1 SD range, 14.6-59.0) pmol/l on diet therapy to 18.7 (7.3-48.1) pmol/l (P < 0.05). A similar trend was evident with fasting C-peptide concentrations with a reduction from 0.9 (0.6-1.4) nmol/l on diet therapy to 0.6 (0.4-0.9) nmol/l (P = 0.06), so that the relative hyperproinsulinemia, assessed as the ratio of fasting proinsulin to C-peptide, was unchanged by insulin. Similarly, insulin therapy failed to reduce the ratio of proinsulin to C-peptide concentrations in response to a hyperglycemic clamp and in the acute incremental response to arginine. Failure to improve the relative hyperproinsulinemia of NIDDM, despite significant reduction of hyperglycemia with exogenous insulin therapy, supports the hypothesis that relative hyperproinsulinemia in NIDDM is a reflection of a primary beta-cell defect rather than being secondary to hyperglycemia.

Topics: Adult; Aged; Arginine; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Fasting; Gliclazide; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Proinsulin

Insulin lispro is a rapid-acting analog of human insulin that can be used to target the postprandial rise in plasma glucose. We designed an open-label randomized crossover study of type 2 diabetic patients with secondary failure of sulfonylurea therapy to determine whether improvement of postprandial hyperglycemia would affect total daily glucose control.. Twenty-five type 2 diabetic patients who were poorly controlled on a maximum dose of sulfonylureas were studied in a university hospital clinical research center. In one arm of the study, patients continued therapy with maximum-dose sulfonylureas. In the other arm, patients used a combination therapy with insulin lispro before meals and sulfonylureas. After 4 months, patients were crossed over to the opposite arm. Fasting plasma glucose (FPG) and 1- and 2-h postprandial glucose (after a standardized meal), HbA1c, total, HDL, and LDL cholesterol, and triglyceride levels were measured at the end of each arm of the study.. Insulin lispro in combination with sulfonylurea therapy significantly reduced 2-h postprandial glucose concentrations compared with sulfonylureas alone, from 18.6 to 14.2 mmol/l (P < 0.0001), and incremental postprandial glucose area from 617.8 to 472.9 mmol.min.1-1 (P < 0.0007). FPG levels were decreased from 10.9 to 8.5 mmol/l (P < 0.0001), and HbA1c values were reduced form 9.0 to 7.1% (P < 0.0001). Total cholesterol was significantly decreased in the lispro arm from 5.44 to 5.10 mmol/l (P < 0.02). HDL cholesterol concentrations were increased in the lispro arm from 0.88 to 0.96 mmol/l (P < 0.01). The patients weighed significantly more after lispro therapy than after sulfonylureas alone, but the difference was small in absolute terms (sulfonylurea therapy alone, 90.6 kg; lispro therapy, 93.8 kg; P < 0.0001). Two episodes of hypoglycemia (glucose concentrations, < 2.8 mmol/l) were reported by the patients while using lispro.. Previously, it has not been possible to address the effect of treatment of postprandial hyperglycemia specifically. We have now shown that the treatment of postprandial hyperglycemia with insulin lispro markedly improves overall glucose control and some lipid parameters in patients with type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Lispro; Male; Middle Aged; Postprandial Period; Sulfonylurea Compounds; Triglycerides

Some non-insulin-dependent diabetes mellitus (NIDDM) patients are positive for antibodies to glutamic acid decarboxylase (anti-GAD), and they tend to develop insulin deficiency. The aim of this study was to evaluate the prevalence of anti-GAD in NIDDM with secondary failure of sulfonylurea agents (NIDDM-SF) and to investigate the diagnostic significance of seropositivity for anti-GAD in NIDDM-SF patients by evaluating human leukocyte antigen (HLA)-DRB1 alleles concurrently. The prevalence of anti-GAD in NIDDM-SF, NIDDM, and new-onset (within 1 year after onset) insulin-dependent diabetes mellitus (IDDM) was 9.3% (39/420), 3.1% (12/392), and 65.0% (13/20), respectively. Pancreatic beta cell function deteriorated in NIDDM-SF patients positive for anti-GAD. HLA-DRB1 allele typing revealed that NIDDM-SF patients positive for anti-GAD were significantly associated with DRB1*0901 (RR = 2.81, P < 0.01), which is one of the susceptible alleles to IDDM. Shorter interval before development of secondary failure and insulin deficiency were significantly associated with the presence of DRB1*0901 (P < 0.05) in NIDDM-SF patients positive for anti-GAD. In conclusion, nearly 10% of NIDDM-SF patients are positive for anti-GAD, suggesting that an autoimmune mechanism might play an important role in the pathogenesis of NIDDM-SF patients. In addition, a combination of serological marker (anti-GAD) and genetic marker (HLA-DRB1) is useful for predicting clinical course of NIDDM patients with secondary failure of sulfonylurea agents.

Topics: Adolescent; Adult; Aged; Alleles; Antibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Hypoglycemic Agents; Male; Middle Aged; Sulfonylurea Compounds; Treatment Failure

Drinking alcohol is associated with a recognised risk of hypoglycaemia. This double-blind, placebo-controlled study was designed to determine whether alcohol taken with the evening meal alters the gluco-regulatory response to troglitazone, (TR), an insulin action enhancer, in non-insulin-dependent diabetes mellitus (NIDDM) subjects to increase the risk of hypoglycaemia. In vitro studies conducted prior to the clinical study presented here showed no evidence of a pharmacokinetic interaction between the two drugs. A total of 23, diet-treated, NIDDM subjects received either TR, 200 mg once daily (n = 11) or placebo (PL) (n = 12) for 45 days. On days 42 and 45 subjects were given, on separate days, an alcohol challenge (AC), 0.6 mg/kg ethanol in orange juice and a control challenge, CC, orange juice alone, with the evening meal. Serum glucose, insulin, proinsulin-like molecules, C-peptide and lipids were measured during the study, for the 4 h after each challenge and the following morning (fasting). The over-night urine cortisol/creatinine ratio (an index of hypoglycaemia) was also determined. For the TR treated group, fasting serum glucose the next morning (adjusted geometric mean: 6.8 mmol/l for AC) and weighted mean were not statistically significantly different following AC compared to CC. Mean trough glucose for TR after the evening meal was 5.7 mmol/l following both the AC and CC. Analysis of the other parameters showed no symptomatic or pharmacodynamic evidence of an acute interaction between TR and alcohol. It can be concluded that occasional drinking of alcohol, with a meal, by TR-treated NIDDM patients is unlikely to be associated with an increased risk of hypoglycaemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chromans; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Ethanol; Fasting; Female; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Proinsulin; Thiazoles; Thiazolidinediones; Troglitazone

It has previously been shown that in normal subjects, physiological elevation of norepinephrine (NE) impairs insulin sensitivity (Si) but does not influence insulin secretion. The aim of this study was to determine the effect of short-term physiological elevation of NE on insulin secretion, Si, and glucose-mediated glucose disposal, or the glucose effectiveness index (Sg), in non-insulin-dependent diabetes mellitus (NIDDM). Two intravenous glucose tolerance tests (IVGTTs) were performed in eight well-controlled NIDDM patients, using a supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. The IVGTTs were performed in random order after 30 minutes of either the saline (SAL) or NE (25 ng/kg/min) infusions, which were continued throughout the 3-hour IVGTT. Sg and Si were estimated by minimal model analysis of the IVGTT data as previously described. Plasma C-peptide was used to estimate insulin secretion rate using the ISEC program. NE infusion produced approximately a threefold increase in plasma NE, associated with (1) a significant reduction in glucose disposal ([KG] SAL v NE, 0.73 +/- 0.06 v 0.61 +/- 0.06 x 10(-2).min-1, P < .05), (2) no reduction in Si (2.33 +/- 0.8 v 2.62 +/- 0.9 x 10(-4).min-1/mU/L, NS), (3) a reduced mean second-phase insulin secretion rate (1.21 +/- 0.19 v 1.01 +/- 0.16 x 10(-3) pmol/kg/min per mmol/L glucose, P < .05), (4) a significant increase in Sg (0.89 +/- 0.08 v 1.63 +/- 0.2 x 10(-2).min-1, P < .05), and (5) a corresponding increase in glucose effectiveness at zero insulin ([GEZI] 0.55 +/- 0.13 v 1.30 +/- 0.33 x 10(-2).min-1, P < .05). These results show that in contrast to normal subjects, physiological elevation of NE in NIDDM does not result in a reduction in Si, but causes a reduction in glucose disposal related to inhibition of insulin secretion that is only partially compensated for by increased Sg.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Catecholamines; Computer Simulation; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Models, Biological; Neurotransmitter Agents; Norepinephrine; Time Factors

Sulfonylureas stimulate insulin secretion as their predominant contribution toward decreasing blood glucose in diabetic patients. We studied eight gliclazide-treated, non-insulin-dependent diabetic patients on two occasions with a protocol of basal observation for 30 minutes, a 60-minute infusion of randomized leucine or arginine, and a further 90-minute hyperglycemic clamp. Basal glucose was the same on both occasions (mean, 7.82 mmol/L for leucine v 7.79 for arginine, P = NS), and glucose levels declined to 7.50 and 7.25 mmol/L, respectively, by 30 minutes. After leucine infusion, the decline of glucose continued, but stabilized or reversed with arginine such that by the end of the infusions, glucose levels were 6.63 +/- 0.69 mmol/L for leucine and 7.62 +/- 0.67 for arginine (P < .02). Arginine caused a sharp increase in insulin secretion (from 17.8 mU/L to 43.8 mU/L in 6 minutes) at the onset of the infusion, and thereafter insulin secretion was not significantly different throughout either the amino acid or hyperglycemic clamp periods (mean, 42.1 v 44.7 mU/L, respectively, P = NS). By contrast, the leucine infusion caused little acute change in secretion, but augmented it with time from the basal period (17.2 mU/L) to the end of the infusion (29.4 mU/L). During the hyperglycemic clamp period, there was significant further augmentation of insulin secretion, increasing to 81.6 +/- 16 mU/L at the end of the study. Leucine significantly augmented insulin secretion compared with arginine (81.6 +/- 16 v 54.0 +/- 8.4 mU/L, respectively, P < .002). These data suggest that leucine is a better priming agent for sulfonylurea than arginine. Additive effects on insulin secretion may allow the use of combinations of branched chain amino acids (BCAAs) and sulfonylureas to augment insulin secretion in the presence of hyperglycemia.

Topics: Aged; Arginine; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Female; Gliclazide; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Secretion; Leucine; Male; Middle Aged; Time Factors

We studied the effects of continuous subcutaneous infusion of octreotide (100 micrograms/day for 5 days) on glycaemic values, counterregulatory hormones secretion, hepatic glucose production (HGP) and glucose disposal during an euglycaemic clamp in 7 C-peptide-negative type 1 diabetic patients and 7 C-peptide positive insulin-treated type 2 diabetic patients. In type 1, but not type 2 diabetic patients, octreotide significantly reduced glycaemic values (P < 0.005) and also diminished HGP during an euglycaemic clamp (P < 0.05). However, insulin stimulated global glucose uptake remained unchanged. GH, glucagon, IGF-I, IGFBP-3 levels, were significantly lowered by octreotide in both type 1 and type 2 diabetic patients whereas cortisol and epinephrine remained unmodified. Moreover in type 2 diabetic patients both basal (P < 0.05) and after-meal (P < 0.01) C-peptide secretion was reduced by octreotide. These data point to different metabolic effects of octreotide in type 1 versus type 2 diabetic patients with the drug only being able to reduce glycaemic values and HGP in the former but not in the latter subjects. The failure of octreotide to diminish glycaemic values and HGP in type 2 diabetic patients in spite of its ability to lower GH and glucagon may probably depend on temporary blockage of residual endogenous insulin secretion induced by octreotide administration.

Topics: Adult; Antineoplastic Agents, Hormonal; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucose; Hormones; Humans; Hyperglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Liver; Male; Middle Aged; Octreotide

Seventeen diabetic patients (5 males and 12 females) treated with long-term metformin therapy received their morning dose after an overnight fast or after one of four types of breakfast: low protein, low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the maximum concentrations (tmax) were calculated for the major biological parameters (glycemia, C-peptide, insulin and glucagon levels). None of the diets were bioequivalent to the fasting condition and only the low carbohydrate diet gave comparable results. A strong relationship was found between the carbohydrate intake (in g) and the AUC of the various markers except glucagon.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet; Female; Glucagon; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged

To determine whether high-ketogenic very-low-energy diets (VLEDs) can reduce hepatic glucose output (HGO) and hyperglycemia more effectively than can low-ketogenic VLEDs in obese patients with non-insulin-dependent diabetes mellitus (NIDDM), seven patients were treated with a high-ketogenic VLED for 3 wk and were compared with six patients treated with a low-ketogenic VLED. All patients were then crossed over and treated with the alternate diet for another 3 wk. Basal HGO, fasting ketone bodies, and glycemia, insulin, and C-peptide after fasting and an oral-glucose-tolerance test (OGTT) were measured. Before treatment, prediet weight and fasting, OGTT, and HGO measurements were not different between groups. After dieting, weight loss was not different between the groups. However, fasting and OGTT glycemia were lower during treatment with the high-ketogenic VLED than with the low-ketogenic VLED (treatment effect: P < 0.05, by analysis of variance). Moreover, there was a strong correlation between basal HGO and fasting plasma ketone bodies (r = -0.71 at 3 wk, r = -0.67 at 6 wk; both P < 0.05). In contrast, fasting and OGTT plasma insulin and C-peptide concentrations were not different between treatment groups. These data indicate that in obese patients with NIDDM, high-ketogenic VLEDs have a more clinically favorable effect on glycemia than do low-ketogenic VLEDs.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet, Reducing; Energy Metabolism; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Ketone Bodies; Ketosis; Liver; Male; Middle Aged; Obesity

Adherence to a low-calorie diet often results in a decrease in blood glucose concentration in persons with non-insulin-dependent diabetes mellitus (NIDDM). Whether this is due to the resultant weight loss or to a decrease in caloric intake has been uncertain. We have obtained data previously that indicated a very short-term reduction in caloric intake (5 hours) resulted in a significant decrease in plasma glucose concentration in subjects with NIDDM. The purpose of the present study was to determine if a further decrease in glucose would occur if the fast was extended from 5 to 24 hours. Seven male subjects with untreated NIDDM were studied after an 11-hour overnight fast. For the subsequent 24-hour period, subjects were given only water. Blood was obtained for glucose, insulin, C-peptide, triglycerides, nonesterified fatty acids (NEFA) alpha-amino acid nitrogen, urea nitrogen, and glucagon at hourly intervals for 24 hours beginning at 8 AM. The amount of glycogen degraded was calculated based on the potassium balance. Plasma glucose decreased from 158 mg/dL at 8 AM to a nadir of 104 mg/dL at 7 PM. It then increased by 30 mg/dL. Corresponding changes occurred in insulin and C-peptide. Serum glucagon remained unchanged. Serum alpha-amino acid nitrogen and urea nitrogen decreased. Triglycerides and NEFA increased. The calculated glycogen utilized over this period was approximately 167 g. This would provide approximately 700 kcal energy. The elevated blood glucose concentration in mild to moderately severe untreated NIDDM subjects was normalized following short-term fasting. Plasma insulin concentrations also decreased to within normal limits. These decreases were highly significant. Glycogenolysis is an important source of fuel during this period.

Topics: Aged; Blood Glucose; Blood Urea Nitrogen; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Insulin; Male; Middle Aged; Nitrogen; Starvation; Time Factors; Triglycerides

Although moderate weight loss improves glycemic control in obese NIDDM patients, quite often it is not normalized. To determine whether the response to weight loss can be improved by altering the macronutrient composition of hypocaloric diets, 17 obese NIDDM patients were studied at I) baseline, 2) after dieting for 6 weeks on a formula diet enriched in either monounsaturated fatty acids (MUFAs, n = 9) or carbohydrates (CHOs, n = 8) at a 50% caloric deficit, and 3) after 4 weeks of postdiet refeeding on the respective formulas with caloric intake titrated to achieve weight maintenance. Fasting, 24-h, and oral glucose tolerance test (OGTT) blood glucose, plasma insulin, and C-peptide levels were measured. All prediet parameters were similar between groups. After dieting, although weight loss was similar between groups, the fasting glucose level decreased significantly more in the MUFA group (-4.6 +/- 0.7 mmol/l) than in the CHO group (-2.4 +/- 1.0 mmol/l; P < 0.05). Twenty-four-hour glycemia decreased in both groups after dieting, but the MUFA group had a greater decrease than the CHO group (P < 0.05, analysis of variance [ANOVA]). Although decreases in fasting glycemia were maintained in both groups after refeeding, postprandial glycemia deteriorated after refeeding with the CHO- but not the MUFA-enriched formula (P < 0.05). After dieting and refeeding, fasting C-peptide increased 204 +/- 47 pmol/l in the MUFA group, but the CHO group remained at prediet levels (P < 0.05). Twenty-four-hour C-peptide levels were similar between groups after dieting and refeeding, despite the lower glycemia and CHO content of the MUFA formula. However, when equal amounts of CHO were consumed during the OGTT, the MUFA group had significantly higher C-peptide levels after both dieting and refeeding (P < 0.05). Fasting, 24-h, and OGTT insulin levels were similar between groups throughout the study. These results indicate that macronutrient composition is an important determinant of the glycemic response to weight-loss therapy in obese NIDDM patients. Based on the C-peptide response during the OGTT, increased CHO-induced insulin secretion is one possible mechanism by which this occurs.

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Combined Modality Therapy; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Dietary Carbohydrates; Dietary Fats; Fatty Acids, Monounsaturated; Female; Glucagon; Humans; Insulin; Male; Middle Aged; Obesity; Time Factors; Triglycerides; Weight Loss

Glucagon-like peptide I(7-36) amide (GLP-1) is a physiological incretin hormone that, in slightly supraphysiological doses, stimulates insulin secretion, lowers glucagon concentrations, and thereby normalizes elevated fasting plasma glucose concentrations in type II diabetic patients. It is not known whether GLP-1 has effects also in fasting type I diabetic patients.. In 11 type I diabetic patients (HbA1c 9.1 +/- 2.1%; normal, 4.2-6.3%), fasting hyperglycemia was provoked by halving their usual evening NPH insulin dose. In random order on two occasions, 1.2 pmol . kg-1 . min-1 GLP-1 or placebo was infused intravenously in the morning (plasma glucose 13.7 +/- 0.9 mmol/l; plasma insulin 26 +/- 4 pmol/l). Glucose (glucose oxidase method), insulin, C-peptide, glucagon, GLP-1, cortisol, growth hormone (immunoassays), triglycerides, cholesterol, and nonesterified fatty acids (enzymatic tests) were measured.. Glucagon was reduced from approximately 8 to 4 pmol/l, and plasma glucose was lowered from 13.4 +/- 1.0 to 10.0 +/- 1.2 mmol/l with GLP-1 administration (plasma concentrations approximately 100 pmol, P < 0.0001), but not with placebo (14.2 +/- 0.7 to 13.2 +/- 1.0). Transiently, C-peptide was stimulated from basal 0.09 +/- 0.02 to 0.19 +/- 0.06 nmol/l by GLP-1 (P < 0.0001), but not by placebo (0.07 +/- 0.02 to 0.07 +/- 0.02). There was no significant effect on nonesterified fatty acids (P = 0.34), triglycerides (P = 0.57), cholesterol (P = 0.64), cortisol (P = 0.40), or growth hormone (P = 0.53).. Therefore, exogenous GLP-1 is able to lower fasting glycemia also in type I diabetic patients, mainly by reducing glucagon concentrations. However, this alone is not sufficient to normalize fasting plasma glucose concentrations, as was previously observed in type II diabetic patients, in whom insulin secretion (C-peptide response) was stimulated 20-fold.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Peptide Fragments; Protein Precursors; Time Factors

To examine the usefulness of alpha-glucosidase inhibitors in glycemic control of patients with NIDDM. The involvement of carbohydrate ingestion in manifestation of the effects of alpha-glucosidase inhibitors was also investigated.. A total of 41 patients hospitalized with NIDDM (22 patients receiving sulfonylurea and 19 receiving insulin therapy) were given alpha-glucosidase inhibitors during the period when their blood glucose levels were well controlled. They were followed for 3 weeks as inpatients and for an additional 6 months as outpatients. They were retrospectively divided into two groups according to the percentage of carbohydrates in all sources of calories during outpatient management: the < 50% group and the > 50% group. Between these two groups, we compared circadian variation in blood glucose levels, HbA1c, and urine C-peptide.. Treatment with alpha-glucosidase inhibitors during the hospital stay markedly improved circadian variation in blood glucose levels and HbA1c and decreased urine C-peptide in both groups. While HbA1c returned to its pretreatment level at 6 months after the treatment in the < 50% group, HbA1c had further improved in the > 50% group at 6 months.. alpha-Glucosidase inhibitors are useful for glycemic control in patients with NIDDM and the percentage of carbohydrate in all calorie sources is an important factor for the expression of their effects.

Topics: Biomarkers; Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Energy Intake; Enzyme Inhibitors; Follow-Up Studies; Glyburide; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Inpatients; Insulin; Middle Aged; Regression Analysis; Retrospective Studies; Sulfonylurea Compounds; Tolbutamide

To investigate the effect of insulin on cholesterol synthesis in vivo we measured plasma mevalonic acid (MVA) concentrations using gas chromatography-mass spectrometry in six non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM) [four men, two women; age 57.5 +/- 2.2 years (mean +/- SEM); glycated haemoglobin (HbA1) 8.5 +/- 0.5%; total cholesterol (TC) 5.7 +/- 0.5 mmol L-1, triglyceride (TG) 3.8 +/- 0.9 mmol L-1] and six non-diabetic, sex- and age-matched control subjects (age 55.7 +/- 2.8 years; HbA1 6.5 +/- 0.1%; TC 5.4 +/- 0.3 mmol L-1, TG 1.2 +/- 0.1 mmol L-1). Subjects were studied twice: during 13-h hyperinsulinaemic (1 mu kg-1 min-1), euglycaemic (5 mmol L-1) clamp and during a saline infusion. Baseline MVA concentration was significantly higher in diabetic patients than in control subjects (9.8 +/- 0.7 ng mL-1 vs. 5.6 +/- 0.9 ng mL-1, P = 0.004). At the end of each study, MVA concentration, expressed as a percentage of baseline, was significantly lower during the hyperinsulinaemic, euglycaemic clamp than during the saline study in both the diabetic (54.4 +/- 5.3% vs. 69.6 +/- 6.3%, P = 0.036) and control subjects (30.5 +/- 3.4% vs. 61.7 +/- 6.0%, P = 0.01). However, the decrease in MVA during the hyperinsulinaemic clamp study was more marked in the control subjects than in the diabetic subjects (P = 0.03). A significant positive correlation was found between percentage decrease of MVA and non-esterified fatty acids following the insulin clamp in NIDDM (r = 0.83, P = 0.04). We conclude that acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with NIDDM than in non-diabetic subjects and that this phenomenon, together with increased basal cholesterol synthesis in NIDDM, may in part be due to insulin resistance.

Topics: Analysis of Variance; Apolipoproteins E; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Gas Chromatography-Mass Spectrometry; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Male; Mevalonic Acid; Middle Aged; Phenotype; Random Allocation; Reference Values; Triglycerides

The aim of this study was to compare the metabolic effects of a combination of daytime glibenclamide and evening NPH insulin with intensive insulin treatment (rapid acting insulin before meals and NPH insulin at bedtime) in patients exhibiting secondary failure to sulphonylurea treatment. Thirty-nine mildly obese NIDDM patients (BMI 25.6 +/- 0.5) were randomized after 6 weeks of intensive insulin treatment to either a combination treatment (CT, n = 20) or continued intensive insulin treatment (IT, n = 19). There were no differences between the two groups in age, diabetes duration, BMI, HbA1c, or basal and glucagon stimulated C-peptide. The patients were followed for 1 year and the findings were analysed on an intent to treat basis. Two patients in the CT group were excluded after 2 and 6 months, respectively, due to unacceptably high postprandial glucose values. There was a significant difference in HbA1c between the CT and IT groups at 6 months (8.2 +/- 0.2, n = 19, vs 6.8 +/- 0.4%, n = 19, p < 0.001)), but not at 12 months (7.8 +/- 0.3, n = 18, vs 7.5 +/- 0.4%, n = 19). After the initial intensive insulin treatment, BMI was constant in the CT group but increased significantly at 6 and 12 months in the IT group. We conclude that both treatments are associated with a marked and long-term improvement of glycaemic control. The intensive insulin treatment leads to a more pronounced weight increase which in the long run might have negative effect on overall metabolic control. Therefore, the combination treatment together with intensified education and dietary advice should be regarded as the initial treatment of choice for oral agent failure in moderately obese NIDDM patients.

Topics: Aged; Albuminuria; Analysis of Variance; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin, Isophane; Insulin, Regular, Pork; Male; Metformin; Middle Aged; Sulfonylurea Compounds; Treatment Failure; Triglycerides

To determine the influence of age on the pharmacokinetics and pharmacodynamics of glyburide after acute and chronic dosing in young and elderly subjects with non-insulin-dependent diabetes mellitus.. Ten elderly (mean age 69.3 +/- 3.1 y) and 10 younger (mean age 45.6 +/- 4.5 y) patients received a glucose challenge test at baseline, with a 2.5-mg dose of glyburide at week 0 (acute dose) and again at weeks 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated to a maximum daily dosage of 20 mg to achieve a glucose concentration of 7.8 mmol/L or less. During 24-h pharmacokinetic determinations at weeks 0, 6, and 12, serial blood samples were obtained for glyburide determination with HPLC. Serial blood samples for glucose, insulin, and C-peptide determinations were obtained at baseline (week -1) and at weeks 0, 6, and 12.. All pharmacokinetic parameters assessed for glyburide were statistically comparable between the two age groups with the exception of a shorter time to peak concentration in the elderly at weeks 0 and 12. The glucose pharmacodynamic response to glyburide was not statistically different between the two groups. However, there was a statistically significant greater C-peptide response in the elderly group at all evaluation weeks.. Aging appears to have no influence on the pharmacokinetics of glyburide. Observed pharmacodynamic differences indicate the necessity for dosage titration to a specified therapeutic response regardless of patient age.

Topics: Adult; Aged; Aging; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glyburide; Half-Life; Humans; Insulin; Male; Middle Aged; Multivariate Analysis

To compare the effects of acarbose or metformin treatment used as an adjunct with a sulfonylurea agent in the treatment of NIDDM not adequately controlled with the use of a sulfonylurea agent alone.. Of the poorly controlled female NIDDM patients on sulfonylurea treatment, 18 were randomly selected from the outpatient diabetic clinic for study. For 8 weeks, they received either acarbose (300 mg/daily) or metformin (1,500 mg/daily) in addition to sulfonylurea in a crossover design using a 3-week washout period between treatments. The efficacy of each drug regimen was assessed by measuring the levels of glycosylated hemoglobin, fasting and 2-h postprandial blood glucose (PPBG) levels, cholesterol, triglyceride, and fibrinogen levels before and after 8 weeks of therapy.. The metabolic parameters measured before initiation of either treatment regimen were similar. Mean fasting and 2-h postprandial glucose levels were reduced moderately at the end of 8 weeks of both combination treatments (P < 0.05). Although the fasting and 2-h postprandial plasma insulin and C-peptide and fibrinogen levels at the end of the 8-week treatment periods were lower than those obtained at the beginning of the study, the differences between these values were not statistically significant. Cholesterol levels remained unchanged. Only the 2-h PPBG level in the group using acarbose plus a sulfonylurea was lower than the level achieved by the group using metformin plus a sulfonylurea (8.1 +/- 0.8 vs. 9.8 +/- 1.0 mmol/l, respectively, P < 0.05). The difference between pre- and posttreatment levels of the 2-h PPBG level in both arms of the study were statistically significant (delta-acarbose, 5.3 +/- 0.4 vs. delta-metformin, 2.9 +/- 0.3) (P < 0.05). Specific drug-associated side effects were observed in 12 patients on acarbose and 3 patients on metformin.. Acarbose or metformin can be used as effective adjuvant therapies with a sulfonylurea agent in NIDDM patients who are poorly controlled with the sulfonylurea agent alone.

Topics: Acarbose; Adult; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Sulfonylurea Compounds; Triglycerides; Trisaccharides

The effects of troglitazone, a novel thiazolidinedione, in non-insulin-dependent diabetic (NIDDM) patients were studied in a double-blind, parallel-group, placebo-controlled, dose-ranging trial. A total of 330 patients (63% male), mean age 57 years (range 39-72), with two fasting capillary blood glucose values > or = 7 and < or = 15 mmol/l (within 2.5 mmol/l of each other) were randomised to treatment with placebo or troglitazone at doses of 200, 400, 600 or 800 mg once daily, or 200 or 400 mg twice daily, for 12 weeks. Prior to the study, treatment had been with diet alone (38% patients) or with oral hypoglycaemic agents which were stopped 3-4 weeks before study treatment started. During treatment, HbA1c tended to rise in patients taking placebo (7.2-8.0%), but remained unchanged with all doses of troglitazone. After 12 weeks of treatment, HbA1c was significantly lower in the troglitazone-treated (mean 7.0-7.4%) compared to the placebo-treated (8.0%) patients (p = 0.055 to < 0.001), as was fasting serum glucose concentration (troglitazone, 9.3-11.0 mmol/l vs placebo, 12.9 mmol/l, p < 0.001). All doses of troglitazone were equally effective. Troglitazone also lowered fasting plasma insulin concentration, by 12-26% compared to placebo (p = 0.074 to < 0.001). Insulin sensitivity assessed by homeostasis model assessment (HOMA) was greater after 12 weeks of treatment in troglitazone-treated patients (troglitazone, 34.3-42.8% vs placebo, 29.9%, p < 0.05). In addition, serum triglyceride and non-esterified fatty acid concentrations were significantly lower and HDL cholesterol higher at troglitazone doses of 600 and 800 mg/day. LDL cholesterol increased at 400 and 600 mg doses only (from 4.3 and 3.9 mmol/l at baseline to 4.8 and 4.5 mmol/l, respectively at 12 weeks, p < 0.05), but not at doses of 800 mg once daily or 400 mg twice daily. LDL/HDL ratio did not change during treatment. All doses were well tolerated; incidence of adverse events in troglitazone-treated patients was no higher than in those treated with placebo. However, a tendency to reduced neutrophil counts was observed in patients taking the highest doses of troglitazone. We conclude that troglitazone is effective and well-tolerated and shows potential as a new therapeutic agent for the treatment of NIDDM.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol; Chromans; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Fatty Acids, Nonesterified; Female; Fructosamine; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leukocyte Count; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Neutrophils; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone

It has been suggested that kallikrein-kinin system may influence carbohydrate metabolism via a kinin-mediated increment of insulin-mediated glucose uptake. To evaluate the effect of acute inhibition of the kallikrein-kinin system on insulin sensitivity, a randomized, placebo-controlled, double-blind study was performed in 15 male non-insulin-dependent diabetic patients. After basal evaluation of insulin sensitivity with a 2-h euglycaemic hyperinsulinaemic clamp (40 mU m-2 min-1), patients were infused either with aprotinin (200,000 U.I.C. as intravenous bolus injection) or placebo (10 ml isotonic saline) in a cross-over fashion, at 1 week intervals. After both saline and aprotinin infusions, insulin sensitivity was reassessed by continuing the euglycaemic hyperinsulinaemic clamp for a further 1 h. Resulting data showed that aprotinin significantly improved total glucose uptake (from 16.2 +/- 2.9 mumol kg min-1 to 20.6 +/- 4.9 mumol kg min-1 p < 0.01), and decreased metabolic clearance rate of insulin (from 586 +/- 57 ml m-2 min-1 to 442 +/- 155 ml m-2 min-1, p < 0.05). Thus, in spite of the suggested positive effects of kinins on insulin-mediated glucose uptake, acute inhibition of the kallikrein-kinins system resulted in a paradoxical increment of insulin sensitivity, which was probably mediated by the reduced metabolic clearance rate of insulin.

Topics: Adult; Aprotinin; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Male; Metabolic Clearance Rate; Middle Aged; Serine Proteinase Inhibitors

To determine whether the abnormal glucagon and amylin secretions in NIDDM are secondary to hyperglycemia and relative hypoinsulinemia.. A total of 13 patients with NIDDM were studied before and after treatment with glipizide gastrointestinal therapeutic system (GITS) in a randomized double-blind placebo-controlled fashion. Of the 13 subjects, 9 were randomized to the glipizide GITS arm and 4 were randomized to the placebo arm of the study. Serum glucose, insulin, C-peptide, plasma glucagon, and plasma amylin concentrations were measured under fasting and postprandial (post-Sustacal ingestion) conditions. The Sustacal challenge was performed at baseline and after 12 weeks of treatment with either glipizide GITS or placebo.. Glipizide GITS treatment resulted in a significant reduction in hyperglycemia and increases in insulin and C-peptide secretion. Hyperglucagonemia was not ameliorated, and amylin secretion was not altered after glipizide GITS treatment. Placebo-treated patients did not show significant changes in any of the parameters measured.. Glipizide GITS treatment failed to ameliorate the hyperglucagonemia of NIDDM and did not alter amylin secretion even though it increased insulin secretion and significantly ameliorated the hyperglycemia. These observations suggest that NIDDM related abnormalities in some of the islet cell hormonal responses are the result of changes inherent in the islet cells and may be independent of hyperglycemia and relative hypoinsulinemia.

Topics: Amyloid; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Eating; Fasting; Female; Glipizide; Glucagon; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islet Amyloid Polypeptide; Male; Middle Aged; Placebos; Postprandial Period; Single-Blind Method

The pharmacokinetics and pharmacodynamics of glipizide were evaluated in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). The group consisted of 12 obese subjects (seven women, five men; mean +/- SD age, 53.5 +/- 8.5 years; total body weight (TBW), 95.5 +/- 17.2 kg; percentage > IBW (ideal body weight), 57.8 +/- 31.7%); and eight nonobese subjects (two women, six men; age, 57.8 +/- 11.7 years; TBW, 80.8 +/- 9.9 kg; percentage > IBW, 15.6 +/- 10.3%). After a 2-week antidiabetic drug-free period, patients were started on glipizide therapy for 12 weeks. Glipizide dosages were titrated to achieve specified therapeutic goals or a maximum daily dose of 40 mg. Glipizide pharmacokinetics were assessed by serum concentrations obtained during a 24-h pharmacokinetic evaluation performed after the first 5-mg dose (SD) and after 12 weeks of chronic therapy (CD). Glipizide pharmacodynamics were evaluated with serum glucose, insulin, and C-peptide responses to Sustacal tolerance test done at baseline, after SD, and after CD. No statistically significant differences in the SD pharmacokinetic parameters (Tmax = 3.1 +/- 1.2 vs. 2.8 +/- 1.6 h; Cmax = 332.5 +/- 92.5 vs. 420.8 +/- 142 g/L; area under the curve extrapolated to infinity (AUCI) = 2,598.3 +/- 1,148 vs. 3,138.9 +/- 1,847 g/h/L; oral clearance/bioavailability (CL/F), 2.3 +/- 1.0 vs. 2.0 +/- 1.0 L/h; volume of distribution/bioavailability (V/F), 19.5 +/- 4.4 vs. 17.2 +/- 4.3 L; t1/2 = 5.0 +/- 2.3 vs. 5.2 +/- 2.0 h) were observed between the obese and nonobese groups, respectively. The pharmacokinetic parameters assessed under CD conditions were also closely matched in the two groups. No differences in glucose responses to Sustacal challenge at baseline, SD, and CD (AUC0-->4.glucose:baseline, 52.3 +/- 18.0 vs. 44.9 +/- 9.8; SD, 50.4 +/- 20.9 vs. 36.1 +/- 11.0; CD, 37.8 +/- 10.7 vs. 36.6 +/- 8.5 mM/h) were noted between the obese and nonobese groups, respectively. However, glucose concentrations increased more and decreased to a smaller extent after SD in the obese as compared to nonobese subjects. Mean fasting serum insulin and C-peptide concentrations were not statistically different between the two groups. However, obese subjects exhibited higher fasting insulin (114.0 +/- 69 vs. 68.8 +/- 52 pM) at week 12 evaluation and C-peptide concentrations (0.83 +/- 0.2 vs. 0.63 +/- 0.2 nM) after SD as compared to the nonobese group. A smaller percentage increase in C peptide in response to Sustacal challenge

Topics: Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Retrospective Studies

Most obese patients with noninsulin-dependent diabetes mellitus (NIDDM) are initially treated with diet, then with oral hypoglycemic agents, eventually with insulin. However several reports indicate that in these patients insulin therapy has little chance to control glucose metabolism, promotes weight gain and arterial hypertension, and is likely to aggravate insulin resistance. In this randomized, double-blind trial vs. placebo (P) we evaluated in 29 obese NIDDM patients poorly controlled by insulin (daily insulin doses 48.7 +/- 4.0 U/day, HbA1c 10 +/- 0.27%, mean daily blood glucose levels 12.3 +/- 0.3 mmol/L, fasting C-peptide 1.8 +/- 0.2, C-peptide after 1 mg iv glucagon 3.2 +/- 0.3 ng/mL, means +/- SE), the clinical and metabolic effects of benfluorex (B), a lipid-lowering drug able to improve insulin sensitivity. After a 2-3 week run-in period (1 tablet P at dinner and diet 800 cal/day to lose 5% of the initial body weight (BWi), patients received a 1000 kcal/day diet and were randomized to B, 150 mg/ tablet, or P (3 tablets/day); the time limit was set at a 10% decrease of BWi or at 90 days. At the end of run-in there was a significant reduction of BWi (P < 0.001), fasting (P = 0.002) and mean daily blood glucose levels (P < 0.001), triglycerides (P = 0.02), cholesterol (P < 0.001) and daily insulin doses (P < 0.001). At the end of the double-blind trial, weight-loss was greater (P < 0.05), faster (P = 0.018), and more frequent (P < 0.05) with B than with P, and systolic blood pressure (P < 0.05) decreased only with B. Considering only patients with a 10% decrease of BWi (B = 15, P = 10), HbA1c (P < 0.001) decreased only with B, while fasting insulin levels decreased with both B (P < 0.01) and with P (P < 0.05). Insulin sensitivity was evaluated by means of a double infusion test (LDIGIT, insulin 25 mU/Kg/h plus glucose 4 mg/kg/min, lasting 150 min) at the end of run-in and at the end of the double-blind trial; at the end of the double-blind trial steady state blood glucose (SSBG, P < 0.05), free fatty acids (FFA, P < 0.05) and blood beta-hydroxybutyrate (P < 0.05) decreased only with B, while blood glycerol decreased both with both P (P < 0.05) and B (P < 0.06). At the end of the double-blind trial, C-peptide release was unchanged with either P or B. In conclusion, benfluorex potentiates the effects of hypocaloric diet on weight loss and on glycemic control in obese NIDDM patients treated with insulin, and this effect seems to be the result of an

Topics: 3-Hydroxybutyric Acid; Appetite Depressants; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Fenfluramine; Glucose; Glycerol; Humans; Hydroxybutyrates; Insulin; Insulin Resistance; Insulin Secretion; Middle Aged; Obesity; Placebos

To examine the effect of a single high oral dose of the novel noncaloric sweetener sucralose on short-term glucose homeostasis in patients with IDDM or NIDDM.. A total of 13 IDDM and 13 NIDDM patients with glycosylated hemoglobin levels < 10% completed this double-blind cross-over study. After an overnight fast, patients were administered opaque capsules containing either 1,000 mg sucralose or cellulose placebo, followed by a standardized 360-kcal liquid breakfast. Plasma glucose and serum C-peptide levels were measured over the next 4 h.. Regardless of the type of diabetes, areas under the curves for changes of plasma glucose and serum C-peptide levels after sucralose administration were not significantly different from those after placebo. During test meals with sucralose, one episode of symptomatic hypoglycemia occurred in each of three IDDM patients, but these episodes were not considered the result of sucralose administration.. The present results support the conclusion that sucralose consumption does not adversely affect short-term blood glucose control in patients with diabetes.

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Homeostasis; Humans; Male; Middle Aged; Sucrose; Sweetening Agents

To compare results obtained with metformin versus those obtained with DNA-recombinant insulin in obese patients with NIDDM suffering from secondary failure to sulfonylureas.. We conducted an open, prospective, randomized, and comparative study comprising a total of 60 patients selected and placed in two parallel groups. We had previously confirmed that the subjects had secondary failure to high doses of sulfonylureas. The initial metformin dosage was a single 850 mg tablet, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. The initial dosage of DNA-recombinant insulin was 24 U, subcutaneously administered and divided into two portions: two-thirds at around 8:00 A.M., before breakfast, and the remaining third at 8:00 P.M., before dinner. The dosage was adjusted based on the patient's clinical and metabolic response.. The initial average glucose value for the metformin group was 269.1 +/- 32.2 mg/dl, decreasing by the end of the study to 159.7 +/- 30.5 mg/dl. For the insulin group, these figures went from 270.7 +/- 24.0 mg/dl at the beginning of the study to 134.8 +/- 26.7 mg/dl. This decrease correlates with the reduction in glycosylated hemoglobin from 12.8 to 8.9% for the first group and from 12.3 to 8.2% for the second, as well as with the reduction in triglyceride values from 230.3 to 183.1 mg/dl and from 218.4 to 186.3 mg/dl, respectively. The BMI (27.5-26.4), blood pressure (systolic from 145.7-132.1 mmHg, diastolic from 90.3-84.8 mmHg), and total cholesterol levels (235-202 mg/dl) decreased in only the metformin group.. Metformin is an effective, safe, and well-tolerated treatment that improves metabolic control and favorably modifies secondary clinical alterations due to insulin resistance, such as arterial hypertension, overweight, and hyperlipidemia, in obese patients with NIDDM suffering from secondary failure to sulfonylureas.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metformin; Middle Aged; Obesity; Recombinant Proteins; Regression Analysis; Sulfonylurea Compounds; Treatment Failure; Triglycerides

To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM.. Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d.. Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile.. Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Postprandial Period; Sulfonylurea Compounds; Time Factors

To investigate the long-term antidiabetogenic effect of glucagon-like peptide 1 (GLP-1) and its influence on diabetic dyslipoproteinemia, patients with NIDDM were treated with GLP-1 subcutaneously for 1 week.. Twelve patients participated in the study. The 1st week of the study, all of them were on intensive insulin treatment and from day 8, four were randomized to a control group continuing with insulin, and eight to a treatment group where GLP-1 was given at meals together with regular insulin from day 8 to 12. On days 13 and 14, they were only given GLP-1 at meals. NPH insulin at bedtime was given throughout the study.. In the GLP-1-treated patients, the doses of regular insulin, given to keep a satisfactory blood glucose control, were reduced compared with treatment with insulin only. GLP-1 virtually inhibited the early increase in blood glucose after the meals, whereas an increase of approximately 2 mmol was seen during an optimized insulin treatment. In agreement with the short half-life of the peptide, 2-h postprandial plasma insulin levels were significantly decreased both at day 12 and 14, suggesting that there was not enough GLP-1 left to stimulate endogenous insulin release and compensate for the decrease in the dose of exogenous insulin. Therefore, the effect of GLP-1 was lost before the next meal, resulting in increased preprandial blood glucose values at lunch and dinner. The concentration of VLDL triglycerides decreased already during the 1st week. This decrease persisted during the 2nd week when GLP-1 was included in the treatment. No changes were observed in the levels of LDL and HDL cholesterol. The LDL particle diameter increased from a mean of 22.3 to 22.6 nm (P < 0.01) in response to insulin treatment. A further increment to 22.9 nm (P < 0.05) was seen after GLP-1 treatment. The LDL particle size did not change in the control group. Lipoprotein lipase activity was decreased by 27% and hepatic lipase was reduced by 13% in the GLP-1-treated group.. We confirm the antidiabetogenic effect of GLP-1 in NIDDM patients. This effect was maintained during 7 days, which implies that the patients did not develop tolerance during this treatment period. Intensive insulin treatment, leading to normotriglyceridemia, increased the mean LDL particle diameter, which is likely to lower the risk of future coronary heart disease in patients with NIDDM. Furthermore, an additive effect of GLP-1 is indicated. Hence, this study gives additional evidence that GLP-1 may be useful as an agent for treating NIDDM.

Topics: Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperlipoproteinemias; Hypoglycemic Agents; Insulin; Lipoproteins, VLDL; Male; Middle Aged; Peptide Fragments; Protein Precursors; Time Factors; Triglycerides

The objective of this study is to compare the effect of intraperitoneal versus subcutaneous insulin injection on hepatic glucose production (HGP) and systemic glucose utilization (Rd) in patients with NIDDM.. Eight male volunteers with NIDDM, each of whom had a programmable-rate, implantable insulin pump, were given an injection of insulin (0.15 units/kg body wt) by intraperitoneal or subcutaneous injection on separate days in randomized order. Plasma glucose was kept constant for 5 h using the glucose clamp technique, and HGP and Rd were measured using isotope dilution.. Intraperitoneal insulin injection resulted in higher and earlier peak systemic insulin concentrations (1,469 +/- 245 vs. 454 +/- 48 pmol/l, P < 0.01). Glucose Rd doubled within 1 h after intraperitoneal injection and was greater than that attained with subcutaneous injection (3.91 +/- 0.27 vs. 2.60 +/- 0.19 mg.kg-1.min-1, P < 0.01). Intraperitoneal and subcutaneous injections suppressed HGP and plasma free fatty acid to a similar extent during the first 3 h, effects tht persisted through 5 h after subcutaneous insulin injection but waned 3-4 h after intraperitoneal injection.. In patients with NIDDM, intraperitoneal insulin injection achieves more rapid and greater peak values for stimulation of glucose Rd than subcutaneous insulin injection. With regard to HGP and lipolysis, intraperitoneal and subcutaneous injections achieve similar initial suppression but this is maintained for a more limited duration with intraperitoneal as compared with subcutaneous injection. These differences in insulin action seem directly related to the rapidity of insulin absorption with intraperitoneal injection.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucagon; Glucose; Homeostasis; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Insulin, Regular, Pork; Kinetics; Male; Middle Aged; Recombinant Proteins; Time Factors

We report on the results of a one-year, multicenter, randomized, double-blind, parallel-group titration study of the new sulfonylurea agent, glimepiride, versus use of non-micronized glyburide to treat 577 patients with non-insulin dependent diabetes mellitus (NIDDM). Similar decreases in both fasting plasma glucose and HbA1C were found using glimepiride and glyburide. There was a lower incidence of hypoglycemia with glimepiride than glyburide.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds

The comparative effects of glimepiride (Amaryl; HOE 490) and glibenclamide on insulin and glucose metabolism under hyperglycaemic and hyperinsulinaemic, euglycaemic clamp conditions were studied in a double-blind, placebo-controlled, cross-over trial. Patients with sulfonylurea-controlled non insulin-dependent diabetes were allocated in random order to placebo, glimepiride (5 mg) or glibenclamide (5 mg) and received one week treatment of each with no wash-out period. At the end of each treatment week a clamp study was performed. Two protocols were used. Protocol 1 used a 5 h hyperglycaemic clamp at 10.9 mmol/l whole blood glucose concentration and Protocol II used a 3 h hyperinsulinaemic, euglycaemic damp at 3.5 mmol/l whole blood glucose concentration. Both glimepiride and glibenclamide exhibited a hypoglycaemic effect. A significant reduction in fasting whole blood glucose concentration was observed after one-week treatment of each active agent (fasting glucose: glimepiride v. placebo, 9.3 +/- 0.7 v. 10.7 +/- 0.8 mmol/l, p < 0.02; glibenclamide v. placebo, 8.9 +/- 0.9 v. 10.7 +/- 0.8 mmol/l, p < 0.005). This hypoglycaemic action of both preparations administered in equivalent daily dose appeared comparable. Glimepiride and glibenclamide stimulated beta-cell secretion and in the basal state both beta-cell secretory products insulin and C-peptide, were elevated in the plasma (basal C-peptide concentration: glimepiride v. placebo, 0.79 +/- 0.08 v. 0.68 +/- 0.07 nmol/l, p < 0.01; glibenclamide v. placebo, 0.79 +/- 0.07 v. 0.68 +/- 0.07 nmol/l, p < 0.004). This insulinotropic effect appeared to be comparable with no demonstrable difference in the efficacy of the two preparations. Under steady-state hyperglycaemic conditions both agents promoted insulin release (stimulated C-peptide concentration; glimepiride v. placebo, 1.39 +/- 0.16 v. 1.11 +/- 0.20 nmol/l, p < 0.006; glibenclamide v. placebo. 1.60 +/- 0.18 v. 1.11 +/- 0.20 nmol/l, p < 0.001) and there was no statistically significant difference between active treatments. Under steady-state euglycaemia both preparations continued to stimulate insulin release as evidenced by the mean plasma C-peptide concentrations (glimepiride v. placebo, 0.69 +/- 0.10 v. 0.28 +/- 0.06 nmol/l, p < 0.01; glibenclamide v. placebo, 0.76 +/- 0.12 v. 0.28 +/- 0.06 nmol/l, p < 0.01). Both glimepiride and glibenclamide had a comparable and significant enhancing effect on glucose metabolism (Protocol II: M: glimepiride v. placebo 4

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Glucose Clamp Technique; Glyburide; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Placebos; Sulfonylurea Compounds

The effects of exercise on metabolic control in type II diabetic patients given glimepiride or glibenclamide were studied in a multinational phase II clinical trial (14 centers in 4 countries). A total of 167 type II diabetic out-patients (117 men, 50 women) completed the trial as planned. The study was of parallel group, 2 x 2 factorial design: patients were first stabilized in a randomized, double-blind manner on 3 mg of glimepiride or 10 mg of glibenclamide treatment once daily over 14-28 days and were then assigned in randomized open fashion to a group with or without exercise. Exercise consisted of riding a bicycle ergometer for 1 hour at pulse rate 120 beats per minute. Three-hour blood glucose, insulin, and C-peptide profiles were made after the stabilization phase (baseline profiles) and 7 days later with or without exercise (endpoint profiles). Pairwise comparisons of changes in blood glucose AUC/1-3 h revealed a statistically significant decrease in patients who exercised vs those who did not, which was comparable for both sulfonylureas used. There was a statistically significant decrease in C-peptide AUC/1-3 h and insulin AUC/1-3 h in the glimepiride exercise group vs the glimepiride group without exercise. Physical exercise did not lead to statistically significant changes in C-peptide AUC/1-3 h and insulin AUC/1-3 h under glibenclamide treatment. In conclusion, a blood-glucose-lowering response to acute exercise was demonstrated in type II diabetic patients treated with either sulfonylurea, but a significant suppression of endogenous insulin secretion was observed for glimepiride only.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise; Female; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds

To compare the metabolic effects of three different frequently used regimens of insulin administration on blood glucose control and serum lipids, and the costs associated with this treatment, in subjects with NIDDM, who were poorly controlled with oral antihyperglycemic agents.. We studied 95 elderly patients with NIDDM (age 68 +/- 9 years, BMI 26.0 +/- 4.6 kg/m2, and median time since diagnosis of diabetes 9 years [range 1-37]; 37 men, 58 women), who were poorly controlled, despite diet and maximal doses of oral antihyperglycemic agents. Three insulin administration regimens were compared during a 6-month period: patients were randomized for treatment with a two-injection scheme (regimen A) or a combination of glibenclamide with one injection of NPH insulin, administered either at bedtime (regimen B) or before breakfast (regimen C), and insulin treatment was mainly instituted in an outpatient setting.. After 6 months of insulin treatment, fasting blood glucose of the total patient population had decreased from an average of 14.1 +/- 2.2 to 8.3 +/- 2.0 mmol/L (P < 0.001), and HbA1c fell from 11.0 +/- 1.3 to 8.3 +/- 1.2% (P < 0.001); 34 patients reached HbA1c levels below 8.0%, 25 of them even below 7.5%. With two insulin injections daily, HbA1c decreased from 11.2 +/- 1.3 to 8.2 +/- 1.2%, while during combined treatment, HbA1c fell from 10.5 +/- 1.2 to 8.1 +/- 1.1% (regimen B) and from 11.1 +/- 1.3 to 8.5 +/- 1.1% (regimen C). Comparable improvement of the other measures of glycemic control, lipids and lipoproteins, was observed in the different treatment regimens. Body weight increase was moderate (mean +/- 4.0 kg) and similar in all patient groups. One-third of patients starting with one insulin injection daily needed a second injection to control glycemia. One episode of severe hypoglycemia was observed. Combined insulin-sulfonylurea treatment was almost 20% more expensive than twice-daily administration of insulin alone.. Insulin treatment can safely be instituted in elderly patients with NIDDM. However, it is difficult to obtain optimal glycemic control. Insulin has moderate beneficial effects on serum lipoproteins. Although on the basis of glycemic control and weight gain, no preference for any treatment regimen can be discerned, twice-daily insulin administration is the most simple and cost-effective regimen.

Topics: Aged; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Costs and Cost Analysis; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fatty Acids, Nonesterified; Female; Fructosamine; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Lipids; Lipoprotein(a); Male; Netherlands; Triglycerides

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Emptying; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Insulin; Male; Middle Aged; Peptide Fragments; Peptides

The treatment of NIDDM patients with secondary failure to sulfonylureas is still a debated problem. In this study we compared in NIDDM patients with secondary failure to glyburide, the effect of adding a single, low-dose bed time either NPH or ultralent insulin injection (0.15-0.2 U/kg) to the previously ineffective sulfonylurea treatment. Both NPH and ultralent insulin therapy have been demonstrated to be effective in ameliorating metabolic control in NIDDM patients with secondary failure to sulfonylureas. However, the addition of bed-time ultralent insulin caused a greater and significant decrease in post prandial plasma glucose. In contrast, the average fasting plasma glucose decrease was significantly greater after NPH insulin administration. These results indicate that in NIDDM patients with secondary failure to glyburide bed-time ultralent insulin administration is a better tool to improve the post prandial plasma glucose.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Drug Tolerance; Eating; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged; Treatment Outcome

Insulin sensitivity was measured by insulin tolerance test using KITT as an index of insulin mediated glucose metabolism in 9 non-obese healthy offspring of conjugal diabetic parents (OCDP) and 9 non-obese NIDDM patients. The mean KITT value in the offspring of conjugal diabetic parents was 3.85 +/- 1.64 min-1 x 100 which was lower (P < 0.05) than the value of 5.49 +/- 1.9 min-1 x 100 in the control subjects. While, the mean KITT value in NIDDM patients was 1.85 +/- 0.9 min-1 x 100 which was significantly lower (P < 0.001) than that in the control subjects. Estimation of plasma immunoreactive insulin (IRI) and C-peptide in these subjects and in subjects with impaired glucose tolerance (IGT) showed significantly higher levels of insulin than that in the control subjects but there was no corresponding increase in the C-peptide levels. The mean area under the insulin curve (IRI) was 242 +/- 69 microU/ml in the control subjects versus 527 +/- 206 microU/ml in IGT (P < 0.001), 648 +/- 215 microU/ml in NIDDM (P < 0.001) and 466 +/- 130 microU/ml in OCDP (P < 0.001). These results suggest that 1) healthy offspring of two type II diabetic parents have decreased insulin sensitivity and insulin resistance is present in all the NIDDM patients, 2) peripheral hyperinsulinism is a common feature in healthy offspring of conjugal diabetic parents, and in subjects with IGT and mild NIDDM and this hyperinsulinism is not due to increased B-Cell secretion but due to some metabolic alterations of insulin occurring at the extra pancreatic levels.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male

Fourteen patients with non-insulin-dependent diabetes (NIDDM) attended the study centre on 4 mornings separated by at least 3 days, to receive in random order 75 g carbohydrate breakfast meals of control or guar breads with jam and butter. Guar gum flours of low, medium, and high molecular weight (MW) were incorporated into wheat bread rolls to provide 7.6 g guar per meal. Venous blood samples were taken via an indwelling cannula in a forearm vein at fasting and at eight postprandial times and then analysed for blood glucose, plasma insulin, C-peptide, and gastric inhibitory polypeptide (GIP). Guar gum bread significantly reduced the postprandial rise in blood glucose, plasma insulin, and, except for bread containing low MW guar gum, plasma GIP levels compared to the control. Thus, the partial depolymerization of guar gum does not diminish its physiological activity. No reductions in postprandial plasma C-peptide levels were seen after any of the guar bread meals. This suggests that guar gum attenuates the insulin concentration in peripheral venous blood in patients with NIDDM by increasing the hepatic extraction of insulin.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dietary Fiber; Female; Galactans; Gastric Inhibitory Polypeptide; Humans; Insulin; Male; Mannans; Middle Aged; Plant Gums; Polymers; Postprandial Period; Time Factors

Optimal insulin regimens for non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure are controversial. We evaluated the efficacy, side effects, and quality of life of patients receiving insulin either alone or in combination with their previous oral hypoglycemic agents (OHAs).. Fifty-three Chinese patients with NIDDM (mean age 53.9 +/- 12.6 years, duration of diabetes 9.0 +/- 4.9 years, body wt 60.4 +/- 13.3 kg with corresponding body mass index 24.2 +/- 4.3 kg/m2, receiving the maximum dose of sulfonylurea and/or metformin) were confirmed to have OHA failure. Twenty-seven patients were randomized to continue OHAs and were given additional bedtime insulin (combination group); 26 patients were randomized to insulin therapy alone with twice-daily insulin (insulin group). Insulin doses were increased incrementally, aiming at fasting plasma glucose (FPG) < 7.8 mmol/l during a stabilization period of up to 8 weeks. Insulin dosage, body weight, glycemic control, and quality of life were assessed before and at 3 and 6 months after stabilization.. Both groups showed similar improvement of glycemic control. For the combination group, FPG decreased from 13.5 +/- 2.7 to 8.9 +/- 3.0 mmol/l at 3 months (P < 0.0001) and to 8.6 +/- 2.5 mmol/l at 6 months (P < 0.0001). For the insulin group, FPG decreased from 13.5 +/- 3.6 to 7.5 +/-3.0 mmol/l at 3 months (P < 0.0001) and to 9.8 +/- 3.5 mmol/l at 6 months (P < 0.0001). No significant differences were observed between the groups. Similarly, both groups had significant improvement of fructosamine and glycosylated hemoglobin (HbA1c). Fructosamine fell from a mean of 458 to 365 mumol/l at 3 months (P < 0.0001) and to 371 mumol/l at 6 months (P < 0.0001) and from 484 to 325 mumol/l at 3 months (P < 0.0001) and to 350 mumol/l at 6 months (P < 0.0001) for the combination and insulin groups, respectively. HbA1c decreased from 10.2 to 8.4% at 3 months (P < 0.0001) and to 8.7% at 6 months (P < 0.0001) in the combination group and from 10.7 to 7.8% at 3 months (P < 0.0001) and to 8.4% at 6 months (P < 0.0001) in the insulin group. Despite similar improvement of glycemia, insulin requirements were very different. At 3 months, the combination group was receiving a mean of 14.4 U/day compared with 57.5 U/day in the insulin group (P < 0.0001). Similar findings were observed at 6 months (15.0 vs 57.2 U/day, P < 0>0001). Both groups gained weight. However, for the combination group, weight gain was 1.6 +/- 1.8 kg at 3 months and 2.1 +/- 2.5% kg at 6 months (both P < 0.0001 vs baseline), whereas for the insulin group, weight gain was 3.5 +/- 4.3 and 5.2 +/- 4.1 kg, respectively (both P < 0.0001 vs baseline). Weight gain was significantly greater in the insulin group (P < 0.05 at 3 months, and P < 0.005 at 6 months). Fasting plasma triglyceride decreased in the insulin group (1.8 +/- 1.0 to 1.4 +/- 0.8 mmol/l at 3 months [P < 0.005] and to 1.4 +/ 0.7 mmol/l at 6 months [P < 0.02] but not in the combination group. No changes were observed in total and high-density lipoprotein cholesterol. No severe hypoglycemic reactions were recorded in either group. Mild reactions occurred with similar frequency in both groups. Well-being and quality of life improved significantly in both groups. The majority of patients (82.7%) wanted to continue insulin beyond 6 months, irrespective of the treatment group.. In NIDDM patients with secondary OHA failure, therapy with a combination of OHAs and insulin and with insulin alone was equally effective and well tolerated. However, combination therapy was associated with a lower insulin dose and less weight gain. Combination treatment may be considered when OHA failure occurs as a potential intermediate stage before full insulin replacement.

Topics: Analysis of Variance; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Fructosamine; Gliclazide; Glipizide; Glyburide; Glycated Hemoglobin; Hexosamines; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Treatment Failure; Triglycerides

To examine the safety and overall clinical effects of normalizing the fasting plasma glucose (FPG) level with bedtime NPH insulin alone in patients with non-insulin-dependent diabetes mellitus (NIDDM) that is poorly controlled with maximal doses of sulfonylureas.. Twelve obese male NIDDM subjects were treated for 16 weeks with bedtime insulin after a 4-week sulfonylurea washout. The insulin dosage was increased until the FPG level was normalized. The 24-h plasma glucose profiles and lipid and HbA1c levels were measured at the beginning and end of the study, and the incidence and severity of hypoglycemic episodes were closely monitored. In addition, hyperglycemic clamp studies were performed to assess insulin secretion and provide an indirect measurement of insulin sensitivity.. FPG (14.6 +/- 0.9 mmol/l at week 0) was normalized ( < 6.4 mmol/l) within 6 weeks (5.9 +/- 0.6 mmol/l) and remained at target levels until the end of the study (4.0 +/- 0.03 mmol/l at week 16, P < 0.001). The insulin dose was 80 +/- 9 U/day (0.86 +/- 0.10 U/kg). Improved glycemic control was confirmed by a reduction in HbA1c (10.9 +/- 0.05 vs. 7.2 +/- 0.2%, P < 0.001) and mean 24-h glucose (17.2 +/- 0.2 vs. 7.4 +/- 0.2 mmol/l, P < 0.001). The incidence of mild or moderate hypoglycemic episodes was 3.4 +/- 1/patient for the entire 16-week study, and no patient experienced severe hypoglycemia. Bedtime insulin significantly improved total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglyceride levels (P < 0.01). Weight gain was 2.4 +/- 0.7 kg, and blood pressure was unchanged. During the hyperglycemic clamp, there was an improvement in the first phase (P < 0.001) and in the second phase (P < 0.01) of insulin secretion. There also was an increase in the rate of exogenous glucose infused (M) (P < 0.01) and in the M/C-peptide ratio (P < 0.02), suggesting enhanced insulin sensitivity.. NPH insulin given at bedtime in amounts sufficient to achieve a normal FPG level does not cause excessive or severe hypoglycemia and does lead to good glycemic and lipid control in NIDDM. Bedtime insulin therapy also is accompanied by improved insulin secretion and insulin sensitivity. We conclude that a single dose of insulin alone at bedtime merits consideration as a therapeutic strategy in patients with poorly controlled NIDDM.

Topics: Analysis of Variance; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Glucose; Glycated Hemoglobin; Humans; Insulin, Isophane; Liver; Male; Middle Aged; Obesity; Reference Values; Time Factors; Triglycerides

The effectiveness of combined therapy with insulin and sulfonylurea in non-insulin dependent diabetes mellitus (NIDDM) patients has, for decades, been a debated issue. In order to probe this question, we studied 33 diabetes mellitus patients aged 40 years and over, having a history of this disease for more than 5 years, treated with one of the sulfonylureas at maximal dosage for three weeks but without effect. These 33 cases were divided into three groups randomly: group A: treated with glurenorm and insulin. B insulin and C glurenorm. The treatment lasted 4 months. During the course of the trial, estimation of the free-insulin, C-peptide, blood glucose etc. was carried out three times i.e. one before the trial and then 2, 4 months after the trial. The data were dealed with U-test and comparison was made before and after the trial and between the three groups. It is shown that combined therapy with sulfonylurea and insulin is effective in NIDDM patients, especially in those with secondary failure of beta-cell function and the combined therapy may be used in NIDDM patients during the transitional period from treatment with sulfonylurea alone to traditional insulin cure.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Insulin; Male; Middle Aged; Sulfonylurea Compounds

To compare the effect of bedtime NPH insulin or preprandial regular insulin combined with glibenclamide on metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure to sulfonylurea therapy.. Eighty NIDDM patients were randomized to treatment with either three preprandial doses of regular insulin (daytime group D) or a bedtime dose of NPH insulin (nocturnal insulinization, group N), both regimens being combined with 10.5 mg of glibenclamide. Metabolic profiles were obtained at 0, 6, 16 weeks.. Glycemic control had improved significantly in both groups after 4 months. Fasting blood glucose was significantly lower compared with baseline in both groups. The mean change +/- SD in group D was -2.8 +/- 3.5 mmol/l and in group N -6.4 +/- 3.0 mmol/L, the reduction being more pronounced in group N compared with group D (P < 0.0001). HbA1c was lowered similarly, from 9.2 +/- 1.4 to 7.1 +/- 1.2% in group D (P < 0.0001) and from 9.1 to 1.1 to 7.5 +/- 1.5% in group N (P < 0.0001). The total daily insulin doses were similar, 29 +/- 11 U in group D and 26 +/- 9 U in group N, and the circulating insulin levels during daytime were higher in group D than in group N. Total serum cholesterol and triglycerides were similarly and significantly lowered compared with baseline in both groups. Weight gain was more pronounced in group D (3.4 +/- 0.3 kg) than in group N (1.9 +/- 1.9 kg; D vs. N, P < 0.002), and the change was inversely correlated with initial eight but not with the improvement in HbA1c.. The two insulin regimens exert similar effect on glucose metabolism and serum lipids in NIDDM patients on combination therapy. Weight gain is more pronounced in patients given insulin during the daytime when preprandial doses of short-acting insulin are used.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Eating; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin, Isophane; Middle Aged; Time Factors; Treatment Failure; Triglycerides

To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangio

Topics: Albuminuria; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; Insulin; Japan; Male; Middle Aged; Neural Conduction; Prospective Studies; Statistics, Nonparametric; Time Factors; Triglycerides

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Anticholesteremic Agents; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diclofenac; Drug Interactions; Fatty Acids, Monounsaturated; Fluvastatin; Glyburide; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Insulin; Lovastatin; Placebos; Simvastatin; Tolbutamide

Women with a history of gestational diabetes mellitus (GDM) tend to be insulin-resistant and hyperinsulinemic and are predisposed to the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM). In the evolution of glucose intolerance, the first clinically detectable abnormality has not been defined and the relative importance of contributions of abnormal insulin secretion and insulin resistance is controversial. The present study was performed to evaluate the insulin secretory responses to oral and intravenous glucose and to mixed meals in women with a history of GDM, and to determine if the hyperinsulinemia present in these subjects is appropriate for the degree of insulin resistance. To address these questions, we studied the insulin secretory responses to oral glucose over a 3-hour period and to three mixed meals over a 24-hour period, and quantified the acute insulin response to glucose (AIRglucose) and insulin sensitivity (SI) during frequently sampled intravenous glucose tolerance tests (FSIVGTTs). Studies were performed in seven subjects with a history of GDM and in seven matched controls. Insulin secretion rates (ISRs) were derived by deconvolution of peripheral C-peptide values using a two-compartment model and standard C-peptide kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Causality; Diabetes Mellitus, Type 2; Diabetes, Gestational; Eating; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Injections, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Pregnancy; Proinsulin; Time Factors

To examine the effect of different profiles of insulin administration on glycaemia and thermogenesis, we studied 10 subjects with mild non-insulin-dependent diabetes mellitus on four occasions after a standard mixed meal: (1) with no supplementary insulin (control), (2) with intravenous insulin (1.8U over 15 min = short), (3) as for short but extended over 30 min to simulate the normal initial rise in portal vein insulin levels (medium), (4) as for medium with additional insulin to normalize the profile from 30-60 min (3.6U over 60 min, long). All studies in which supplemental insulin was administered lowered the integrated glucose response above baseline versus the control study (short 76%, medium 71%, and long 56% of control, p = 0.003). The insulin infusions also increased the non-protein respiratory quotient in the first hour following the meal (0.82 +/- 0.01 (control) vs 0.87 +/- 0.01 (short), 0.86 +/- 0.01 (medium) and 0.87 +/- 0.01 (long), p = 0.003) and augmented thermogenesis (7.6 +/- 1.5 (control) vs 10.5 +/- 2.9 (short), 13.0 +/- 1.9 (medium) and 13.2 +/- 2.8% (long), p = 0.02). Total integrated insulin area above baseline was significantly greater in the long study (short 121, medium 111 vs long 179% of control, p = 0.02). Thus the greatest glycaemic benefit in relation to insulinaemia was obtained with the two shorter insulin infusions (short and medium). In conclusion, this study confirms the role of early prandial insulin secretion (or delivery) in limiting prandial glycaemia in NIDDM and increasing thermogenesis and highlights the pivotal role of the timing of elevation of insulin levels in modulating hyperglycaemia and hyperinsulinaemia.

Topics: Aged; Basal Metabolism; Blood Glucose; Body Temperature Regulation; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Food; Glucagon; Humans; Insulin; Male; Middle Aged; Time Factors

In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 +/- 0.4% [mean +/- SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 +/- 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 +/- 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-(13)C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg.kg-1. h-1). VLDL apoB isotopic enrichment was determined with gas chromatography-mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 +/- 3.6 vs. 24.5 +/- 7.1 mg.kg-1.day-1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.

Topics: Apolipoprotein B-100; Apolipoproteins B; Apolipoproteins E; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Kinetics; Lipoproteins, VLDL; Liver; Male; Middle Aged; Phenotype; Time Factors

Insulin resistance that exists in patients with essential hypertension and in those with non-insulin-dependent diabetes mellitus (NIDDM) may be the common denominator for the impaired glucose homeostasis and elevated blood pressure (BP) levels in patients with NIDDM. Therefore, treatment that improves insulin action may also improve BP levels. Consequently, a four-phase (glipizide v insulin) cross-over design study was conducted to determine a better effect of glipizide treatment on insulin sensitivity and the effect this has on BP in 19 NIDDM patients. Patients were subjected to 1 month of diet only (phase I) followed by 3 months of glipizide treatment (phase II), then an additional 1 month of diet only (phase III), and finally 3 months of insulin treatment (phase IV). At the end of phases I, II, and IV oral glucose tolerance tests (OGTT) were performed and plasma glucose, insulin, and C-peptide levels were analyzed. Fasting plasma glucose, insulin, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides, glycated hemoglobin, fructosamine, and 2-h postprandial plasma glucose were also analyzed at each phase. Supine and sitting BP levels and body weights were determined biweekly during the study. With the exception of higher plasma insulin and C-peptide levels during the OGTT (area under the curve) in phase IV (insulin) v phase II (glipizide) (both P < .05), and higher fasting plasma insulin levels (P < .06), there were no consistently significant metabolic differences between phases IV and II.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Glipizide; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Prospective Studies

Exercise enhances insulin sensitivity in people with non-insulin-dependent diabetes mellitus (NIDDM), but the intensity of exercise necessary to optimize the effect is unknown. Eight women with NIDDM were studied on a metabolic ward in each of three conditions: 1) low-intensity exercise (LO) that consisted of treadmill walking at 50% of maximal O2 consumption on days 1 and 2, 2) high-intensity exercise (HI) that consisted of walking at 75% of maximal O2 consumption, and 3) no exercise (NX). The duration of exercise was adjusted so that energy expenditure was equal in both exercise conditions. On day 3, glucose, [6,6-2H]glucose, and insulin were infused at fixed rates for 3 h. Insulin sensitivity was determined both by steady-state plasma glucose concentration and rate of glucose disposal per unit plasma insulin. Steady-state plasma glucose concentration and rate of glucose disposal per unit plasma insulin were almost identical after LO or HI; values were significantly greater than after NX. Plasma glucose response to a test meal was the same among the three conditions, but plasma insulin response was lower for HI and LO compared with NX. We conclude that under these conditions LO is as effective as HI in enhancing insulin sensitivity in people with NIDDM.

Topics: Adult; Blood Glucose; Body Composition; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet; Exercise; Female; Humans; Insulin; Middle Aged; Oxidation-Reduction

We studied insulin and C-peptide levels in patients with non-insulin-dependent diabetes mellitus (NIDDM) during standard oral or intravenous glucose tolerance tests (GTT) at the time of diagnosis and after 3 months dietary therapy. On the second occasion they also had an 'augmented' GTT, in which slow intravenous infusion of glucose raised basal plasma glucose to a level similar to that at the time of diagnosis. Eight patients had oral tests, and seven patients intravenous tests. In both groups, dietary therapy significantly reduced fasting and peak plasma glucose (p < 0.05 for oral; p < 0.01 for intravenous GTT). Serum insulin levels during conventional oral GTT were not significantly different after dietary therapy compared to diagnosis, but were significantly higher during the 'augmented' oral GTT (p < 0.05). In those patients who underwent intravenous GTT, there was a significant increase in both the total amount of insulin secreted (0-60 min) and in first-phase insulin secretion (0-10 min) during the 'augmented' test compared to diagnosis (p < 0.01), but first-phase insulin secretion during the conventional intravenous GTT was unchanged. Serum C-peptide responses were also greater during 'augmented' tests (p < 0.05), similar in pattern to serum insulin. There is a relative deficiency in insulin secretion in untreated NIDDM, which can be reversed by dietary therapy. It is essential to study insulin and C-peptide secretion in controlled 'fasting' glucose conditions.

Topics: Administration, Oral; Aged; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Humans; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.

Topics: Age of Onset; Aged; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Gluconeogenesis; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Liver; Middle Aged; Obesity; Reference Values; Triglycerides; Tritium; Twins, Monozygotic

The alpha-glucosidase inhibitor voglibose (AO-128) was designed to prevent rapid postprandial blood glucose rises in non-insulin-dependent diabetics. We analyzed its effect on the entero-insular axis in 72 healthy volunteers in a double-blind study design before, after the 1st dose, and on the 7th day of a 7-day treatment protocol (3 daily loads). Six parallel groups of 12 volunteers received voglibose (0.5, 1.0, 2.0, or 5.0 mg) or placebo (two groups). Blood was drawn at regular intervals up to 180 min after a standardized breakfast to analyze the levels of glucose, insulin, C peptide, gastric inhibitory polypeptide, and glucagon-like peptide 1 (GLP-1). As expected, after ingestion of voglibose, slight to moderate gastro-intestinal discomfort but no severe side-effects were reported. In a dose-dependent manner, voglibose significantly reduced postprandial increases of blood glucose, insulin, and C peptide. At the lower loads (0.5 and 1 mg voglibose three times daily), these effects were more pronounced after 7 days. The postprandial increase of gastric inhibitory polypeptide was already reduced after the first load of 2 and 5 mg voglibose. In comparison to the placebo group, this inhibition became also significant for the lower loads after 7 days. Interestingly, GLP-1, originating from the lower intestines, was increasingly released under voglibose treatment. The first administration of 1 mg voglibose enhanced GLP-1 secretion > 80% above controls. Treatment with 1 mg voglibose three times daily over 7 days revealed a maximal mobilizing effect on endogenous GLP-1 (> 90% above controls) which was not further increased by 2- or 5-mg loads. We conclude that voglibose treatment effectively inhibits intestinal disaccharidases and thereby mobilizes the endogenous pool of insulinotropic GLP-1.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cyclohexanols; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Insulin; Male; Peptide Fragments; Protein Precursors

To clarify the optimum timing for ingestion of acarbose, a 100 mg dose of this oral hypoglycaemic agent was administered 30 min before, at the beginning, and 15 min after ingestion of a test meal, and the effects of the drug on blood glucose rises were compared with increases observed after a control meal (no drug). Twenty-four patients with Type 2 diabetes were included in a randomized, open, cross-over study. The smallest increases in blood glucose (p < 0.001) occurred when acarbose was taken at the beginning and 15 min after starting the test meal (3.3 +/- 1.6 mmol l-1 and 3.3 +/- 1.4 mmol l-1). The increase in blood glucose levels when acarbose was taken 30 min before the test meal was significantly higher (4.2 +/- 1.8 mmol l-1) and it was at its maximum following the control meal (5.2 +/- 1.7 mmol l-1). Similar results were observed when the effects of acarbose on insulin and C-peptide levels were measured. It is recommended that patients should be instructed to take acarbose with their first mouthful of food.

Topics: Acarbose; Administration, Oral; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Time Factors; Trisaccharides

Insulin resistance is a significant pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM). A new class of drugs, the thiazolidinediones, have been shown to lower blood glucose levels without stimulating insulin secretion. We report the metabolic effect of the thiazolidinedione, darglitazone, in obese NIDDM subjects. Nineteen subjects were enrolled in a double-blind placebo-controlled study in which 25 mg of darglitazone was given once a day for 14 days. Nine subjects received the active drug and ten subjects received placebo. Darglitazone-treated subjects showed; 1) a decrease in 24-h plasma glucose area under the curve from 292.8 +/- 31.2 to 235.2 +/- 21.6 mmol.h-1.l-1 p = 0.002; 2) a decrease in 24-h serum insulin area under the curve from 1027.2 +/- 254.4 to 765.6 +/- 170.4 microU.h-1.l-1 p = 0.045; 3) a decrease in 24-h non-esterified fatty acid area under the curve from 1900 +/- 236 to 947 +/- 63 g.h-1.l-1 p = 0.002; 4) a decrease in mean 24-h serum triglyceride by 25.9 +/- 6.2% as compared to -3.9 +/- 4.8% for the placebo-treated group, p = 0.012. Placebo-treated subjects showed no change in their metabolic parameters after treatment. Thus, darglitazone is effective in increasing insulin effectiveness in obese NIDDM subjects. The potential for this and similar drugs to treat or prevent NIDDM as well as the insulin-resistance syndrome needs to be explored.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Obesity; Thiazoles; Thiazolidinediones

Comparison of the effectiveness of combined therapy vs. an insulin regimen in NIDDM patients with secondary failure of oral hypoglycemic agents. RESEARCH DESIGN, PATIENTS AND METHODS: 27 NIDDM patients were randomly allocated to Group A (n = 14, insulin) and Group B (n = 13, insulin and sulfonylurea) with crossover after 3 months. After the next 3 months a decision was made about the further treatment according to the metabolic control. The patients were then treated for another year with the more successful regimen. Metabolic control, residual beta-cell secretory capacity, degree of peripheral insulin resistance (clamp) and insulin dose were followed during the whole study.. (median, interquartile range, in brackets; *, statistically significant difference at P < 0.05): the combined therapy was better than insulin alone in 2/3 of patients. Glycemic control was better (HbA1c at 3 months: Group A = 7.9(1.1)% vs. Group B = 7.0(0.5)%*; HbA1c at 6 months: Group A = 7.4(1.5)% vs. Group B = 8.1(1.5)%. Insulin dose was lower during the combined therapy in the first 3 months: Group A = 0.62(0.18) U/kg body weight vs. Group B = 0.39(0.16) U/kg body weight*. Combined treatment was associated with increased C-peptide excretion both fasting and postprandially. No significant differences in peripheral insulin resistance were noted between the two groups. The combined treatment remained successful even after one year. The two groups of patients with different effective treatment did not differ significantly in any of the observed parameters.. the combined therapy was more effective than insulin alone. Its favourable effect persisted after treatment for a year. It seems better to start the treatment of the oral failure with combined therapy compared with insulin first and later followed by combined therapy. On the basis of the observed parameters it is impossible to determine in advance which kind of treatment is more suitable for the individual patient.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Middle Aged; Sulfonylurea Compounds; Time Factors; Treatment Failure

We investigated the relationship between the improvement in insulin secretion and glycemic control in non-insulin-dependent diabetes mellitus (NIDDM). Fifty-two patients were classified into three groups according to their pretreatment fasting plasma glucose (FPG) level: Group A, FPG < 7.8 mM, n = 20; Group B, 7.8 mM < or = FPG < 11.1 mM, n = 17; and Group C, 11.1 mM < or = FPG, n = 15. A 75-g oral glucose tolerance test (OGTT) and a glucagon loading test were performed to evaluate insulin secretion before and after treatment. Plasma glucose levels during a 75-g OGTT were decreased significantly after treatment in all groups (P < 0.01). In Group A, there was no significant change in insulin secretion before and after treatment (1466 +/- 213 pM to 1565 +/- 191 pM, P = 0.35). In contrast, in Groups B and C, insulin secretion was poor and suppressed initially, but increased significantly when good glycemic control was obtained after treatment (respectively, 587 +/- 70 pM to 863 +/- 79 pM, P < 0.01, and 621 +/- 94 pM to 1236 +/- 232 pM, P < 0.01). The degree of improvement in insulin secretion in 75-g OGTT correlated positively with the degree of improvement in FPG level after treatment (r = 0.5, P < 0.001). However, the C-peptide response to glucagon did not change before and after treatment. In conclusion, impaired insulin secretion recovered by the good glycemic control in NIDDM with FPG levels above 7.8 mM. Therefore, strict glycemic control (FPG below 7.8 mM) seems important for maintaining good insulin secretion.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Fasting; Female; Gliclazide; Glucagon; Glucose Tolerance Test; Glyburide; Humans; Insulin; Male; Middle Aged

To evaluate the long-term efficacy of acarbose, an alpha-glucosidase inhibitor, in improving glycemic control in patients with non-insulin-dependent diabetes mellitus.. A 1-year, multicenter, randomized, double-blind, placebo-controlled study.. Seven university-affiliated, community-based, tertiary care diabetes clinics.. 354 patients with non-insulin-dependent diabetes mellitus were recruited; 77 were being treated with diet alone, 83 with diet and metformin, 103 with diet and sulfonylurea, and 91 with diet and insulin. Patients in each treatment group were randomly assigned to either acarbose or placebo for 1 year. Eighty-seven percent of patients receiving acarbose and 92% of those receiving placebo were included in the efficacy analysis (n = 316).. At baseline and at 3-month intervals, levels of hemoglobin A1c (HbA1c), fasting and postprandial plasma glucose, fasting and postprandial serum C-peptide, and fasting serum lipids were measured.. Compared with placebo, acarbose treatment caused a significant decrease in the mean postprandial plasma glucose peak (90 minutes) in all four groups (19.0 +/- 0.4 mmol/L to 15.5 +/- 0.4 mmol/L; P < 0.001). Analysis of the postprandial plasma glucose incremental area under the curve showed that the change from baseline to the end of the treatment period differed for placebo and acarbose recipients by 4.73 mmol.h/L in the diet alone group (P < 0.001), 2.06 mmol.h/L in the metformin group (P = 0.01), 2.65 mmol.h/L in the sulfonylurea group (P < 0.001), and 3.13 mmol.h/L in the insulin group (P = 0.001). Corresponding decreases in HbA1c levels occurred; these were 0.9% in the diet alone group (P = 0.005), 0.8% in the metformin group (P = 0.011), 0.9% in the sulfonylurea group (P = 0.002), and 0.4% in the insulin group (P = 0.077). Acarbose did not significantly affect mean serum C-peptide or mean serum lipid levels.. Acarbose improved long-term glycemic control in patients with non-insulin-dependent diabetes mellitus regardless of concomitant antidiabetic medication.

Topics: Acarbose; Blood Glucose; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Insulin; Lipids; Male; Metformin; Middle Aged; Sulfonylurea Compounds; Trisaccharides

The aim of the study was to investigate whether oral application of misoprostol (MI), which is an analogue of prostaglandin E1, does change the secretion of insulin and the blood glucose level. The investigations were carried out in 15 subjects, aged 21-40 yrs, with a gastric or duodenal ulcer and without any disturbances of the digestive tract motility. In 7 of them (group A), without stated diabetes a single oral dose of 400 mg MI versus placebo (PL) and 15 min later 75 g glucose p.o., was applied in randomized order, on different days, in fasting state. In 8 subjects with mild diabetes type II (gr B) MI versus PL and after 15 min. i.v. 1.0 mg glucagon was similarly administered. In both groups the concentrations of glucose and C-peptide in blood were determined. In comparison to PL, the application of MI did not cause any statistically significant differences of C-peptide in serum and blood glucose levels neither before and after oral glucose loading nor after i.v. administration of glucagon. Statistically not significant were also the differences in AUC (p > 0.05).

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Duodenal Ulcer; Glucagon; Humans; Male; Misoprostol; Radioimmunoassay; Stomach Ulcer

To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM).. Of 165 patients (fasting blood glucose [FBG] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, with FBG < 6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration.. The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups.. Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Lipids; Male; Metformin; Middle Aged

In this study left ventricular diastolic function at rest was evaluated in ten newly diagnosed, non-insulin-dependent diabetic patients by Doppler echocardiography, performed at the onset of disease and after 6 and 12 months of adequate glycaemic control. Glycosylated haemoglobin A1C, total cholesterol and triglyceride levels were assessed at the same time. The control group consisted of ten healthy subjects of matching age and body mass index. The following parameters of left ventricular function were evaluated: ejection fraction (EF), peak velocity of the early (E) and late atrial (A) mitral flow, A/E ratio, duration of the early (Ei) and of the atrial (Ai) filling phase, and heart rate. The diabetic patients had significantly higher total cholesterol and triglyceride levels compared with healthy subjects. These remained elevated throughout the follow-up period, in spite of improved glycaemic control. A significantly shorter duration of Ei (0.15 +/- 0.008 vs 0.18 +/- 0.004, P < 0.01) and a higher value of A (0.51 +/- 0.02 vs 0.39 +/- 0.01, P < 0.001) and A/E (1.06 +/- 0.05 vs 0.73 +/- 0.02, P < 0.001) were found in the diabetic patients before treatment. The parameters did not significantly change after 1 year of adequate glycaemic control. These results indicate a left ventricular filling abnormality which is present in newly diagnosed non-insulin-dependent diabetic patients and does not reverse with improved glycaemic control.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Chlorpropamide; Cholesterol; Diabetes Mellitus, Type 2; Diet, Diabetic; Echocardiography, Doppler; Female; Follow-Up Studies; Glucagon; Glyburide; Glycated Hemoglobin; Heart Rate; Humans; Male; Middle Aged; Reference Values; Triglycerides; Ventricular Function, Left

In spite of the high prevalence of diabetes mellitus (DM) in patients with liver cirrhosis (LC) few studies have focused on the clinical implications of this association. We investigated the clinical and pancreatic-endocrine features of 34 patients who developed DM after LC (Group I). Results were compared with 34 carefully matched patients with only Type II DM (Group II). A standard meal test was performed in 26 patients with normal renal function from each group to assess beta-cell function. Group I patients, less frequently had retinopathy (14.7% vs. 45.5%, P < 0.05) and a family history of diabetes (23.5% vs. 58.8%, P < 0.01). Group I patients also showed signs of enhanced insulin resistance, reflected by higher insulin dose requirements in insulin-treated patients (0.87 +/- 0.10 vs. 0.62 +/- 0.05 IU/kg/day, P < 0.01) and increased basal C-peptide values (0.88 +/- 0.06 vs. 0.68 +/- 0.07 pmol/l, P < 0.05, respectively) than those in Group II. These results suggest that several clinical features, probably related to the hepatopathy, define DM occurring in patients with LC.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Liver Cirrhosis; Male; Middle Aged; Prevalence

This study was conducted to determine whether improvements in glucose tolerance could be observed after a single bout of resistance exercise in young (27.1 +/- 1.24 yr) control subjects, older (53.3 +/- 1.7 yr) patients with non-insulin-dependent diabetes mellitus (NIDDM), and older (50.7 +/- 1.9 yr) age-matched control subjects. Each subject was screened for fitness level and any contraindications to exercise before inclusion in the study. A 75-g oral glucose tolerance test was administered 2 wk after the subjects were screened, and the subjects were familiarized with the exercise equipment. The maximum weight that could be lifted with one repetition was determined on seven Nautilus machines that utilized the upper and lower body. After a 48-h rest period, a 3-set x 10-repetition protocol based on the subject's one repetition maximum was completed by each participant on each machine. Eighteen hours after the lifting protocol, a second oral glucose tolerance test was administered. There was no change in the pre- to post-exercise glucose levels in any of the treatment groups, but the total insulin responses (area under the curve) of the young control and NIDDM groups were significantly lower after exercise: from 6.93 +/- 0.8 x 10(3) to 5.38 +/- 0.65 x 10(3) pM in the young control group and from 9.83 +/- 1.95 x 10(3) to 7.77 +/- 1.50 x 10(3) pM in the NIDDM group. The postexercise C-peptide levels were unchanged in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Exercise; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Oxygen Consumption; Weight Lifting

Hyperinsulinaemia and abnormalities in hepatic insulin extraction commonly coexist in ethnic groups with severe insulin resistance. Therefore, we compared the effects of ethnicity on glucose/insulin/C-peptide dynamics, hepatic insulin extraction, and insulin sensitivity in healthy black (n = 32) and white (n = 30) Americans. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified, frequently sampled, intravenous glucose tolerance (FSIVGT) tests were performed in each subject. Insulin sensitivity index (S1)) was calculated using the MINIMOD method described by Bergman et al. Basal and post-stimulation hepatic insulin extraction were calculated by the molar ratios of C-peptide and insulin concentrations during the basal steady state and areas under the post-stimulation hormone curves, respectively. Apart from a slightly greater mean serum glucose peak response after oral glucose in the whites, mean glucose levels were identical in the blacks and whites during both stimulations. In contrast, serum insulin levels at basal and during both stimulations were significantly greater (2-3 fold) in the blacks than whites. However, the corresponding C-peptide responses were identical in both groups. The basal and postprandial hepatic insulin extraction were 33% and 45% lower in the blacks when compared to whites, respectively. The mean S1 was significantly (p < 0.02) lower in the blacks (4.93 +/- 0.46) than the whites (7.17 +/- 0.88 x 10(-4).min-1 (mU l-1)-1). We conclude that ethnicity may be a major determinant of the mechanism of peripheral hyperinsulinaemia and insulin insensitivity in black and white Americans.

Topics: Administration, Oral; Adult; Black People; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; United States; White People

Glucose intolerance or diabetes mellitus, hyperlipidemia, obesity and hypertension may have a close interrelation based on insulin resistance. We selected 28 impaired glucose tolerance (IGT) patients with hyperlipidemia. The IGT patients demonstrated hypertriglyceridemia associated with hyperinsulinemia, a typical manifestation of insulin resistance. Administration of bezafibrate at 400 mg/day for 4 weeks to the IGT patients with hypertriglyceridemia resulted in an improvement of the plasma glucose level and insulin response to 75 g oral glucose loading associated with a concomitant decrease in non-esterified fatty acids. The ratio of the level of serum C-peptide to that of insulin after a 75 g oral glucose tolerance test (OGTT) was augmented after 4 weeks of bezafibrate administration. However, reduction of the cholesterol level with pravastatin did not alter these parameters. These results suggest that treatment to reduce the level of serum triglycerides, but not that of cholesterol, may have a beneficial effect for improving insulin resistance even in the non-obese subjects with IGT and decreasing the risk of coronary heart disease.

Topics: Bezafibrate; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Male; Middle Aged; Pravastatin

To compare the efficacy and safety of controlled-release glipizide (glipizide-GITS [gastrointestinal therapeutic system]) and immediate-release glipizide in patients with non-insulin-dependent diabetes mellitus (NIDDM).. In a multicenter, open-label, randomized, two-way crossover study, 132 patients with NIDDM received daily doses of 5, 20, or 40 mg of either glipizide-GITS or immediate-release glipizide for 8 weeks followed by 8 weeks of the alternate formulation. Plasma glucose, serum insulin, C-peptide, and plasma glipizide levels were measured at fasting and post-Sustacal challenge at the end of 1 and 8 weeks of each treatment phase. HbA1c was measured at the end of weeks 7 and 8 of each treatment phase.. Both formulations of glipizide yielded similar mean HbA1c values. However, mean fasting plasma glucose (FPG) levels were significantly lower with glipizide-GITS treatment than with immediate-release glipizide at the end of week 1 (11.0 vs. 11.6 mmol/l; P < 0.01) and at the end of the 8-week treatment phase (10.9 vs. 11.7 mmol/l; P < 0.001). Fasting insulin and C-peptide levels were lower after 5 mg glipizide-GITS vs. immediate-release glipizide. Glucose responses to Sustacal were similar after both formulations of glipizide; however, serum insulin (P < 0.01) and C-peptide responses (P < 0.05) were lower with glipizide-GITS than with immediate-release glipizide treatment at the end of the 8-week treatment phase. Mean plasma glipizide concentrations were stable by the end of week 1, and the concentrations increased proportionately with dose. Once-daily Glipizide-GITS provided effective mean glipizide concentrations (> 50 ng/ml) 24 h after dosing, even at the lowest (5 mg) dose level. Both formulations were well tolerated.. Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Glipizide; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Radioimmunoassay

To determine whether previously reported abnormalities in fibrinolytic activity and plasma lipoprotein (a) levels could reflect obesity rather than diabetes per se, plasma concentrations of tissue-type plasminogen activator (t-PA), type 1 plasminogen activator inhibitor (PAI-1), and lipoprotein (a) (Lp (a)) were investigated in sixty-four type 2 diabetic patients (56.1 +/- 9.5 years; body mass index, 24.6 +/- 3.3 kg/m2) and thirty-two control subjects (57.9 +/- 8.9 years; body mass index, 24.6 +/- 3.4 kg/m2). Both the plasma t-PA and PAI-1 antigen levels were similar between the diabetic group (10.6 +/- 3.8 ng/ml; 27.7 +/- 11.6 ng/ml) and the control group (12.2 +/- 3.5 ng/ml; 27.7 +/- 9.6 ng/ml). The PAI-1 levels were evenly distributed from 5.93 to 52.7 ng/ml in diabetic patients. The difference of Lp (a) levels between the two groups was negligible (the diabetic group, median 11 mg/dl (range 0-72 mg/dl); the control group, median 13 mg/dl (range 0-55 mg/dl)). Significant correlations between PAI-1 levels and body mass index (BMI) were observed in both groups. In the diabetic group, PAI-1 levels also correlated with fasting C-peptide levels (r = 0.54, P < 0.01) and serum triglyceride levels (r = 0.28, P < 0.05). However, we could not find a significant association between either t-PA or PAI-1 levels and Lp (a) levels in the diabetic and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibrinolysis; Glycated Hemoglobin; Humans; Hypertension; Korea; Lipids; Lipoprotein(a); Male; Middle Aged; Obesity; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator

A total of 507, newly diagnosed, white Caucasian Type 2 diabetic patients entered into UK Prospective Diabetes Study, mean age 52 +/- 9 (SD) years have been compared with 195 age-matched normal subjects (fasting plasma glucose < 6 mmol l-1) who had no known first degree relatives with diabetes. Diabetic patients were more obese BMI(kg m-2) 30.1 +/- 6.2 vs 26.2 +/- 4.0, respectively, with female (F) diabetic patients more so than male (M). Fasting plasma glucose (mmol l-1) was 12.2 +/- 3.8 vs 5.0 +/- 0.6 in diabetic and normal subjects, and, haemoglobin A1c(%) 9.3 +/- 2.3 vs 5.4 +/- 0.4. Hyperinsulinaemia (mU l-1) was prevalent in both male and female diabetic patients, after adjustment for BMI (geometric mean 1SD interval, M 12.1 (11.8 to 12.4) vs 8.3(7.8 to 8.9) and F 13.3 (12.9 to 13.7) vs 7.4 (7.1 to 7.7). Plasma triglyceride (mmol l-1) was higher in diabetic patients, 1.8 (1.1 to 2.9) vs 1.1 (0.6 to 1.8). Total cholesterol (mmol-1) was slightly elevated in diabetic patients, with females in both populations higher than males, M 5.5 +/- 1.2 vs 5.2 +/- 0.9 and F 5.8 +/- 1.1 vs 5.5 +/- 1.1. HDL cholesterol (mmol l-1) was slightly lower in male and markedly lower in female diabetic patients than in normal subjects, M 1.00 +/- 0.26 vs 1.11 +/- 0.22 and F 1.12 +/- 0.27 vs 1.42 +/- 0.33. Urine albumin was raised in diabetic patients (mg l-1) 16.3 (5.2 to 50.9) vs 7.2 (3.2 to 16.5), as was urine N-acetylglucosaminidase (U l-1 6.4 (3.5 to 11.7) vs 2.9 (1.9 to 4.5) and plasma N-acetylglucosaminidase (U l-1) 11.5 +/- 3.2 vs 10.2 +/- 2.3. Normal subjects aged above 65 years, had slightly higher haemoglobin A1c, insulin, C-peptide, plasma and LDL cholesterol, triglyceride, plasma and urine N-acetylglucosaminidase and lower HDL cholesterol than younger subjects. The 2.5 and 97.5 percentiles for biochemical variables are presented for both populations aged 25-65 years.

Topics: Acetylglucosaminidase; Adult; Age Factors; Aged; Albuminuria; Biomarkers; Blood Glucose; C-Peptide; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Female; Fructosamine; Glycated Hemoglobin; Growth Hormone; Hexosamines; Humans; Hyperinsulinism; Insulin; Laboratories; Male; Middle Aged; Prevalence; Prospective Studies; Quality Control; Reference Values; Risk Factors; Sex Characteristics; Triglycerides; United Kingdom

A randomized prospective study was conducted to determine whether the insulin regimen for NIDDM subjects poorly controlled on oral therapy should be designed primarily to control basal metabolism or to control mealtime hyperglycaemia. Grossly obese subjects were excluded. After a 2-month run-in phase involving intensive education, subjects were randomized to therapy with twice daily isophane or three times daily soluble insulin. Both Protaphane and Actrapid brought about similar improvement in HbA1 (9.5 +/- 0.5 and 9.7 +/- 0.4%) compared with baseline (11.7 +/- 0.5%; p < 0.001). Diurnal blood glucose profiles showed that despite the good post-prandial control achieved by pre-meal soluble insulin, loss of control occurred overnight, resulting in higher fasting blood glucose levels compared with Protaphane therapy (8.0 +/- 0.8 vs 10.6 +/- 0.8 mmol l-1; p < 0.05). The overall rate of hypoglycaemia was 0.44 patient-1 year-1. Thirty-two mild hypoglycaemic episodes occurred on Protaphane therapy and 79 on Actrapid therapy. Using formal psychometric tests it was shown that insulin therapy was associated with improved treatment satisfaction and that this was greater on Protaphane therapy (p < 0.05). Overall well-being increased similarly in the two groups. All subjects wished to continue with insulin therapy after the conclusion of the study. The insulin regimen for moderately or poorly controlled non-insulin-dependent diabetes should primarily be designed to correct the basal insulin deficiency rather than to mimic normal meal-induced insulin secretion.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Eating; Glycated Hemoglobin; Humans; Insulin; Insulin, Isophane; Insulin, Regular, Pork; Middle Aged; Patient Education as Topic; Patient Satisfaction; Prospective Studies; Quality of Life; Surveys and Questionnaires; Triglycerides; Weight Gain

The question of whether to use insulin in the evening or in the morning during combination therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM) is controversial. We compared the acute effects of 12-h nocturnal or daytime insulin infusions on the 24-h glucose profile in 20 patients with NIDDM.. NIDDM patients were 56 +/- 2 (mean +/- SE) years of age and had a body mass index of 29.6 +/- 1.1 kg/m2; fasting plasma glucose concentration of 12.2 +/- 0.5 mM; and fasting C-peptide concentration of 0.9 +/- 0.2 nM. Each patient was studied twice. On one occasion, the patient received a 12-h intravenous infusion of insulin (mean 1.5 +/- 0.1 IU/h) during the day, and on the other occasion an identical dose of insulin was infused during the night. Blood glucose, insulin, c-peptide, and free fatty acid concentrations were determined for 24 h.. The mean 24-h free insulin concentrations were similar in both studies (150 +/- 12 vs. 162 +/- 12 pM, daytime versus nocturnal insulin infusion). The mean 24-h free fatty acid concentration was 18% lower in the nocturnal than in the daytime (309 +/- 30 vs. 376 +/- 30 microM, P < 0.001) insulin infusion study. The mean 24-h C-peptide concentration was less suppressed if insulin was infused overnight than during the day (1.3 +/- 0.2 vs. 1.1 +/- 0.2 nM, P < 0.01). The mean 24-h plasma glucose concentrations were identical in both studies (11.1 +/- 0.6 vs. 11.4 +/- 0.7 mM, daytime versus nocturnal insulin infusion). We also searched for factors predicting the decrease in the blood glucose concentration during the nocturnal insulin infusion. The best predictors were a high initial blood glucose concentration at 2200 and a low fasting C-peptide concentration. These factors explained, independent of each other, 50% of the rate of decrease in the plasma glucose concentration.. Despite better suppression of lipolysis and less suppression of endogenous insulin secretion by nocturnal than daytime insulinization, the hypoglycemic effect of these two treatments is similar.

Topics: Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fatty Acids, Nonesterified; Female; Homeostasis; Humans; Infusions, Intravenous; Insulin; Male; Middle Aged

To determine plasma apolipoprotein A-IV (apoA-IV) levels and phenotype distribution in non-insulin-dependent diabetes mellitus (NIDDM) patients and to analyze the influence of apoA-IV phenotype on lipid profiles in NIDDM.. Total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, HDL3 cholesterol, free fatty acid, and apoA-IV levels were measured in 83 NIDDM patients and 100 normal control subjects. The apoA-IV phenotype was determined in each individual.. In both sexes, NIDDM patients had significantly higher levels of triglyceride and free fatty acid and significantly lower levels of HDL cholesterol and HDL2 cholesterol than control subjects. In men and women, apoA-IV levels were significantly higher in diabetic patients than in control subjects (men: 17.1 +/- 7.9 vs. 12.3 +/- 3.6 mg/dl, P < 0.001; women: 18.9 +/- 9.9 vs. 11.9 +/- 3.5 mg/dl, P < 0.001). The multiple regression analysis showed that the apoA-IV level in NIDDM patients was significantly and independently related to log triglyceride (P = 0.0001) and HDL cholesterol (P = 0.01) levels. The apoA-IV phenotype distribution was not significantly different between NIDDM patients and control subjects. In the control subjects, the apoA-IV-1-2 phenotype was associated with significantly higher levels of HDL cholesterol (69 +/- 12 vs. 56 +/- 11 mg/dl, P < 0.01) and of HDL2 cholesterol (36 +/- 15 vs. 25 +/- 12 mg/dl, P < 0.05) compared with the apoA-IV-1-1 phenotype; on the other hand, HDL cholesterol and HDL2 cholesterol levels were not different between the two apoA-IV phenotypes in NIDDM patients.. Plasma apoA-IV levels are increased in NIDDM patients. This increase in apoA-IV is related mainly to hypertriglyceridemia and, to a lesser extent, to HDL cholesterol level. The apoA-IV phenotype distribution is not different between NIDDM patients and nondiabetic control subjects. The potential protective lipid profile (characterized by increased HDL and HDL2 cholesterol levels) linked with apoA-IV-1-2 phenotype in control subjects is no longer found in NIDDM patients. We suggest that the metabolic state of NIDDM has erased the potential protective lipid profile associated with the apoA-IV-1-2 phenotype.

Topics: Apolipoproteins A; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Humans; Insulin; Male; Middle Aged; Phenotype; Reference Values; Regression Analysis; Sex Characteristics; Triglycerides

To compare platelet plasminogen activator inhibitor 1 (PAI-1) concentration in type II diabetic patients and healthy control subjects.. We studied a group of 12 diabetic patients whose disease was controlled by diet or sulfonylurea therapy and a group of 17 nondiabetic control subjects. All subjects were free of clinically advanced vascular disease. PAI-1 antigen concentrations were measured in 5 x 10(8) isolated platelets, which were lysed by 1% Triton X-100.. Mean platelet PAI-1 was significantly higher in diabetic patients (264 +/- 83 ng/5 x 10(8) platelets) compared with control subjects (202 +/- 71 ng/5 x 10(8) platelets) (P < 0.05). A significant independent positive correlation was found between platelet PAI-1 concentrations and fasting plasma specific insulin levels in the diabetic patients (r = 0.63, P = 0.03).. These findings suggest that 1) a higher platelet PAI-1 concentration may contribute to enhanced thrombosis in type II diabetes and 2) megakaryocyte PAI-1 synthesis may be under the control of insulin.

Topics: beta-Thromboglobulin; Blood Platelets; Blood Pressure; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; In Vitro Techniques; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Platelet Factor 4; Reference Values; Triglycerides

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Humans; Insulin; Islets of Langerhans; Middle Aged; Proinsulin

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aldosterone; Angiotensin II; Blood Pressure; C-Peptide; Cardiac Output; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Heart Rate; Humans; Insulin; Male; Middle Aged; Placebos; Potassium; Triglycerides

To investigate the effect of subcutaneously injected glucagon-like peptide 1 (GLP-1) (7-36)amide on postprandial plasma glucose, insulin, and C-peptide levels in patients with non-insulin-dependent diabetes mellitus (NIDDM) and a secondary failure to sulfonylureas.. GLP-1 (25 nmol) was injected subcutaneously into either the abdominal wall or the gluteal region at a standardized depth and speed. The injection device was guided by the ultrasound determination of the depth of the fat layer. The peptide was given 5 min before a standard meal. Plasma concentrations of glucose, C-peptide, insulin, glucagon, and GLP-1 were followed during 240 min after the injection.. In control experiments, a significant hyperglycemia was attained after the meal. GLP-1 given into the abdominal wall not only virtually abolished the post-prandial blood glucose rise but significantly decreased glucose concentrations, with a nadir at approximately 25 min after the injection. A rapid rise of C-peptide and insulin levels was observed 10-15 min after the injection of GLP-1. The stimulatory effect of GLP-1 was transient, and, at 45 min after the meal, both insulin and C-peptide levels were almost identical in GLP-1 and control experiments. Significantly lower glucagon concentrations were observed 35-65 min after the peptide injection. GLP-1 concentration in plasma increased from 10 pM to a peak concentration (Cmax) of 70 pM at Tmax 30 min after injection. Then GLP-1 levels rapidly decreased to 25 pM at 95 min and returned to basal at 215 min. The gluteal injection of GLP-1 had similar effects compared with the abdominal administration on plasma levels of glucose, insulin, C-peptide, and glucagon.. GLP-1 is promptly absorbed from the subcutaneous tissue. It exerts a significant blood glucose lowering effect when administered before meals in overweight patients with NIDDM.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Injections, Subcutaneous; Insulin; Male; Middle Aged; Peptide Fragments; Protein Precursors; Radioimmunoassay; Time Factors

To study the effects on blood pressure and glucose homeostasis of felodipine, a calcium antagonist.. A double-blind randomized cross-over study comparing felodipine ER and placebo.. A university centre of diabetic care in Malmö, Sweden.. Seventeen hypertensive type II diabetic males on oral sulfonylurea (glibenclamide) treatment.. Four-week treatment periods separated by a 2-week wash-out period. Felodipine 10-20 mg once daily was given.. Blood pressure, heart rate, HbA1c and response to oral glucose tolerance test; glucose, insulin and c-peptide. Measured before randomization and at the end of each double-blind treatment period.. Blood pressure was significantly reduced during felodipine treatment and heart rate slightly increased. Felodipine did not influence insulin or c-peptide levels. There was no significant change in glucose levels but an increase in HbA1c.. The study demonstrated that felodipine is an effective agent for type II diabetic patients on glibenclamide treatment. The effect on HbA1c is noteworthy even if not of clinical significance in the short term. Controlled long-term studies in diabetic patients are needed to fully evaluate antihypertensive agents.

Topics: Aged; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Felodipine; Heart Rate; Hemoglobin A; Humans; Hypertension; Insulin; Male; Middle Aged; Sulfonylurea Compounds; Time Factors

To better understand abnormal insulin production (IP) in states of carbohydrate intolerance, insulin release was quantified following equimolar (2.4 mmol/kg) infusions of glucose, arginine, and valine in healthy subjects ([HS] age, 45 +/- 3 years; body mass index [BMI, kg/m2], 26.3 +/- 2.4; means +/- SEM), obese subjects with impaired glucose tolerance ([IGT] age, 43 +/- 5 years; BMI, 35.4 +/- 2.4), and non-obese patients with chronic non-insulin-dependent diabetes mellitus ([NIDDM] age, 55 +/- 3 years; BMI, 26.4 +/- 1.4; duration of disease, 13 +/- 3 years). There were eight subjects per group. Incremental IP (metabolic clearance rate of C-peptide [MCRCP] x total incremental area under the curve of plasma C-peptide [AUCCP], pmol/kg) following substrate infusion was as follows: glucose: HS, 227 +/- 14; IGT, 1,050 +/- 184 (P < .001 v HS); NIDDM, 114 +/- 27 (P < .001 v HS); arginine: HS, 139 +/- 23; IGT, 488 +/- 106 (P < .01 v HS); NIDDM, 206 +/- 47; and valine: HS, 21 +/- 7; IGT, 32 +/- 10; NIDDM, 54 +/- 12 (P < .01 v HS). The fractional clearance rate ([FCR] k, %/min) was impaired in IGT and NIDDM for glucose (HS, 3.9 +/- 0.4; IGT, 2.3 +/- 0.3 [P < .01 v HS]; NIDDM, 1.4 +/- 0.1 [P < .001 v HS]), arginine (2.4 +/- 0.1; 1.9 +/- 0.2 [P < .01 v HS]; 1.9 +/- 0.2 [P < .01 v HS]), and valine (0.95 +/- 0.06; 0.65 +/- 0.09 [P < .05 v HS]; 0.74 +/- 0.1 [P < .05 v HS]).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arginine; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Intolerance; Humans; Injections, Intravenous; Insulin; Male; Middle Aged; Valine

Vitamin D has been shown to increase insulin release from pancreatic islet cells in vitro, and to improve insulin secretion in vitamin D-deficient animals. Few attempts have been made to evaluate this issue directly in humans. We studied 35 otherwise healthy diabetic subjects in the early spring at the seasonal nadir of 25-hydroxyvitamin D [25(OH)D] concentrations (mean 35 +/- 7 nmol/L). Fasting glucose, insulin, C-peptide, and glucagon concentrations, and their responses to Sustacal stimulation were not related to indexes of mineral metabolism. In 20 subjects, a double-blinded, placebo-controlled, crossover trials of 1,25-dihydroxyvitamin D[1,25](OH)2D] treatment (1 micrograms/d for 4 d) had no effect on fasting or stimulated glucose, insulin, C-peptide, or glucagon concentrations. However, insulin and C-peptide responses to Sustacal after 1,25(OH)2D treatment were related to duration of diabetes (r2 = 0.28, P = 0.052 and r2 = 0.25, P = 0.002, respectively) in that short duration correlated with improvement after 1,25(OH)2D treatment. Hence, vitamin D nutrition, or 1,25(OH)2D therapy, had no major effect on glucose homeostasis in non-insulin-dependent diabetes mellitus.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Calcifediol; Calcitriol; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucagon; Humans; Insulin; Insulin Secretion; Male; Middle Aged

The aim of the present study was to investigate the effects of magnesium supplementation on glucose uptake and substrate oxidation in noninsulin-dependent (type II) diabetic patients. Nine elderly non-obese noninsulin-dependent (type II) diabetic patients, treated by diet only, participated in the study, which was designed as randomized, double blind, and cross-over. Each patient was followed up for a prestudy period of 3 weeks before inviting him/her to receive placebo or magnesium supplementation (15.8 mmol/day) for 4 weeks. At the end of each treatment period, a euglycemic hyperinsulinemic glucose clamp with simultaneous D-[3-3H]glucose infusion and indirect calorimetry was performed. Magnesium supplementation resulted in significantly increased plasma and erythrocyte magnesium levels, whereas body weight and fasting plasma glucose did not change. In the last 60 min of the glucose clamp, insulin-mediated glucose disappearance, total body glucose disposal (24.5 +/- 0.4 vs. 28.2 +/- 0.7 mumol/kg.min; P < 0.005), and glucose oxidation (13.0 +/- 0.4 vs. 16.3 +/- 0.8 mumol/kg.min; P < 0.01) were increased after chronic magnesium supplementation. Endogenous glucose production, nonoxidative glucose disposal, lipid and protein oxidation, and insulin MCR were not affected. In conclusion, a 4-week magnesium supplementation improves insulin sensitivity and glucose oxidation in the course of a euglycemic-hyperinsulinemic glucose clamp in noninsulin-dependent diabetic patients. Long term studies are needed to determine whether magnesium supplementation is useful in the management of type II diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Erythrocytes; Female; Glucagon; Glucose; Humans; Insulin; Magnesium; Male; Oxidation-Reduction

Insulin-like growth factor I (65 micrograms/kg) or insulin (0.1 IU/kg) were injected i.v. on two separate occasions in random order in normal and in Type 2 (non-insulin-dependent) diabetic subjects. Insulin-like growth factor I and insulin injection resulted in identical decrements of plasma glucose concentrations after 30 min but in delayed recovery after insulin-like growth factor I as compared to insulin in both groups (p < 0.05 insulin-like growth factor I vs insulin). Counterregulatory increases in plasma glucagon, adrenaline, cortisol and growth hormone concentrations after hypoglycaemia (1.9 +/- 0.2 mmol/l) in normal subjects were blunted after insulin-like growth factor I administration compared to insulin (p < 0.05). Plasma glucose in Type 2 diabetic subjects did not reach hypoglycaemic levels but the acute glucose decrease to 4.5 +/- 0.8 mmol/l was associated with significantly lower responses of plasma glucagon and adrenaline but higher cortisol levels after insulin-like growth factor I compared to insulin (p < 0.003). Plasma concentrations of non-esterified fatty acids and leucine decreased similarly after insulin-like growth factor I and insulin in both groups. The present results demonstrate that insulin-like growth factor I is capable of mimicking the acute effects of insulin on metabolic substrates (plasma glucose, non-esterified fatty acids, leucine). The decreases of plasma glucose were similar after both peptides in normal and in diabetic subjects who were presumably insulin resistant. Counterregulatory hormone responses to plasma glucose decrements differed, however, between insulin-like growth factor I and insulin and in the diabetic and the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Growth Hormone; Hormones; Humans; Hydrocortisone; Insulin; Insulin-Like Growth Factor I; Kinetics; Leucine; Male; Middle Aged; Norepinephrine; Recombinant Proteins

The metabolic effects of a 3-week dietary supplement of a fish oil concentrate was examined in mildly obese, normotriglyceridemic men with non-insulin-dependent diabetes mellitus (NIDDM) treated with hypoglycemic agents (n = 20). Patients were randomized into two groups, receiving 15 ml per day of fish oil (Martens Oil, Norway) containing 3.1 g of omega-3 fatty acids (FA) (n = 10) or placebo (n = 10). Whereas fish oil led to the expected increase in the ratio of omega-3 to omega-6 FA in serum phospholipids, reflecting the increase in omega-3 FA intake, it did not alter fasting or mixed meal stimulated blood glucose, plasma insulin, and C-peptide concentrations. No changes in insulin action were noted, estimated by the metabolic clearance rates of glucose at plasma insulin levels of approximately 100 microU/ml and 1,400 microU/ml during a hyperinsulinemic, isoglycemic clamp; no changes were seen in insulin binding to erythrocytes. We conclude that during short-term administration, no adverse effects of low dose fish oil on glucose homeostasis were found in mildly obese NIDDM patients treated with oral hypoglycemic agents.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Fish Oils; Glyburide; Humans; Insulin; Kinetics; Male; Middle Aged; Obesity; Triglycerides

To ascertain whether childbearing would decrease oral glucose-stimulated insulin and C-peptide levels and increase the risk of NIDDM and impaired glucose tolerance in a population of Hispanic and non-Hispanic white women residing in the San Luis Valley of Colorado. Several investigators have related childbearing to subsequent abnormal glucose tolerance.. In a population-based case-control epidemiological study, diabetic patients 20-74 yr of age (n = 196) and randomly sampled control women subjects (n = 735) underwent a glucose tolerance test, a physical examination, and an in-person standardized interview. The relations between the live-birth number and fasting and oral glucose stimulated glucose, insulin and C-peptide concentrations, and NIDDM and impaired glucose tolerance were estimated using linear or logistic regression to adjust for extraneous variables.. In women selected as control subjects, the live-birth number was related to a significant decrease in the sum of 1- and 2-h C-peptide concentrations (coefficient = -0.077, P < 0.001) and the logarithm of the sum of 1- and 2-h insulin concentrations (coefficient = -0.014, P = 0.02). After adjustment for subscapular skin-fold thickness, the relative odds of NIDDM for the live-birth number, which was small and of borderline significance, diminished (odds ratio = 1.04 for one birth, P = 0.18). Findings were similar for impaired glucose tolerance.. Childbearing was related to lower C-peptide and insulin levels in Hispanic and non-Hispanic women of the San Luis Valley. It had little apparent effect on later risk of NIDDM or impaired glucose tolerance.

Topics: Adult; Age Factors; Aged; Blood Glucose; C-Peptide; Colorado; Diabetes Mellitus, Type 2; Ethnicity; Female; Glucose Intolerance; Glucose Tolerance Test; Hispanic or Latino; Humans; Insulin; Medical History Taking; Middle Aged; Parity; Pregnancy; Regression Analysis; Risk Factors; White People

Benfluorex hydrochloride has known lipid- and glucose-lowering effects. We evaluated the change in lipids, fasting glucose, and insulin sensitivity in ten obese type 2 diabetic patients after treatment with benfluorex or a placebo for 2 weeks using a double-blind, cross-over design. Insulin sensitivity was measured using the euglycaemic-hyperinsulinaemic glucose clamp technique at two insulin infusion rates for 2 h each: 0.05 U/kg per h (clamp 1) and 0.10 U/kg per h (clamp 2). Mean fasting glucose decreased from 13.1 +/- 1.1 to 10.2 +/- 0.9 mmol/l after benfluorex (p < 0.001) and rose from 11.9 +/- 0.9 to 13.3 +/- 1.0 mmol/l after the placebo (p = 0.028). Insulin did not change significantly. Glucose uptake (GU) as a parameter for insulin sensitivity was compared for treatment with benfluorex versus the placebo. Total GU during clamp 1 was 643.4 +/- 323.8 mmol after benfluorex and 250.1 +/- 193.3 mmol after the placebo (p = 0.035), and during clamp 2, 2490.7 +/- 490.5 mmol after benfluorex and 1544.3 +/- 693.9 mmol after the placebo (p = 0.018). The dynamic analysis on the last 30 min of clamp 2 showed a significant difference in glucose infusion rate (GIR) profile, with mean levels yielding 5.36 mmol/kg per min after benfluorex and 3.87 mmol/kg per min after the placebo (p = 0.018); there were no differences in plasma insulin concentrations or plasma glucose levels. It is concluded that in this short-term study benfluorex increases insulin sensitivity in obese type 2 diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Fenfluramine; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Middle Aged; Obesity

Altogether 86 patients with recently diagnosed NIDDM, aged 40-64 years were randomised after 3 months of basic education to intensified diet (Int. group, 21 men, 19 women) or conventional treatment groups (Conv. group, 28 men, 18 women). The aim was to examine whether an intensified diet education would result in a better metabolic control and greater reduction in cardiovascular risk factors than conventional treatment for obese patients with recently diagnosed type 2 diabetes mellitus. Furthermore, both groups were re-examined after a second year of observation period to find out the maintenance of the results after intervention. After basic education, Int. group participated in 12-months diet education, while Conv. group was treated in local health centres. During the intervention period, only Int. group showed further weight reduction. Only 20% of patients in Int. and 6% of patients in Conv. group had BMI < 27 kg/m2 at the end of the intervention, while 75% of patients in Int. and 52% of patients in Conv. group had achieved a good metabolic control (fasting blood glucose < 6.7 mmol/l; P = 0.005 between groups). Serum total cholesterol did not change significantly, but the changes in HDL-cholesterol, triglycerides and apolipoprotein B level were significant in Int. group only. The proposed acceptable values for serum lipids were achieved by 52 to 88% of patients without major differences between the two groups. During the second year of observation, weight gained in both groups and a deterioration was seen in metabolic control. Despite that a greater proportion of patients in the Int. group still was in good metabolic control (55.3% vs. 31.8%, P = 0.016), furthermore Int. group was receiving less frequently oral drugs for hyperglycaemia than Conv. group. No differences in serum lipids were observed between the groups after the observation period. HDL-cholesterol showed a persistent improvement in both groups.

Topics: Adult; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Blood Pressure; C-Peptide; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Female; Follow-Up Studies; Glucagon; Glycated Hemoglobin; Humans; Male; Middle Aged; Sex Factors; Triglycerides

New treatment options are needed for glycemic control in NIDDM. We evaluated the effects of bedtime or morning insulin treatment, combined with daytime glyburide or given alone.. Twenty-nine male patients with NIDDM, mean age 63 +/- 1.7 yr, body weight 124 +/- 2.98% of DBW, received a maximum glyburide dose (20 mg/day) for a minimum of 6 wk, to confirm sulfonylurea failure. Human lente insulin was added for 12 wk either AM (n = 14) or HS (n = 15) and adjusted to obtain fasting euglycemia (FPG; combination treatment phase). Glyburide was then stopped, and insulin was continued for 6 wk, aiming for normal FPG (insulin phase).. After combination treatment phase, FPG decreased (P < 0.02) from 12.43 +/- 0.68 to 5.73 +/- 0.65 mM (AM) and from 12.68 +/- 0.76 to 5.51 +/- 0.48 mM (HS) (AM vs. HS, NS). Postbreakfast, presupper, and 0200 AM plasma glucose levels fell equally (P < 0.02) except for 1-h postprandial (AM 12.46 +/- 0.51 mM, HS 10.88 +/- 0.62 mM, AM vs. HS, P < 0.1). Mean HBA1c fell similarly in both AM and HS groups. At 2 wk of the insulin phase, FPG was higher in AM than HS, 9.8 +/- 0.76 vs. 7.56 +/- 0.7 mM (P < 0.1). At the end of insulin phase, plasma glucose levels were similar to the end of combination treatment phase, but the insulin dose had to be raised in AM by 39% (P < 0.02) and HS by 30% (P < 0.05). After the combination treatment phase, fasting C-peptide was significantly suppressed in HS group only, from 1.22 +/- 0.12 to 0.82 +/- 0.09 nM (P < 0.02). At the end of insulin phase, fasting C-peptide was further suppressed in both groups, but 2-h postprandial C-peptide levels decreased significantly in AM group only, from 1.85 +/- 0.23 to 1.42 +/- 0.13 nM (P < 0.02). Triglycerides and total and HDL cholesterol did not change significantly after either combination treatment phase or insulin phase. Mean weight gain was 6.5 lb during combination treatment phase (NS from baseline), without further change during insulin phase. Hypoglycemic reactions, all mild, were recorded at a rate of 1.35/patient in the AM group and 0.4/patient in the HS group (P < 0.025).. Normal fasting glycemia and near-normal postprandial glucose profile could be obtained with combination therapy in NIDDM. Results were similar if insulin, alone or in combination with glyburide, was given before breakfast or at bedtime, but hypoglycemic reactions were more common with conventional morning insulin injections.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Fasting; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin, Long-Acting; Male; Middle Aged; Recombinant Proteins; Time Factors

The effects of 15 g guar gum/d on glycemic control, lipids, and insulin secretion were studied in 15 (8 male, 7 female) diet-treated subjects with non-insulin-dependent diabetes mellitus for 48 wk. Mean age (+/- SD) was 60 +/- 2 y (range 45-70 y), body mass index (in kg/m2) 28.6 +/- 0.9 (range 21.6 +/- 39.2), and duration of diabetes 6 +/- 1 y (range 2-14 y). Guar gum was preceded and followed by 8-wk placebo periods. Guar gum improved long-term glycemic control, postprandial glucose tolerance and lipid concentrations. The C-peptide response to a test meal increased by time during guar gum treatment, whereas the insulin response remained unchanged. This indicates that insulin secretion is enhanced by guar gum as reflected by increased C-peptide. A decreased molar ratio of insulin to C-peptide suggests that guar gum may increase hepatic insulin extraction. In conclusion, guar gum has favorable long-term effects on glycemic control and lipid concentrations.

Topics: Aged; Blood Glucose; C-Peptide; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dietary Fiber; Female; Galactans; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Mannans; Middle Aged; Plant Gums

Patients with NIDDM have a two- to fourfold increased risk of macrovascular disease. The constellation of elevated TGs and decreased HDL cholesterol are recognized as risk factors and constitute the major dyslipidemia in NIDDM. We therefore sought to determine if gemfibrozil (600 mg b.i.d.) was effective in correcting the dyslipidemia of NIDDM.. After 8 wk of placebo stabilization, 442 patients from 46 study centers were randomized to double-blind treatment, in a designated 2:1 ratio, 295 received gemfibrozil and 147 received placebo for 20 wk. The primary end point was plasma TG; secondary end points were TC, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and HbA1c. No baseline differences were noted between groups in sex, age, weight, type of diabetic therapy, fasting plasma levels of TGs, HbA1c, or C-peptide. About two-thirds received oral hypoglycemic drugs, one-third insulin.. TG fell 26.4% in the gemfibrozil group and rose 7.4% in the placebo group (P < 0.023), by an intent-to-treat analysis. When patients who were noncompliant or with inadequate data were excluded, similar results were found--a 30.4% fall with gemfibrozil and a 4.8% increase with placebo (P < 0.0001). TG levels fell within 4 wk and remained low for 20 wk (P < 0.001). Mean HDL cholesterol rose by 4 wk and increased further at 12 wk (8-12%), P < 0.0001. TC fell. We observed a significant rise in LDL cholesterol in both gemfibrozil- and placebo-treated groups, with no significant differences between these groups. Changes in HbA1c were similar in gemfibrozil and placebo groups. No differences were observed in responses in groups treated with insulin and or oral hypoglycemic drugs. Overall AEs that were clinically important occurred in 6.1% in the gemfibrozil group vs. 2.0% in the placebo group (NS).. We conclude that gemfibrozil is an effective and safe agent in combating the dyslipidemia of NIDDM, irrespective of type of diabetic therapy.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gemfibrozil; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Male; Middle Aged; Triglycerides

In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Peptide Fragments; Protein Precursors; Reference Values; Time Factors

The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose -4.1 mmol.l-1; glycosylated haemoglobin A1 decrease -1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These positive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile < 10 mmol.l-1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile > 10 mmol.l-1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (-21.6 U/day). Metformin was well tolerated by all diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glycated Hemoglobin; Homeostasis; Humans; Islets of Langerhans; Lipids; Male; Metformin; Middle Aged; Obesity; Prospective Studies; Risk Factors; Single-Blind Method

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35% pre-determined VO2max. Fasting plasma NEFA levels were similar (0.40 +/- 0.06 (SEM) and 0.45 +/- 0.05 mmol l-1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 +/- 0.07 and 0.73 +/- 0.10 mmol l-1). Acipimox lowered basal NEFA levels (0.14 +/- 0.03 and 0.28 +/- 0.04 mmol l-1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 +/- 0.3 and 2.8 +/- 0.3 mg kg-1 min-1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 +/- 0.4 and 2.1 +/- 0.5 mg kg-1 min-1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Blood Glucose; C-Peptide; Calorimetry; Carbon Dioxide; Diabetes Mellitus, Type 2; Energy Metabolism; Exercise; Fatty Acids, Nonesterified; Female; Glucagon; Glycerol; Growth Hormone; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Lactates; Male; Middle Aged; Nitrogen; Oxygen Consumption; Pyrazines; Reference Values

To evaluate the change in lipids and insulin sensitivity in 10 obese type II diabetic patients after treatment with benfluorex or placebo for 2 wk.. The study had a double-blind, cross-over design. Insulin sensitivity was measured with the euglycemic hyperinsulinemic glucose clamp technique at two different insulin infusion rates: 0.05 (clamp 1) and 0.10 U.kg-1.h-1 (clamp 2).. Subanalysis of the glucose infusion rate under steady-state conditions in the last 30 min of clamp 2 yielded a glucose infusion rate of 5.36 and 3.87 mmol.kg-1.min-1 after benfluorex and placebo, respectively (P = 0.018).. Benfluorex increases insulin sensitivity in obese type II diabetic patients.

Topics: Apolipoprotein A-I; Apolipoproteins B; Appetite Depressants; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fenfluramine; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lipids; Middle Aged; Multivariate Analysis; Obesity; Placebos; Triglycerides

To study the effects of gemfibrozil treatment on LDL particle size, density distribution, and composition in NIDDM patients.. We performed LDL analyses on 16 NIDDM patients with stable glycemic control. They were randomly allocated to receive either gemfibrozil (n = 8) or a placebo (n = 8) for 3 mo in a double-blind study. The LDL particle size distribution and the particle diameter of the major LDL peak were measured with nondenaturing polyacrylamide gradient gel electrophoresis. The density distribution and composition of LDL were determined with the density gradient ultracentrifugation method.. In the gemfibrozil group the mean serum TG concentration decreased by 38%, HDL cholesterol concentration increased by 10%, and LDL cholesterol concentration by 17% (P < 0.05). During gemfibrozil therapy the mean particle diameter of the major LDL peak increased from 244 to 251 A (P < 0.05), whereas in the placebo group the mean LDL particle diameter remained unchanged. We found an inverse correlation between the changes of serum TG and the particle diameters of the major LDL peak (r = 0.85, P < 0.01). Gemfibrozil produced a shift in the LDL density distribution toward lower density. The mean peak density decreased from 1.0371 to 1.0345 g/ml because of a significant rise in the light LDL concentration from 141.0 to 183.2 mg/dl (P < 0.05), whereas the concentration of dense LDL had a tendency to decrease. In the placebo group the LDL density distribution did not change. Gemfibrozil increased the CE-to-TG ratio in LDL core lipids by 27% (P < 0.05); otherwise, the LDL composition was only slightly affected.. The results indicate gemfibrozil-induced changes in LDL properties in NIDDM patients are similar to those previously reported in nondiabetic individuals and are related to changes in serum TG level.

Topics: Apolipoproteins B; Blood Glucose; C-Peptide; Cholesterol, HDL; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gemfibrozil; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Metformin; Middle Aged; Phospholipids; Placebos; Triglycerides

To investigate the effects of metformin on glycemic control, insulin resistance, and risk factors for cardiovascular disease in NIDDM subjects from two ethnic groups (Caucasian and Asian) with different risks of cardiovascular disease.. A total of 27 subjects with NIDDM (17 Caucasian, 10 Asian) were given metformin and placebo each for a 12-wk period in a randomized, double-blind, placebo-controlled crossover study, and the dose was increased after 1 and 6 wk, up to a maximum of 850 mg three times a day. Insulin resistance, glycemic control, and cardiovascular risk factors were assessed before and after each treatment phase. The end of 12 wk of metformin treatment was compared with the end of 12 wk of placebo treatment.. Metformin treatment was associated with significant improvement in FPG at 6 and 12 wk (mean difference at 12 wk, -3.08 mM, 95% CI -4.12 to -2.04 mM, P < 0.0001) and MCR of glucose (median difference 0.40 ml.kg-1.min-1, interquartile range -0.10 to 1.30 ml.kg-1.min-1, P = 0.036). beta-cell function calculated by HOMA also improved significantly (median difference 14%, interquartile range 7 to 23%, P < 0.001). Total triglyceride (median difference -0.2 mM, interquartile range -0.6 to 0.1 mM, P = 0.034), total cholesterol (mean difference -0.52 mM, 95% CI -0.83 to -0.22 mM, P = 0.002), and LDL cholesterol (mean difference -0.40 mM, 95% CI -0.64 to -0.16 mM, P = 0.002) fell significantly on metformin treatment, whereas no significant changes were observed in HDL cholesterol. PAI-1 activity fell significantly (mean difference -5.3 AU/ml, 95% CI -8.2 to -2.4 AU/ml, P = 0.001), but plasma fibrinogen concentrations and platelet function, spontaneous or agonist induced, were unaffected. UAE was lower on metformin treatment (median difference -2.4 micrograms/min, interquartile range -4.4 to -0.2 micrograms/min, P = 0.004), but metformin had no significant effect on BP. The effects of metformin on glycemic control and cardiovascular risk factors were generally similar in the two ethnic groups.. These findings indicate that metformin treatment improves glycemic control, and lowers insulin resistance and risk factors for cardiovascular disease, including PAI-1, and may therefore be useful in the long-term management of NIDDM subjects who have a high risk of cardiovascular disease.

Topics: Albuminuria; Asia; Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Ethnicity; Fructosamine; Hexosamines; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Metabolic Clearance Rate; Metformin; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Risk Factors; Triglycerides; United Kingdom; White People

The short-term administration of a nicotinic acid analogue (acipimox) increases insulin sensitivity and consequently glucose disposal, both in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in patients with cirrhosis. This effect has been attributed to a decrease in plasma nonesterified fatty acid (NEFA) levels and fatty acid oxidation rates, and a corresponding increase in carbohydrate oxidation. The aim of the present study was to determine whether acipimox influenced glucose disposal independent of changes in lipid metabolism. Seven normal men (age, 31 +/- 4 years; body mass index, 23.2 +/- 1.8 kg.m-2; fat-free mass [FFM], 66.8 +/- 4.2 kg) were studied on two separate occasions with hyperinsulinemic (0.06 U.kg FFM-1.h-1) euglycemic clamps (duration, 150 minutes). A primed (150 U), continuous (0.4 U.kg-1.min-1) infusion of heparin together with 10% intralipid (25 mL.h-1) was infused in both studies from -90 to 150 minutes to maintain comparable levels of plasma NEFA and lipid oxidation rates. Acipimox (500-mg capsules) or placebo were administered orally in a double-blind random fashion at t = -90 and t = 0 minutes. Whole-body lipid and carbohydrate oxidation were measured in the last 30 minutes of both the basal (preclamp) period (-30 to 0 minutes) and the clamp period (120 to 150 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alanine; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Glucagon; Glucose; Glycerol; Growth Hormone; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Lactates; Lipid Metabolism; Male; Oxidation-Reduction; Pyrazines; Pyruvates; Radioimmunoassay; Time Factors

Using carefully selected relatively non-obese non insulin dependent diabetic patients, we were not able to show differences in standard measures of insulin production or insulin action between patients treated with a long acting crystalline zinc insulin, with glibenclamide, or with metformin for a six week period. All three drugs were hypoglycaemic, but a fall in basal hepatic glucose output measured by the 3H3 glucose technique was only seen in those patients who had an initial fasting plasma glucose above 12.0 mmol/l, irrespective of treatment.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Glyburide; Glycated Hemoglobin; Glycosuria; Humans; Insulin; Insulin Resistance; Insulin Secretion; Metabolic Clearance Rate; Metformin; Middle Aged; Radioisotope Dilution Technique; Tritium

We studied in a group of elderly (mean age 77 yr) non-obese Type 2 diabetic patients (n = 9) in a randomised, placebo-controlled prospective cross-over study of 8 months duration, the effects of substituting maximal sulfonylurea medication with a single injection of human zinc insulin taken either at bedtime (BTI) or morning (MI). All patients were poorly controlled with oral antidiabetic agents. After a 2-month regimen with either BTI or MI, a glibenclamide (GL, 3.5 mg/day) was given for an additional 2 months. Both insulin regimens decreased mean diurnal blood glucose and glycosylated HbA1c values to a similar extent (2.6-2.7%; p < 0.01-0.05), but with a lower daily insulin dose with BTI (0.30 +/- 0.03 IU/kg) as compared with MI (0.39 +/- 0.05 IU/kg; p < 0.01). A further improvement in metabolic control was observed in both groups after the introduction of GL; the mean reduction in glycosylated HbA1c was 1.4% for BTI and 0.7% for MI (p < 0.01 and 0.05, respectively), In conclusion, a subgroup of poorly controlled elderly Type 2 diabetic patients showed an improvement in metabolic control after a single injection of insulin despite discontinuation of maximal doses of oral antidiabetic agents. After 2 months of insulin treatment, a further improvement was achieved by a low dose of sulfonylurea in these patients who were formerly considered unresponsive to oral antidiabetic agents.

Topics: Aged; Apolipoprotein A-I; Apolipoproteins B; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glyburide; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Prospective Studies; Recombinant Proteins; Treatment Failure; Triglycerides

Insulin resistance contributes to the metabolic defects in non-insulin-dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. The serotonin-reuptake inhibiting agent fluoxetine has recently been recognized as an anorectic agent. The effect of fluoxetine on insulin action has not yet been determined. In a double blind placebo controlled crossover study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinemic euglycemic clamp technique with infusion of 3-3H-glucose in eight obese NIDDM and in eight obese nondiabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu 180.5 +/- 25.8 vs 225.3 +/- 39.9 mU/l, P less than 0.05), but not in nondiabetics (140 +/- 15.3 vs 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Basal hepatic glucose production (HGP) was reduced after fluoxetine in both NIDDM (9.45 vs 10.37 mumol/kg/min) and in nondiabetics (8.57 vs 9.16 mumol/kg/min), although the difference was only significant in nondiabetics (P less than 0.05). Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and nondiabetics. When nondiabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P less than 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production is completely suppressed (HGP0) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fluoxetine; Glucose; Humans; Insulin; Insulin Secretion; Liver; Male; Middle Aged; Multivariate Analysis; Obesity

To assess the efficacy of combination therapy with insulin and sulfonylurea in the treatment of NIDDM.. Studies published between January 1966 and January 1991 were identified through a computerized Medline search and by hand searching the bibliographies of identified articles. We identified 17 eligible randomized, controlled trials of combination therapy in NIDDM. These trials had a minimum duration of 8 wk and at least one of three outcome measures (fasting glucose, HbA1, or C-peptide) with SD or SE of the mean reported to do metaanalysis. With standardized forms, three independent reviews abstracted measures of study quality and specific descriptive information about population, intervention, and outcome measurements.. We calculated effect size and weighted mean changes of the three outcome measures for control and treatment groups. In the treatment group, the fasting plasma glucose decreased from a mean of 11.4 mM (206 mg/dl) at baseline to a mean of 9.16 mM (165 mg/dl) posttreatment, whereas the control group decreased from (11.3 to 10.8 mM) (204 to 194 mg/dl) (effect size 0.39, P less than 0.0001). For HbA1, the treatment group decreased from a baseline of 11.0 to 10.2% compared to 11.0 and 11.2% in the control group (effect size 0.43, P less than 0.0001). For fasting C-peptide, the treatment group increased from 0.49 to 0.58 nM (1.45 to 1.75 ng/ml) compared with 0.47 and 0.43 (1.42 and 1.30) for the control group (effect size 0.26, P less than 0.017).. Combined insulin-sulfonylurea therapy leads to modest improvement in glycemic control compared with insulin therapy alone. With combined therapy, lower insulin doses may be used to achieve similar control. Obese patients with higher fasting C-peptides may be more likely to respond than others.

Topics: Blood Glucose; C-Peptide; Chlorpropamide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Gliclazide; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; MEDLINE; Meta-Analysis as Topic; Middle Aged; Periodicals as Topic; Sulfonylurea Compounds; Tolazamide; Treatment Outcome; United States

Benfluorex is a hypolipidemic agent with biguanide-like properties. Its action on glucose metabolism was evaluated in 6 NIDDM patients previously treated with diet alone. Before and after 1 month of benfluorex therapy (450 mg/day p.o.), an euglycemic (100 mg/dl) insulin (40 mU/m2/min) clamp was performed along with 3-3H-glucose infusion and indirect calorimetry. Benfluorex did not affect body weight, while it reduced fasting plasma glucose (144 +/- 16 vs 119 +/- 8 mg/dl; P < 0.05), glycosylated hemoglobin (6.8 +/- 0.8 vs 6.4 +/- 0.4 percent) and fructosamine (2.9 +/- 0.6 vs 2.4 +/- 0.2 mmol/l; P < 0.05). Both triglycerides (2.3 +/- 0.6 vs 1.9 +/- 0.5 mmol/l) and total cholesterol (5.7 +/- 0.7 vs 5.2 +/- 0.6 mmol/l) declined. No changes occurred in plasma fatty acid, insulin, and C-peptide. Basal hepatic glucose production did not change and it was completely suppressed during the clamp studies both before and after benfluorex. Basal oxidation rates of carbohydrates and lipids did not change significantly. During the insulin clamp study, insulin-mediated glucose disposal increased after benfluorex (5.7 +/- 0.3 vs 4.8 +/- 0.2 mg/kg/min; P < 0.01). Lipid oxidation was equally suppressed before and after therapy with benfluorex. Glucose oxidation was not enhanced after benfluorex while non-oxidative glucose metabolism was significantly improved (2.2 +/- 0.7 vs 3.4 +/- 0.4 mg/kg/min; P < 0.05).. short-term benfluorex administration a) improves glucose and lipid control, b) improves insulin action by enhancing non-oxidative glucose metabolism, c) does not affect basal insulin secretion. The long-term effect of benfluorex treatment remains to be evaluated.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Fenfluramine; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; Hypolipidemic Agents; Insulin; Liver; Male; Middle Aged

To examine changes in glycemia and insulin secretion in response to SU per se and in response to a standard diet plus OD or TD SU therapy during chronic GP and GB therapy.. Randomized (between agents and in order of dosing regimens), prospective, open, crossover study among 14 NIDDM patients to compare glucose, insulin, and C-peptide responses to a standard diet and to 10 mg of oral GP or GB taken without food 1) after 2 wk without therapy, 2) after 4 wk of either GP (n = 7) or GB (n = 7) treatment OD, and 3) after 4 wk of TD therapy with the same agent. Each patient received the same drug for maintenance therapy and for assessment of the response to the drug alone.. We observed a comparable reduction in overall glycemia with both agents, with more marked postprandial effects for GP. Similar glucose, insulin, and C-peptide profiles for both agents during OD and TD therapy. Augmented insulin secretion in response to meals contrasting with reduced insulinotropic effects of the drugs per se with chronic therapy.. Therapeutic equivalence of OD and TD dosing with GP and GB during chronic therapy. In view of the improved insulin secretion in response to nutrient stimuli, the attenuation of responses to SU per se during chronic therapy does not imply impairment of beta-cell secretory capacity or represent a therapeutic disadvantage.

Topics: Adult; Aged; Analysis of Variance; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Eating; Fasting; Glipizide; Glyburide; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Kinetics; Middle Aged; Time Factors

To determine the efficacy of the alpha-glucosidase inhibitor miglitol (BAYm 1099) regarding the starch content of food.. Thirty-six non-insulin-dependent diabetes mellitus (NIDDM) subjects were studied in a double-blind randomized study comparing treatment with a single dosage of 100 mg miglitol or placebo and a single-blind crossover comparison of three test meals in which the carbohydrate contained either 30, 50, or 70% starch, and quantities of fat and protein were kept constant.. Postprandial blood glucose excursions were reduced by approximately 50% with miglitol after all test meals. In contrast, after miglitol treatment, maximum postprandial serum C-peptide and insulin values reached the same levels as after placebo treatment, although the time to reach these maximum levels was delayed. Free fatty acid values decreased after both miglitol and placebo similarly. Twenty-eight untoward events in 15 patients were reported in the miglitol treatment group and 11 events in 7 patients in the placebo treatment group.. Miglitol reduces postprandial blood glucose excursions independent of the starch content of the meal. Because no effects were found on incremental postprandial maximal levels of serum insulin and C-peptide, it may be that miglitol exerts, in addition to a delay of intestinal carbohydrate absorption, extraintestinal effects as well, particularly effects on disposition of glucose or anti-insulin counterregulatory factors.

Topics: 1-Deoxynojirimycin; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Dietary Carbohydrates; Fatty Acids, Nonesterified; Female; Glucosamine; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Imino Pyranoses; Insulin; Male; Middle Aged

To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas.. A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment.. Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients.. The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Eating; Fasting; Glyburide; Glycated Hemoglobin; Humans; Insulin, Isophane; Metformin; Middle Aged; Obesity

The effect of the calcium antagonist nicardipine on insulin secretion and glucose homoeostasis was investigated in elderly hypertensives with and without diabetes mellitus; 15 patients with essential hypertension for at least 10 years and normal glucose tolerance according to standard criteria (Group I) and 15 elderly hypertensive patients affected by Type 2 diabetes mellitus and on treatment with diet or oral drugs (Group 2). In the basal state, all patients were submitted to an oral glucose tolerance test (OGTT, 75 g) and an iv arginine test (30 g), on two different days and in random order. The same tests were repeated after one month of treatment with nicardipine 60 mg/day, in three spaced doses, the last being given 1 h before the post-treatment test. Nicardipine did not change overall glucose homoestasis, as assessed by haemoglobin Alc and fructosamine, nor did it significantly affect the plasma insulin response either to glucose or arginine in Groups 1 and 2. Only the glucagon response to arginine was significantly reduced in diabetic hypertensives. Small, non-significant variations in the metabolic and hormonal parameters were seen in additional two groups of patients (Groups 3 and 4), matched with Groups 1 and 2 for age, sex and diseases, who took capsules containing placebo. Thus, nicardipine did not produce any significant overall alteration in glucose homoestasis when given to elderly diabetic or nondiabetic hypertensive subjects.

Topics: Aged; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Homeostasis; Humans; Hypertension; Insulin; Male; Nicardipine; Reproducibility of Results

The mechanism of action of sulphonylureas is not completely understood. In the present study we evaluated the effects of gliquidone, a second-generation compound, on several metabolic parameters in 22 patients with untreated newly-diagnosed type II (noninsulin-dependent) diabetes mellitus. After either 1 or 6 months of treatment with gliquidone plus isocaloric diet we observed: 1) a significant decrease in fasting plasma glucose and glycemic profile after oral glucose load; 2) unchanged fasting and postglucose plasma insulin levels; 3) no change in fasting C-peptide levels but a significant increase in C-peptide concentrations after glucose challenge; 4) a significant increase in glucose disappearance rate from plasma following iv insulin injection; 5) an increase in the insulin-induced reduction of plasma levels of free-fatty acids; 6) no change in plasma C-peptide levels following iv insulin injection; 7) a significant increase in specific insulin binding to monocytes. After 6 but not 1 month of gliquidone therapy we also found an increase in the activity of hexokinase in circulating mononuclear leukocytes. These results suggest that the hypoglycemic effect of gliquidone occurs through either an increased beta cell response to glucose stimulus or an enhanced insulin sensitivity. The latter effect seems to depend on both receptor and postreceptor mechanisms.

Topics: Administration, Oral; Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Hexokinase; Humans; Hypoglycemic Agents; Injections, Intravenous; Insulin; Islets of Langerhans; Leukocytes, Mononuclear; Male; Middle Aged; Receptor, Insulin; Sulfonylurea Compounds

Eight men with untreated type II diabetes were given 480 mL water containing 15 g, 25 g, 35 g, and 50 g fructose orally, in random sequence. The same subjects were given the same volume of water as a control. They also were given 50 g glucose on two occasions for comparative purposes. Plasma glucose, urea nitrogen, and glucagon, and serum insulin, C-peptide, alpha-amino-nitrogen (AAN), nonesterified fatty acids (NEFA), and triglycerides were determined over the subsequent 5-hour period. The area responses to each dose of fructose were calculated and compared with the water control. The integrated glucose area dose-response was curvilinear, with little increase in glucose until 50 g fructose was ingested. With the 50-g dose, the area response was 25% of the response to 50 g glucose. The insulin response also was curvilinear, but the curve was opposite to that of the glucose curve. Even the smallest dose of fructose resulted in a relatively large increase in insulin, and a near-maximal response occurred with 35 g. The area response to 50 g fructose was 39% of that to 50 g glucose. The C-peptide data were similar to the insulin data. The AAN area response to fructose ingestion was negative. However, the response was progressively less negative with increasing doses. The glucagon area response was positive, but a dose-response relationship was not apparent. The glucagon area response was negative after glucose ingestion, as expected. The urea nitrogen area response was negative, but again, a dose-response relationship to fructose ingestion was not present.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Amino Acids; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Fructose; Glucagon; Humans; Insulin; Middle Aged; Nitrogen; Osmolar Concentration

Combined insulin and sulfonylurea therapy for type 2 diabetes may improve the effectiveness of a single injection of insulin, thereby postponing the need for multiple injections. This concept was tested in 21 obese subjects imperfectly controlled by 20 mg of glyburide daily in a double masked, placebo-controlled, parallel design, 16-week protocol. Premixed 70% NPH/30% Regular insulin was taken before supper, and the dosage was adjusted weekly by an algorithm seeking nearly normal fasting glycemia. Eleven subjects using insulin plus 10 mg glyburide before breakfast had lower mean fasting glucose at 10-16 weeks than 10 subjects using insulin with placebo (mean +/- SEM; 5.9 +/- 0.3 versus 7.5 +/- 0.7 mmol/L; p less than 0.05), and had a greater decrement of glycosylated hemoglobin from baseline values (1.3 +/- 0.1 versus 0.8 +/- 0.2% A1, p less than 0.05). After 16 weeks the combined therapy group used half as much insulin as the insulin-only group (50 +/- 5 versus 101 +/- 13 units/d; p less than 0.01). Fasting serum free insulin values increased 58% from baseline after insulin therapy in the insulin-only group (p less than 0.05) but did not increase with combined therapy. Weight gain was similar in the two groups. These data support this form of combined therapy as one option for treating obese persons with type 2 diabetes no longer responsive to oral therapy alone.

Topics: Adult; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Glyburide; Glycated Hemoglobin; Humans; Insulin; Lipoproteins; Obesity; Triglycerides

The objective of the study was to evaluate the effect of insulin treatment on insulin secretion in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ten patients with NIDDM were first investigated while still taking oral hypoglycemic agents, and then randomized to a crossover study with two eight-week periods of insulin treatment (oral treatment having been stopped) given either as mainly intermediate-acting insulin twice daily (2-dose) or as preprandial regular insulin and intermediate-acting insulin at bedtime (4-dose). In the patients treated with oral agents the 24-h C-peptide area under the curve was similar to that in the controls, but the profile was different with a rise at breakfast but with almost absent meal peaks during the rest of the day. Insulin treatment improved glycemic control markedly, lowered urinary C-peptide excretion and the serum C-peptide concentrations being reduced by more than 50%. The shape of the C-peptide profiles was unaltered and there were no significant differences between the two insulin regimens. The decrease in serum C-peptide concentration during insulin treatment correlated with the change in blood glucose. Fasting serum C-peptide concentrations correlated closely with the 24-h C-peptide area under the curve. In conclusion, insulin treatment of NIDDM patients with secondary failure to oral agents greatly reduces the insulin secretion, probably owing to the reduction in blood glucose.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Food; Glucagon; Humans; Hypoglycemic Agents; Insulin; Kinetics; Male

To compare the efficacy, benefits, and risks of glyburide and glipizide in elderly patients with non-insulin-dependent diabetes mellitus (NIDDM).. Twenty-one elderly outpatients (mean age 70 yr) were treated for 8 wk, after being dose-titrated to achieve a fasting plasma glucose (FPG) concentration of less than 7.8 mM with glyburide or glipizide in a randomized crossover trial. FPG and postprandial plasma glucose, serum C-peptide, and HbA1c levels were measured. In 13 patients, self-monitoring of blood glucose (SMBG) with a memory meter was performed seven times per week.. Glipizide (11.9 mg) and glyburide (8.4 mg) produced similar fasting and postprandial plasma glucose and HbA1c concentrations. No significant differences in basal or stimulated C-peptide levels were detected. Despite a few patient reports of hypoglycemia, a high incidence of SMBG readings less than 4.5 mM was attributed to the use of both drugs.. Both treatments proved effective for glycemic control; however, both second-generation sulfonylureas are associated with a significant risk of hypoglycemia in elderly NIDDM patients. The proper use of sulfonylureas in this population should include close surveillance of ambulatory glucose monitoring and intensive and repeated patient education about the risks of hypoglycemia.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Fasting; Female; Glipizide; Glyburide; Glycated Hemoglobin; Humans; Male

Twenty-two NIDDM patients completed an open randomized cross-over study comparing metformin and glibenclamide over 1 year. The drugs had an equivalent effect on glycaemic control, but, in contrast to glibenclamide, metformin reduced body weight. Neither drug affected triglycerides, total- and LDL-cholesterol or C-peptide. Metformin caused a slight elevation of HDL-cholesterol (P less than 0.05). No serious adverse effects were observed. The results show that oral hypoglycaemic agents are not associated with undesirable effects on lipids and lipoproteins.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Insulin; Insulin Secretion; Lipids; Lipoproteins; Male; Metformin; Middle Aged; Prospective Studies; Triglycerides

The effects of metformin on glycaemia, insulin and c-peptide levels, hepatic glucose production and insulin sensitivity (using the euglycaemic, hyperinsulinaemic clamp) were evaluated at fortnightly intervals in 9 Type 2 diabetic patients using a stepwise dosing protocol: Stage 1--no metformin for four weeks; stage 2--metformin 500mg mane; stage 3--metformin 500mg thrice daily; stage 4--metformin 1000mg thrice daily. Results are expressed as Mean +/- SEM. Fasting blood glucose decreased from basal values (9.7 +/- 1.0 mmol/L) by 13% at stage 2, 34% at stage 3 and 41% at stage 4 (p less than 0.02 vs basal for all stages; p less than 0.02 stage 2 vs stage 3). Post-prandial glycaemia was significantly improved only with metformin 3000mg/day (p less than 0.05). Fasting, meal-stimulated and total insulin and c-peptide levels showed no change. Hepatic glucose output did not change significantly with metformin. Insulin sensitivity, measured as total glucose utilisation during hyperinsulinaemia, increased from stage 1 (10.3 +/- 2.1 mumoL/kg/min) by 23% at stage 3 (p less than 0.05) and by 29% at stage 4 (p less than 0.02). Basal metabolic clearance of glucose increased compared to stage 1 (1.69 +/- 0.16 mL/kg/min) by 30% at stage 2, 53% at stage 3 and 44% at stage 4 (all p less than 0.02). This study demonstrates that improved efficiency of glucose utilisation, both basally and under conditions of euglycaemic hyperinsulinaemia, is the basis of metformin's antihyperglycaemic action.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Liver; Male; Metformin; Middle Aged; Prospective Studies

The effect of a rapid-acting sulphonylurea, glipizide, on the dose-response relationship between the beta-cell response (insulin and C-peptide secretion) and the ambient plasma glucose concentration was examined in 12 healthy and 6 non-insulin-dependent diabetic subjects. The subjects participated in two sets of experiments which were performed in random order: (A) four hyperglycaemic clamp studies, during which the plasma glucose concentration was raised for 120 min by 1 (only in healthy subjects), 3, 7, and 17 mmol/l; and (B) the same four hyperglycaemic clamp studies preceded by ingestion of 5 mg glipizide. All subjects participated in a further study, in which glipizide was ingested and the plasma glucose concentration was maintained at the basal level. In control subjects in the absence of glipizide, the first-phase plasma insulin response (0-10 min) increased progressively with increasing plasma glucose concentration up to 10 mmol/l, above which it tended to plateau. Glipizide augmented the first-phase insulin response without changing the slope of the regression line relating plasma insulin to glucose concentrations. The second-phase plasma insulin response (20-120 min) increased linearly with increasing hyperglycaemia (r = 0.997). Glipizide alone increased the plasma insulin response by 180 pmol/l. A similar increase in plasma insulin response following glipizide was observed at each hyperglycaemic step, indicating that glipizide did not affect the sensitivity of the beta-cell to glucose. First-phase insulin secretion was reduced in the type 2 (non-insulin-dependent) diabetic patients, and was not influenced by glipizide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glipizide; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Reference Values; Time Factors

Ten newly presenting, Type 2 (non-insulin-dependent), Caucasian diabetic patients were studied before and after 8 weeks treatment with the sulphonylurea gliclazide, and in parallel 13 similar patients were studied before and after 8 weeks treatment with diet alone. Eight non-diabetic subjects were also studied. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) prior to and during a 4-h hyperinsulinaemic euglycaemic clamp (100 mU kg-1 h-1). Fasting plasma glucose (+/- SE) and glycosylated haemoglobin decreased to a greater extent in the gliclazide treated patients (fall of 6.2 +/- 0.7 vs 2.1 +/- 0.5 mmol l-1, p less than 0.005 and 4.7 +/- 0.5 vs 2.1 +/- 0.5%, p less than 0.005). This was accompanied by an increase in fasting serum insulin concentrations in the gliclazide treated patients (7.0 +/- 1.3 to 10.1 +/- 1.1 mU l-1, p less than 0.005), but no change in the diet treated patients. Fractional GS activity did not increase during the clamp at presentation in either treatment group (change +2.9 +/- 1.8 and -1.5 +/- 1.9%, respectively) whereas it increased markedly in the control subjects (+16.4 +/- 3.4%, both p less than 0.001). After 8-week treatment there was a significant increase in GS activity during the clamp in the patients receiving gliclazide (+6.9 +/- 2.7%, p less than 0.05), but no change in GS activity in the patients on diet alone (+0.5 +/- 1.4%). The difference in post-treatment muscle insulin action was significant (p less than 0.05). There was no correlation between the degree of improvement in metabolic control and the improvement in response of GS to insulin in the gliclazide treated patients (r = -0.06), suggesting a possible direct drug effect on skeletal muscle. Glucose requirement during the clamp at presentation was markedly lower in both treatment groups than in the non-diabetic subjects (gliclazide 2.1 +/- 0.3, diet 2.0 +/- 0.6 vs 7.8 +/- 0.4 mg kg-1 min-1, both p less than 0.001), and despite a marked improvement in both groups after treatment (4.3 +/- 0.4 and 3.1 +/- 0.5 mg kg-1 min-1, both p less than 0.001) remained lower than in the non-diabetic subjects (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Fasting; Female; Gliclazide; Glycated Hemoglobin; Glycogen Synthase; Humans; Insulin; Insulin Secretion; Insulin, Regular, Pork; Male; Middle Aged; Muscles; Random Allocation; Recombinant Proteins

Correction of the deficiency of early meal-time insulin secretion, using intravenous insulin in patients with Type 2 diabetes causes substantial improvement in post-prandial hyperglycaemia. The present study was designed to determine whether similar benefit would result from physiological supplementation using intranasal insulin delivery. Six patients with Type 2 diabetes were studied twice during a standard mixed meal. At the start of the meal they received a single intranasal spray containing either 15 units of insulin in 1% sodium glycocholate (adjuvant agent) or glycocholate alone (placebo) in a single-blind fashion. Intranasal insulin delivery resulted in rapid absorption of insulin with peak levels (92 +/- 8 (+/- SE) mU l-1) within 5-10 min. Peak insulin levels were at least equal to those in non-diabetic subjects, though occurring at an earlier time-point. However, no significant improvement in post-prandial hyperglycaemia was seen (peak blood glucose increment 4.9 +/- 0.6 vs 5.4 +/- 0.5 mmol l-1; total 3-h response 611 +/- 53 vs 668 +/- 41 mmol l-1 min). We conclude that an elevation of insulin levels, earlier and more transient than the normal physiological response, achieved by intranasal insulin delivery at the start of a meal, fails to significantly improve the blood glucose excursion in Type 2 diabetes.

Topics: Administration, Intranasal; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Fatty Acids, Nonesterified; Female; Glucagon; Humans; Insulin; Kinetics; Male; Time Factors

In the present study a randomized cross-over design was used to determine the clinical usefulness of adding 16 g of beet fiber to the ordinary diet of non-insulin dependent diabetic (NIDDM) out-patients. In addition, fiber effects on the gastrointestinal hormone responses to a standardized test meal were evaluated. The study included five patients treated with diet alone and eight patients treated with diet and sulphonylurea (SU). Beet fiber supplementation resulted in a 10% reduction (P less than 0.01) of serum cholesterol in SU-treated patients. No differences were found for fasting blood glucose, glycated hemoglobin, serum triglycerides or body weight. In the diet-treated patients, fasting plasma somatostatin was elevated during the fiber period. However, postprandial responses of insulin, C-peptide, glucagon, gastric inhibitory peptide and somatostatin were not influenced by an increased fiber intake in any group. All patients experienced mild gastrointestinal discomfort during the fiber period. In view of the limited metabolic benefit of beet fiber treatment we conclude that there is little use for this type of dietary fiber in the routine treatment of patients with NIDDM.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Diet, Diabetic; Dietary Fiber; Female; Glycated Hemoglobin; Hormones; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Triglycerides; Vegetables

Seven men with well-controlled, noninsulin-dependent (type 2) diabetes ingested on two different mornings, in random order, meals with or without a 5.0-g sodium alginate supplement (algae-isolate, 75% soluble fiber). The meals contained similar amounts of digestible carbohydrates, fat and protein. The gastric emptying rate of the meal containing sodium alginate, measured by detection of 51Cr mixed into the meals, was significantly slower than that of the fiber-free meal. Sodium alginate also induced significantly lower postprandial rises in blood glucose, serum insulin and plasma C-peptide. The diminished glucose response after the addition of sodium alginate could be correlated to the delayed gastric emptying rate induced by the fiber (rs = 0.92, P less than 0.01).

Topics: Adult; Alginates; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet, Reducing; Dietary Fiber; Gastric Emptying; Glucuronic Acid; Hexuronic Acids; Humans; Insulin; Male; Middle Aged; Solubility

We investigated the dose-response characteristics of glucose-induced insulin release and the influence of hyperglycaemia on arginine-induced insulin secretion in eight non-obese subjects with NIDDM and in eight non-diabetic volunteers. Plasma C-peptide levels, achieved during 60 min hyperglycaemic clamps with and without the infusion of a primed continuous infusion of arginine (infusion rate 15 mg kg-1 min-1) during the last 30 min, were analysed with a modified Michaelis-Menten equation. The insulin secretory capacity (Vmax) for glucose-stimulated insulin release showed a trend towards a negative correlation with the fasting blood glucose in the NIDDM subjects (r = 0.68, P = 0.6); it was lower than the Vmax of non-diabetic controls (2.2 +/- 0.2 vs 4.2 +/- 0.4 nmol l-1 respectively; P less than 0.001). The ED50 (half maximal stimulating blood glucose concentration) of the second-phase glucose-stimulated insulin release (determined from the plasma C-peptide levels at 60 min) was not significantly different from the ED50 of the controls (11.9 +/- 0.8 vs 13.3 +/- 1.9 mmol l-1 respectively; P greater than 0.2). Combined glucose-arginine stimulation significantly increased insulin release. The Vmax for both phases were significantly lower in NIDDM patients than in controls (2.3 +/- 0.2 vs 5.0 +/- 0.9 and 3.8 +/- 0.5 vs 8.5 +/- 0.9 nmol l-1 respectively; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged

Acarbose inhibits alpha-glucosidases of the small intestine and thus delays glucose release from complex carbohydrates. Therefore, its efficacy and acceptability as a first-line drug in non-insulin-dependent diabetes mellitus (NIDDM) insufficiently treated with diet alone was tested in a randomized double-blind placebo-controlled study.. Ninety-four NIDDM subjects, aged 43-70 yr with average body mass index of 28 kg/m2 and undergoing a pretreatment period of at least 3 mo with diet alone, were treated with 100 mg acarbose three times daily or placebo for 24 wk. The patients were recruited after a 4-wk screening period of dietary reinforcement. The inclusion limits for patients termed diet not satisfactory were fasting blood glucose (FBG) greater than or equal to 7.8 mM and/or postprandial blood glucose (BG) greater than or equal to 10 mM.. FBG was lowered in the acarbose group from 9.8 to 8.4 mM and in the placebo group from 10.2 to 9.6 mM after 24 wk (P = 0.007 vs. placebo). The most impressive therapeutic effect was a highly significant reduction of postprandial hyperglycemia for at least 5 h after the test meal (1-h postprandial BG with acarbose 10.4 mM and placebo 13.5 mM at 24 wk, P less than 0.001) accompanied by a significant decrease in HbA1 (acarbose 8.65%, placebo 9.32%, P = 0.003). Whereas C-peptide and fasting serum insulin were not significantly affected by acarbose, postprandial insulin increment was approximately 30% lower after 24 wk compared with placebo. Furthermore, acarbose significantly reduced 1-h postprandial triglyceride levels. After an initial phase of greater than 4 wk (when 76.6% in the acarbose group vs. 28% on placebo complained about flatulence, P less than 0.001), the drug was well accepted. At the end of the study, only 32% showed mild or moderate gastrointestinal sensations.. Extrapolation shows that acarbose is an efficient and acceptable drug for the treatment of NIDDM with poor metabolic control by diet alone. It has beneficial effects on postprandial hyperinsulinemia and postprandial hypertriglyceridemia.

Topics: Acarbose; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Eating; Fasting; Female; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Insulin; Male; Middle Aged; Triglycerides; Trisaccharides

To compare the effects of continuous subcutaneous insulin infusion (CSII) and conventional insulin therapy (CIT) in patients with poorly controlled sulfonylurea-treated diabetes mellitus.. Twenty-five patients aged 40-65 yr and poorly controlled with sulfonylureas and without severe diabetic complications comprised the study group. Five patients left the study (3 achieved satisfactory glycemic control without insulin, 1 defaulted, 1 developed ketonuria). Ten patients were treated with CSII and 10 with CIT. Outpatient treatment consisted of CIT (twice-daily injections of regular and NPH insulin) or CSII (basal infusion and prandial boluses of regular insulin).. Glycosylated hemoglobin improved with both methods of insulin delivery (P less than 0.01), but 8 of 10 CSII-treated patients achieved satisfactory glycemic control (HbA1 less than 50 mmol hydroxymethylfurfural/mol Hb), whereas only 3 of 10 CIT-treated patients achieved this (P less than 0.05). Weight gain, insulin dosage, and prevalence of hypoglycemia were similar in the two groups. Retinal deterioration occurred in one CSII-treated patient and three CIT-treated patients, but there were no episodes of infusion site infection or metabolic decompensation. Patients' satisfaction with treatment improved during insulin therapy (P less than 0.02), and significant changes in beliefs about diabetes and its treatment were observed in CSII-treated patients (P less than 0.05).. Glycemic control improved with both methods of insulin treated patients achieved satisfactory glycemic control (HbA1 less than 50 mmol hydroxymethylfurfural/mol Hb), whereas only 3 of 10 CIT-treated patients achieved this CSII. Patients' satisfaction with treatment improved during insulin therapy.

Topics: Adult; Attitude to Health; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Male; Middle Aged; Patient Satisfaction; Treatment Outcome; Triglycerides

The effect of felodipine on glucose tolerance was evaluated in 18 male type II diabetic patients treated with diet alone, who were hypertensive despite beta-blocker treatment. The study was a double-bind cross-over comparison of placebo and felodipine in addition to beta-blockade. Oral glucose tolerance tests were performed at randomization and at the end of each 4-week double-blind treatment period. The doses of felodipine given were 5 mg b.i.d. for 2 weeks followed by 10 mg b.i.d. for a further 2 weeks. Blood pressure was significantly reduced during felodipine treatment, whereas heart rate remained unaltered. HbA1c and fasting insulin levels did not change during the treatment periods. Fasting and maximal blood glucose levels were not altered between any of the treatment periods. However, there was a small but statistically significant increase (median increase 4%) in the area under the glucose concentration vs. time curve after felodipine as compared to placebo treatment. This increase was not considered to be clinically significant in the short term, but the finding merits further investigation in a rigorous long-term study.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Felodipine; Glucose Tolerance Test; Heart Rate; Humans; Hypertension; Insulin; Male; Middle Aged; Statistics as Topic

Clinical studies have demonstrated that chloroquine and hydroxychloroquine improve glucose metabolism in patients with insulin-resistant diabetes mellitus. The mechanism of action has not been determined. We undertook a randomized double-blind placebo-controlled trial of 3 days of oral chloroquine phosphate, 250 mg four times daily, in 20 patients with non-insulin-dependent diabetes mellitus controlled by diet. Rates of glucose appearance (Ra) and disappearance (Rd) were evaluated by infusion of stable isotopically labeled D-glucose ([6,6-2H2]glucose) during hyperinsulinemic euglycemic clamps before and after treatment with chloroquine or placebo. Chloroquine significantly improved fasting plasma glucose from 199.8 +/- 8.6 to 165.6 +/- 7.6 mg/dl (P less than 0.01). Total exogenous glucose infusion required to maintain euglycemia significantly increased (1,792.6-2,040.1 mg.kg-1.330 min-1, P less than 0.05) due to an increase in Rd (2,348.0-2,618.9 mg.kg-1.330 min-1, P less than 0.01) without change in Ra. Metabolic clearance rate of insulin decreased by 39% from 14.4 +/- 1.3 to 11.0 +/- 0.6 ml.kg-1.min-1 (P less than 0.01) at plasma insulin levels of 150-200 mU/l but not at levels of 2,000-3,000 mU/l. In addition, chloroquine increased fasting C-peptide secretion by 17% and reduced feedback inhibition of C-peptide by 9.1 and 10.6% during low- and high-dose insulin infusions, respectively.

Topics: Blood Glucose; C-Peptide; Chloroquine; Deuterium; Diabetes Mellitus, Type 2; Fasting; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Kinetics; Liver; Male; Metabolic Clearance Rate; Middle Aged; Radioisotope Dilution Technique

The metabolic response to the postoperative delivery of a sole glucose solution or a glucose-fructose-xylitol solution, and their effects upon carbohydrate metabolism, in patients with glucose tolerance impairment, were evaluated. Twenty four patients who showed an abnormal 75g-OGTT or were noninsulin-dependent diabetics were divided in two groups. The GFX-B group (n = 11) received a 10.5% solution, containing glucose, fructose and xylitol at 4:2:1 ratio, and the PHY-3 group (n = 13) received a 10% glucose solution, both, continuously infused for 3 days postoperatively. The infusion of PHY-3 tended to produce a higher increase in blood glucose than the infusion of GFX-B, that was significantly different on the 3POD (P less than 0.05). The increase in IRI and CPR was also significantly greater in PHY-3 group than in GFX-B group on the 3POD (P less than 0.05). We concluded that it was not only the slight lower glucose load of the GFX-B solution, but also, the different infused carbohydrate substrate which had influenced the magnitude of insulin secretion and the blood glucose level. Then, its use in glucose intolerant patients may be of some benefit to partially minimize the postoperative hyperglycemic response.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Fructose; Glucagon; Glucose; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Postoperative Care; Randomized Controlled Trials as Topic; Surgical Procedures, Operative; Xylitol

The role of insulin in the therapy of NIDDM is still under discussion. To clarify the problem we performed a randomized double-blind placebo controlled crossover study of insulin treatment for 4 weeks in diabetic patients (n = 18, age 52-74 years) who were unsatisfactorily controlled by oral antidiabetic agents. The patients continued to use these agents during the study. Special attention was given to informing the patients about the trial and, in particular, about self-monitoring the blood glucose by the use of a reflectance meter. Insulin treatment produced the following significant changes: decreases in blood glucose (at 7.00, 10.00, 16.00), mean daily blood glucose, HbA1, urinary glucose and low density lipoprotein (LDL) cholesterol and increased postglucose immunoreactive insulin (IRI) levels. Significant changes were also observed during the placebo periods: decreases in HbA1 urinary glucose and LDL cholesterol (but not in blood glucose). Therapy with insulin increased the body weight, whereas the placebo insulin had the opposite effect. The finding emphasizes the importance of using not only a run-in period but also a placebo design when the metabolic effects of antidiabetes therapy are to be evaluated. The study indicates that insulin therapy for patients with type 2 diabetes can be initiated at home.

Topics: Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glipizide; Glyburide; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Metformin; Middle Aged; Placebos; Random Allocation; Sulfonylurea Compounds

The relationship between plasma C-peptide and the frequency and severity of diabetic retinopathy was examined in a population-based study in Wisconsin in 1984-1986. Individuals with younger- (n = 835) and older- (n = 940) onset diabetes were included. C-peptide was measured by radioimmunoassay with Heding's M1230 antiserum. Retinopathy was determined from stereoscopic fundus photographs. The highest frequencies and most severe retinopathy were found in insulin-using individuals with undetectable or low plasma C-peptide (less than 0.3 nM), whereas the lowest frequencies of retinopathy were found in older-onset overweight individuals not using insulin. In older-onset individuals using insulin, having no detectable C-peptide was significantly associated with the presence of proliferative retinopathy. Otherwise, within each group (younger onset using insulin, older onset using insulin, and older onset not using insulin), after controlling for other characteristics associated with retinopathy, there was no relationship between higher levels of C-peptide and lower frequency of or less severe retinopathy.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diagnosis-Related Groups; Humans; Incidence; Insulin; Insulin Secretion; Radioimmunoassay; Sampling Studies; Wisconsin

Metabolic control, insulin secretion and insulin action were evaluated in seven Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral antidiabetic agents before and after two months of combined therapy with supper-time insulin (Ultratard: 0.4 U/kg body weight/day) plus premeal glibenclamide (15 mg/day). Metabolic control was assessed by 24 h plasma glucose, NEFA, and substrate (lactate, alanine, glycerol, ketone bodies) profile. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, hyperglycaemic clamp (+ 7 mmol/l) and 24 h free-insulin and C-peptide profiles. The repeat studies, after two months of combined therapy, were performed at least 72 h after supper-time insulin withdrawal. Combining insulin and sulfonylurea agents resulted in a reduction in fasting plasma glucose (12.9 +/- 7 vs 10.4 +/- 1.2 mmol/l; p less than 0.05) and hepatic glucose production (13.9 +/- 1.1 vs 11.1 +/- 1.1 mumol.kg-1.min-1; p less than 0.05). Mean 24 h plasma glucose was also lower (13.7 +/- 1.2 vs 11.1 +/- 1.4 mmol/l; p less than 0.05). Decrements in fasting plasma glucose and mean 24 h profile were correlated (r = 0.90; p less than 0.01). HbA1c also improved (11.8 +/- 0.8 vs 8.9 +/- 0.5%; p less than 0.05). Twenty-four hour profile for NEFA, glycerol, and ketone bodies was lower after treatment, while no difference occurred in the blood lactate and alanine profile. Insulin secretion in response to glucagon (C-peptide = +0.53 +/- 0.07 vs +0.43 +/- 0.07 pmol/ml) and hyperglycaemia (freeinsulin = 13.1 +/- 2.0 vs 12.3 +/- 2.2 mU/l) did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; C-Peptide; Circadian Rhythm; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Glucose; Glyburide; Humans; Injections; Insulin; Insulin Secretion; Insulin, Long-Acting; Liver; Male; Middle Aged; Sulfonylurea Compounds

Consumption of dihydroxyacetone and pyruvate (DHP) increases muscle extraction of glucose in normal men. To test the hypothesis that these three-carbon compounds would improve glycemic control in diabetes, we evaluated the effect of DHP on plasma glucose concentration, turnover, recycling, and tolerance in 7 women with noninsulin-dependent diabetes. The subjects consumed a 1,500-calorie diet (55% carbohydrate, 30% fat, 15% protein), randomly containing 13% of the calories as DHP (1/1) or Polycose (placebo; PL), as a drink three times daily for 7 days. On the 8th day, primed continuous infusions of [6-3H]-glucose and [U-14C]-glucose were begun at 05.00 h, and at 09.00 h a 3-hour glucose tolerance test (75 g glucola) was performed. Two weeks later the subjects repeated the study with the other diet. The fasting plasma glucose level decreased by 14% with DHP (DHP = 8.0 +/- 0.9 mmol/l; PL = 9.3 +/- 1.0 mmol/l, p less than 0.05) which accounted for lower postoral glucose glycemia (DHP = 13.1 +/- 0.8 mmol/l, PL = 14.7 +/- 0.8 mmol/l, p less than 0.05). [6-3H]-glucose turnover (DHP = 1.50 +/- 0.19 mg.kg-1.min-1, PL = 1.77 +/- 0.21 mg.kg-1.min-1, p less than 0.05) and glucose recycling, the difference in [6-3H]-glucose and [U-14C]-glucose turnover rates, decreased with DHP (DHP = 0.25 +/- 0.07 mg.kg-1.min-1, PL = 0.54 +/- 0.10 mg.kg-1.min-1, p less than 0.05). Fasting and postoral glucose, plasma insulin, glucagon, and C peptide levels were unaffected by DHP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dihydroxyacetone; Female; Food, Formulated; Glucagon; Glucose Tolerance Test; Humans; Insulin; Isotope Labeling; Middle Aged; Pyruvates

Twenty Type 2 diabetic patients, recently converted to insulin because of inadequate control on oral hypoglycaemic agents, were studied. Endogenous insulin reserve was measured by glucagon stimulation, and insulin-mediated peripheral glucose disposal by a hyperglycaemic (11 mmol l-1) clamp, measurements being repeated after 8 weeks of glipizide or placebo therapy in addition to the patients' usual insulin. The study was randomized and double blind. Fasting and stimulated C-peptide levels did not change on glipizide or placebo. Insulin-mediated glucose disposal rose from 2.5 (1.5-8.0) (median (range] to 4.2 (2.3-8.4) mg kg-1 min-1 in the glipizide group (n = 9, p less than 0.01), but did not change in the placebo group. Glycosylated haemoglobin did not change in either group, but median fasting plasma glucose fell from 10.6 (6.1-15.1) to 9.0 (6.4-11.2) mmol l-1 in the glipizide group (p less than 0.02). Fasting insulin rose on glipizide from 10.1 (4.0-23.2) to 13.0 (6.4-33.8) mU l-1 (p less than 0.02). Insulin dosage fell in the glipizide group from 36 to 26 U day-1, as 4 patients experienced hypoglycaemic symptoms. HDL-Cholesterol fell in all patients on glipizide, from 0.94 (0.79-2.13) to 0.79 (0.62-1.95) mmol l-1 (p less than 0.01). Combination of insulin with the sulphonylurea glipizide in secondary failure Type 2 diabetic patients leads to increased insulin-mediated peripheral glucose disposal. Glipizide may have an adverse effect on HDL-cholesterol, which is unrelated to change in diabetic control.

Topics: Aged; Blood Glucose; C-Peptide; Cholesterol; Cholesterol Esters; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glipizide; Glucagon; Glucose Clamp Technique; Glyburide; Glycated Hemoglobin; Humans; Insulin; Lipoproteins; Male; Middle Aged; Sulfonylurea Compounds

Our objective was to determine whether 1) hydrogenated starch hydrolysates (HSHs), bulking/sweetening agents used in hard candies, produce a diminished postmeal glycemic response relative to glucose in individuals with and without diabetes and 2) any diminished glycemia is secondary to altered carbohydrate absorption. This study followed a randomized double-blind crossover design and was performed in 12 individuals with diabetes (6 non-insulin dependent, 6 insulin dependent) and 6 nondiabetic individuals. Each group consisted of 3 men and 3 women, none with known neuropathy. After an overnight fast, each subject was challenged with 50 g of glucose, HSH 5875 (7% sorbitol/60% maltitol), and HSH 6075 (14% sorbitol/78% hydrogenated maltooligosaccharides)/1.73 m2 of body surface area in random order on 3 successive days. Individuals with diabetes were maintained on continuous subcutaneous insulin infusion throughout the study to achieve prechallenge glucose levels between 4.5 and 6.7 mM. For all groups, the order of plasma glucose responses over 5 h postchallenge was glucose greater than HSH 6075 greater than HSH 5875, P less than 0.001 (glucose vs. HSH). Pooled data for all groups for areas under the curve confirmed that HSH 6075 resulted in greater glycemia than HSH 5875 (P less than 0.05). This was reflected in the order of C-peptide responses seen in the nondiabetic and non-insulin-dependent groups (glucose greater than HSH 6075 greater than HSH 5875, P less than 0.001). Breath H2 after glucose was low, whereas HSH 5875 greater than HSH 6075 (P = 0.003). Gastric distress was noticed with all products.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucose; Humans; Insulin; Insulin Infusion Systems; Male; Middle Aged; Random Allocation; Reference Values; Sugar Alcohols

The effect of a blood pressure reduction by 10 mg extended release felodipine once daily on urinary albumin excretion (UAE) as well as the possible diabetogenic effect of felodipine was studied. A 2 X 12 week placebo-controlled double-blind crossover study was performed in 12 hypertensive non-insulin-dependent diabetic (NIDDM) patients without nephropathy on concomitant treatment with beta-blocker and/or a diuretic agent. Metabolic control as estimated by fasting plasma glucose, hemoglobin A1c and fasting plasma C-peptide was unaltered after felodipine. Blood pressure was significantly reduced by felodipine: systolic 166 +/- 26 mm Hg (placebo) v 153 +/- 26 mm Hg (felodipine) (P less than .05) and diastolic 95 +/- 7 mm Hg v 90 +/- 8 mm Hg (P less than .05). Heart rate was unchanged. There was no correlation between blood pressure and UAE, but the relative change in UAE expressed as UAE placebo/UAE felodipine was significantly correlated to the fall in systolic blood pressure (r = 0.64, P = .03) and mean blood pressure (r = 0.66, P = .02). Since microalbuminuria predicts proteinuria and reduced survival, early antihypertensive treatment may be beneficial in NIDDM as it is in IDDM. Long-term consequences on kidney function and mortality remains, however, to be elucidated.

Topics: Aged; Albuminuria; Blood Pressure; C-Peptide; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Fasting; Felodipine; Female; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Male; Middle Aged

Hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) stimulates peripheral glucose uptake, which tends to compensate for impaired insulin-mediated glucose uptake. The metabolic fate of glucose and suppression of fat oxidation may differ, however, when glucose uptake is stimulated primarily by insulin or hyperglycemia. To address this issue, three hyperinsulinemic glucose-clamp studies were performed in combination with indirect calorimetry in seven nonobese subjects with NIDDM. In the first two experiments, when glucose uptake was matched at approximately 8 mg.kg-1 fat-free mass (FFM).min-1 with primarily hyperinsulinemia (1350 +/- 445 pM) or hyperglycemia (20.8 +/- 1.8 mM), identical rates of glucose oxidation (3.21 +/- 0.29 and 3.10 +/- 0.23 mg.kg-1 FFM.min-1, NS) and nonoxidative glucose metabolism (5.19 +/- 0.75 and 5.46 +/- 0.61 mg.kg-1 FFM.min-1, NS) were achieved. When glucose uptake was increased further to 11.11 +/- 0.36 mg.kg-1 FFM.min-1 with less insulin (625 +/- 70 pM) and hyperglycemia, glucose oxidation (3.85 +/- 0.26 mg.kg-1 FFM.min-1) and nonoxidative glucose metabolism (7.26 +/- 0.51 mg.kg-1 FFM.min-1) rose significantly (both P less than 0.05 from matched studies at lower rates of glucose uptake). During all glucose-clamp studies, free fatty acids were comparably suppressed by 40-46% (all P less than 0.005 vs. basal values), whereas fat oxidation was suppressed by 70-80% (all P less than 0.005 vs. basal values). A strong negative correlation was observed between rates of glucose and fat oxidation (r = -0.88, P less than 0.001) when all studies were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Calorimetry; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Lipid Metabolism; Male; Middle Aged; Obesity; Oxidation-Reduction

It is well established that patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin. However, the contribution of hepatic and extrahepatic tissues to insulin resistance remains controversial. The uncertainty may be at least in part due to errors introduced by the unknowing use in previous studies of impure isotopes to measure glucose turnover. To determine hepatic and extrahepatic responses to insulin in the absence of these errors, steady-state glucose turnover was measured simultaneously with [6-3H]- and [6-14C]glucose during sequential 5- and 4-h infusions of insulin at rates of 0.4 and 10 mU.kg-1.min-1 in diabetic and nondiabetic subjects. At low insulin concentrations, [6-3H]- and [6-14C]glucose gave similar estimates of glucose turnover. Hepatic glucose release was equal to but not below zero in the nondiabetic subjects, but persistent glucose release (P less than 0.001) and decreased glucose uptake (P less than 0.001) was observed in the diabetic patients. At high insulin concentrations, both isotopes underestimated glucose turnover during the 1st h after initiation of the high-dose insulin infusion. More time (P less than 0.05) was required to reachieve steady state in NIDDM than nondiabetic subjects. At steady state, [6-3H]- but not [6-14C]glucose systematically underestimated (P less than 0.05) glucose turnover in both groups due to the presence of a tritiated nonglucose contaminant. The percentage of radioactivity in plasma due to tritiated contaminants was linearly related to turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Infusion Pumps; Insulin; Insulin Resistance; Liver; Male; Middle Aged; Tritium

In 6 type II diabetic patients, which showed no satisfactory blood sugar profiles under oral sulfonylurea monotherapy, a placebo controlled cross over pilot trial was performed to evaluate the effect of additive transdermal insulin application. In comparison to the monotherapy with sulfonylurea, the combination with transdermal insulin showed in 4 of the 6 patients a significant reduction of the daily mean blood sugar values as well as a slight increase of insulin serum concentrations. The 2 patients, who had no glucose reductions also showed a slight increase of insulin levels during the combination phase. Relevant adverse reactions were not seen. The results suggest, that in suited patients an improvement of sulfonylurea therapy by combination with transdermal insulin is possible.

Topics: Administration, Cutaneous; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Male; Pilot Projects; Prospective Studies; Sulfonylurea Compounds

Twelve outpatients with type II diabetes mellitus and mild clinical signs and history of cardiac failure were studied to assess the effects of ibopamine on glucose and lipid metabolism. For the assessment of cardiac failure a clinical score was computed, based on the evidence of dyspnea and ankle oedema. The patients were randomly allocated to ibopamine 100 mg t.i.d. or placebo in a double-blind cross-over 3 weeks design. Daily plasma glucose profile, glycaemia and plasma insulin during glucose tolerance test, serum C-peptide, lactacidemia, free fatty acids, triglycerides, urinary glucose, diuresis and clinical evaluation were the studied parameters. During the study, a clinically favourable trend for ibopamine was observed, as far as cardiac failure was concerned. No significant differences were found between ibopamine and placebo in any of the metabolic parameters. No change in diet or in the previous dosage of the antidiabetic drugs occurred during the study in any patient. We conclude that ibopamine 100 mg t.i.d. does not affect metabolic control and lipid pattern in type II diabetic patients, therefore representing a safe tool for the treatment of chronic heart failure in these patients.

Topics: Aged; C-Peptide; Cardiotonic Agents; Deoxyepinephrine; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Heart Failure; Hemodynamics; Humans; Lactates; Lactic Acid; Male; Vasodilator Agents

We studied 12 subjects with diabetes to determine how well the glycemic index (GI) predicted the ranking of glycemic responses of different foods in individuals. All subjects ate three mixed meals (bread, rice, or spaghetti with GIs of 100, 79, and 61, respectively) four times in a randomized complete block design. The mean glycemic response areas of the different meals ranked according to the predicted GI in every individual. The observed mean +/- SD GI values of the meals were significantly different from each other (bread 100 +/- 7, rice 75 +/- 9, spaghetti 54 +/- 9), with no significant difference in response between subjects. It is concluded that individuals share common mean GI values for different foods. Within confidence limits determined by the variability of glycemic responses, the number of repeated tests conducted, and the expected GI difference, the GI can be used to predict the ranking of the mean glycemic responses of mixed meals taken by individuals.

Topics: Adult; Aged; Blood Glucose; Bread; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Energy Intake; Fasting; Female; Flour; Humans; Male; Middle Aged; Oryza; Random Allocation

The Wadena City Health Study was undertaken to assess the nature of type II (non-insulin-dependent) diabetes and its relationship to aging. This article reports the study methodology and prevalence estimates for type II diabetes and impaired glucose tolerance (IGT) for the adult population of Wadena, Minnesota. The sampling frame for the study included all known diabetic individuals and all other residents based on a complete citywide census of residents greater than or equal to 20yr of age. A stratified random sample that included three stratifying factors (age [20-39, 40-59, greater than or equal to 60 yr], sex, and self-reported weekly use of any prescribed medication was drawn from the other residents). The study protocol required diet preparation and two full mornings of testing. Data collected included height, weight, and blood pressure measurements and both a personal interview and a medications questionnaire. A 75-g oral glucose tolerance test (OGTT) and a test with a standard liquid meal (Ensure-Plus challenge test [EPCT], Ross) were done on two mornings, with the order of testing randomly assigned. Clinical tests included one-time samples for hemoglobin, glycosylated hemoglobin, plasma cholesterol, triglycerides, and lipoproteins. Blood samples for glucose and creatinine assays were taken during the OGTT; blood samples for glucose, free fatty acid, creatinine, and C-peptide were taken during the EPCT. Urine collections were performed for both challenge tests and assayed for C-peptide and creatinine. Seventy-one percent of the known diabetic subjects, and 65% of the stratified random sample participated in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Aging; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Lipids; Male; Middle Aged; Minnesota; Prevalence; Random Allocation

Forty-two obese subjects with non-insulin-dependent diabetes mellitus had their plasma insulin, C peptide, and glucose levels measured after an overnight fast and in response to a 75-g oral glucose loading. Subjects were then prospectively followed up with dietary treatment, and the same measurements were repeated at 1 year. Although insulin values tended to be lower with greater fasting hyperglycemia at baseline, no correlation was observed among three parameters. However, near-normalization of glycemia (measured as the level of hemoglobin A1) was associated with significantly higher fasting and stimulated plasma insulin concentrations. Sixteen subjects were matched to each other for equivalent baseline hyperglycemia (by glycosylated hemoglobin) and divided into group 1 (normalization of the hemoglobin A1 value to 7.0% +/- 0.3% [mean +/- SE]) and group 2 (persistent hyperglycemia) (hemoglobin A1 value, 10.7% +/- 0.7% [mean +/- SE]). Before dietary therapy, the plasma insulin concentrations were twofold to threefold higher in group 1, and despite similar degrees of weight loss, group 2 failed to demonstrate improved glycemia. We concluded that the outcome of diet therapy for non-insulin-dependent diabetes mellitus is dependent on the duration of diabetes and endogenous insulin secretory reserve. There is a subgroup of patients with non-insulin-dependent diabetes mellitus in whom delayed dietary intervention may have a beneficial effect.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Female; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Time Factors

These studies examined the effect of fenfluramine on insulin action and insulin secretion in healthy subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). In the first study, a double-blind crossover design was used in healthy subjects to compare the effect of short-term fenfluramine therapy (60 mg orally for 3 days) with placebo. Insulin secretion and whole-body insulin sensitivity (determined by frequently sampled intravenous glucose tolerance tests with analysis by the minimal-model method) were unchanged by fenfluramine. In the second study, involving patients with NIDDM inadequately controlled on submaximal to maximal doses of oral hypoglycemic agents, a double-blind crossover strategy was used to compare baseline studies (conducted after a run-in period) with fenfluramine (60 mg orally) or placebo for 4 wk. There was a significant fall in fasting blood glucose after therapy with fenfluramine compared with the baseline study period (13.0 +/- 1.2 vs. 8.4 +/- 0.89 mM, mean +/- SE, P less than .01) with no significant fall in fasting serum insulin (20 +/- 2 vs. 24 +/- 3 microU/ml) or C-peptide (1.3 +/- 0.2 vs. 1.3 +/- 0.1 nM). During euglycemic-hyperinsulinemic (1 mU.kg-1.min-1) clamp studies there was a significant increase in insulin action from 12.7 +/- 2.3 to 17.3 +/- 1.8 min-1.10(3) microU.ml-1 (P less than .05), although clamp insulin levels were lower after fenfluramine treatment (136 +/- 14 vs. 96 +/- 9 microU/ml, P less than .02), reflecting an enhanced metabolic clearance rate for insulin (12.7 +/- 1.5 vs. 20.1 +/- 2.1 ml.kg-1.min-1, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fenfluramine; Glyburide; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Reference Values

We conducted a double-blind crossover study to determine which patient characteristics best predict a beneficial response to combined insulin-glyburide therapy. Glyburide (15 mg/day) or placebo was added to the treatment regimen of 31 insulin-treated type II (non-insulin-dependent) diabetic subjects. During glyburide therapy, there was a significant improvement in glycemic control with a reduction in glycosylated hemoglobin from 9.9 +/- 1.3 to 9.1 +/- 1.3% (P less than .001). Patients who responded had higher fasting C-peptide levels (P less than .001) and shorter durations of insulin therapy (P less than .01) than those who did not respond. Glyburide withdrawal was associated with a greater than expected deterioration in glycemic control. Patients on insulin therapy for greater than 8 yr are unlikely to benefit significantly from the addition of glyburide to their treatment regimen.

Topics: Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Insulin; Male

In a clinical study efficacy and tolerance of Neogluconin (2.5 mg) a new galenical form of glibenclamide were compared with a conventional preparation (Euglucon 5). Neogluconin showed an improved absorption and comparable blood sugar levels at a dosage reduced by 25%. 25 outpatients suffering from Type II diabetes in a well balanced metabolic state and previously under Euglucon therapy for at least one year were changed to the new product. After 2 months of Neogluconin therapy blood sugar profiles, HbA1, C-peptide and cholesterin levels were unchanged in comparison to values determined during the previous Euglucon treatment. This confirms that Neogluconin produces a comparable favorable blood glucose lowering effect despite a 25% reduction in dosage.

Topics: Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glyburide; Glycated Hemoglobin; Humans; Male; Middle Aged; Prospective Studies

In 13 non-obese patients with Type 2 diabetes mellitus who failed to achieve adequate blood glucose control on dietary treatment (fasting blood glucose 13.4 +/- 2.7 (+/- SD) mmol l-1, glycosylated haemoglobin 13.0 +/- 1.7%), the effects of 6 months insulin or sulphonylurea therapy on blood glucose control and lipid metabolism were compared in a randomized crossover study. Three patients, who showed a clear improvement on insulin (median glycosylated haemoglobin fell from 14.7 to 8.6%), withdrew from the study prematurely because of subjective and objective signs of hyperglycaemia after crossover from insulin to sulphonylurea. Daily dose after 6 months was 2000 mg tolbutamide (n = 3), 18 +/- 1 mg glibenclamide (n = 7), or 34 +/- 3 U insulin. On insulin, fasting (8.0 +/- 1.9 mmol l-1) and postprandial blood glucose (10.4 +/- 2.7 mmol l-1), and glycosylated haemoglobin (9.5 +/- 1.1%) were lower than on sulphonylurea (11.0 +/- 3.4 mmol l-1, 14.4 +/- 4.8 mmol l-1 and 11.0 +/- 2.5%, respectively, p less than 0.05 in each case). Median increase in body weight was greater on insulin (4.2 vs 1.1 kg, p less than 0.05). Six patients experienced improved well-being on insulin compared with sulphonylurea. Median plasma non-esterified fatty acids decreased from 825 mumol l-1 to 476 mumol l-1 (sulphonylurea) and 642 mumol l-1 (insulin, both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diet, Diabetic; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Random Allocation; Tolbutamide

The effects of an intravenous infusion of porcine GIP on beta-cell secretion in patients with untreated type 2 diabetes mellitus have been studied. The subjects were studied on two separate days. After a 10 h overnight fast and a further 120 min basal period they were given an intravenous infusion of porcine GIP (2 pmol.kg-1.min-1) or control solution in random order from 120-140 min. Frequent plasma glucose, insulin, C-peptide and GIP measurements were made throughout and the study was continued until 200 min. Plasma glucose levels were similar throughout both tests. During the GIP infusion there was an early significant rise in insulin concentration from 0.058 +/- 0.006 nmol/l to 0.106 +/- 0.007 nmol/l (P less than 0.01) within 6 min of commencing the GIP infusion and insulin levels reached a peak of 0.131 +/- 0.011 nmol/l at 10 min (P less than 0.01). Insulin levels remained significantly elevated during the rest of the GIP infusion (P less than 0.01-0.001) and returned to basal values 20 min post infusion. No change in basal insulin values was seen during the control infusion. C-peptide levels were similarly raised during the GIP infusion and the increase was significant just 4 min after commencing the GIP infusion (P less than 0.05). GIP levels increased from 16 +/- 3 pmol/l prior to the infusion to a peak of 286 +/- 24 pmol/l 20 min later. At 4 min when a significant beta-cell response was observed GIP levels were well within the physiological range.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Gastric Inhibitory Polypeptide; Humans; Insulin; Middle Aged

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS).. 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Circadian Rhythm; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Humans; Insulin; Lactates; Lactic Acid; Liver; Metformin; Middle Aged; Obesity

Miglitol (BAYm 1099), an alpha-glucosidase inhibitor, reduces the postprandial increase of blood glucose and serum insulin levels in type II (non-insulin-dependent) diabetes mellitus, as shown in short-term studies. In this study, the effects of long-term miglitol treatment on metabolic control, C-peptide secretion, hepatic glucose output, and peripheral insulin sensitivity (euglycemic clamp) were tested in 15 type II diabetic patients (8 receiving insulin, 7 receiving oral hypoglycemic agents). For 8 wk they received either miglitol (300 mg/day) or placebo with a double-blind crossover design that had a 4-wk washout period between treatments. Miglitol therapy induced a reduction of postprandial blood glucose levels (miglitol compared with placebo; areas under the curve; P less than .002), whereas fasting blood glucose levels were not influenced. Miglitol caused a slight reduction of glycosylated hemoglobin levels (mean +/- SE miglitol and placebo 9.50 +/- 0.3 and 10.0 +/- 0.4%, respectively; P less than .05), which was more pronounced in insulin-treated patients. Miglitol caused a reduction of postprandial C-peptide increase (P less than .03). Hepatic glucose output (both in the basal state and during euglycemic clamp conditions) and peripheral insulin sensitivity were not influenced by miglitol therapy. Specific side effects were observed in 11 patients; in 6 patients only to a moderate degree. Long-term miglitol treatment induces a persistent reduction of postprandial blood glucose increase. This effect is more pronounced in type II diabetic patients on insulin therapy, which can cause a moderate improvement of overall metabolic control.

Topics: 1-Deoxynojirimycin; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucosamine; Glycoside Hydrolase Inhibitors; Humans; Imino Pyranoses; Insulin; Liver; Male; Middle Aged

Considerable disagreement exists regarding the levels of immunoreactive glucose dependent insulinotropic polypeptide in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Glucose dependent insulinotropic polypeptide levels were therefore studied during oral glucose and mixed meal tolerance tests in normal subjects (n = 31) and newly presenting previously untreated patients with Type 2 diabetes mellitus (n = 68). The tests were performed in random order after overnight fasts and blood samples were taken at 30 min intervals for 4 h. During the oral glucose tolerance test plasma glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a fasting value of 20 +/- 3 pmol/l to a peak of 68 +/- 5 pmol/l at 30 min and in the Type 2 diabetic patients from a similar fasting level of 27 +/- 3 pmol/l to a higher peak value of 104 +/- 6 pmol/l at 30 min (p less than 0.001). Glucose dependent insulinotropic polypeptide levels were significantly higher in the diabetic patients compared with the normal subjects from 30-90 min (p less than 0.01-0.001) following oral glucose. During the meal tolerance test glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a pre-prandial value of 22 +/- 4 pmol/l to a peak of 93 +/- 6 pmol/l at 90 min and in the Type 2 diabetic patients from a similar basal level of 25 +/- 2 pmol/l to a higher peak of 133 +/- 7 pmol/l at 60 min. Glucose dependent insulinotropic polypeptide concentrations were significantly higher in Type 2 diabetic patients compared with the normal subjects at 30 min (p less than 0.001), 60 min (p less than 0.01) and from 210-240 min (p less than 0.05) during the meal tolerance test. The groups were subdivided on the basis of degree of obesity and glucose dependent insulinotropic polypeptide concentrations were still higher in the diabetic subgroups compared with the normal subjects matched for weight. Type 2 diabetes mellitus is associated with an exaggerated glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals which is independent of any effect of obesity.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Eating; Female; Gastric Inhibitory Polypeptide; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Obesity; Random Allocation; Reference Values

Newly diagnosed, previously untreated patients with type 2 diabetes mellitus (n = 6) were studied on two separate days after overnight fasts. On each day they were given a 500-kcal mixed meal plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (GIP) (0.75 pmol/kg/min) or control solution (CS) from 0 to 30 min in random order. Frequent measurements of plasma glucose, C-peptide, insulin and GIP concentrations were made. Fasting GIP levels were similar on both days. During the meal plus GIP infusion plasma GIP levels increased from a basal value of 7.6 +/- 1.5 pmol/1 to a peak of 88.6 +/- 5.4 pmol/1 at 30 min. Following the meal infusion of CS GIP increased from a fasting level of 10.3 +/- 1.2 pmol/1 to a significantly lower peak of 58.0 +/- 8.3 pmol/1 at 60 min. During the meal plus GIP infusion GIP levels were higher at 10-45 min and at 90 min (P less than 0.05-0.001). Fasting and postprandial glucose, C-peptide and insulin levels were, however, similar on both study day. A supplementary infusion of porcine GIP with a mixed meal did not significantly alter the beta cell response or glucose tolerance in this group of patients with type 2 diabetes mellitus.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Energy Intake; Fasting; Gastric Inhibitory Polypeptide; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Random Allocation; Swine

We evaluated the role of insulin availability in the induction therapy of non-insulin dependent diabetes mellitus (NIDDM). Plasma glucose (BG) and insulin (IRI) response to glucose loading (OGTT) was investigated before and after placebo and phenobarbitone (PB) therapy in patients with glucose intolerance and NIDDM treated with diet only, sulphonylureas (SU) plus metformin (M) or insulin. The antipyrine test was used to reflect the liver mixed function oxidase system. Therapy with PB, but not placebo, reduced fasting IRI and BG in subjects with glucose intolerance and improved the glucose tolerance, insulin response to glucose and antipyrine metabolism. The effects of PB on patients with NIDDM were dependent on the insulin availability and duration of the disease. Best responses were seen in hyperinsulinemic patients at the early phase of the disease. They had lowered fasting BG and IRI values, improved glucose tolerance, insulin response to OGTT and antipyrine metabolism after PB therapy. The SU plus M treated patients responded beneficially if they had high fasting and postglucose IRI values and were non-responders if they had relative insulin deficiency. Antipyrine metabolism improved among the responders and non-responders. The hyperglycemic patients treated with insulin showed improved glucose metabolism, an improved C-peptide response and antipyrine metabolism. The subjects could be classified into responders and non-responders by calculating the ratio of areas above the fasting level curve of insulin and glucose (sigma delta I-OGTT/sigma delta G-OGTT). These values for the former were 0.2-0.4 and the latter 0.03-0.04, as compared to healthy volunteers (1.0) and subjects with glucose intolerance (1.4). A PB type inducer improves insulin sensitivity but does not alter its production or secretion. The outcome of glucose metabolism is therefore dependent on insulin availability.

Topics: Adult; Antipyrine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Microsomes, Liver; Middle Aged; Mixed Function Oxygenases; Models, Biological; Phenobarbital; Reference Values

Administration of synthetic human corticotropin-releasing factor (hCRF, 2 micrograms/kg body weight) during simultaneous application of the opioid antagonist naloxone (1.6 mg i.v. bolus, followed by an infusion at a rate of 1.2 mg/h) produced a significant increase in plasma C-peptide levels of six male Type 2 diabetic patients which even exceeded the postprandial values. This stimulatory effect of hCRF/naloxone on plasma C-peptide was less pronounced in six healthy men. hCRF alone did not provoke any reaction of plasma C-peptide in either group. The possibility of a paracrine, CRF-dependent mechanism in pancreatic islets which somehow involves inhibitory opioid receptors is preferentially discussed. Such a mechanism may underlie the stimulatory action of hCRF/naloxone on B cells and would explain the absent reaction of peripheral venous plasma C-peptide to hCRF alone as well as the amplifying effect of simultaneous opioid receptor blockade.

Topics: Blood Glucose; C-Peptide; Corticotropin-Releasing Hormone; Diabetes Mellitus, Type 2; Eating; Humans; Naloxone; Receptors, Opioid

Studies with phentolamine, an alpha-adrenergic antagonist, in normal subjects and diabetic patients have indicated that insulin secretion may be inhibited by tonic alpha-adrenergic stimulation of pancreatic B-cells. We evaluated, with the use of the highly selective alpha 2-adrenoceptor antagonist idazoxan, the role of alpha 2-adrenergic receptors in the regulation of glucose-induced insulin secretion. A glucose infusion test (GIT) was performed after the administration of idazoxan or placebo in normal men (n = 15) and men with noninsulin-dependent diabetes mellitus (n = 6). The normal men were divided into two groups on the basis of high (n = 8) and low (n = 7) insulin responses to prior GITs. The blood glucose and plasma insulin and C-peptide responses to the GIT were similar after idazoxan (40 mg, orally) or placebo treatment in all three groups, although the responses differed among the groups. In the diabetic group iv administration of idazoxan 20 min before the GIT did not alter the insulin response to the GIT. We conclude that alpha 2-adrenergic blockade does not affect glucose-induced insulin secretion in normal men, nor does it improve the impaired first phase of insulin secretion in low insulin responders and noninsulin-dependent diabetes mellitus patients. Phentolamine probably stimulates insulin secretion by a mechanism not involving alpha 2-adrenergic receptors directly.

Topics: Adrenergic alpha-Antagonists; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dioxanes; Dioxins; Glucose; Humans; Idazoxan; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged

Sixty-six patients with secondary failure to oral hypoglycaemic therapy were assessed in hospital, and those whose fasting blood glucose concentration was greater than or equal to 10.0 mmol l-1 were treated with insulin once a day for 6 months. Only 22 patients fulfilled this criterion, and they were randomly allocated to a daily injection of either Humulin-Zn (12 patients) or Neulente insulin (10 patients). The remaining patients were considered to be noncompliant with therapy. At the end of 6 months' insulin therapy a significant (p less than 0.05) improvement occurred in HbA1c from a median (range) of 13.2(9.8-16.4)% and 13.1(10.5-16.2)% to 10.6(8-14.2)% and 11.2(8.7-13.5)% in patients given Humulin-Zn and Neulente, respectively. However, there were 46 episodes of hypoglycaemia reported by patients who received Humulin-Zn, 36 of which occurred between 0300 and 0600 h. Only four episodes were reported by the Neulente-treated group. In addition, six patients treated with Humulin-Zn (but only one patient on Neulente insulin) required the addition of short-acting insulin. The patients not treated with insulin showed a significant (p less than 0.05) improvement in blood glucose control 2 months after in-patient assessment but this improvement was not sustained to 6 months.

Topics: Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Eating; Fasting; Humans; Hypoglycemic Agents; Insulin; Middle Aged

Eight patients with noninsulin-dependent diabetes underwent two 2-wk study periods in random order during which they were provided with carbohydrate foods with either a high or low glycemic index (GI). Over both high-GI and low-GI periods there were significant reductions in body weight, serum fructosamine, and cholesterol. Reductions in fasting blood glucose, HbA1c, and urinary c-peptide-to-creatinine ratio were significant only over the low-GI period despite a smaller mean weight loss. Reductions in triglyceride were significant only over the high-GI diet. Inclusion of low-GI foods into diets of patients with diabetes may be an additional measure that favorably influences carbohydrate metabolism without increasing insulin demand.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; Male; Middle Aged

The pharmacokinetics and pharmacological properties of a new micronized preparation of glibenclamide (HB420, 3.5 mg/tablet) were compared to those of the classical formulation (HB419, 5 mg/tablet) in non insulin-dependent diabetics. In a double-blind cross-over randomized acute study, blood glucose, plasma insulin, C-peptide and glibenclamide levels were determined in 10 patients after a standardized breakfast taken 15 min following the ingestion of 1.1 +/- 0.2 tablets of HB419 or HB420. Plasma glibenclamide levels rose faster, the peak value was higher (637 +/- 154 versus 411 +/- 76 nmol/l, p less than 0.05) and the area under the curve from 0 to 240 min was 35% greater (p less than 0.05) on HB420 than on HB419. Nevertheless, the post-breakfast hormonal and metabolic changes were similar with both preparations. In a single-blind cross-over chronic study, 12 patients were treated during 3 successive 6 to 8-week periods--HB419, HB420, HB419--with glibenclamide at a dose of 1.8 +/- 0.3 tablets/day. While fasting blood glucose concentrations remained unchanged throughout the study, postprandial levels decreased from 10.9 +/- 0.8 mmol/l during the HB419 pre-period to 9.2 +/- 0.6 mmol/l during HB420 (p less than 0.02) and rose again up to 10.4 +/- 0.8 mmol/l during the last HB419 period (p less than 0.05). Similarly HbA1c decreased slightly from 7.4 +/- 0.3 to 7.2 +/- 0.4% (NS) and increased again up to 7.8 +/- 0.4% (p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Compounding; Female; Glyburide; Humans; Insulin; Kinetics; Male; Methods; Middle Aged; Random Allocation

This study examined the potential beneficial effects of the addition of a second-generation sulfonylurea to insulin therapy for poorly controlled type II diabetes. A randomized, double-blind, crossover experimental design was utilized in 16 type II diabetic patients for a period of eight months. Treatment with glyburide, 20 mg/d (plus insulin), compared with placebo (plus insulin) resulted in a significant reduction in mean basal glucose (232 +/- 12 vs 262 +/- 11 mg/dL [12.8 vs 14.4 mmol/L]) and hemoglobin A1C (10.2% +/- 0.5% vs 10.9% +/- 03%) concentrations. Concomitant with this change, basal C-peptide and free insulin values increased with glyburide therapy, but this pharmacological agent did not alter the ability of the patient's erythrocytes to bind insulin. We conclude that in type II diabetic subjects receiving more than 28 units of insulin per day, the addition of glyburide results in a marginal, but statistically significant improvement in basal glucose concentration, but not in glucose tolerance as assessed by integrated glucose concentration. Whether this small improvement in glycemia is worth the additional cost of sulfonylureas or the risk of drug side effects is not known.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Random Allocation; Receptor, Insulin

The long-term efficacy of combined insulin-glibenclamide treatment was investigated in 79 secondary drug failure patients by means of a double-blind, randomized placebo-controlled study. During a one-year follow-up period the patients on insulin plus glibenclamide required significantly lower exogenous insulin doses. Coincidentally, C-peptide concentrations were significantly raised in the verum versus the placebo group. Additionally, the administration of glibenclamide resulted in a decreased level of hyperglycaemia during the first six months of the observation period. Glibenclamide withdrawal after six and again after twelve months of the combined therapy provoked a deterioration of glycaemic control, as well as a lowering of the C-peptide concentrations. The findings demonstrate a prolonged beneficial effect of the combined treatment, in contrast to the solely short-term effects predicted by numerous studies. The metabolic improvement must be ascribed in part to the beta-cytotropic effect of glibenclamide. Extrapancreatic pathways via receptor/postreceptor mechanisms cannot be excluded.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Male; Middle Aged

Serum C-peptide was measured fasting and 6 minutes after glucagon (1 mg given intravenously) in 49 patients with non-insulin-dependent diabetes mellitus, after 4 and 6 months of successive periods of treatment with insulin and oral hypoglycaemics (glibenclamide and metformin), given in random order. Glycaemic control was not significantly different on the two treatments, but C-peptide was much higher while the patients were on glibenclamide. We conclude that glibenclamide stimulates pancreatic insulin production even after 6 months treatment.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Insulin; Male; Metformin; Middle Aged; Time Factors

Present treatment of type II diabetes mellitus often fails to normalize post-prandial glucoses. A placebo-controlled, double-blinded design tested the effects of combined glyburide-insulin therapy over 4 months in 20 patients after achieving good control of fasting glucose with diet and intermediate insulin alone. Insulin requirements significantly decreased in both groups during the initial hospitalization when drug or placebo was added, presumably because of enforced dietary compliance. Thereafter, post-prandial glucoses worsened in the placebo group, as did hemoglobin A1c; neither of these parameters changed on the glyburide group by week 16, except for modest reduction of the 2h post-lunch glucose. Thus, while combined therapy provides little advantage beyond what can be accomplished with effective doses of intermediate insulin alone, it did reduce the need for this exogenous insulin.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Evaluation Studies as Topic; Glyburide; Glycosuria; Humans; Insulin; Male; Middle Aged

The effect of highly purified natural porcine GIP on C-peptide release was examined in six type I (insulin-dependent) diabetics (IDD) with residual beta-cell function, six type II non-insulin-dependent) diabetics (NIDD), and six normal subjects. All subjects were normal weight. From -120 minutes to 180 minutes glucose or insulin was infused IV to achieve a constant plasma glucose level of 8 mmol/L. On two separate days GIP (2 pmol/kg/min) or isotonic NaCl at random were infused from 0 to 30 minutes. After 10 minutes of GIP infusion plasma IR-GIP concentrations were in the physiologic postprandial range. At 30 minutes a further increase in IR-GIP to supraphysiologic levels occurred. In all subjects plasma, C-peptide increased more after 10 minutes of GIP infusion (IDD, 0.48 +/- 0.05; NIDD, 0.79 +/- 0.11; normal subjects, 2.27 +/- 0.29 nmol/L) than on the corresponding day with NaCl infusion (IDD, 0.35 +/- 0.03; NIDD, 0.62 +/- 0.08; normal subjects, 1.22 +/- 0.13 nmol/L, P less than .05 for all). The responses of the diabetics were significantly lower than that of the normal subjects (P less than .001 for both groups). No further increase in C-peptide occurred during the remaining 20 minutes of the GIP infusion in the diabetic subjects (IDD, 0.49 +/- 0.05; NIDD, 0.83 +/- 0.10 nmol/L). In the presence of a plasma glucose concentration of 8 mmol/L, physiologic concentrations of porcine GIP caused an immediate but impaired beta-cell response in IDD and NIDD patients.

Topics: Adult; Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Swine

The diabetes intervention study (DIS) is an intervention and examination programme which in dietetically conducible diabetics who freshly became manifest shall decrease the incidence of cardiovascular diseases and analyse the influence of various steps of intervention on the course of diabetes. In the course of 5 years 54 out of 988 patients were insulinized by reason of deteriorations of metabolism. There were no significant differences between the intervention and control group concerning age, sex, index of ideal weight, fasting blood glucose, quantity of injected insulin and duration of the insulin treatment. By means of a C-peptide short-time test following glucagon stimulation an attempt of differentiation into type 1 and type 2 diabetics, was performed and compared with the results in literature.

Topics: Blood Glucose; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Follow-Up Studies; Humans; Insulin; Male; Middle Aged

20 patients with non insulin dependent diabetes mellitus (NIDDM), and within 20% of their ideal body weight were studied. They had failed to achieve adequate diabetic control following 3 months of dietary therapy. They were randomly allocated to insulin or sulphonylurea therapy for 3 months and then "crossed over" for the same period of time. Patients were maintained at euglycaemia (plasma glucose 4-7 mmol/l) for 24 hr using an open-loop intravenous insulin infusion, and then underwent a standard 75 gm oral glucose tolerance test (OGTT) following each mode of therapy. Mean glycosylated haemoglobin and preprandial blood glucose were 8.7% and 7.7 mmol/l respectively after sulphonylurea, and 7.8% (p less than 0.05) and 6.6 mmol/l (p less than 0.05) after insulin therapy. There was no significant difference in change in body weight. Following a 75 gm OGTT mean plasma insulin at 1/2 hr and 1 hr was 14.0 mu/l and 16.5 mu/l after sulphonylurea, and 23.4 mu/l (p less than 0.05) and 22.1 mu/l (p less than 0.05) after insulin therapy. Plasma C-peptide responses were also improved at 1/2, 1 and 1 1/2 hr after a period of insulin therapy being 0.61 nmol/l, 0.65 nmol/l and 0.59 nmol/l respectively. After sulphonylurea therapy comparable plasma C-peptide responses were 0.31, 0.41 and 0.37 nmol/l respectively (p less than 0.05). There was no significant difference in the total amount of intravenous insulin required for 24 hr euglycaemia. Our study shows that short term insulin therapy in patients with NIDDM who had failed on diet alone has advantages over sulphonylurea therapy in that it achieves better diabetic control and an improved B-cell response to glucose stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diet, Diabetic; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Middle Aged; Tolbutamide

To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 +/- 0.7 to 7.6 +/- 0.5 and 7.1 +/- 0.2%, respectively, P less than .01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P less than .001). Both agents comparably increased (P less than .01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P less than .05). Tolazamide (P less than .05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P less than .05) lowered postabsorptive hepatic glucose release (from 2.8 +/- 0.3 to 2.3 +/- 0.2 mg . kg-1 . min-1), but not to normal rates (1.8 +/- 0.1 mg . kg-1 . min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Food; Glucose; Humans; Insulin; Kinetics; Liver; Male; Middle Aged; Random Allocation; Tolazamide

This study presents the first multiday therapy trial of linogliride fumarate, a representative of a new class of oral hypoglycemic agents. Linogliride demonstrated a significant hypoglycemic activity in 26 patients with non-insulin-dependent diabetes mellitus receiving 1 week of therapy. In a dose range of 150 to 400 mg b.i.d., fasting glucose levels fell from 237 +/- 52 mg to 199 +/- 59 mg by day 7 (P less than 0.01). Eight-hour glucose AUCs fell from 2121 +/- 617 mg/dl/8 hr baseline to 1781 +/- 631 mg/dl/8 hr on day 7 of treatment (P less than 0.01). This was associated with a significant increase in insulin AUC from 380 +/- 327 to 610 +/- 417 on day 7 (P less than 0.01). Thus its initial action appears to be by an insulin secretagogue mechanism. No patient had any major adverse effect. This initial study indicates that linogliride fumarate is an effective hypoglycemic agent that significantly lowers fasting and postprandial glucose levels with short-term use. Linogliride fumarate represents a new group of hypoglycemic agents that may be shown to have therapeutic utility.

Topics: Administration, Oral; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fasting; Humans; Hypoglycemic Agents; Insulin; Pyrrolidines; Random Allocation; Time Factors

The present study aimed at 1) investigating the effect of a combined insulin + glipizide treatment on the metabolic control (HbA1c levels) and insulin requirements (Biostator assessment) in ten non-obese Type-II diabetic patients with recent secondary failure to sulfonylureas; and 2) characterizing the relative contributions of changes in endogenous insulin secretion (C-peptide response) and insulin sensitivity (insulin-induced glucose disposal in clamped conditions) to this effect. The patients were treated in a randomized cross-over order with either insulin alone or insulin + glipizide (3 X 10 mg/day) during two periods averaging 6 weeks each. Mean HbA1c levels were similar in both experimental conditions (8.2 +/- 0.6 vs 7.9 +/- 0.6%, NS). In fact, during the combined therapy, HbA1c levels decreased in five subjects (from 8.6 +/- 0.7 to 7.1 +/- 0.5%; 'responder'), but not in the five others ('non-responders'); the 20-h Biostator insulin infusion was significantly decreased in the responders (29%; P less than 0.05), but not in the non-responders. Basal (0.271 +/- 0.086 vs 0.086 +/- 0.017 nmol/l; P less than 0.05) and post-glucagon (0.468 +/- 0.121 vs 0.180 +/- 0.060 nmol/l; P less than 0.05) C-peptide plasma levels were significantly higher in the responders than in the non-responders; in addition, glipizide significantly increased basal C-peptide concentrations in the responders only (+68%; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glipizide; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Sulfonylurea Compounds

A double-blind, placebo-controlled investigation has been made into the effects of 8 weeks of glipizide treatment in diabetics previously classified as Type 2 but with subsequent attenuation of insulin secretion and thence maintained on exogenous insulin. Although all patients were exposed to therapeutic plasma concentrations of glipizide, fasting blood glucose, haemoglobin A1 and plasma lipoproteins (HDL, LDL, total cholesterol and triglycerides) did not show any consistent improvement following this treatment. It appears unlikely that SU (glipizide) has any primary effect on insulin action or on plasma lipoproteins. Its primary action is to augment insulin release and availability, so, its use should be restricted to Type 2 diabetics who retain insulin secretion.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Glipizide; Glycated Hemoglobin; Humans; Insulin; Lipids; Lipoproteins; Male; Middle Aged; Random Allocation; Sulfonylurea Compounds

Insulin requirements, C-peptide levels, and serum lipids have been assessed in 12 obese, insulin-requiring (greater than 60 U/day) patients with type II diabetes mellitus, in a randomized crossover fashion with two treatment regimens: NPH alone and combined NPH and tolazamide, over a period of 3 months each, with maintenance of weight and glycemic control (HgA1, 2hpp and mean 24h glucose profile) at comparable levels. Serum cholesterol improved in both groups compared to their respective baseline values (p less than 0.05). In addition, serum triglyceride was lower (p less than 0.05) in the combined therapy as compared with NPH alone therapy. Insulin requirements were decreased by 23% (p less than 0.002) in the combined therapy group, without significant change in weight, glycemic control, or C-peptide levels. However, C-peptide increments in the combined therapy group were significantly higher than the baseline by 70% (p less than 0.02). NPH plus tolazamide therapy as compared with NPH alone lowers insulin requirement in obese, type II diabetic women without significant alteration in glycemic control, possibly by an increased tissue sensitivity to insulin, and decreases serum triglyceride levels.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Insulin, Isophane; Middle Aged; Obesity; Prospective Studies; Random Allocation; Tolazamide; Triglycerides

Slowing starch digestion by inhibiting amylase activity in the intestinal lumen should improve postprandial carbohydrate tolerance in patients with diabetes mellitus. Crude bean-derived amylase inhibitor ("starch blocker") that contains only minimal antiamylase activity, however, does not modify carbohydrate assimilation. To test the validity of the "starch blockade" concept, we assessed the effect of a partially purified bean-derived amylase inhibitor with increased antiamylase activity on carbohydrate tolerance in normal subjects and in patients with non-insulin-dependent diabetes mellitus. In comparison with a placebo, ingestion of this inhibitor with 50 g of starch substantially reduced postprandial increases in plasma concentrations of glucose and insulin in both normal subjects and those with diabetes. We conclude that a purified amylase inhibitor is effective and potentially beneficial in the treatment of diabetes mellitus.

Topics: Adult; Amylases; Blood Glucose; Breath Tests; C-Peptide; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Humans; Hydrogen; Insulin; Intestinal Absorption; Lactulose; Male; Middle Aged; Starch

An insulin suppression test performed in random order with either biosynthetic human insulin or purified pork insulin was used to compare biological activity of these two insulins in obese patients suffering from varying degrees of glucose intolerance. Blood glucose curve, steady-state blood glucose levels, insulin sensitivity indices and steady-state plasma insulin levels were identical during the two sets of tests. Furthermore endogenous insulin and glucagon secretion were similarly suppressed. The insulin suppression test is a simple and rapid procedure to compare the biological activity of fast-acting insulins. Our results confirm the insulin-resistance in obesity and clearly show that biosynthetic human and porcine insulins have similar biological potency.

Topics: Adult; Aged; Animals; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Pork; Male; Middle Aged; Obesity; Recombinant Proteins; Somatostatin; Swine

We have studied the effect of the combination of a sulfonylurea (Hb 420 or glibenclamide) with insulin in 22 type II diabetic patients, treated with insulin and with residual insulin secretion (fasting plasma C peptide level greater than 0.2 pmol/ml). After a 3 week run-in period, the patients received either glibenclamide (7 mg of Hb 420 before breakfast and 3.5 mg before supper) or placebo in double blind fashion. Clinical and biological parameters (body weight, number of hypoglycemic episodes, daily insulin dose, fasting and postprandial glucose and C peptide levels after a standard meal) were collected during the basal (run-in) period and after 8 and 16 weeks of treatment. In the glibenclamide group, a significant increase in the number of hypoglycemic episodes was observed in spite of a 8 to 10% reduction in insulin requirements. A 18% reduction of both fasting and postprandial plasma glucose levels was found after 8 and 16 weeks of glibenclamide therapy. Concomitantly, a 35% increase of fasting and postprandial plasma C peptide levels occurred. The data suggest that the use of combined sulfonylurea and insulin therapy may be beneficial to type II diabetic patients with residual insulin secretion and poor glycemic control under insulin therapy alone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glyburide; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Triglycerides

In a double-blind placebo-controlled cross-over study eight type II diabetics (three men, five women), of whom six were at the point of late failure to oral treatment, were given an insulin infusion of 22 U human insulin/patient for 45 min (approximately 7 microU/kg X min); 30 min before infusion either glibenclamide (1 tablet Euglucon N) or placebo was administered. Glucose in venous blood, C-peptide, insulin, and glibenclamide concentrations in the blood plasma were simultaneously determined over a period of 210 min. The monitoring of glucose was handled using a Biostator. The insulin level reached a mean maximum of 400 to 500 microU/ml and was in a behavior of 100 microU/ml for 60 min. The areas under the concentration-time curves (AUCs) were practically identical in the two regimes. The blood glucose fell (in mean) from 260 mg/dl to 135 mg/dl and at the end of the experiment was in the range of 155 mg/dl. The glibenclamide concentrations reached maximal concentrations of 185 ng/ml 90 min after administration. The C-peptide concentrations fell in the placebo phase by more than 40%. In contrast, in the glibenclamide period there was at first a slight rise and later a slight marginal fall (initial, 2.0 ng/ml vs 1.9 ng/ml; 60 min, 1.3 ng/ml vs 1.8 ng/ml; 180 min, 1.2 ng/ml vs 1.8 ng/ml). Values after 90, 120, and 180 min were statistically different. The AUCs (0-180 min) were different (329 ng X min/ml vs 251 ng X min/ml). The inhibition of insulin secretion (measured by C-peptide) caused by exogenous insulin administration is largely abolished by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Insulin Infusion Systems; Male; Middle Aged

We have previously demonstrated that oral glipizide suppresses the absorption of xylose in diabetics treated with diet alone. We suggested that glipizide might influence postprandial glucose levels by interfering with absorptive mechanisms. In the present study we have extended our observations to insulin-dependent diabetics (IDDM). Nine non-obese diabetics without residual beta-cell function and with normal respiratory sinus arrhythmia and Valsalva ratio were studied on two occasions. Their ordinary insulin treatment was discontinued 24 hours before the study and glucose control was maintained by i.v. insulin infusion. The experiments began at 8 a.m. after an overnight fast. Insulin was given as a continuous i.v. infusion of 0.01 U/kg/h at 8-11 a.m. and 0.005 U/kg/h at 11 a.m. -2 p.m. At 8 a.m. the patients ingested 25 g of xylose and 15 g of glucose in 300 ml of water. Glipizide (5 mg) or placebo were given 30 min prior to the glucose-xylose load in random order, each patient serving as his own control. Blood samples were taken every 60 min for analysis of glucose, xylose, C-peptide and glipizide. The rise in blood glucose in the control experiment was similar to that previously seen in non-insulin-dependent diabetics (NIDDM) given the same xylose-glucose load. Glipizide did not exert any effects on either blood C-peptide, glucose or xylose levels. We conclude that oral glipizide administered in a therapeutic dose does not reduce xylose absorption in IDDM, in contrast to its previously demonstrated effect in NIDDM.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glipizide; Glucose Tolerance Test; Humans; Intestinal Absorption; Islets of Langerhans; Sulfonylurea Compounds; Xylose

Using a double-blind crossover design, we studied the effect of tolazamide, an orally administered sulfonylurea, in 11 patients with non-insulin-dependent diabetes mellitus, poorly controlled on 40 units/day or more of insulin; all had previously failed to respond adequately to oral hypoglycemic agents and diet. In addition, six nondiabetic sex-, age-, and weight-matched controls were studied. Tolazamide significantly lowered fasting plasma glucose level from 272 +/- 21 to 222 +/- 31 mg/dL, increased fasting C peptide concentration from 0.09 +/- 0.03 to 0.28 +/- 0.10 pmole/mL (controls, 0.23 +/- 0.2 pmole/mL), and increased integrated C peptide concentration during a test meal (area under the curve) from 42 +/- 18 to 95 +/- 22 pmole/mL X min (controls, 94 +/- 8 pmole/mL X min). These data show that addition of tolazamide markedly increased fasting and meal-stimulated insulin secretion and modestly lowered fasting plasma glucose concentrations. We conclude that some patients who cannot achieve satisfactory control with oral hypoglycemic agents and diet may benefit from combined therapy with oral sulfonylurea agents plus insulin.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Random Allocation; Time Factors; Tolazamide

To determine whether sulfonylureas and exogenous insulin have different effects on insulin action, we studied eight patients with non-insulin-dependent diabetes mellitus before and after three months of treatment with tolazamide and exogenous semisynthetic human insulin, using a randomized crossover design. Therapy with tolazamide and therapy with insulin resulted in similar improvement of glycemic control, as measured by a decrease in mean glycosylated hemoglobin (+/- SEM) from 9.4 +/- 0.7 percent to 7.7 +/- 0.5 percent with tolazamide and to 7.1 +/- 0.2 percent with exogenous insulin (P less than 0.01 for both comparisons). Therapy with either tolazamide or exogenous insulin resulted in a similar lowering (P less than 0.05) of postabsorptive glucose-production rates (from 2.3 +/- 0.1 to 2.0 +/- 0.2 and 1.8 +/- 0.1 mg per kilogram of body weight per minute, respectively) but not to normal (1.5 +/- 0.1 mg per kilogram per minute). Both tolazamide and exogenous insulin increased (P less than 0.05) glucose utilization at supraphysiologic insulin concentrations (from 6.2 +/- 0.7 to 7.7 +/- 0.6 mg per kilogram per minute with tolazamide and to 7.8 +/- 0.6 mg per kilogram per minute with exogenous insulin) to nondiabetic rates (7.9 +/- 0.5 mg per kilogram per minute). Neither agent altered erythrocyte insulin binding at physiologic insulin concentrations. We conclude that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus. Therefore, the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.

Topics: Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Erythrocytes; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Middle Aged; Random Allocation; Tolazamide

Bay m 1099 is a newly developed inhibitor of intestinal alpha-glucosidase. Its ability to lower postprandial plasma glucose, serum insulin and C-peptide levels in Type II diabetics has been investigated. Fifteen obese Type II diabetic patients with inadequate metabolic control during sulphonylurea treatment received a standardized diet and were treated either with Bay m 1099, b.d. (100 mg before breakfast and dinner) or placebo for 3 days, according to a double-blind cross-over design. The postprandial blood glucose level was significantly lower during Bay m 1099 treatment compared to placebo after breakfast and dinner (AUC after breakfast p less than 0.001). The reduced postprandial hyperglycaemia was associated with a decrease in meal stimulated serum insulin and C-peptide levels. Thus, Bay m 1099 may be a useful addition in the treatment of Type II diabetic patients.

Topics: 1-Deoxynojirimycin; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Eating; Female; Glucosamine; Glycoside Hydrolase Inhibitors; Humans; Imino Pyranoses; Insulin; Male; Middle Aged; Obesity; Pancreatic Hormones

We studied the influence of chronic sulfonylurea treatment on glucose metabolism and beta-cell secretory activity in diabetic patients requiring insulin after secondary failure to oral drugs. Thirty diabetics were allocated at random into two groups, each consisting of 15 subjects: group A continued insulin treatment, while group B received combined insulin plus sulfonylurea. Daily doses of the sulfonylurea gliclazide ranged from 40 to 240 mg, and dose adjustment was made on the basis of periodic monthly control. This treatment (12 months) caused a significant improvement of both diurnal glucose profile and HbA1 levels; the beta-cell secretory response to 1 mg glucagon was significantly increased at the end of the study. There was on average a 40% reduction of the daily insulin dose in the diabetics receiving combined treatment. None of these improvements were seen in the control group receiving only insulin for the same period of time. We suggest that combining a sulfonylurea with insulin can be useful in insulin-requiring type-2 diabetics who still secrete some endogenous insulin.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Follow-Up Studies; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Sulfonylurea Compounds

A population-based study on the therapeutic effects of a diabetes teaching programme (DTP) based on problem oriented participatory education (POPE)--a method based on learner activity in group meetings--was undertaken at the Primary Health Care Centre, Kisa, Sweden, in collaboration with educationalists. A control group was given conventional classroom teaching. To be included a patient had to be aged 55-73 years, to live in his own home, and to have non-insulin-treated type II diabetes mellitus. The therapeutic effects of the DTP were studied before, during, and after POPE with regard to three factors, diabetes related knowledge, behaviour assessed by dietary and exercise habits, and the quality of the anti-diabetic therapy as assessed by metabolic profile including Hb-A1. Significant improvement in knowledge and transient improvement in Hb-A1 concentration were recorded among patients taking part in a DTP adjusted to their individual problems and needs. When improvement in metabolic control does not last, group meetings should be continued for more than the three months used in the present study. We believe that such improvement is intimately bound up with the psycho-social process that is involved in the group meetings and that helps the patient to cope with the disease in particular and life in general.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 2; Energy Intake; Female; Hemoglobin A; Humans; Male; Middle Aged; Patient Education as Topic; Patient Participation

The post-prandial glucose and hormonal responses were followed in nine non-insulin-dependent diabetics after four randomized breakfast meals containing mainly wheat products. The effect of conventionally baked breads was compared with extruded crispbread-like products prepared from white or whole-grain wheat flour, respectively. The extruded whole-grain product gave significantly larger areas under the glucose and insulin curves than the corresponding baked bread, and resulted in higher C-peptide, gastric inhibitory polypeptide, and glucagon concentrations at certain time points. The mean incremental areas under the glucose curves were similar after white bread and the two extruded crispbread-like products. There were no significant differences between white and whole-grain bread. The results indicate that baked whole-grain wheat bread is to be preferred to corresponding extruded products in non-insulin-dependent diabetes mellitus.

Topics: Adult; Aged; Blood Glucose; Bread; C-Peptide; Diabetes Mellitus, Type 2; Dietary Fiber; Female; Gastric Inhibitory Polypeptide; Glucagon; Glycerol; Humans; Insulin; Male; Middle Aged; Triglycerides; Triticum

In a double-blind cross-over study we compared the effects of insulin plus glibenclamide, 5 mg twice daily, with insulin plus placebo during 8-week periods on metabolic parameters in 13 non-insulin dependent diabetic (NIDDM) patients poorly controlled with insulin alone. The combination therapy improved diabetic control as assessed by fasting blood glucose (p less than 0.001), 24-hour urinary glucose (p less than 0.01) and glycohemoglobin (HbA1) concentrations (p less than 0.05 at week 12). The effect tended to cease with time. Significantly higher C-peptide values were found during combination treatment than during insulin-placebo (p less than 0.01) and the changes in fasting C-peptide concentrations correlated positively with the changes in HbA1 concentrations (r = 0.56, p less than 0.05). There was no difference in glucagon concentrations, insulin binding to erythrocytes or insulin sensitivity between the two study periods. Neither did the combination therapy influence blood lipids significantly. The present study shows that the combination of insulin and glibenclamide may be of limited value in the treatment of NIDDM patients poorly controlled with insulin alone. However, thus far the long-term results are uncertain. In the absence of significant effects on insulin binding and insulin sensitivity, the improved diabetic control seems to be explained, at least partly, by glibenclamide-induced stimulation of insulin secretion.

Topics: Blood Glucose; Body Weight; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon; Glyburide; Glycated Hemoglobin; Glycosuria; Humans; Insulin; Lipids; Male; Middle Aged

A randomized double-blind, placebo-controlled trial of insulin plus glyburide was carried out in 22 insulin-treated patients with poorly controlled type II diabetes mellitus. Glycemic control and lipoprotein responses were assessed for 16 weeks. Oral glucose tolerance testing was performed at weeks 0, 4, and 16. Clinical characteristics and glycemic control were similar at week 0 in the placebo/insulin group (n = 12) and the glyburide/insulin group (n = 10). Throughout the study, the dose of insulin was fixed. The placebo group had no change in any metabolic parameter throughout the protocol period. After four weeks, glyburide significantly lowered fasting blood glucose and integrated glucose areas (p less than 0.01) after oral glucose testing compared with week 0 (fasting blood glucose 225 +/- 20 mg/dl versus 286 +/- 27 mg/dl, p less than 0.02). Associated with this were mean fasting, stimulated, and integrated C-peptide levels that were significantly higher (p less than 0.02) at week 4 versus week 0. After 16 weeks, mean fasting blood glucose remained significantly lower compared with baseline values (252 +/- 25 mg/dl versus 286 +/- 27 mg/dl, p less than 0.05). Glycosylated hemoglobin (hemoglobin A1c) levels decreased significantly (p less than 0.05) at weeks 4 to 16 compared with the baseline value. Although integrated areas were no different after oral glucose, fasting and stimulated C-peptide levels were significantly higher (p less than 0.05) at week 16 versus week 0. Total cholesterol, triglycerides, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol did not change during the study. After the code was broken, comparisons were made between those with response to combination therapy (reduction of fasting blood glucose by at least 50 mg/dl or fasting blood glucose of 140 mg/dl or less at the end of the first week of treatment that persisted for four consecutive weeks) and those without response. Baseline clinical and laboratory characteristics were identical in both groups. Mean fasting and stimulated serum C-peptide levels after oral glucose, however, were significantly higher in the patients with response at week 4 compared with the patients without response. The mean maximal incremental C-peptide level was 1.50 +/- 0.19 ng/ml at week 0 in the patients with response compared with 0.67 +/- 0.28 ng/ml in the patients without response (p less than 0.01). Lipoproteins were not differen

Topics: Blood Glucose; Blood Proteins; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucose Tolerance Test; Glyburide; Glycated Hemoglobin; Humans; Insulin; Lipids; Lipoproteins; Male; Middle Aged; Placebos

A double-blind crossover study was undertaken to determine whether glibenclamide could improve glycaemic control in patients not adequately controlled by insulin. Nine elderly outpatients with non-insulin dependent (type 2) diabetes participated in the study. In addition to their regular insulin treatment, the patients were given either glibenclamide 5 mg twice daily or placebo tablets for 2 months followed by the opposite combination for a further 2 months. The fasting plasma glucose concentrations were lower during the insulin plus glibenclamide period than during the insulin plus placebo period and the difference tended to increase at the end of each study period (p less than 0.01 and 0.001). The level of haemoglobin A, (HbA1) decreased significantly from 13.8 +/- 0.6% (mean +/- SE) to 12.4 +/- 0.6% during the insulin + glibenclamide period (p less than 0.01); in contrast, there was no change during the insulin + placebo period. The 24-hour urinary glucose excretion was reduced during the insulin + glibenclamide period compared with insulin + placebo (p less than 0.05). Basal and glucagon stimulated C-peptide concentrations did not significantly differ between the two treatment regimens. The results suggest that glibenclamide can improve the glycaemic control in insulin-treated elderly diabetics by mechanisms which still are to be elucidated.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Male

Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol. Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter. On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide. Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment. Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide. Plasma glucagon and GIP concentrations were not significantly affected. Insulin sensitivity was increased by glibenclamide but not by glipizide. Neither therapy affected insulin binding to erythrocytes. It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide. Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels. The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Erythrocytes; Female; Gastric Inhibitory Polypeptide; Glipizide; Glucagon; Glyburide; Glycosuria; Humans; Insulin; Insulin Resistance; Kinetics; Male; Middle Aged; Random Allocation; Sulfonylurea Compounds

A double-blind, placebo-controlled, crossover-therapy study was carried out using intraindividual comparisons on 18 type II diabetics. All patients were secondary drug failure patients and had been on insulin-glibenclamide combination therapy for periods of 1-14 months. On the last day of each of the 2-week-treatment periods (insulin-glibenclamide [verum phase] versus insulin-placebo [placebo phase]) the patients received a standard breakfast equivalent to 100 g glucose. Medication was given 30 minutes before the standard breakfast. The blood glucose level during insulin-glibenclamide therapy was 35-45 mg/dl below that during insulin-placebo treatment at all time points investigated. Correspondingly, the glucose excretion was reduced by about 40% during the verum phase. beta-Hydroxybutyrate in serum and urine and glycosylated haemoglobin (HbA1) measurements made during the verum phase were also significantly lower. As expected, the insulin level in serum showed no change. In contrast, C peptide concentrations were significantly raised by 15-40% during the verum phase. Combination therapy with insulin and glibenclamide produced therefore a marked improvement in the metabolic status of C peptide-positive patients classified as secondary drug failure patients to oral therapy.

Topics: Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hydroxybutyrates; Insulin; Male; Middle Aged; Time Factors

The utilisation of blood glucose may be used for definition of insulin resistance in type II diabetes mellitus. To evaluate this possibility we adapted an infusion test of somatostatin in 10 normal persons (age 26 +/- 3 years, relative body weight 26 +/- 10% according to Broca) in a randomized cross-over therapy with bezafibrate (3 X 200 mg/die). As the coefficient of variation (VC) of measured blood glucose continuously increased the best time of a steady state was between 90 and 130 min after beginning the infusion (mean VC 8.9%). While insulin remained nearly constant (41 (45; 38) microU/ml) blood glucose dropped by about 14% and reached a steady state of 89 (134; 45) mg/dl. During the therapy of bezafibrate blood glucose was significantly decreased by 36% 130 min after beginning the infusion. Although the effect was not significant during the whole time of the steady state it became evident by a negative correlation with lactate (r = -0.687) and pyruvate (r = -0.843). A correlation with a concomitant decrease of triglyceride and cholesterol also induced by bezafibrate could not be proven. The results show that the infusion test of somatostatin is fitted to measure a steady state of blood glucose and insulin and that it is possible by this technique to quantify a changed utilisation of blood glucose induced by specific therapy.

Topics: Adult; Bezafibrate; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Insulin Resistance; Somatostatin; Time Factors

Peripheral blood glucose, plasma insulin and C-peptide levels were investigated after giving a standardized breakfast (500 kcal, 60 g carbohydrates) to 10 nonobese Type 2 diabetic patients previously treated by diet alone. Each patient received at random, at 1 week intervals, either 5 mg glipizide (meal + glipizide) or a placebo (meal alone) 30 min before breakfast. Basal values of blood glucose, plasma insulin and C-peptide were similar on both occasions. After meal + glipizide, the blood glucose increase was sharply limited whereas the rise in plasma insulin was steeper and reached twice as high a level. In contrast, the rise in plasma C-peptide was similar in both conditions. Consequently, the areas under the curves (0-300 min) showed a marked reduction in blood glucose after meal + glipizide (2289 +/- 149 versus 3101 +/- 169 mmol X min/1; 2p less than 0.001), associated with a significant increase in plasma insulin (14219 +/- 3261 versus 7591 +/- 1173 microU X min/ml; 2p less than 0.025) but no significant change in plasma C-peptide (342 +/- 45 versus 326 +/- 34 pmol X min/ml; N.S.). The insulin/C-peptide molar ratio was thus significantly increased after meal + glipizide (0.41 +/- 0.06 versus 0.23 +/- 0.04 at the 60th min; 2p less than 0.02). The dissociation between the responses of insulin and C-peptide suggests that a single dose of 5 mg glipizide in Type 2 diabetic subjects may enhance availability of peripheral insulin by extrapancreatic mechanism(s). This phenomenon may result in a higher circulating level of the hormone and therefore represent a further mode of action of sulphonylureas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Female; Glipizide; Humans; Insulin; Male; Middle Aged; Stimulation, Chemical; Sulfonylurea Compounds

Acarbose, 300 mg/day, was administered over one month in a cross-over trial to 18 hyperglycemic patients aged 41-66 years with non-insulin-dependent diabetes mellitus (NIDDM). All showed "normal" or exaggerated insulin release after a glucose challenge and remained in poor control (random glucose levels greater than or equal to 13 mmol/l) despite involvement in a diabetes intervention programme and prior use of oral hypoglycemic agents. During the one month treatment with Acarbose, fasting glucose and % HbAl concentrations were not different from those observed during placebo therapy. Furthermore, glucose tolerance was unchanged by Acarbose treatment. Glucose concentrations after a 1.6 MJ test meal were reduced by Acarbose from peak values of 17.3 +/- 1.0 to 15.0 +/- 1.1 mmol/l and were associated with lower post-prandial C-peptide (CPR) and insulin responses. Nevertheless, daily insulin production, as assessed by CPR excretion rates and plasma CPR and insulin concentrations, was not reduced by Acarbose. In fact, fasting plasma insulin and CPR levels were significantly higher during Acarbose then placebo therapy. Acarbose (100-400 mg/day) was continued for six months in 12 of these patients. During treatment, post-prandial glucose levels remained lower but monthly MBG values, determined by self-measurement of blood glucose, were unchanged except for small reductions in the 4th and 5th treatment months. % HbAl levels did not change. These data show that Acarbose treatment of a defined group of patients with poorly controlled NIDDM: resulted in small but sustained reductions of post-prandial glucose levels but without improving glucose tolerance, and reduced the circulating concentrations of insulin and CPR postprandially, but overall did not reduce daily production.

Topics: Acarbose; Adult; Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Food; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Oligosaccharides; Time Factors; Trisaccharides

A new galenic form of glibenclamide (with a higher specific surface area for better absorption) was compared with the conventional form in 12 insulin-dependent and glibenclamide-treated diabetics (three women, nine men; aged 37-60 years) in a double-blind controlled crossover study. There was more rapid absorption, with a maximal serum concentration after 1 1/2 hours, compared with the usual preparation which gave a lower longer-sustained maximum of serum-glibenclamide level between 1 1/2 and 4 hours. In addition, there was more complete absorption so that the needed daily dose was decreased: 3.5 mg of the new form was bio-equivalent to 5 mg of the ordinary form. Duration of effect of the new form was not shorter despite different pharmacokinetics. Response of serum insulin and C-peptide level was the same in the two forms. On the other hand, the blood-glucose profile was significantly better with the new form.

Topics: Adult; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glyburide; Humans; Insulin; Male; Middle Aged; Random Allocation

Thirteen patients (6 females and 7 males) who were secondary failures on oral drug therapy were randomly allocated to either 2 months of treatment with insulin + glibenclamide or insulin + placebo. Thereafter the treatment schedules of the two groups were switched over for another two months. The combination of insulin and glibenclamide was more effective in lowering the fasting blood glucose (P = 0.026) and 24 h urine glucose (P = 0.042) than the combination of insulin and placebo. The combination therapy with insulin and glibenclamide revealed higher basal (P = 0.021) and glucagon-stimulated C-peptide concentrations (P = 0.037) than therapy with insulin and placebo. However, insulin binding to erythrocytes did not differ between the two study periods. The results indicate that the addition of glibenclamide to insulin in type II diabetics poorly controlled by oral antidiabetics alone may slightly improve diabetic control. The mechanism of this action is due at least partly to sulphonylurea-induced stimulation of endogenous insulin secretion. The effectiveness of the combination treatment during long-term therapy still remains to be proven, however.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Glycosuria; Humans; Insulin; Male; Middle Aged; Random Allocation

Patients with maturity onset diabetes that is poorly controlled on maximal doses of oral hypoglycaemic agents are difficult to treat. A prospective randomised crossover study was performed in 58 predominantly non-obese patients on maximal doses of glibenclamide or metformin, or both, to find out if insulin would improve control or well being. The patients were given daily injections of up to 48 units of highly purified porcine lente insulin. Glycaemic control was improved by 15% or more in only 18 patients; 14 others felt better but their diabetes was no better controlled. Those whose control was improved by insulin could not be distinguished by age, duration of diabetes, body mass index, or their own treatment preference. C peptide concentrations, however, did help predict the response to insulin, the fasting C peptide to glucose ratio being considerably lower in those patients whose control was better on insulin. These findings suggest that a simple insulin regimen does not necessarily lead to better glycaemic control in maturity onset diabetes. Nevertheless, a trial of insulin is often justified since it poses few practical difficulties and makes some patients feel better even if their control is not improved. A more complex regimen might improve control in more cases, but it might also be less acceptable to older patients.

Topics: Adult; Aged; Attitude to Health; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin, Long-Acting; Male; Metformin; Middle Aged; Prospective Studies; Random Allocation; Tablets

Recent evidence suggests concomitant insulin and sulfonylurea therapy has a theoretical potential in the management of type II diabetes mellitus. In a long-term double-blind, randomized placebo-controlled study of combination therapy, serum glucose, C-peptide, total cholesterol, triglyceride, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were evaluated in insulin-treated patients with poorly controlled, type II diabetes mellitus after addition of either glyburide (n = 10) or placebo (n = 12). Oral glucose tolerance testing was performed at weeks 0, 4, and 16. Clinical characteristics and glycemic control (fasting blood glucose and glycosylated hemoglobin values) were similar at week 0 in both groups. The placebo group had no change in any metabolic parameter throughout the study period. At week 4, glyburide significantly lowered fasting blood glucose and integrated glucose areas (p less than 0.01) compared with values at week 0 (fasting blood glucose 225 +/- 20 versus 286 +/- 27 mg/dl, p less than 0.02). Mean fasting, stimulated, and integrated C-peptide levels were significantly higher (p less than 0.02) at week 4 versus week 0. At week 16, mean fasting blood glucose values remained significantly lower compared with baseline values (252 +/- 25 versus 286 +/- 27 mg/dl, p less than 0.05). Glycosylated hemoglobin levels decreased significantly (p less than 0.05) at weeks 4 to 16 compared with the baseline values. Although glucose responses and integrated areas were no different after oral glucose tolerance testing, fasting and stimulated C-peptide levels were significantly higher (p less than 0.05) at week 16 versus week 0. Lipid and lipoprotein levels remained unchanged. In summary, combination therapy consisting of glyburide and insulin moderately improved glucose control in type II diabetes mellitus at the end of four weeks. Despite significantly lower fasting serum glucose and glycosylated hemoglobin levels after 16 weeks, combination treatment did not normalize glycemic control. Glucose tolerance decreased further after 16 weeks despite persistence of increased endogenous insulin secretion. The role of the combination therapy in the long-term care of patients with type II diabetes mellitus needs further investigation.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Glucose Tolerance Test; Glyburide; Glycated Hemoglobin; Humans; Insulin; Lipid Metabolism; Lipoproteins; Male; Middle Aged; Time Factors

We compared the glycemic efficacy of treatment intensification between quadruple oral antidiabetic drug therapy and once-weekly glucagon-like peptide-1 receptor agonist (GLP-1RA)-based triple therapy in patients with poorly controlled type 2 diabetes mellitus refractory to triple oral therapy. For 24 weeks, changes in glycosylated hemoglobin (HbA1c) from baseline were compared between the two treatment groups. Of all 96 patients, 50 patients were treated with quadruple therapy, and 46 were treated with GLP-1RA therapy. Reductions in HbA1c for 24 weeks were comparable (in both, 1.1% reduction from baseline; P=0.59). Meanwhile, lower C-peptide level was associated with a lower glucose-lowering response of GLP-1RA therapy (R=0.3, P=0.04) but not with quadruple therapy (R=-0.13, P=0.40). HbA1c reduction by GLP-1RA therapy was inferior to that by quadruple therapy in the low C-peptide subgroup (mean, -0.1% vs. -1.3%; P=0.04). Treatment intensification by switching to quadruple oral therapy showed similar glucose-lowering efficacy to weekly GLP-1RA-based triple therapy. Meanwhile, the therapeutic response was affected by C-peptide levels in the GLP-1RA therapy group but not in the quadruple therapy group.

Topics: Autoimmune Diseases; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin

Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes.. This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210).. We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient -0.35; 95% CI -0.44, -0.25) and men (coefficient -0.09; 95% CI -0.15, -0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men.. We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Middle Aged; Proteomics; South Africa

To investigate the impact of family history of type 2 diabetes (T2D) on the clinical phenotypes of patients with idiopathic type 1 diabetes (T1D).. In clinically diagnosed T1D cases, a total of 335 idopathic T1D patients were included in the study, after excluding autoimmune T1D using islet autoantibody testing and monogenic diabetes using a custom monogenic diabetes gene panel obtained from clinically diagnosed T1D cases. A semi-structured questionnaire was used to collect information on the presence of T2D in first-degree relatives. The demographic and metabolic markers of idiopathic T1D patients were analysed. Subgroup analysis was performed to investigate potential interactions between T2D family history and human leukocyte antigen (HLA) genotypes.. A total of 18.2% of individuals with idiopathic T1D had a T2D family history, and these individuals were more likely to have features associated with T2D, such as older age of onset, higher body mass index at diagnosis, lower insulin dosage and better beta-cell function, as indicated by higher levels of fasting C-peptide and 2-hour postprandial C-peptide (all P < 0.05). Additionally, regardless of HLA susceptible genotypes, the impact of family history of T2D was consistently observed in idiopathic T1D patients. Multivariable analyses showed that T2D family history was negatively correlated with the risk of beta-cell function failure in idiopathic T1D patients (P < 0.05).. Family history of T2D may be implicated in the heterogeneity of idiopathic T1D patients.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genotype; Humans; Insulin

Monogenetic diabetes mellitus (DM) describes a collection of single-gene diseases marked by hyperglycemia presenting in childhood or adulthood and the absence of immunological markers of type 1 DM. Mutations in the human insulin gene INS give rise to two separate clinical syndromes: permanent neonatal DM, type 4 (PNDM4), and maturity-onset diabetes of youth, type 10 (MODY10); the former presents shortly after birth and the latter presents in childhood and adulthood. We describe a 40-year-old man in a kindred with high prevalence of DM who presented with severe hyperglycemia but not ketoacidosis or hypertriglyceridemia. Twelve years after initial presentation, the patient had elevated proinsulin and normal plasma C-peptide when nearly euglycemic on treatment with insulin glargine. A novel INS mutation, Gln65Arg, within the C-peptide region was identified. The INS (p.Gln65Arg) mutation may cause MODY10 by disrupting proinsulin maturation.

Topics: Adolescent; Adult; C-Peptide; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Infant, Newborn; Insulin; Male; Mutation; Proinsulin

We aimed to assess the distribution of transcription factor 7-like 2 gene TCF7L2 (rs7903146) polymorphism and to find possible associations between TCF7L2 and the characteristics of type 1 diabetes.. We studied 190 newly diagnosed type 1 diabetes patients (median age 12.7 years, range 2.0-72.5) and 246 controls (median age 23.8 years, range 1.4-81.5) for TCF7L2 single nucleotide polymorphism. We determined anti-islet autoantibodies, random C-peptide levels, diabetes associated HLA DR/DQ haplotypes and genotypes in all patients.. There were no differences in the distribution of TCF7L2 single nucleotide polymorphism between patients and controls. However, patients with in type 1 diabetes, after adjusting for age and sex, subjects carrying C allele were at risk for a C-peptide level lower than 0.5 nmol/L (OR 5.65 [95% CI: 1.14-27.92]) and for zinc transporter 8 autoantibody positivity (5.22 [1.34-20.24]). Participants without T allele were associated with a higher level of islet antigen-2 autoantibodies (3.51 [1.49-8.27]) and zinc transporter 8 autoantibodies (2.39 [1.14-4.99]).. The connection of TCF7L2 polymorphism with zinc transporter 8 and islet antigen-2 autoantibodies and C-peptide levels in patients supports the viewpoint that TCF7L2 is associated with the clinical signs and autoimmune characteristics of type 1 diabetes. The mechanisms of the interaction between the TCF7L2 risk genotype and anti-islet autoantibodies need to be studied further.

Topics: Adolescent; Adult; Aged; Autoantibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Polymorphism, Single Nucleotide; T Cell Transcription Factor 1; Young Adult; Zinc Transporter 8

This study investigated insulinoma-associated-2 autoantibody (IA-2A) and zinc transporter 8 autoantibody (ZnT8A) distribution in patients with type 1 diabetes (T1D) and latent autoimmune diabetes (LAD) and the autoantibodies' association with clinical characteristics and HLA-DR-DQ genes.. This cross-sectional study recruited 17,536 patients with diabetes from 46 hospitals across China. A total of 189 patients with T1D and 58 patients with LAD with IA-2A positivity, 126 patients with T1D and 86 patients with LAD with ZnT8A positivity, and 231 patients with type 2 diabetes (T2D) were selected to evaluate islet autoantibodies, clinical phenotypes, and HLA-DR-DQ gene frequency.. IA-2A was bimodally distributed in patients with T1D and LAD. Patients with low IA-2A titre LAD had lower fasting C-peptide (FCP) (p < 0.01), lower postprandial C-peptide (PCP) (p < 0.001), and higher haemoglobin A1c (HbA1c) levels (p < 0.05) than patients with T2D. Patients with high IA-2A titre LAD were younger than patients with low IA-2A titre LAD (p < 0.05). Patients with low IA-2A titre T1D had lower FCP (p < 0.01), lower PCP (p < 0.01), and higher HbA1c levels (p < 0.05) than patients with high IA-2A titre LAD. HLA-DR-DQ genetic analysis demonstrated that the frequency of susceptible HLA haplotypes was higher in IA-2A-positive patients (p < 0.001) than in patients with T2D. Patients with high ZnT8A titre LAD had lower FCP (p = 0.045), lower PCP (p = 0.023), and higher HbA1c levels (p = 0.009) and a higher frequency of total susceptible haplotypes (p < 0.001) than patients with low ZnT8A titre LAD.. IA-2A in patients with T1D and LAD was bimodally distributed, and the presence of IA-2A could demonstrate partial LAD clinical characteristics. ZnT8A titre had a certain predictive value for islet functions in patients with LAD.

Topics: Autoantibodies; C-Peptide; Cation Transport Proteins; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Intolerance; Glutamate Decarboxylase; Glycated Hemoglobin; HLA-DR Antigens; Humans; Insulinoma; Pancreatic Neoplasms; Zinc Transporter 8

Topics: C-Peptide; Diabetes Mellitus, Type 2; Humans; Kidney Transplantation; Pancreas Transplantation

During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccination-induced hyperglycemia and related complications have been reported. However, there have been few reports of type 1 diabetes triggered by COVID-19 vaccines in subjects without diabetes. Here, we report the case of a 56-year-old female patient who developed hyperglycemia after the second dose of COVID-19 mRNA-based vaccination without a prior history of diabetes. She visited our hospital with uncontrolled hyperglycemia despite administration of oral hyperglycemic agents. Her initial glycated hemoglobin level was high (11.0%), and fasting serum C-peptide level was normal. The fasting serum C-peptide level decreased to 0.269 ng/mL 5 days after admission, and the anti-glutamic acid decarboxylase antibody was positive. The patient was discharged in stable condition with insulin treatment. To our knowledge, this is the first case of the development of type 1 diabetes without diabetic ketoacidosis after mRNA-based COVID-19 vaccination, and is the oldest case of type 1 diabetes development under such circumstances.

Topics: Adult; C-Peptide; COVID-19; COVID-19 Vaccines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Middle Aged; Vaccination

To compare the clinical and biochemical profile and prevalence of complications among childhood/adolescent-onset (CAO; onset of diabetes< 20 years of age) and adult-onset (AO; onset of diabetes- ≥ 20 years of age) type 1 diabetes (T1D), seen at a tertiary care diabetes center in south India.. Data of 5578 individuals with T1D, diagnosed based on a history of diabetic ketoacidosis or ketonuria, fasting C-peptide < 0.3 pmol/mL and stimulated C-peptide values < 0.6 pmol/mL, and requirement of insulin right from the time of diagnosis, presenting to our center between 1991 and 2021, were retrieved from our electronic medical records. Retinopathy was assessed by retinal photography, chronic kidney disease (CKD) by urinary albumin excretion ≥ 30 µg/mg of creatinine and/or eGFR < 60 mL/min, and neuropathy by vibration perception threshold >= 20v on biothesiometry.. Overall, 3559 (63.8%) of individuals with T1D, belonged to CAO group and 2019 (36.2%) to AO category. AO had higher prevalence of all microvascular complications compared to CAO at every diabetes duration interval, even after adjusting for A1c. Among the AO group, prevalence of retinopathy, CKD, and neuropathy was higher in the GAD negative group. Among CAO there were no differences between the GAD negative and GAD positive groups with respect to prevalence of complications of diabetes.. AO with T1D had higher prevalence of microvascular complications compared to CAO. Among AO, GAD negative individuals had higher percentage of retinopathy and CKD compared to GAD positive group.

Topics: Adolescent; Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Prevalence; Retinal Diseases

Therapeutic targets in type 2 diabetes mellitus (T2D) are oriented towards nephron- and cardio-protection and the prescription of antihyperglycemic agents with proven renal and cardiovascular benefits are increasing over time. Failure to promptly diagnose insulinopenic diabetes may adversely affect the adequacy of treatment and have harmful consequences, including severe hyperglycemia and diabetic ketoacidosis.. Deprescribing insulin therapy in T2D patients in favor of other antihyperglycemic medications has become a growing therapeutic opportunity to provide adequate glucose control, promote weight loss, improve insulin sensitivity, and ameliorate cardiovascular and renal outcomes. However, a blunted insulin reserve poses significant restriction on the prescription of non-insulin agents (e.g., diabetic ketoacidosis due to gliflozins). According to our experience, the routine testing of insulin reserve provides detailed information on diabetes pathophysiology with positive implications for the appropriateness of pharmacological prescriptions.. As part of our routine evaluation of diabetic patients, C-peptide measurement is a valuable and inexpensive tool to reclassify diabetes types and provide more appropriate disease management.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Hypoglycemic Agents; Insulin; Middle Aged

The primary purpose of the current study was to test the hypothesis that the proinsulin-to-C-peptide (PI-to-CP) ratio, as an index of proinsulin secretion, would be higher and associated with indices of β-cell function in African American adults relative to European American adults without type 2 diabetes.. Participants were 114 African American and European American adult men and women. A 2-h oral glucose tolerance test was conducted to measure glucose, insulin, C-peptide, and proinsulin and derive indices of β-cell response to glucose. The Matsuda index was calculated as a measure of insulin sensitivity. The disposition index (DI), the product of insulin sensitivity and β-cell response, was calculated for each phase of β-cell responsivity. Pearson correlations were used to investigate the relationship of the PI-to-CP ratio with each phase of β-cell response (basal, Φb; dynamic, Φd; static, Φs; total, Φtot), disposition indices (DId, DIs, DItot), and insulin sensitivity. Multiple linear regression analysis was used to evaluate independent contributions of race, BMI, and glucose tolerance status on PI-to-CP levels before and after adjustment for insulin sensitivity.. African American participants had higher fasting and 2-h PI-to-CP ratios. The fasting PI-to-CP ratio was positively associated with Φb, and the fasting PI-to-CP ratio and 2-h PI-to-CP ratio were inversely associated with DId and insulin sensitivity only in African American participants.. The PI-to-CP ratio could be useful in identifying African American individuals at highest risk for β-cell dysfunction and ultimately type 2 diabetes.

Topics: Adult; Black or African American; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Male; Proinsulin

To examine whether the different patterns of post-load insulin secretion can identify the heterogeneity of type 2 diabetes mellitus (T2DM).. Six hundred twenty-five inpatients with T2DM at Jining No. 1 People's Hospital were recruited from January 2019 to October 2021. The 140 g steamed bread meal test (SBMT) was conducted on patients with T2DM, and glucose, insulin, and C-peptide levels were recorded at 0, 60, 120, and 180 min. To avoid the effect of exogenous insulin, patients were categorized into three different classes by latent class trajectory analysis based on the post-load secretion patterns of C-peptide. The difference in short- and long-term glycemic status and prevalence of complications distributed among the three classes were compared by multiple linear regression and multiple logistic regression, respectively.. There were significant differences in long-term glycemic status (e. g., HbA1c) and short-term glycemic status (e. g., mean blood glucose, time in range) among the three classes. The difference in short-term glycemic status was similar in terms of the whole day, daytime, and nighttime. The prevalence of severe diabetic retinopathy and atherosclerosis showed a decreasing trend among the three classes.. The post-load insulin secretion patterns could well identify the heterogeneity of patients with T2DM in short- and long-term glycemic status and prevalence of complications, providing recommendations for the timely adjustment in treatment regimes of patients with T2DM and promotion of personalized treatment.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Insulin; Insulin Secretion

To determine whether presentation, progression, and genetic susceptibility of robustly defined adult-onset type 1 diabetes (T1D) are altered by diagnosis age.. We compared the relationship between diagnosis age and presentation, C-peptide loss (annual change in urine C-peptide-creatinine ratio [UCPCR]), and genetic susceptibility (T1D genetic risk score [GRS]) in adults with confirmed T1D in the prospective StartRight study, 1,798 adults with new-onset diabetes. T1D was defined in two ways: two or more positive islet autoantibodies (of GAD antibody, IA-2 antigen, and ZnT8 autoantibody) irrespective of clinical diagnosis (n = 385) or one positive islet autoantibody and a clinical diagnosis of T1D (n = 180).. In continuous analysis, age of diagnosis was not associated with C-peptide loss for either definition of T1D (P > 0.1), with mean (95% CI) annual C-peptide loss in those diagnosed before and after 35 years of age (median age of T1D defined by two or more positive autoantibodies): 39% (31-46) vs. 44% (38-50) with two or more positive islet autoantibodies and 43% (33-51) vs. 39% (31-46) with clinician diagnosis confirmed by one positive islet autoantibody (P > 0.1). Baseline C-peptide and T1D GRS were unaffected by age of diagnosis or T1D definition (P > 0.1). In T1D defined by two or more autoantibodies, presentation severity was similar in those diagnosed before and after 35 years of age: unintentional weight loss, 80% (95% CI 74-85) vs. 82% (76-87); ketoacidosis, 24% (18-30) vs. 19% (14-25); and presentation glucose, 21 mmol/L (19-22) vs. 21 mmol/L (20-22) (all P ≥ 0.1). Despite similar presentation, older adults were less likely to be diagnosed with T1D, insulin-treated, or admitted to hospital.. When adult-onset T1D is robustly defined, the presentation characteristics, progression, and T1D genetic susceptibility are not altered by age of diagnosis.

Topics: Aged; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Humans; Prospective Studies

Peripheral neuropathy is the most common microvascular complication of diabetes mellitus. In subjects with type 1 diabetes (T1D) relationship of C-peptide levels and neuropathy has been observed in several studies, however, there are very few studies in type 2 diabetes (T2D) subjects. In this study we aim to assess the association of C-peptide levels with peripheral neuropathy in Indian subjects with T2D.. One hundred patients of T2D were included in this study. Clinical and laboratory parameter was assessed for all participants. The C-peptide level was measured by fluorometric enzyme immunoassay method. Assessment of diabetic peripheral neuropathy was based on diabetic neuropathy symptom score and the diabetic neuropathy examination scores.. Total 100 patients completed the study. Mean age of subjects was 60.03 years and male: female ratio was 1.17. Peripheral neuropathy was detected in 47% of subjects evaluated. Subjects were further divided in to neuropathy group and no-neuropathy group for analysis. Age in neuropathy group was significantly higher than no-neuropathy group [65.62 ± 10.5 vs 55.08 ± 9.41 yrs (p-value <0.0001)] and similarly duration of T2D was significantly higher in neuropathy group [10.11 ± 6.13 vs 4.16 ± 3.7 yrs (p-value <0.0001)]. Importantly mean fasting C-peptide (2.27 ± 0.98 vs 3.12 ± 0.84 ng/ml) and mean post meal C-peptide (4.27 ± 1.34 vs 5.33 ± 0.89 ng/ml) were significantly lower in neuropathy group compared to no-neuropathy group. An association of HbA1c level and neuropathy was statistically not significant (p = 0.793).. Serum C-peptide concentrations are associated with peripheral neuropathy in T2DM patients, independent of the degree of glycemic control.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Male; Middle Aged

Elevated C-peptide has been suggested as a risk factor for coronary artery disease (CAD). Elevated urinary C-peptide to creatinine ratio (UCPCR) as an alternative measurement is shown to be related to insulin secretion dysfunction; however, data regarding UCPCR predictive value for CAD in diabetes mellitus (DM) are scarce. Therefore, we aimed to assess the UCPCR association with CAD in type 1 DM (T1DM) patients.. 279 patients previously diagnosed with T1DM included and categorized into two groups of CAD (n = 84) and without-CAD (n = 195). Furthermore, each group was divided into obese (body mass index (BMI) ≥ 30) and non-obese (BMI < 30) groups. Four models utilizing the binary logistic regression were designed to evaluate the role of UCPCR in CAD adjusted for well-known risk factors and mediators.. Median level of UCPCR was higher in CAD group compared to non-CAD group (0.07 vs. 0.04, respectively). Also, the well-acknowledged risk factors including being active smoker, hypertension, duration of diabetes, and body mass index (BMI) as well as higher levels of haemoglobin A1C (HbA1C), total cholesterol (TC), low-density lipoprotein (LDL) and estimated glomeruli filtration rate (e-GFR) had more significant pervasiveness in CAD patients. Based on multiple adjustments by logistic regression, UCPCR was a strong risk factor of CAD among T1DM patients independent of hypertension, demographic variables (gender, age, smoking, alcohol consumption), diabetes-related factors (diabetes duration, FBS, HbA1C), lipid profile (TC, LDL, HDL, TG) and renal-related indicators (creatinine, e-GFR, albuminuria, uric acid) in both patients with BMI≥30 and BMI < 30.. UCPCR is associated with clinical CAD, independent of CAD classic risk factors, glycaemic control, insulin resistance and BMI in type 1 DM patients.

Topics: C-Peptide; Coronary Artery Disease; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypertension

Previous studies on the relationship between fructose intake and cardiometabolic biomarkers have yielded inconsistent results, and the metabolic effects of fructose are likely to vary across food sources such as fruit versus sugar-sweetened beverages (SSB).. We aimed to examine associations of fructose from 3 major sources (SSB, fruit juice, and fruit) with 14 insulinemic/glycemic, inflammatory, and lipid markers.. We utilized cross-sectional data from 6858 men in the Health Professionals Follow-up Study, 15,400 women in NHS, and 19,456 women in NHSII who were free of type 2 diabetes, CVDs, and cancer at blood draw. Fructose intake was assessed via a validated FFQ. Multivariable linear regression was used to estimate the percentage differences of biomarker concentrations according to fructose intake.. We found a 20 g/d increase in total fructose intake was associated with 1.5%- 1.9% higher concentrations of proinflammatory markers plus 3.5% lower adiponectin, as well as 5.9% higher TG/HDL cholesterol ratio. Unfavorable profiles of most biomarkers were only associated with fructose from SSB and juice. In contrast, fruit fructose was associated with lower concentrations of C-peptide, CRP, IL-6, leptin, and total cholesterol. Substituting 20 g/d fruit fructose for SSB fructose was associated with 10.1% lower C-peptide, 2.7%-14.5% lower proinflammatory markers and 1.8%-5.2% lower blood lipids.. Beverage fructose intake was associated with adverse profiles of multiple cardiometabolic biomarkers.

Topics: Beverages; Biomarkers; C-Peptide; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Fructose; Humans; Male

The conclusion between Connecting peptide (C-peptide) and diabetic chronic complication was controversial. The purpose of this study is to explore the possible association between average C-peptide with diabetic retinopathy (DR) progression in Chinese patients with type 2 diabetes.. This is a retro-prospective study. 622 patients with type 2 diabetes were included. DR was evaluated using non-mydriatic fundus photography and DR progression was defined as any deterioration of either eye. Fasting and postprandial c-peptide levels were assayed at baseline and follow-up period. Differences between continuous variables were compared using the Mann-Whitney U test; and categorical variables were analyzed by the chi-square test. Correlation between parameters and 30-minute postprandial C-peptide were determined by Spearman correlation test. The relationship between C-peptide and DR progression was evaluated by multivariable binary logistic regression. Two-tailed P-values < 0.05 were regarded as statistically significant.. DR was present in 162 (26.0%) patients at baseline, and 26.4% of patients were found progression of DR at follow-up. Patients with progression of DR had lower average levels of 30-minute postprandial C-peptide (2.01 ng/ml vs. 2.6 ng/ml, p = 0.015) and 120-minute postprandial C-peptide (3.17 ng/ml vs. 3.92 ng/ml, p < 0.029), as well as average increment of 30-minute (0.41 ng/ml vs. 0.64 ng/ml, p = 0.015) and 120-minute postprandial C-peptide (1.48 ng/ml vs. 1.93 ng/ml, p < 0.017), than those without DR aggravation. Multivariate logistic regression analysis determined that 30-minute postprandial C-peptide and its increment were related to reduced odds ratios for DR progression (odds ratios [OR] = 0.83 and 0.74, respectively).. Our results suggest that the Average 30-minute post-prandial C-peptide and increment were negatively correlated with DR progression, which further demonstrates the importance to preserve β-cell residual function in the prevention for DR progression.. Not applicable.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Prospective Studies

We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D).. In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide.. During follow-up (median 4.8 years), high (>3 mg/L) versus low (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07-1.96]) and with even greater risk of all-cause mortality (2.47 [1.88-3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (<1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10-2.34]) and all-cause mortality risk (2.36 [1.73-3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did.. The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

Topics: Biomarkers; C-Peptide; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Myocardial Infarction; Prospective Studies; Risk Factors

C-peptide has been reported to provide renoprotective effects. This study aims to explore the relationship between C-peptide and progression of renal function in patients with type 2 diabetes mellitus (T2DM).. We retrospectively collected clinical data from 854 T2DM patients over a median follow-up of 5 years. Renal events included an annual decline in estimated glomerular filtration rate (eGFR), a rapid kidney function decline and a renal composite endpoint. A linear mixed-effects model and Cox regression analysis were used to investigate the effect of C-peptide on renal events, and a subgroup analysis was performed after stratification by risk factors.. The highest-level C-peptide group had a smaller annual eGFR decline compared with those in the group with the lowest level (p<0.05). Higher levels of 2 h postprandial C-peptide (2hPCP) (adjusted HR 0.53; 95% CI 0.31 to 0.92), difference between 2 h postprandial and fasting C-peptide (ΔCP) (adjusted HR 0.39; 95% CI 0.22 to 0.69), and 2 h postprandial C-peptide-to-glucose ratio (PCGR) (adjusted HR 0.44; 95% CI 0.24 to 0.82) were independently related to a decreased risk for the renal composite endpoint. 2hPCP <2.92 ng/mL, ΔCP <1.86 ng/mL, and PCGR <1.11 significantly increased the risk of progression in kidney function (adjusted HRs <0.50, p<0.05) among T2DM patients with male sex, an age of <65 years old, a disease course of <10 years, an glycosylated hemoglobin value of ≥7%, or a history of hypertension.. Higher levels of 2hPCP, ΔCP and PCGR could protect T2DM patients from renal progression, especially in the aforementioned population with diabetes.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 2; Humans; Kidney; Male; Retrospective Studies; Risk Factors

To investigate the association between Hemoglobin Glycation Index (HGI) and Diabetic Kidney Disease (DKD) in Chinese type 2 diabetic individuals and to construct a risk score based on HGI to predict a person's risk of DKD.. We retrospectively analyzed 1622 patients with type 2 diabetes mellitus (T2DM). HGI was obtained by calculating the fasting plasma glucose (FPG) level into the formula, and they were grouped into low HGI group (L-HGI), medium HGI group (H-HGI) and high HGI group (H-HGI) according to tri-sectional quantile of HGI. The occurrence of DKD was analyzed in patients with different levels of HGI. Multivariate logistics regression analysis was used to analyze the risk factors of DKD in patients with T2DM.. A total of 1622 patients with T2DM were enrolled in the study. Among them, 390 cases were DKD. The prevalence of DKD among the three groups was 16.6%, 24.2% and 31.3%. The difference was statistically significant (P = 0.000). There were significant differences in age (P=0.033), T2DM duration (P=0.005), systolic blood pressure (SBP) (P=0.003), glycosylated hemoglobin (HbA1c) (P=0.000), FPG (P=0.032), 2-hour postprandial plasma glucose (2h-PPG) (P=0.000), fasting C-peptide FCP (P=0.000), 2-hour postprandial C-peptide (2h-CP) (P=0.000), total cholesterol (TC) (P=0.003), low density lipoprotein cholesterol (LDL-C) (P=0.000), serum creatinine (sCr) (P=0.001), estimated glomerular filtration rate (eGFR) (P=0.000) among the three groups. Mantel-Haenszel chi-square test showed that there was a linear relationship between HGI and DKD (x2=177.469, p < 0.001). Pearson correlation analysis showed that with the increase of HGI level the prevalence of DKD was increasing (R= 0.445, P=0.000). It was indicated by univariate logistic regression analysis that individuals in H-HGI was more likely to develop DKD (OR: 2.283, 95% CI: 1.708~ 3.052) when compared with L-HGI. Adjusted to multiple factors, this trend still remained significant (OR: 2.660, 95% CI: 1.935~ 3.657). The combined DKD risk score based on HGI resulted in an area under the receiver operator characteristic curve (AUROC) of 0.702.. High HGI is associated with an increased risk of DKD. DKD risk score may be used as one of the risk predictors of DKD in type 2 diabetic population.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycated Hemoglobin; Humans; Inpatients; Maillard Reaction; Retrospective Studies

Both obesity and a poor diet are considered major risk factors for triggering insulin resistance syndrome (IRS) and the development of type 2 diabetes mellitus (T2DM). Owing to the impact of low-carbohydrate diets, such as the keto diet and the Atkins diet, on weight loss in individuals with obesity, these diets have become an effective strategy for a healthy lifestyle. However, the impact of the ketogenic diet on IRS in healthy individuals of a normal weight has been less well researched. This study presents a cross-sectional observational study that aimed to investigate the effect of low carbohydrate intake in healthy individuals of a normal weight with regard to glucose homeostasis, inflammatory, and metabolic parameters.. The study included 120 participants who were healthy, had a normal weight (BMI 25 kg/m. Low carbohydrate intake (<45% of total energy) was found to significantly correlate with dysregulated glucose homeostasis as measured by elevations in HOMA-IR, HOMA-β% assessment, and C-peptide levels. Low carbohydrate intake was also found to be coupled with lower serum bicarbonate and serum albumin levels, with an increased anion gap indicating metabolic acidosis. The elevation in C-peptide under low carbohydrate intake was found to be positively correlated with the secretion of IRS-related inflammatory markers, including FGF2, IP-10, IL-6, IL-17A, and MDC, but negatively correlated with IL-3.. Overall, the findings of the study showed that, for the first time, low-carbohydrate intake in healthy individuals of a normal weight might lead to dysfunctional glucose homeostasis, increased metabolic acidosis, and the possibility of triggering inflammation by C-peptide elevation in plasma.

Topics: Acidosis; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Obesity

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes.. We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19.. Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines.. Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Topics: Adipokines; Adiponectin; C-Peptide; Child; Complement Factor D; COVID-19; Cytokines; Diabetes Mellitus, Type 2; Ghrelin; Glucagon; Granulocyte Colony-Stimulating Factor; Humans; Incretins; Interleukin-12; Interleukin-17; Interleukin-6; Leptin; Pancreatic Hormones; SARS-CoV-2; Tumor Necrosis Factor-alpha

Previous studies had showed divergent findings on the associations of C-peptide and/or uric acid (UA) with renal dysfunction odds in patients with type 2 diabetes mellitus (T2DM). We hypothesized that there were non-linear relationships between C-peptide, UA and renal dysfunction odds. This study aimed to further investigate the relationships of different stratification of C-peptide and UA with renal dysfunction in patients with T2DM.. We conducted a cross-sectional real-world observational study of 411 patients with T2DM. The levels of fasting C-peptide, 2h postprandial C-peptide, the ratio of fasting C-peptide to 2h postprandial C-peptide (C0/C2 ratio), UA and other characteristics were recorded. Restricted cubic spline (RCS) curves was performed to evaluated the associations of stratified C-peptide and UA with renal dysfunction odds.. Fasting C-peptide, C0/C2 ratio and UA were independently and significantly associated with renal dysfunction in patients with T2DM as assessed by multivariate analyses (p < 0.05). In especial, non-linear relationships with threshold effects were observed among fasting C-peptide, UA and renal dysfunction according to RCS analyses. Compared with patients with 0.28 ≤ fasting C-peptide ≤ 0.56 nmol/L, patients with fasting C-peptide < 0.28 nmol/L (OR = 1.38, p = 0.246) or fasting C-peptide > 0.56 nmol/L (OR = 1.85, p = 0.021) had relatively higher renal dysfunction odds after adjusting for confounding factors. Similarly, compared with patients with 276 ≤ UA ≤ 409 μmol/L, patients with UA < 276 μmol/L (OR = 1.32, p = 0.262) or UA > 409 μmol/L (OR = 6.24, p < 0.001) had relatively higher odds of renal dysfunction.. The renal dysfunction odds in patients with T2DM was non-linearly associated with the levels of serum fasting C-peptide and UA. Fasting C-peptide and UA might have the potential role in odds stratification of renal dysfunction.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Humans; Kidney Diseases; Uric Acid

We examined the associations of GAD antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses, and severe hypoglycemia in type 2 diabetes (T2D).. In 5,230 Chinese patients (47.6% men) with T2D (mean ± SD age: 56.5 ± 13.9 years; median diabetes duration: 6 [interquartile range 1, 12] years), enrolled consecutively in 1996-2012 and prospectively observed until 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes.. At baseline, 28.6% (n = 1,494) had low CP (<200 pmol/L) and 4.9% (n = 257) had positive GADA (GADA+). In the low-CP group, 8.0% had GADA+, and, in the GADA+ group, 46.3% had low CP. The GADA+ group had an adjusted hazard ratio (aHR) of 1.46 (95% CI 1.15-1.84, P = 0.002) for insulin initiation versus the GADA- group, while the low-CP group had an aHR of 0.88 (0.77-1.00, P = 0.051) versus the high-CP group. Following insulin initiation, the GADA+ plus low-CP group had the largest decrements in HbA1c (-1.9% at month 6; -1.5% at month 12 vs. -1% in the other three groups). The aHR of severe hypoglycemia was 1.29 (95% CI 1.10-1.52, P = 0.002) in the low-CP group and 1.38 (95% CI 1.04-1.83, P = 0.024) in the GADA+ group.. There is considerable heterogeneity in autoimmunity and β-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation, while GADA+ and low CP, increased the risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.

Topics: Adult; Aged; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Hypoglycemia; Insulin; Insulin, Regular, Human; Male; Middle Aged; Retrospective Studies

Sacubitril/valsartan, a novel therapy in chronic heart failure (CHF), inhibits the breakdown of various peptides. However, whether or not sacubitril/valsartan administration affects urinary C-peptide levels is unclear. We herein report a 70-year-old man with type 2 diabetes mellitus (T2DM) and hypertension coexisting with CHF and nephrotic syndrome. The patient's urinary C-peptide levels dramatically increased after sacubitril/valsartan administration and decreased after discontinuation of the drug. Furthermore, sacubitril/valsartan administration to five other patients with hypertension and T2DM markedly increased urinary C-peptide levels. Thus, the insulin secretory capacity of patients with T2DM receiving sacubitril/valsartan may be overestimated when their urinary C-peptide level is measured.

Topics: Aged; Angiotensin Receptor Antagonists; Biphenyl Compounds; C-Peptide; Diabetes Mellitus, Type 2; Drug Combinations; Heart Failure; Humans; Hypertension; Male; Stroke Volume; Tetrazoles; Valsartan

To evaluate the therapeutic effects of two therapeutic strategies based on metformin hydrochloride/vildagliptin and liraglutide on type 2 diabetes mellitus (T2DM) in obese patients.. In both of the groups, the patients all showed significant reductions of BMI, waist circumference, FBG, postprandial blood glucose and HbA1C (all. Both metformin hydrochloride/vildagliptin and liraglutide have good therapeutic effects on T2DM in obese patients and can achieve good blood glucose and weight control, but liraglutide has a better effect for weight control.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Obesity; Retrospective Studies; Treatment Outcome; Vildagliptin

Metabolic syndrome (Syndrome X, insulin resistance syndrome) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease and diabetes mellitus. Serum uric acid and end product of purine metabolism, has been shown to be associated with an increased risk of hypertension, cardiovascular disorder and chronic kidney disease. Excess of intra abdominal or visceral adipose and not the amount of subcutaneous abdominal fat which is the key correlate of the metabolic abnormalities observed in overweight/obese patients. It is well documented that high level of insulin are associated with elevated "connecting peptide"(c-peptide) levels as both are produced in equimolar Amounts since metabolic syndrome is a well established major risk factor preceding the onset of type 2 diabetes mellitus, pre and post prandial c peptide and itís correlation with serum uric acid further strengthens this understanding and may help take preventive measures to delay/reverse the onset of type 2 diabetes mellitus.. This is a cross sectional study conducted on 60 patients with metabolic syndrome satisfying inclusion and exclusion criteria admitted in hospitals attached to Bangalore Medical College & Research Institute. All necessary investigations were done. The patients with other co-morbid condition that could affect nutritional status (diabetes mellitus, sepis, congestive heart failure, cancer) and pregnant females were excluded. Anthropometric measures, biochemical parameters were used for correlation with fasting c-peptide and post prandial c-peptide with serum uric acid in metabolic syndrome.. Patients with metabolic syndrome We can observe that the Blood urea level showed positive correlation with uric acid level (p value 0.276), uric acid showed positive correlation with fasting c-peptide (p value 0.001) and post prandial c-peptide with (p value < 0.023), very low density lipoprotein showed positive correlation with post prandial c-peptide (p value < 0.022), very low density lipoprotein showed positive correlation with uric acid (p value< 0.002) triglyceride showed postive correlation with uric acid (p value < 0.001,) body mass index showed positive correlation with post prandial c peptide (p value < 0.002), body mass index showed positive correlation with uric acid (p value < 0.006).. Patients diagnosed as Metabolic syndrome after clinical, biochemical and anthropometric findings should be investigated for c-peptide in them which can be used as additional diagnosis factor in metabolic syndrome post prandial cpeptide being a better investigation when compared to fasting c-peptide. References Iliesiu A, Campeanu A, Dusceac D. Serum uric acid and cardiovascular disease. Maedica (Bucur) 2021;5(3):186-192. Abdullah A, Hasan H, Raigangar V, et al. C-Peptide versus insulin: relationships with risk biomarkers of cardiovascular disease in metabolic syndrome in young arab females. Int J Endocrinol 2012;2012:420792.

Topics: Body Mass Index; C-Peptide; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; India; Insulin; Metabolic Syndrome; Uric Acid

Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99-1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60-1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97-2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.

Topics: Blood Glucose; C-Peptide; Colorectal Neoplasms; Diabetes Mellitus, Type 2; East Asian People; Genome-Wide Association Study; Glucose; Glycated Hemoglobin; Humans; Insulin Resistance; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors

This study revealed that there was no significant linear relationship between fasting C-peptide (FCP) level and bone mineral density (BMD) or fracture risk in type 2 diabetes mellitus (T2DM) patients. However, in the FCP ≤ 1.14 ng/ml group, FCP is positively correlated with whole body (WB), lumbar spine (LS), and femoral neck (FN) BMD and negatively correlated with fracture risk.. To explore the relationship between C-peptide and BMD and fracture risk in T2DM patients.. 530 T2DM patients were enrolled and divided into three groups by FCP tertiles, and the clinical data were collected. BMD was measured by dual-energy X-ray absorptiometry (DXA). The 10-year probability of major osteoporotic fractures (MOFs) and hip fractures (HFs) was evaluated by adjusted fracture risk assessment tool (FRAX).. In the FCP ≤ 1.14 ng/ml group, FCP level was positively correlated with WB, LS, and FN BMD, while FCP was negatively correlated with fracture risk and osteoporotic fracture history. However, FCP was not correlated with BMD and fracture risk and osteoporotic fracture history in the 1.14 < FCP ≤ 1.73 ng/ml and FCP > 1.73 ng/ml groups. The study has shown that FCP was an independent factor influencing BMD and fracture risk in the FCP ≤ 1.14 ng/ml group.. There is no significant linear relationship between FCP level and BMD or fracture risk in T2DM patients. In the FCP ≤ 1.14 ng/ml group, FCP is positively correlated with WB, LS, and FN BMD and negatively correlated with fracture risk, and FCP is an independent influencing factor of BMD and fracture risk. The findings suggest that FCP may predict the risk of osteoporosis or fracture in some T2DM patients, which has a certain clinical value.

Topics: Absorptiometry, Photon; Bone Density; C-Peptide; Diabetes Mellitus, Type 2; Humans; Osteoporosis; Osteoporotic Fractures; Risk Assessment; Risk Factors

Contrary to the presumption that type 1 diabetes leads to an absolute insulin deficiency, many individuals with type 1 diabetes have circulating C-peptide years after the diagnosis. We studied factors affecting random serum C-peptide concentration in individuals with type 1 diabetes and the association with diabetic complications.. Our longitudinal analysis included individuals newly diagnosed with type 1 diabetes from Helsinki University Hospital (Helsinki, Finland) with repeated random serum C-peptide and concomitant glucose measurements from within 3 months of diagnosis and at least once later. The long-term cross-sectional analysis included data from participants from 57 centres in Finland who had type 1 diabetes diagnosed after 5 years of age, initiation of insulin treatment within 1 year from diagnosis, and a C-peptide concentration of less than 1·0 nmol/L (FinnDiane study) and patients with type 1 diabetes from the DIREVA study. We tested the association of random serum C-peptide concentrations and polygenic risk scores with one-way ANOVA, and association of random serum C-peptide concentrations, polygenic risk scores, and clinical factors with logistic regression.. The longitudinal analysis included 847 participants younger than 16 years and 110 aged 16 years or older. In the longitudinal analysis, age at diagnosis strongly correlated with the decline in C-peptide secretion. The cross-sectional analysis included 3984 participants from FinnDiane and 645 from DIREVA. In the cross-sectional analysis, at a median duration of 21·6 years (IQR 12·5-31·2), 776 (19·4%) of 3984 FinnDiane participants had residual random serum C-peptide secretion (>0·02 nmol/L), which was associated with lower type 1 diabetes polygenic risk compared with participants without random serum C-peptide (p<0·0001). Random serum C-peptide was inversely associated with hypertension, HbA. Although children with multiple autoantibodies and HLA risk genotypes progressed to absolute insulin deficiency rapidly, many adolescents and adults had residual random serum C-peptide decades after the diagnosis. Polygenic risk of type 1 and type 2 diabetes affected residual random serum C-peptide. Even low residual random serum C-peptide concentrations seemed to be associated with a beneficial complications profile.. Folkhälsan Research Foundation; Academy of Finland; University of Helsinki and Helsinki University Hospital; Medical Society of Finland; the Sigrid Juselius Foundation; the "Liv and Hälsa" Society; Novo Nordisk Foundation; and State Research Funding via the Helsinki University Hospital, the Vasa Hospital District, Turku University Hospital, Vasa Central Hospital, Jakobstadsnejdens Heart Foundation, and the Medical Foundation of Vaasa.

Topics: Adolescent; Adult; C-Peptide; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Finland; Humans; Insulin; Insulin Secretion

The purpose of this retrospective clinic chart review study was to determine the potential of a combination therapy (CT) consisting of γ-aminobutyric acid (GABA), a dipeptidyl peptidase-4 inhibitor (DPP-4i), and a proton pump inhibitor (PPI) to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes (T1D).. Nineteen patients with T1D on insulin therapy were treated with additional CT in oral form. Fasting blood glucose (FBG), HbA1c, insulin dose-adjusted HbA1c (IDA-A1c), daily insulin dose, insulin/weight ratio (IWR), and fasting plasma C-peptide were measured after 26-42 weeks of treatments.. FBG, HbA1c, IDA-A1c, insulin dose and IWR were all significantly decreased while plasma C-peptide was significantly increased by the CT. Treatment outcomes were further analyzed by separation of the 19 patients into two groups. One group started on the CT within 12 months of insulin treatment (early therapy, 10 patients) and another group started on this therapy only after 12 months of insulin treatment (late therapy, 9 patients). FBG, IDA-A1c, insulin dose, and IWR decreased significantly in both the early and late CT groups, however to a better extent in the early therapy group. Moreover, plasma C-peptide increased significantly only in the early therapy group, and 7 of the 10 patients in this group were able to discontinue insulin treatment while maintaining good glycemic control to study end compared with none of the 9 patients in the late therapy group.. These results support the concept that the combination of GABA, a DPP-4i and a PPI as an adjunct to insulin therapy improves glycemic control in patients with T1D, and that the insulin dose required for glycemic control can be reduced or even eliminated in some patients receiving this novel therapy.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; gamma-Aminobutyric Acid; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Proton Pump Inhibitors; Retrospective Studies

In the recently published consensus statement on the treatment and management of type 1 diabetes issued by experts from the American (ADA) and European (EASD) diabetes societies, measurement of endogenous insulin secretion using fasting C-peptide is recommended as a diagnostic criterion. In contrast, our group recently suggested fasting C-peptide/glucose ratio (CGR) for the determination of endogenous insulin secretion. In addition, this ratio may turn out as a potential decision aid for pathophysiologically based differential therapy of diabetes. In this comment, the following points will be discussed: i) CGR as the basis of differential diagnosis of type 1 diabetes, ii) CGR as the basis of treatment decisions for or against insulin in diabetes, and iii) the ease of application of CGR in clinical practice. The use of CGR may complement the ADA/EASD recommendations and should provide a practical application in clinical practice.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; United States

To observe the effect of electroacupuncture (EA) on liver protein kinase B (Akt)/forkhead box transcription factor 1 (FoxO1) signaling pathway in Zucker diabetic fatty (ZDF) rats, and to explore the possible mechanism of EA on improving liver insulin resistance of type 2 diabetes mellitus.. Twelve male 2-month-old ZDF rats were fed with high-fat diet for 4 weeks to establish diabetes model. After modeling, the rats were randomly divided into a model group and an EA group, with 6 rats in each group. In addition, six male Zucker lean (ZL) rats were used as the blank group. The rats in the EA group were treated with EA at bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6), "Weiwanxiashu" (EX-B 3), and "Pishu" (BL 20). The ipsilateral "Zusanli" (ST 36) and "Weiwanxiashu" (EX-B 3) were connected to EA device, continuous wave, frequency of 15 Hz, 20 min each time, once a day, six times a week, for a total of 4 weeks. The fasting blood glucose (FBG) in each group was compared before modeling, before intervention and after intervention; the serum levels of insulin (INS) and C-peptide were measured by radioimmunoassay method, and the insulin resistance index (HOMA-IR) was calculated; HE staining method was used to observe the liver tissue morphology; Western blot method was used to detect the protein expression of Akt, FoxO1 and phosphoenolpyruvate carboxykinase (PEPCK) in the liver.. Before intervention, compared with the blank group, FBG was increased in the model group and the EA group (. EA could reduce FBG and HOMA-IR in ZDF rats, improve liver insulin resistance, which may be related to regulating Akt/FoxO1 signaling pathway.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 2; Electroacupuncture; Insulin; Insulin Resistance; Lipids; Liver; Male; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Signal Transduction

Idiopathic type 1 diabetes (T1D) is a neglected subtype of T1D. Our aim was to investigate the frequency, clinical characteristics, and human leucocyte antigen (HLA) genotypes of idiopathic T1D.. We enrolled 1205 newly diagnosed T1D patients in our analysis. To exclude monogenic diabetes in autoantibody-negative patients, we utilised a custom monogenic diabetes gene panel. Individuals negative for autoantibodies and subsequently excluded for monogenic diabetes were diagnosed with idiopathic T1D. We collected clinical characteristics, measured islet autoantibodies by radioligand assay and obtained HLA data.. After excluding 11 patients with monogenic diabetes, 284 cases were diagnosed with idiopathic T1D, accounting for 23.8% (284/1194) of all newly diagnosed T1D cases. When compared with autoimmune T1D, idiopathic T1D patients showed an older onset age, higher body mass index among adults, lower haemoglobin A1c, higher levels of fasting C-peptide and 2-h postprandial C-peptide, and were likely to have type 2 diabetes (T2D) family history and carry 0 susceptible HLA haplotype (all p < 0.01). A lower proportion of individuals carrying 2 susceptible HLA haplotypes in idiopathic T1D was observed in the adult-onset subgroup (15.7% vs. 38.0% in child-onset subgroup, p < 0.001) and in subgroup with preserved beta-cell function (11.0% vs. 30.1% in subgroup with poor beta-cell function, p < 0.001). Multivariable correlation analyses indicated that being overweight, having T2D family history and lacking susceptible HLA haplotypes were associated with negative autoantibodies.. Idiopathic T1D represents about 1/4 of newly diagnosed T1D, with adult-onset and preserved beta-cell function patients showing lower HLA susceptibility and more insulin resistance.

Topics: Adult; Autoantibodies; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genotype; HLA Antigens; Humans; Prevalence

Topics: Adolescent; C-Peptide; Cholesterol, HDL; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; India; Mutation

To estimate vitamin D levelsin children with type 1 diabetes, and to evaluate itsrole in the pathogenesis and progress of the disease.. The cross-sectional study was conducted at the Paediatric Department of Kafrelsheikh University Hospital, Egypt, from November 2019 to August 2021, and comprised children of either gender aged 3-18 years who were either inpatients or visiting the paediatric outpatient clinic. The subjects were enrolled into 3 groups. Those with newly diagnosed type 1 diabetes were in group A, those with established type 1 diabetes were in group B, and healthy children matched for age and gender and randomly selected were in the control group C. Glycated haemoglobin, serum fasting C-peptide, and serum vitamin D levels were evaluated using quantitative colorimetric determination, an automated analyser, and enzyme-linked immunosorbent assay, respectively. Data was analysed using SPSS 25.. Of the 80 subjects, 30(37.5%) were in group A; 17(56.7%) boys and 13(43.3%) girls with mean age 7.77±2.95 years. In group B, there were 30(37.5%) subjects; 14(46.7%) boys and 16(53.3%) girls with mean age 9.6±3.62 years. There were 20(25%) subjects in group C; 10(50%) boys and as many girls with mean age 8.38±2.68 years (p>0.05). Glycated haemoglobin,serum fasting C-peptide and serum vitamin D wassignificantly different between the control group and the treatment groups (p<0.05). Between the treatment groups, group B had better markers than group A (p<0.05).. Serum vitamin D deficiency may play a role in the pathogenesis and insulin sensitivity in cases of type 1 diabetes.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child, Preschool; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Vitamin D; Vitamin D Deficiency

There is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs).. Selected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194).. Eleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family.. The association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes.

Topics: Adolescent; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Glucose; Humans; Insulin; Proteomics

Our previous cross-sectional study has demonstrated the independently non-linear relationship between fasting C-peptide with renal dysfunction odds in patients with type 2 diabetes (T2D) in China. This longitudinal observational study aims to explore the role of serum C-peptide in risk prediction of new-onset renal dysfunction, then construct a predictive model based on serum C-peptide and other clinical parameters.. The patients with T2D and normal renal function at baseline were recruited in this study. The LASSO algorithm was performed to filter potential predictors from the baseline variables. Logistic regression (LR) was performed to construct the predictive model for new-onset renal dysfunction risk. Power analysis was performed to assess the statistical power of the model.. During a 2-year follow-up period, 21.08% (35/166) of subjects with T2D and normal renal function at baseline progressed to renal dysfunction. Six predictors were determined using LASSO regression, including baseline albumin-to-creatinine ratio, glycated hemoglobin, hypertension, retinol-binding protein-to-creatinine ratio, quartiles of fasting C-peptide, and quartiles of fasting C-peptide to 2h postprandial C-peptide ratio. These 6 predictors were incorporated to develop model for renal dysfunction risk prediction using LR. Finally, the LR model achieved a high efficiency, with an AUC of 0.83 (0.76 - 0.91), an accuracy of 75.80%, a sensitivity of 88.60%, and a specificity of 70.80%. According to the power analysis, the statistical power of the LR model was found to be 0.81, which was at a relatively high level. Finally, a nomogram was developed to make the model more available for individualized prediction in clinical practice.. Our results indicated that the baseline level of serum C-peptide had the potential role in the risk prediction of new-onset renal dysfunction. The LR model demonstrated high efficiency and had the potential to guide individualized risk assessments for renal dysfunction in clinical practice.

Topics: C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Kidney Diseases

This study investigates the connection between abnormal liver enzymes and macro vascular disease in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). Clinical data from 276 T2DM patients with NAFLD were retrospectively examined and divided into two groups based on the presence or absence of macro vascular disease. Various biochemical markers were tested, including fasting C-peptide, total bilirubin (TBil), total protein (TP), albumin (Alb), C-reactive protein (CRP) and the insulin resistance index (HOMA-IR). The study found no significant differences in demographic variables between the two groups. However, patients with macro vascular disease had significantly higher levels of fasting C-peptide, CRP, HOMA-IR, TBil, TP, Alb and certain blood lipid markers. The study concludes that in T2DM patients with NAFLD, increased blood lipids, liver function and inflammatory factors are risk factors for macro vascular disease, suggesting the importance of clinical management to lower macro vascular disease prevalence.

Topics: Albumins; Bilirubin; C-Peptide; C-Reactive Protein; Diabetes Mellitus, Type 2; Humans; Non-alcoholic Fatty Liver Disease; Retrospective Studies; Risk Factors; Vascular Diseases

The liver plays a key role in glucose homeostasis. Serum liver enzyme levels, including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), are reportedly predictive of the risk of type 2 diabetes (T2D). However, the link between the liver enzyme profile and metabolic derangements in T2D, particularly the secretion of both insulin and glucagon, is not clear. This study evaluated its relationships with glycemia, insulin and glucagon both during fasting and after an oral glucose load or a mixed meal in T2D. 15 healthy and 43 T2D subjects ingested a 75 g glucose drink. 86 T2D subjects consumed a mixed meal. Venous blood was sampled for measurements of blood glucose and plasma insulin, C-peptide and glucagon. Blood glucose, plasma insulin, C-peptide and glucagon concentrations, both fasting and after oral glucose, correlated directly with ALT, while fewer and weaker correlations were observed with GGT or AST. Subgroup analysis in T2D subjects ascertained that plasma insulin, C-peptide and glucagon concentrations after oral glucose were higher with increasing ALT. Similar findings were observed in the T2D subjects who received a mixed meal. In conclusion, serum liver enzyme profile, particularly ALT, reflects dysregulated fasting and nutrient-stimulated plasma insulin and glucagon concentrations in T2D.

Topics: Alanine Transaminase; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glucagon; Glucose; Humans; Insulin

First-phase glucose-stimulated insulin secretion is mechanistically linked to type 2 diabetes, yet the underlying metabolism is difficult to discern due to significant islet-to-islet variability. Here, we miniaturize a fluorescence anisotropy immunoassay onto a microfluidic device to measure C-peptide secretion from individual islets as a surrogate for insulin (InsC-chip). This method measures secretion from up to four islets at a time with ∼7 s resolution while providing an optical window for real-time live-cell imaging. Using the InsC-chip, we reveal two glucose-dependent peaks of insulin secretion (i.e., a double peak) within the classically defined 1

Topics: C-Peptide; Diabetes Mellitus, Type 2; Glucose; Humans; Islets of Langerhans; Lab-On-A-Chip Devices

Limited research exists regarding the relationship between fasting plasma C-peptide levels and sarcopenia. As a result, our study aimed to examine this association in elderly Chinese diabetic patients. This cross-sectional study included 288 elderly patients with diabetes mellitus from the Fourth People's Hospital in Guiyang who were enrolled prospectively between March 2020 and February 2023. The independent variable of interest was fasting plasma C-peptide, while the dependent variable was sarcopenia. Data on several covariates, including demographic factors, lifestyle habits, co-morbidities, anthropometric indicators, and laboratory indicators, were also collected. Of the 288 participants, 27.43% (79/288) had sarcopenia. After adjusting for potential confounding variables, we found a U-shaped association between fasting plasma C-peptide levels and sarcopenia, with inflection points identified at approximately 774 pmol/L and 939 mmol/L. Within the range of 50-744 pmol/L, each 100 pmol/L increase in CysC was associated with a 37% decrease in the odds of sarcopenia (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.49 to 0.83; P < 0.001). Additionally, within the range of 939-1694 pmol/L, each 100 pmol/L increase in fasting plasma C-peptide was associated with a 76% increase in the odds of sarcopenia (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.11 to 2.81; P = 0.017). Our study revealed a U-shaped association between fasting plasma C-peptide levels and the likelihood of sarcopenia, with lower risk in the range of 774-939 pmol/L. These findings may assist in the development of more effective prevention and treatment strategies for sarcopenia in elderly diabetic patients.

Topics: Aged; C-Peptide; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; East Asian People; Humans; Sarcopenia

This study sought to examine the impacts of a high dietary fiber cereal meal in comparison to conventional dietary management for diabetes on body weight, distribution of adipose tissue, and cardiovascular risk among individuals diagnosed with type 2 diabetes (T2DM).. A cohort of 120 patients diagnosed with T2DM was enlisted as the study population and divided into two groups using a ratio of 2:1-namely, the W group (n=80) and the U group (n=40). The U group (control) received usual diet, while the W group (intervention) incorporated a high dietary fiber cereal meal in place of their regular staple food in addition to adhering to conventional diabetes dietary recommendations. The high dietary fiber cereal meal was based on whole grains, traditional Chinese medicinal foods, and prebiotics. A subsequent follow-up period of 3 months ensued, during which diverse parameters such as body mass index (BMI),waist-hip ratio (WHR), glycated hemoglobin (HbA1c),fasting blood glucose(FBG),C-peptide levels, blood pressure, blood lipids, high-sensitivity C-reactive protein (hsCRP),10-year cardiovascular disease (CVD) risk, and Lifetime CVD risk were assessed before and after the intervention.. Among the participants, a total of 107 successfully completed the intervention and follow-up, including 72 individuals from the W group and 35 from the U group. Following the intervention, both cohorts exhibited decrease in BMI, WHR, HbA1c, FBG, blood pressure, and blood lipid levels in contrast to their initial measurements. Remarkably, the improvements in BMI, WHR, HbA1c, FBG, total cholesterol (TC), triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C), and the ratio of 2-hour C-peptide (2hCP) to fasting C-peptide (FCP) were more marked within the W group, exhibiting statistically significant disparities (. The intervention centred on a cereal-based dietary approach showcased favourable outcomes with regard to body weight, adipose distribution, and cardiovascular risk in overweight individuals grappling with T2DM.

Topics: Body Weight; C-Peptide; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dietary Fiber; Edible Grain; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Lipids; Obesity; Risk Factors; Triglycerides

Glucolipid metabolism plays an important role in the occurrence and development of diabetes mellitus. However, there is limited research on the characteristics of glucolipid metabolism and complications in different subgroups of newly diagnosed diabetes. This study aimed to investigate the characteristics of glucolipid metabolism and complications in novel cluster-based diabetes subgroups and explore the contributions of different glucolipid metabolism indicators to the occurrence of complications and pancreatic function.. This retrospective study included 547 newly diagnosed type 2 diabetes patients. Age, body mass index (BMI), glycated hemoglobin (HbA. Total cholesterol (TC), triglycerides (TG), triglyceride glucose index (TyG), HbA. There were differences in the characteristics of glucolipid metabolism as well as complications among different subgroups of newly diagnosed type 2 diabetes. 2hCP, FCP, FINS, FPG, TyG, HbA

Topics: Blood Glucose; C-Peptide; Cholesterol, HDL; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Lipoproteins, HDL; Non-alcoholic Fatty Liver Disease; Renal Insufficiency, Chronic; Retrospective Studies; Triglycerides

The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications.. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels.. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C-peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C-peptide levels.. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypertension; Obesity

To screen for maturity-onset diabetes of the young (MODY) variants in subjects with an early age of onset and positive family history of diabetes mellitus.. 60 subjects with onset of diabetes between 3 and 30 years of age and parental history (onset < 35 years) of diabetes were recruited after excluding autoimmune, pancreatic and syndromic forms of diabetes. Detailed pedigree chart and clinical data were recorded. MODY genetic testing (MODY 1-13) was performed and variant classification was done adhering to the ACMG guidelines.. A genetic diagnosis of MODY could be confirmed in only 6.6% (4/60) of patients clinically classifiable as MODY. This is less than that reported in clinically diagnosed MODY subjects of European descent. Newly published population data and more stringent criteria for assessment of pathogenicity and younger age of onset of type 2 diabetes in Indians could have contributed to the lower genetic confirmation rate. Apart from variants in the classical genes (HNF1A, HNF4A), a likely pathogenic variant in a non-classical gene (ABCC8) was noted in this study.

Topics: Age of Onset; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Genetic Testing; Genetic Variation; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4; High-Throughput Nucleotide Sequencing; Humans; India; Male; Mutation; Pedigree; Sulfonylurea Receptors; Young Adult

We assessed the association between insulin resistance and blood glucose concentrations at type 2 diabetes diagnosis and future development of diabetes-related complications and mortality.. This retrospective cohort study included 864 individuals with type 2 diabetes (median age 60 years) whose fasting C-peptide and HbA1c were measured at diabetes diagnosis. The median follow-up time until death or study end was 16.4 years (interquartile range 13.3-19.6). The association between C-peptide and mortality/complications was estimated by Cox regression adjusted for sex, age at diabetes diagnosis, smoking, hypertension, BMI, total cholesterol, and HbA1c. C-peptide and HbA1c were converted to Z scores before the Cox regression analysis.. An increase by one standard deviation in fasting C-peptide at diabetes diagnosis was associated with all-cause (hazard ratio [HR] 1.33; 95% confidence intervals [CI] 1.12-1.58; p = 0.001) and cancer mortality (HR 1.51; 95% CI 1.13-2.01; p = 0.005) in the fully adjusted model. An increase by one standard deviation in HbA1c at diabetes diagnosis was associated with all-cause mortality (HR 1.24; 95% CI 1.07-1.44; p = 0.005), major cardiovascular events (HR 1.20; 95% CI 1.04-1.39; p = 0.015), stroke (HR 1.36; 95% CI 1.09-1.70; p = 0.006), and retinopathy (HR 1.54; 95% CI 1.34-1.76; p < 0.0001) in the fully adjusted model.. Fasting C-peptide at type 2 diabetes diagnosis is an independent risk factor for total and cancer-related mortality. Thus, treatment of type 2 diabetes should focus not only on normalising blood glucose levels but also on mitigating insulin resistance.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Middle Aged; Neoplasms; Retrospective Studies; Risk Factors

To explore the relationship between C-peptide and glycaemic control rate and diabetic complications (microvascular complication and cerebral infarction) and provide evidence for stratified treatment of type 2 diabetes mellitus (T2DM)-based C-peptide.. This is a cross-sectional real-world observational study. According to the inclusion and exclusion criteria, we studied 1377 patients with T2DM, grouped by fasting C-peptide and HOMA-IR. Blood samples were collected after fasting overnight. Logistic regression was used to analyse the relationship among fasting C-peptide, HOMA-IR, C2/C0 ratio (the ratio of 2 h postprandial C-peptide to fasting C-peptide), glycaemic control rate, and occurrence of diabetic complications. Restricted cubic spline (RCS) curves based on logistic regression were used to evaluate the relationship between C-peptide, glycaemic control rate, and diabetic kidney disease (DKD).. Patients were subdivided according to their fasting C-peptide in 4 groups (Q1,Q2,Q3,Q4). Patients of group Q3 (1.71 ≤ C-peptide < 2.51 ng/ml) showed the lowest incidence of DKD, diabetic retinopathy (DR), and rate of insulin absorption as welll as higher glycaemic control rate. Logistic regression shows that the probability of reaching glycemic control increased with higher levels of C-peptide, compared with group Q1, after adjusting for age, gender, duration of diabetes, body mass index, systolic blood pressure, diastolic blood pressure, creatinine, low-density lipoprotein, triglyceride, total cholesterol, and high-density lipoprotein. RCS curve shows that, when C-peptide is ≤2.68 ng/ml, the incidence of not reaching glycaemic control decreases with increasing C-peptide. The possibility of not reaching glycaemic control decreased with increasing C2/C0, when C-peptide is ≥1.71 ng/ml. RCS curve shows that the relationship between C-peptide and DKD follows a U-style curve. When C-peptide is <2.84 ng/ml, the incidence of DKD decreased with increasing C-peptide. With the increase in the C2/C0 ratio, the incidence of DKD, DR, and fatty liver did not decrease.. When C-peptide is ≥ 1.71 and < 2.51 ng/ml, patients with T2DM had a higher glycemic control rate. Excessive C-peptide plays different roles in DKD and DR; C-peptide may promote the incidence of DKD but protects patients from DR. Higher C2/C0 ratio is important for reaching glycaemic control but cannot reduce the risk of DKD, DR, and fatty liver.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Fatty Liver; Female; Glycemic Control; Humans; Male

More than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls.. Sixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed.. Participants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower.. Patients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Pancreatitis, Chronic; Peptide YY

Nowadays, phthalates widely employed in many products are distributed around us which contributed to the development of many chronic diseases. We investigated the incidence of type 2 diabetes mellitus (T2DM) in Saudi subjects and correlated it with urinary phthalate metabolites' screening study.We selected a total of 100 cases early diagnosed as type 2 diabetes mellitus (FBS ≥ 126 mg/dl, PP 2 h, ≥ 140 mg/dl) and 50 normal subjects (FBS ≤ 90 mg/dl) as control. Overnight fasting blood samples were subjected for assay of FBS, glycated hemoglobin, insulin, C-peptide, HOMA-IR, advanced glycation end products (AGEs), and urinary assay of some phthalate metabolite levels.Data obtained showed a significant elevation of FBS, HA1c, AGEs, insulin, and C-peptide and HOMA-IR in diabetic patients compared with the control (p < 0.001). Urinary phthalate metabolites such as mono-ethyl phthalate (mEP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and mono-n-butyl phthalate (mBP) were detected in significant concentrations in diabetic patients compared with control. A positive correlation was found between mEP and mBP and HOMA-IR and C-peptide.Phthalate toxicity is considered as one of the risk factors that contributed to insulin resistance and development of T2DM via increasing the levels of HOMA-IR and C-peptide.This will result in the risk of phthalate exposure for diabetogensis and its economic cost for treatment lifetime.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Environmental Exposure; Environmental Pollutants; Humans; Incidence; Insulin; Phthalic Acids; Saudi Arabia

Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations.. In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters.. In MODY(+) subjects, mutations in. According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Hepatocyte Nuclear Factor 1-alpha; Humans; Mutation

Disordered hepatic energy metabolism is found in obese rats with insulin resistance (IR). There are insufficient experimental studies of electroacupuncture (EA) for IR and type 2 diabetes mellitus (T2DM). The aim of this study was to probe the effect of EA on disordered hepatic energy metabolism and the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase, 70-kDa (p70S6K) signaling pathway.. Zucker Diabetic Fatty (ZDF) rats were randomly divided into three groups: EA group receiving EA treatment; Pi group receiving pioglitazone gavage; and ZF group remaining untreated (n = 8 per group). Inbred non-insulin-resistant Zucker lean rats formed an (untreated) healthy control group (ZL, n = 8). Fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, C-reactive protein (CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) indices were measured. Hematoxylin-eosin (H&E) staining was used to investigate the liver morphologically. The mitochondrial structure of hepatocytes was observed by transmission electron microscopy (TEM). Western blotting was adopted to determine protein expression of insulin receptor substrate 1 (IRS-1), mTOR, mTORC1, AMPK, tuberous sclerosis 2 (TSC2) and p70S6K, and their phosphorylation. RT-PCR was used to quantify IRS-1, mTOR, mTORC1, AMPK and p70S6K mRNA levels.. Compared with the ZF group, FPG, FINS, C-peptide, CRP and HOMA-IR levels were significantly reduced in the EA group (. EA can effectively ameliorate IR and regulate energy metabolism in the ZDF rat model. AMPK/mTORC1/p70S6K and related molecules may represent a potential mechanism of action underlying these effects.

Topics: AMP-Activated Protein Kinases; Animals; C-Peptide; Diabetes Mellitus, Type 2; Electroacupuncture; Energy Metabolism; Insulin; Insulin Resistance; Mammals; Mechanistic Target of Rapamycin Complex 1; Rats; Rats, Zucker; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Glucose Tolerance Test; Humans; Insulin-Secreting Cells; Middle Aged; Mutation

The oral glucose tolerance test (OGTT) classifies subjects as normal, glucose intolerant or diabetic depending on glycemia at 120 min (T120) post-test. Five insulin profiles associated with different incidences of diabetes over 10 years' follow-up were previously described following OGTT. However, insulin measurement is sensitive to hemolysis, and can be replaced by C-peptide assay on hemolyzed samples. However, little is known about patterns of C-peptide response to OGTT.. In total, 128 patients were included, to establish preliminary baseline C-peptide values and to evaluate C-peptide response to OGTT in comparison to insulin response, using the Liaison XL immunoanalyzer.. Hundred patients had a normal glycemic response, 19 were classified as glucose intolerant and 9 as diabetic. In normal subjects, median C-peptide values (nmol/L, with 5-95 percentiles) were 0.53 (0.23-1.37) at baseline, peaking at 2.36 (0.94-1.83) at T60, and decreasing to 2.09 (1.13-4.36) at T120. The C-peptide response pattern was similar but flatter than the insulin pattern because of different catabolism pathways. Nevertheless, C-peptide and insulin response profiles were discordant in only 9.4% of cases. Profile 3 (C-peptide peaking at T60) was the most prevalent in normal patients whereas profile 4 (peak at 120 min and lower level at T30 than at T60) was the most prevalent in glucose intolerant and diabetic patients.. In OGTT, C-peptide could replace insulin determination on hemolyzed blood samples to predict the risk of type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Glucose Tolerance Test; Humans; Insulin

The early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM.. A total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis.. Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP.. PaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Pancreatic Neoplasms

Our study aimed to investigate the C-peptide-releasing effect associated with the risk of elevated serum uric acid (SUA) levels in patients with type 2 diabetes mellitus (T2DM). In the cross-sectional study, 345 patients with T2DM hospitalized at the First Affiliated Hospital of Harbin Medical University were consecutively enrolled, and their baseline data were collected. The study design used two parameters for C-peptide releasing effects: the multiplication effect of 1 h postprandial C-peptide to fasting C-peptide ratio (1hCp/FCp) and 2hCp/FCp; the incremental effect of 1hCp minus FCp (1hΔCp) and 2hΔCp. The patients with T2DM in the upper quartiles of SUA had higher FCp, 1hCp, 1hΔCp, 2hCp, and 2hΔCp. Multiple linear regression analysis revealed that after adjusting all the confounding factors, the serum C-peptide including 1hCp (β = 5.14, p = 0.036), 1hΔCp (β = 7.80, p = 0.010), 2hCp (β = 4.27, p = 0.009) and 2hΔCp (β = 5.20, p = 0.005) were still positively correlated with SUA levels in patients with T2DM. In female patients, only the 2hCp (β = 4.78, p = 0.017) and 2hΔCp (β = 5.28, p = 0.019) were associated with SUA level; however, in male patients, no C-peptide parameter was associated with SUA levels in T2DM (all p > 0.05). Within a certain range, the elevated SUA levels might be associated with the better C-peptide incremental effect of islet β cell function in T2DM, especially in female patients.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Male; Risk Factors; Uric Acid

To explore the association between retinal neurodegeneration and metabolic parameters in progressive dysglycemia.. A cross-sectional study was performed on 68 participants: normal glucose tolerance (n = 23), prediabetes (n = 25), and Type 2 diabetes without diabetic retinopathy (n = 20). Anthropometric assessment and laboratory sampling for HbA1c, fasting glucose, insulin, c-peptide, lipid profile, renal function, and albumin-to-creatinine ratio were conducted. Central and pericentral macular thicknesses on spectral domain optical coherence tomography were compared with systemic parameters.. Baseline demographic characteristics were similar across all groups. Cuzick's trend test revealed progressive full-thickness macular thinning with increasing dysglycemia across all three groups (P = 0.015). The urinary albumin-to-creatinine ratio was significantly correlated with full-thickness superior (R = -0.435; P = 0.0002), inferior (R = -0.409; P = 0.0005), temporal (R = -0.429; P = 0.003), and nasal (R = -0.493; P < 0.0001) pericentral macular thinning, after post hoc Bonferroni adjustment. There was no association between macular thinning and waist circumference, body mass index, blood pressure, lipid profile, or insulin resistance.. Progressive dysglycemia is associated with macular thinning before the onset of visible retinopathy and occurs alongside microalbuminuria. Retinal neurodegenerative changes may help identify those most at risk from dysglycemic end-organ damage.

Topics: Aged; Albuminuria; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose Metabolism Disorders; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Middle Aged; Prediabetic State; Retinal Degeneration; Tomography, Optical Coherence

Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven.. We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet.. In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10. These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Mice; Prediabetic State

Maturity-onset diabetes of the young (MODY) is often misdiagnosed as type 1/type 2 diabetes. We aimed to define patient characteristics to guide the decision to test for MODY in youth with diabetes.. Of 4750 patients enrolled in the Diabetes Registry at Texas Children's Hospital between July 2016 and July 2019, we selected ("Study Cohort", n = 350) those with: (1) diabetes diagnosis <25 years, (2) family history of diabetes in three consecutive generations, and (3) absent islet autoantibodies except for GAD65. We retrospectively studied their clinical and biochemical characteristics and available MODY testing results. Cluster analysis was then performed to identify the cluster with highest rate of MODY diagnosis.. Patients in the Study Cohort were 3.5 times more likely to have been diagnosed with MODY than in the overall Diabetes Registry (4.6% vs. 1.3%, p < 0.001). The cluster (n = 16) with the highest rate of clinician-diagnosed MODY (25%, n = 4/16) had the lowest age (10.9 ± 2.5 year), BMI-z score (0.5 ± 0.9), C-peptide level (1.5 ± 1.2 ng/ml) and acanthosis nigricans frequency (12.5%) at diabetes diagnosis (all p < 0.05). In this cluster, three out of five patients who underwent MODY genetic testing had a pathogenic variant.. Using a stepwise approach, we identified that younger age, lower BMI, lower C-peptide, and absence of acanthosis nigricans increase likelihood of MODY in racially/ethnically diverse children with diabetes who have a multigenerational family history of diabetes and negative islet autoantibodies, and can be used by clinicians to select patients for MODY testing.

Topics: Acanthosis Nigricans; Adolescent; Autoantibodies; C-Peptide; Child; Diabetes Mellitus, Type 2; Humans; Retrospective Studies

Evaluation of residual beta cell function is indispensable in patients with type 2 diabetes as it informs not only diagnoses but also appropriate treatment modalities. However, there is a lack of convenient biomarkers for residual beta cell function. Therefore, we evaluated endogenous insulin level as a biomarker in outpatients who were being treated with insulin therapy and in patients who were introduced to insulin therapy after 4 years.. C-CPI and UCPCR were significantly lower in the insulin-treated patients than in the insulin-untreated patients (0.9 vs. 2.2, p < 0.0001; 24.7 vs. 75.5, p = 0.0003, respectively). Moreover, C-CPI were significantly lower in the insulin-requiring patients for 4 years than in the insulin-unrequiring patients (1.0 vs. 1.7, p = 0.0184). The multivariate logistic regression analysis revealed that both indicators of insulin secretion influenced the requirement for insulin therapy, but C-CPI could serve as the most convenient and useful biomarker for not only current insulin therapy requirements (p = 0.0002) but also the subsequent requirement for insulin therapy (p = 0.0008).. C-CPI could be determined easily, and it was found to be a more practical marker for outpatients; therefore, our findings would have critical implications for primary care.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Male; Outpatients; Primary Health Care

Bariatric surgery is evolving as a successful tool for managing morbid obesity and T2DM. This study aimed to identify predictors of diabetes remission after two types of bariatric procedures.. This prospective study enrolled 172 patients with morbid obesity associated with T2DM scheduled for bariatric surgery. Two laparoscopic bariatric procedures were done; single anastomosis gastric bypass (SAGB, n = 83) and sleeve gastrectomy (LSG, n = 68). Lipid accumulation product index (LAP) and quantitative insulin sensitivity check index (QUICKI) were used to evaluate lipid profile and insulin sensitivity. Two years after surgery condition of DM was evaluated as complete remission (CR), partial remission (PR), or improvement. The primary outcome measure was predictors of diabetes remission.. Two years after surgery, 151 patients were available for evaluation, where 75 patients (49.7%) achieved CR, while PR was found in 36 (23.8%). CR was significantly associated with younger age, shorter duration of DM (p < 0.001, for both), higher C-peptide and GLP-1 levels (p < 0.001 and p = 0.002, respectively), and bypass surgery (p = 0.027). On multivariate analysis, shorter duration of DM, lower BMI, and higher C-peptide levels were the independent factors predicting CR.. Complete remission of T2DM can be achieved in nearly half of the patients two years after SG or SAGB. The duration of diabetes and preoperative BMI and C-peptide levels are the independent factors predicting complete remissions.

Topics: Bariatric Surgery; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Follow-Up Studies; Gastrectomy; Gastric Bypass; Humans; Insulin Resistance; Laparoscopy; Obesity, Morbid; Prospective Studies; Retrospective Studies; Treatment Outcome

The aim of this study was to analyze the clinical characteristics and the pattern of long-term changes of fasting plasma C-peptide in patients with mitochondrial diabetes (MD), and to provide guidance for the diagnosis and treatment of MD.. We retrieved MD patients with long-term follow-up at Peking Union Medical College Hospital from January 2005 to July 2021 through the medical record retrieval system and retrospectively analyzed their clinical data, biochemical parameters, fasting plasma C-peptide, glycosylated hemoglobin and treatment regimens. Non-parametric receiver operating characteristic (ROC) curves were used to assess the relationship between exercise test-related plasma lactate levels and suffering from MD.. A total of 12 MD patients were included, with clinical characteristics of early-onset, normal or low body weight, hearing loss, maternal inheritance, and negative islet-related autoantibodies. In addition, patients with MD exhibited significantly higher mean plasma lactate levels immediately after exercise compared to patients with type 1 diabetes mellitus (T1DM) (8.39 ± 2.75 vs. 3.53 ± 1.47 mmol/L, p=0.003) and delayed recovery time after exercise (6.02 ± 2.65 vs. 2.17 ± 1.27 mmol/L, p=0.011). The optimal cut-off points identified were 5.5 and 3.4 mmol/L for plasma lactate levels immediately after and 30 minutes after exercise, respectively. The fasting plasma C-peptide levels decreased as a negative exponential function with disease progression (Y= 1.343*e. The increased level of plasma lactate during exercise or its delayed recovery after exercise would contribute to the diagnosis of MD. Changes of fasting plasma C-peptide in MD patients over the course of the disease indicated a rapid decline in the early stages, followed by a gradual slowing rate of decline.

Topics: Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Exercise Test; Fasting; Follow-Up Studies; Humans; Lactic Acid; Retrospective Studies

Diabetic retinopathy is a leading cause of vision impairment. Surging diabetic population and poor visual care raises the need for better diagnostic tools. Hence, it is worthwhile to look for biomarkers associated with the disease pathogenesis. Periostin and tenascin-C are matricellular proteins mediating fibrillogenesis in retinopathy. Their serum levels and association with the presence and severity of retinopathy in diabetics is of importance to be explored.. The study involved two groups of type 2 diabetes patients, 38 controls without retinopathy and 38 cases with retinopathy. We obtained serum sample and performed biochemical autoanalysis for routine parameters. Special parameters periostin, tenascin-C, and C-peptide were estimated by ELISA.. Periostin and tenascin-C were significantly elevated in the retinopathy group. Periostin progressively increased among subgroups. C-peptide decreased significantly in retinopathy group and had a negative correlation with duration of DM, duration of retinopathy, HbA1c and tenascin-C. We observed a positive correlation for periostin and tenascin-C with duration of diabetes. The AUC for C-peptide was the highest (0.750) amongst our parameters. HOMA 2 (%B) index was significantly lower in retinopathy group.. Serum Levels of PO and TnC increased in retinopathy. As the disease advances, periostin level increases, indicating continuing fibrosis and fibrovascular membrane formation. Periostin and tenascin-C increase with duration of retinopathy whereas levels of C-peptide decrease. C-peptide has a better differentiating potential for DR from DM. Reduced insulin production as indicated by declined HOMA 2-%BETA in retinopathy favors hyperglycemia and chronic inflammatory state for the disease progression.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Fibrosis; Humans; Tenascin

To investigate factors influencing glycemic control in diabetes mellitus complicated by autoimmune pancreatitis.. This retrospective cohort study investigated 33 patients with diabetes mellitus complicated by autoimmune pancreatitis who had received steroid therapy at Toranomon Hospital between January 1, 2011, and December 31, 2020. The course of glycemic control at 12 months after starting steroids was classified into three groups: Improved, Unchanged, or Worsened. Factors affecting these groups were investigated. Furthermore, we created two scores: (1) time of diabetes mellitus onset and baseline body mass index; (2) time of diabetes mellitus onset and baseline C-peptide index. Diabetes mellitus occurring at the same time as autoimmune pancreatitis, body mass index ≥22 kg/m. Ten patients were in the Improved group, 10 were in the Unchanged group, and 13 were in the Worsened group. The baseline body mass index and baseline C-peptide index were lower in the Worsened group than in the Improved group (P < 0.05 each). In addition, the scores were lower in the Worsened group than in the other groups (P < 0.05).. Patients with a lower baseline body mass index and a decreased baseline C-peptide index may experience worse glycemic control on steroid therapy.

Topics: Autoimmune Pancreatitis; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Glycemic Control; Humans; Retrospective Studies; Steroids

Severe insulin resistance syndromes, such as lipodystrophy, lead to diabetes, which is challenging to control. This study explored the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in a series of 12 patients with severe insulin resistance due to partial lipodystrophy.. A retrospective chart review of the safety (N = 22) and efficacy (N = 12) of SGLT2is in patients with partial lipodystrophy was conducted at our institution. The efficacy outcomes included hemoglobin A1C level, insulin dose, fasting plasma glucose level, C-peptide level, lipid profile, 24-hour urinary glucose excretion, estimated glomerular filtration rate, and blood pressure before and after 12 months of SGLT2i treatment.. The hemoglobin A1C level decreased after SGLT2i treatment (at baseline: 9.2% ± 2.0% [77.0 ± 21.9 mmol/mol]; after 12 months: 8.4% ± 1.8% [68.0 ± 19.7 mmol/mol]; P = .028). Significant reductions were also noted in systolic (P = .011) and diastolic blood pressure (P = .013). There was a trend toward a decreased C-peptide level (P = .071). The fasting plasma glucose level, lipid level, and estimated glomerular filtration rate remained unchanged. The adverse effects included extremity pain, hypoglycemia, diabetic ketoacidosis (in a patient who was nonadherent to insulin), pancreatitis (in a patient with prior pancreatitis), and fungal infections.. SGLT2is reduced the hemoglobin A1C level in patients with partial lipodystrophy, with a similar safety profile compared with that in patients with type 2 diabetes. After individual consideration of the risks and benefits of SGLT2is, these may be considered a part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose Transporter Type 2; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lipodystrophy; Pancreatitis; Retrospective Studies; Sodium-Glucose Transporter 2 Inhibitors

Many C-peptide assays are commercially available for research and routine use. However, not all assays yield consistent results, especially in the low concentration ranges. We searched the literature describing C-peptide measurements to assess which assays are mainly used in the diabetes research field and if they are specified. Percentages of publications on C-peptide measurements in type 1 diabetes (T1D), type 2 diabetes (T2D) and other forms of diabetes were 32%, 54% and 14%, respectively. In only 54% of the publications the used assay was specified. Information on detection limit, measurement range and variation was provided in 12%, 2% and 11% of publications, respectively. In 22% of all publications no C-peptides concentrations were mentioned. This may be a problem especially for T1D research, where measuring very low levels of C-peptide is becoming increasingly important and concordance between assays is low.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans

Objective This study analyzed the clinical and laboratory parameters that might influence the clinical outcomes of patients with type 2 diabetes who develop diabetic ketoacidosis (DKA), which has not been well investigated. Methods We reviewed the clinical and laboratory data of 158 patients who were hospitalized due to DKA between January 2006 and June 2019 and compared the data of patients stratified by the type of diabetes. In addition, the patients with type 2 diabetes were subdivided according to age, and their clinical and laboratory findings were evaluated. Results Patients with type 2 diabetes had a longer symptom duration associated with DKA, higher body mass index (BMI), and higher C-peptide levels than those with type 1 diabetes (p<0.05). Among patients with type 2 diabetes, elderly patients (≥65 years old) had a longer duration of diabetes, higher frequency of DKA onset under diabetes treatment, higher effective osmolarity, lower BMI, and lower urinary C-peptide levels than nonelderly patients (<65 years old) (p<0.05). A correlation analysis showed that age was significantly negatively correlated with the index of insulin secretory capacity. Conclusion Patients with DKA and type 2 diabetes had a higher BMI and insulin secretion capacity than those with type 1 diabetes. However, elderly patients with type 2 diabetes, unlike younger patients, were characterized by a lean body, impaired insulin secretion, and more frequent DKA development while undergoing treatment for diabetes.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Humans; Insulin Secretion; Retrospective Studies

A literature search was conducted to identify publications addressing the early phases of lipid phenotypes in children and adults with either type 1 diabetes or type 2 diabetes. Medline, EMBASE, and Ovid were searched using the following search terms:

Topics: Adolescent; Atherosclerosis; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Lipids; Remission Induction

Diabetes mellitus refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. The worldwide prevalence of DM has risen dramatically over the past two decades.Diabetes mellitus is a major cause of mortality and morbidity worldwide. Assay for C-peptide can be used to provide an index of endogenous insulin production and pancreatic beta cell function.. This is a hospital based cross section study involving 50 newly detected diabetic subjects of age group 35-40 years. The subjects were evaluated with their fasting and stimulated c-peptide levels assay, fasting and postprandial blood sugars, HbA1c.. Eight subjects out of 50 subjects had a fasting serum C-peptide value less than normal value. Thirteen subjects out of 50 subjects had a low stimulated serum C-peptide.. This study suggests measurement of C-peptide levels in newly detected diabetic subjects especially of younger age group is of value in differentiating type of diabetes and appropriate next line of management.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Humans; Insulin

Insulin and insulin-like growth factor (IGF)-1 signaling is a proposed mechanism linking dietary protein and major chronic diseases. However, it is unclear whether animal and plant proteins are associated with biomarkers of insulin and IGF axis.. We analyzed a total of 14,709 participants from Nurses' Health Study and Health Professionals Follow-up Study who had provided a blood sample. Detailed dietary information was assessed using validated food frequency questionnaires. We assessed C-peptide, insulin, IGF-1, and IGF binding proteins (BP). Multivariable-adjusted linear regressions were used to examine associations of animal and plant protein intake with biomarkers after adjusting for confounders.. The medians (5th-95th percentiles) of animal and plant protein intake (% of total energy) were 13% (8-19%) and 5% (4-7%), respectively. Compared to participants in the lowest quintile, those in the highest quintile of animal protein had 4.8% (95% CI: 1.9, 7.9; P-trend<0.001) higher concentration of IGF-1 and -7.2% (95% CI: -14.8, 1.1; P for trend = 0.03) and -11.8% (95% CI: -20.6, -1.9; P-trend<0.001) lower concentration of IGFBP-1 and IGFBP-2, respectively, after adjustment for major lifestyle factors and diet quality. In contrast, no association was observed between animal protein intake and C-peptide, insulin and IGFBP-3. The associations were restricted to participants with at least one unhealthy lifestyle risk factor (i.e., overweight/obese, physical inactivity, smoking, and heavy alcohol intake). Plant protein tended to be strongly associated with numerous biomarkers in age-adjusted analyses but these became largely attenuated or non-significant in multivariable adjustment. Plant protein intake remained positively associated with IGF-1 (P-trend = 0.002) and possibly IGFBP-1 (P-trend = 0.02) after multivariable adjustment. Substitution of plant protein with animal protein sources was associated with lower IGFBP-1. In additional analysis, IGF-1 and IGFBPs were estimated to mediate approximately 5-20% of the association between animal protein and type 2 diabetes.. Higher animal protein intake was associated with higher IGF-1 and lower IGFBP-1 and IGFBP-2, whereas higher plant protein intake was associated with higher IGF-1 and IGFBP-1.

Topics: Animal Proteins, Dietary; Animals; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Dietary Proteins; Follow-Up Studies; Humans; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Plant Proteins, Dietary

The objective of this study was to adopt the high-resolution computed tomography (HRCT) technology based on the faster-region recurrent convolutional neural network (Faster-RCNN) algorithm to evaluate the lung infection in patients with type 2 diabetes, so as to analyze the application value of imaging features in the assessment of pulmonary disease in type 2 diabetes. In this study, 176 patients with type 2 diabetes were selected as the research objects, and they were divided into different groups based on gender, course of disease, age, glycosylated hemoglobin level (HbA1c), 2 h C peptide (2 h C-P) after meal, fasting C peptide (FC-P), and complications. The research objects were performed with HRCT scan, and the Faster-RCNN algorithm model was built to obtain the imaging features. The relationships between HRCT imaging features and 2 h C-P, FC-P, HbA1c, gender, course of disease, age, and complications were analyzed comprehensively. The results showed that there were no significant differences in HRCT scores between male and female patients, patients of various ages, and patients with different HbA1c contents (

Topics: Algorithms; C-Peptide; Computers; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Lung; Male; Neural Networks, Computer; Tomography, X-Ray Computed

Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM−) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Meals; Pituitary ACTH Hypersecretion; Somatostatin

The effectiveness of continuous glucose monitoring (CGM) in maintaining glycaemic control in type 1 diabetes mellitus and type 2 diabetes mellitus has been well demonstrated. However, the degree of glycaemic variability (GV) in people with type 3c diabetes mellitus has not been fully explored using CGM. This study aims to evaluate GV in type 3c diabetes mellitus participants and compare it to type 1 diabetes mellitus and type 2 diabetes mellitus.. Participants were grouped according to type of diabetes. GV, defined as percentage coefficient of variation (%CV), and other glycaemic indices were obtained using CGM (FreeStyle Libre, Abbott, Australia) from 82 participants across all three cohorts over a 14-day period. Comparison of baseline characteristics and GV were performed across all groups. Correlation of GV with C-peptide values, and whether pancreatic supplementation had an effect on GV were also assessed in the type 3c diabetes mellitus cohort.. GV of type 3c diabetes mellitus participants was within the recommended target of less than %CV 36% (p = 0.004). Type 3c diabetes mellitus participants had the lowest GV among the three groups (p = 0.001). There was a trend for lower C-peptide levels to be associated with higher GV in type 3c diabetes mellitus participants (p = 0.22). Pancreatic enzyme supplementation in type 3c diabetes mellitus participants did not have an effect on GV (p = 0.664).. Although type 3c diabetes mellitus participants were the least variable, they had the highest mean glucose levels and estimated HbA

Topics: Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia

There are many tests for evaluating endogenous insulin secretory capacity. However, there are only a limited number of studies that have examined in detail in clinical practice which method most accurately reflects the ability to secrete endogenous insulin especially in hyperglycemic state. The purpose of this study was to find the endogenous insulin secretory capacity and a possible predictor of insulin withdrawal in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia. In the endogenous insulin secretory test during hospitalization, CPR, CPR index, and ΔCPR after glucagon loading were all significantly higher in the insulin withdrawal group. On the other hand, there were no difference in fasting CPR index, HOMA-β, SUIT, and 24-hour urinary CPR excretion between the two groups. In the glucagon test of the insulin withdrawal group, the cutoff value of ΔCPR was 1.0 ng/mL, the withdrawal rate of ΔCPR of 1.0 ng/mL or more was 69.2%, and the withdrawal rate of less than 1.0 ng/mL was 25.0%. In conclusion, it is likely that glucagon test is the most powerful tool for predicting the possibility of insulin withdrawal as well as for evaluating endogenous insulin secretory capacity in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Humans; Hyperglycemia; Insulin

Topics: Adipokines; Adiposity; Bone Density; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Leptin; Obesity; Pregnancy; Prospective Studies; Vascular Endothelial Growth Factor A

Islet transplantation is an effective treatment for the type 1 and severe type 2 diabetes, but it is restricted by the severe lack of pancreas donors. In vitro differentiation of pancreatic progenitors into insulin-secreting cells is one of the hopeful strategies in the cell transplantation therapy of diabetes. Isoastragaloside I is one of the saponin molecules found in Astragalus membranaceus, which has been demonstrated to alleviate insulin resistance and glucose intolerance in obese mice.. We established mouse pancreatic ductal organoids (mPDOs) with progenitor characteristics and an insulin promoter-driven EGFP reporter system to screen astragalus saponin components for monomers that can promote insulin-producing cell differentiation.. mPDOs treated with or without astragalus saponin monomers were investigated by the insulin promoter-driven EGFP reporter, quantitative PCR, immunofluorescence and flow cytometry to evaluate the expression of endocrine progenitor and β-cell markers.. Isoastragaloside I significantly promoted the expression of β-cell differentiation genes, which was demonstrated by the activation of the insulin promoter-driven EGFP reporter, as well as the significant increase of mRNA levels of the endocrine progenitor marker Ngn3 and the β-cell markers insulin1 and insulin2. Immunostaining studies indicated that the β-cell-specific C-peptide was upregulated in isoastragaloside I-treated mPDOs. FACS analysis revealed that the ratio of C-peptide-secreting cells in isoastragaloside I-treated mPDOs was over 40%. Glucose tolerance tests demonstrated that the differentiated mPDOs could secrete C-peptide in response to glucose stimulation.. We discover a novel strategy of inducing pancreatic ductal progenitors to differentiate into insulin-producing cells using isoastragaloside I. This approach can be potentially applied to β-cell transplantation in diabetes therapies.

Topics: Animals; C-Peptide; Cell Differentiation; Diabetes Mellitus, Type 2; Insulin; Insulin-Secreting Cells; Mice; Organoids; Saponins

Abnormal intracellular glucose/fatty acid metabolism of T cells has tremendous effects on their immuno-modulatory function, which is related to the pathogenesis of autoimmune diseases. However, the association between the status of intracellular metabolism of T cells and type 1 diabetes is unclear. This study aimed to investigate the uptake of glucose and fatty acids in T cells and its relationship with disease progression in type 1 diabetes.. A total of 86 individuals with type 1 diabetes were recruited to detect the uptake of glucose and fatty acids in T cells. 2-NBDG uptake and expression of glucose transporter 1 (GLUT1); or BODIPY uptake and expression of carnitine palmitoyltransferase 1A(CPT1A) were used to assess the status of glucose or fatty acid uptake in T cells. Patients with type 1 diabetes were followed up every 3-6 months for 36 months, the progression of beta-cell function was assessed using generalized estimating equations, and survival analysis was performed to determine the status of beta-cell function preservation (defined as 2-hour postprandial C-peptide >200 pmol/L).. Patients with type 1 diabetes demonstrated enhanced intracellular glucose uptake of T cells as indicated by higher 2NBDG uptake and GLUT1 expression, while no significant differences in fatty acid uptake were observed. The increased T cells glucose uptake is associated with lower C-peptide and higher hemoglobin A1c levels. Notably, patients with low T cell glucose uptake at onset maintained high levels of C-peptide within 36 months of the disease course [fasting C-petite and 2-hour postprandial C-peptide are 60.6 (95%CI: 21.1-99.8) pmol/L and 146.3 (95%CI: 14.1-278.5) pmol/L higher respectively], And they also have a higher proportion of beta-cell function preservation during this follow-up period (. Intracellular glucose uptake of T cells is abnormally enhanced in type 1 diabetes and is associated with beta-cell function and its progression.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids; Glucose; Glucose Transporter Type 1; Humans; Insulin; T-Lymphocytes

The Krüppel-like factor 11 (KLF11) gene causes maturity-onset diabetes of the young 7 (MODY7). There are few reports on the clinical and functional characteristics of KLF11 mutations in patients with MODY7, making diagnosis and treatment complicated.. We report a novel KLF11 variant associated with MODY7 in a Chinese family. The proband had hyperglycemia at 9 years of age, and his mother had developed diabetes at age 28 years. Both required insulin injections from the initial phase of the disease. They were negative for islet cell autoantibodies and had normal fasting C-peptide levels. We observed changes in the levels of fasting blood glucose, C-peptide, and islet cell autoantibodies in the proband over 4.5 years.. Whole-exon sequencing was used to screen the proband and his family members for KLF11 variants. The heterozygous KLF11 variant (c.1045C>T, p. Pro349Ser) was identified in the proband, his mother, his maternal grandmother, and an elderly aunt, although the latter two individuals were unaffected. In silico analyses indicated that this variant involved a change in the amino acid side chain in the transcriptional regulatory domain 3. Luciferase reporter assays revealed that the variant had impaired insulin promoter regulation activity. Moreover, in vitro analyses showed that this variant impaired insulin secretion from pancreatic beta cells.. This study documents a novel heterozygous KLF11 variant (p. Pro349Ser) as a potential monogenic mutation associated with MODY7 in a family. This variant impairs insulin secretion from pancreatic beta cells, possibly by repressing insulin promoter regulation activity.

Topics: Adult; Apoptosis Regulatory Proteins; Autoantibodies; C-Peptide; Cell Cycle Proteins; Diabetes Mellitus, Type 2; Female; Humans; Male; Mutation; Pedigree; Repressor Proteins

We investigated quantitative expression, mutual aggregation and relation with hyperglycemia of insulin resistance (IR) and beta-cell dysfunction (BCD) in newly diagnosed type 2 diabetes.. We assessed IR with euglycemic hyperinsulinemic clamp and BCD with modelled glucose/C-peptide response to oral glucose in 729 mostly drug-naïve patients. We measured glycated hemoglobin, pre-prandial, post-prandial and meal-related excursion of blood glucose.. IR was found in 87.8% [95% confidence intervals 85.4-90.2] and BCD in 90.0% [87.8-92.2] of subjects, ranging from mild to moderate or severe. Approximately 20% of subjects had solely one defect: BCD 10.8% [8.6-13.1] or IR 8.6% [6.6-10.7]. Insulin resistance and BCD aggregated in most subjects (79.1% [76.2-82.1]). We arbitrarily set nine possible combinations of mild, moderate or severe IR and mild, moderate or severe BCD, finding that each had a similar frequency (∼10%). In multiple regression analyses parameters of glucose control were related more strongly with BCD than with IR.. In newly-diagnosed type 2 diabetes, IR and BCD are very common with a wide range of expression but no specific pattern of aggregation. Beta-cell dysfunction is likely to play a greater quantitative role than IR in causing/sustaining hyperglycemia in newly-diagnosed type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Resistance

The. 13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women.. In a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Kinetics; Male; Prediabetic State; Receptor, Melatonin, MT2

The optimal screening strategy for dysglycemia (including type 2 diabetes and impaired glucose tolerance) in patients with coronary artery disease (CAD) is debated. We tested the hypothesis that measures of insulin resistance by HOMA indexes may constitute good screening methods.. Insulin, C-peptide, glycated hemoglobin A1c, and an oral glucose tolerance test (OGTT) were centrally assessed in 3,534 patients with CAD without known dysglycemia from the fifth European Survey of Cardiovascular Disease Prevention and Diabetes (EUROASPIRE V). Three different HOMA indexes were calculated: HOMA of insulin resistance (HOMA-IR), HOMA2 based on insulin (HOMA2-ins), and HOMA2 based on C-peptide (HOMA2-Cpep). Dysglycemia was diagnosed based on the 2-h postload glucose value obtained from the OGTT. Information on study participants was obtained by standardized interviews. The optimal thresholds of the three HOMA indexes for dysglycemia diagnosis were obtained by the maximum value of Youden's J statistic on receiver operator characteristic curves. Their correlation with clinical parameters was assessed by Spearman coefficients.. Of 3,534 patients with CAD (mean age 63 years; 25% women), 41% had dysglycemia. Mean insulin, C-peptide, and HOMA indexes were significantly higher in patients with versus without newly detected dysglycemia (all P < 0.0001). Sensitivity and specificity of the three HOMA indexes for the diagnosis of dysglycemia were low, but their correlation with BMI and waist circumference was strong.. Screening for dysglycemia in patients with CAD by HOMA-IR, HOMA2-ins, and HOMA2-Cpep had insufficient diagnostic performance to detect dysglycemia with reference to the yield of an OGTT, which should still be prioritized despite its practical drawbacks.

Topics: Blood Glucose; C-Peptide; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged

The increasing incidence of diabetes continuously stimulates the research on new antidiabetic drugs. Computer simulation can save time and costs, alleviating the need of animal trials and providing useful information for optimal experiment design and drug dosing. We recently presented a type 2 diabetes (T2D) simulator as tool for in silico testing of new molecules and guiding treatment optimization. Here we present a user-friendly interface aimed to increase the usability of the simulator.. The simulator, based on a large-scale glucose, insulin, and C-peptide model and equipped with 100 virtual subjects well describing system dynamics in a real T2D population, is extended to incorporate pharmacokinetics/pharmacodynamics (PK/PD) of a drug of interest. A graphical interface is developed on top of the simulator, allowing an easy design of in silico experiments: specifically, it is possible to select the population size to test, design the experiment (crossover or parallel), its duration and the sampling grid, choose glucose and insulin doses, and define treatment PK/PD and dose administered. The simulator also provides the outcome metrics requested by the user, and performs statistical comparisons among treatments and/or placebo.. To illustrate the potential of the simulator, we provided a case study using metformin and liraglutide. Literature-based PK/PD models of metformin and liraglutide have been incorporated in the simulator, by modulating key drug-sensitive model parameters. An in silico placebo-controlled trial has been done by simulating a three-arm meal tolerance test with subjects receiving placebo, metformin 850 mg, liraglutide 1.80 mg, respectively. The obtained results are in agreement with the clinical evidences, in terms of main glucose, insulin, and C-peptide outcome metrics.. We developed a user-friendly software interface for the T2D simulator to support the design and test of new antidiabetic drugs and treatments. This increases the simulator usability, making it suitable also for users who have low experience with computer programming.

Topics: Blood Glucose; C-Peptide; Computer Simulation; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Metformin; Software

Diabetes in childhood and adolescence includes autoimmune and non-autoimmune forms with heterogeneity in clinical and biochemical presentations. An unresolved question is whether there are subtypes, endotypes, or theratypes within these forms of diabetes.. The multivariable classification and regression tree (CART) analysis method was used to identify subgroups of diabetes with differing residual C-peptide levels in patients with newly diagnosed diabetes before 20 years of age (n=1192). The robustness of the model was assessed in a confirmation and prognosis cohort (n=2722).. The analysis selected age, haemoglobin A1c (HbA1c), and body mass index (BMI) as split parameters that classified patients into seven islet autoantibody-positive and three autoantibody-negative groups. There were substantial differences in genetics, inflammatory markers, diabetes family history, lipids, 25-OH-Vitamin D3, insulin treatment, insulin sensitivity and insulin autoimmunity among the groups, and the method stratified patients with potentially different pathogeneses and prognoses. Interferon-ɣ and/or tumour necrosis factor inflammatory signatures were enriched in the youngest islet autoantibody-positive groups and in patients with the lowest C-peptide values, while higher BMI and type 2 diabetes characteristics were found in older patients. The prognostic relevance was demonstrated by persistent differences in HbA1c at 7 years median follow-up.. This multivariable analysis revealed subgroups of young patients with diabetes that have potential pathogenetic and therapeutic relevance.. The work was supported by funds from the German Federal Ministry of Education and Research (01KX1818; FKZ 01GI0805; DZD e.V.), the Innovative Medicine Initiative 2 Joint Undertaking INNODIA (grant agreement No. 115797), the German Robert Koch Institute, and the German Diabetes Association.

Topics: Adolescent; Autoantibodies; Autoimmunity; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Young Adult

To investigate the relationship between thyroid hormone concentrations and β-cell function in euthyroid patients with obesity and type 2 diabetes.. We performed a single-center cross-sectional study of 254 patients with type 2 diabetes mellitus aged ≥40 years. The participants were allocated to an obesity group or non-obesity group on the basis of their body mass index (BMI). Their β-cell function was assessed by measuring C-peptide concentration during a 75-g oral glucose tolerance test (OGTT); and their serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone concentrations were measured.. The serum FT3 concentration and the C-peptide concentrations at five time points of the OGTT were significantly higher in the obesity group than in the non-obesity group. FT3 was positively associated with the β-cell function of the obesity group, but not that of the non-obesity group, in multiple linear regression analysis, after adjustment for potential confounding factors. Serum FT3 concentration was also significantly associated with indices of obesity (BMI, waist circumference, body fat percentage, fat mass, fat mass/height. Obesity-associated high serum FT3 concentrations might affect β-cell function in euthyroid patients with obesity and type 2 diabetes.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Obesity; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Limited information is available regarding youth-onset diabetes in Mali. We investigated demographic, clinical, biochemical, and genetic features in new diabetes cases in children and adolescents.. The study was conducted at Hôpital du Mali in Bamako. A total of 132 recently-diagnosed cases <21 years were enrolled. Demographic characteristics, clinical information, biochemical parameters (blood glucose, HbA1c, C-peptide, glutamic acid decarboxylase-65 (GAD-65) and islet antigen-2 (IA2) autoantibodies) were assessed. DNA was genotyped for HLA-DRB1 using high-resolution genotyping technology.. A total of 130 cases were clinically diagnosed as type 1 diabetes (T1D), one with type 2 diabetes (T2D), and one with secondary diabetes. A total of 66 (50.8%) T1D cases were males and 64 (49.2%) females, with a mean age at diagnosis of 13.8 ± 4.4 years (range 0.8-20.7 years) peak onset of 15 years. 58 (44.6%) presented in diabetic ketoacidosis; with 28 (21.5%) IA2 positive, 76 (58.5%) GAD-65 positive, and 15 (11.5%) positive for both autoantibodies. HLA was also genotyped in 195 controls without diabetes. HLA-DRB1 genotyping of controls and 98 T1D cases revealed that DRB1*03:01, DRB1*04:05, and DRB1*09:01 alleles were predisposing for T1D (odds ratios [ORs]: 2.82, 14.76, and 3.48, p-values: 9.68E-5, 2.26E-10, and 8.36E-4, respectively), while DRB1*15:03 was protective (OR = 0.27; p-value = 1.73E-3). No significant differences were observed between T1D cases with and without GAD-65 and IA2 autoantibodies. Interestingly, mean C-peptide was 3.6 ± 2.7 ng/ml (1.2 ± 0.9 nmol/L) in T1D cases at diagnosis.. C-peptide values were higher than expected in those diagnosed as T1D and autoantibody rates lower than in European populations. It is quite possible that some cases have an atypical form of T1D, ketosis-prone T2D, or youth-onset T2D. This study will help guide assessment and individual management of Malian diabetes cases, potentially enabling healthier outcomes.

Topics: Adolescent; Adult; Autoantibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Glutamate Decarboxylase; HLA-DRB1 Chains; Humans; Infant; Male; Mali; Young Adult

The aims were (1) to assess beta-cell function in GCK diabetes patients over 2-year period; (2) to evaluate the dynamics of beta-cell function in HNF1A and KCNJ11 patients after treatment optimization; using mixed meal tolerance test (MMTT) as a gold standard for non-invasive beta-cell function assessment.. Twenty-two GCK diabetes patients, 22 healthy subjects, 4 patients with HNF1A and 2 with KCNJ11 were recruited. Firstly, beta-cell function was compared between GCK patients versus controls; the dynamics of beta-cell function were assessed in GCK patients with two MMTTs in 2-year period. Secondly, the change of beta-cell function was evaluated in HNF1A and KCNJ11 patients after successful treatment optimization in 2-year period.. GCK diabetes patients had lower area under the curve (AUC) of C-peptide (CP), average CP and peak CP compared to controls. Also, higher levels of fasting, average, peak and AUC of glycemia during MMTT were found in GCK patients compared to healthy controls. No significant changes in either CP or glycemia dynamics were observed in GCK diabetes group comparing 1st and 2nd MMTTs. Patients with HNF1A and KCNJ11 diabetes had significantly improved diabetes control 2 years after the treatment was optimized (HbA1c 7.1% vs. 5.9% [54 mmol/mol vs. 41 mmol/mol], respectively, p = 0.028). Higher peak CP and lower HbA1c were found during 2nd MMTT in patients with targeted treatment compared to the 1st MMTT before the treatment change.. In short-term perspective, GCK diabetes group revealed no deterioration of beta-cell function. Individualized treatment in monogenic diabetes showed improved beta-cell function.

Topics: Adolescent; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Hepatocyte Nuclear Factor 1-alpha; Humans; Mutation

Maturity-onset diabetes of the young (MODY), an autosomal dominant disease, is frequently misdiagnosed as type 1 or 2 diabetes. Molecular diagnosis is essential to distinguish them. This study was done to investigate the prevalence of MODY subtypes and patients' clinical characteristics.. A total of 43 out of 230 individuals with diabetes were selected based on the age of diagnosis >6 months, family history of diabetes, absence of marked obesity, and measurable C-peptide. Next-generation and direct SANGER sequencing was performed to screen MODY-related mutations. The variants were interpreted using the Genome Aggregation Database (genomAD), Clinical Variation (ClinVar), and pathogenicity prediction tools.. There were 23 males (53.5%), and the mean age at diabetes diagnosis was 6.7 ± 3.6 years. Sixteen heterozygote single nucleotide variations (SNVs) from 14 patients (14/230, 6%) were detected, frequently GCK (37.5%) and BLK (18.7%). Two novel variants were identified in HNF4A and ABCC8. Half of the detected variants were categorized as likely pathogenic. Most prediction tools predicted Ser28Cys in HNF4A as benign and Tyr123Phe in ABCC8 as a pathogenic SNV. Six cases (42.8%) with positive MODY SNVs had islet autoantibodies. At diagnosis, age, HbA. This is the first study investigating 14 variants of MODY in Iran. The results recommend genetic screening for MODY in individuals with unusual type 1 or 2 diabetes even without family history. Treatment modifies depending on the type of patients' MODY and is associated with the quality of life.

Topics: Adolescent; Autoantibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 2; Humans; Infant; Iran; Male; Mutation; Nucleotides; Quality of Life

Long noncoding RNA (lncRNA) in plasma exosomes is a potential non-invasive diagnostic biomarker for diabetic retinopathy (DR). However, the changes in plasma exosomal lncRNAs and diagnostic relevance in patients with DR patients remain unclear.. A case-control study with type 2 diabetes mellitus (T2DM) and patients with comorbid DR were enrolled, and their clinical information and blood samples were collected. Plasma exosomes were extracted, and the relative expression levels of representative differentially expressed exosomal lncRNAs were determined. A logistic regression model was used to analyze the relationships of DR with relative lncRNA expression and DR-related factors, and receiver operating characteristic (ROC) curve analysis was used to evaluate the value of exosomal lncRNAs for DR diagnosis.. Sixty-two patients with T2DM and sixty-two patients with DR were matched by age, sex, and disease duration. The fasting blood glucose concentration, glycosylated hemoglobin level (HbA. The fasting blood glucose concentration, HbA

Topics: Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Exosomes; Female; Glycated Hemoglobin; Humans; Male; RNA, Long Noncoding

This study aimed to retrospectively assess the association between prolactin (PRL) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM).. A retrospective, cross-sectional study was conducted at a single hospital in Anhui, China.. A total of 406 patients with T2DM (230 men and 176 women) was included.. P values for the independent t-test, the Mann-Whitney rank-sum test, the Spearman correlation analysis and multiple logistic regression models were used to explore the association between PRL and NAFLD in patients with T2DM.. The results indicated that in both men and women, the levels of PRL were significantly lower in the T2DM with NAFLD group than in the T2DM without NAFLD group (men: 9.56 ng/mL vs 10.36 ng/mL, women: 10.38 ng/mL vs 12.97 ng/mL). In male patients, the levels of PRL were negatively correlated with hip circumference (r=-0.141, p=0.032), homoeostasis model assessment for insulin resistance (C-peptide) (r=-0.141, p=0.032) and triglyceride (TG) (r=-0.252, p=0.000) values and inversely correlated with high-density lipoprotein (r=0.147, p=0.025) levels. In female patients, PRL levels were negatively related to body mass index (r=-0.192, p=0.011), diastolic blood pressure (r=-0.220, p=0.003), waist circumference (r=-0.152, p=0.044), hip circumference (r=-0.157, p=0.037) and TG (r=-0.258, p=0.001) values. Logistic regression analysis revealed a negative relationship between PRL and NAFLD (men: OR 0.891, 95% CI 0.803 to 0.989, p=0.031; women: OR 0.874, 95% CI 0.797 to 0.957, p=0.004). As PRL levels increased, NAFLD prevalence decreased in both sexes (men: p=0.012, women: p=0.013).. Our results suggest that low levels of PRL in the physiological range were markers of NAFLD in patients with T2DM and that PRL within the biologically high range may play a protective role in the pathogenesis of NAFLD.

Topics: C-Peptide; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Hospitals; Humans; Lipoproteins, HDL; Male; Non-alcoholic Fatty Liver Disease; Prolactin; Retrospective Studies; Triglycerides

Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events.. A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice.. Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM.. The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM.

Topics: Adult; Biomarkers; C-Peptide; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Insulin Resistance; Retrospective Studies; Risk Factors; Troponin T

Pancreatic fat is a form of ectopic fat. Lipid droplets (LDs) are also observed in β cells; however, the pathophysiological significance, especially for β cell function, has not been elucidated. Our aim was to assess LD accumulation in β cells in various stages of glucose intolerance and to clarify its relationship with clinical and histological parameters.. We examined 42 Japanese patients who underwent pancreatectomy. The BODIPY493/503-positive (BODIPY-positive) area in β cells was measured in pancreatic sections from 32 patients. The insulin granule numbers were counted in an additional 10 patients using electron microscopy.. The BODIPY-positive area in β cells in preexisting type 2 diabetes patients was higher than that in normal glucose tolerance patients (p = 0.031). The BODIPY-positive area in β cells was positively correlated with age (r = 0.45, p = 0.0097), HbA1c (r = 0.38, p = 0.0302), fasting plasma glucose (r = 0.37, p = 0.045), and homeostasis model assessment insulin resistance (r = 0.41, p = 0.049) and negatively correlated with an increase in the C-peptide immunoreactivity level by the glucagon test (r = -0.59, p = 0.018). The ratio of mature insulin granule number to total insulin granule number was reduced in the patients with rich LD accumulation in β cells (p = 0.039).. Type 2 diabetes patients had high LD accumulation in β cells, which was associated with insulin resistance, hyperglycemia, aging and β cell dysfunction involving decreased mature insulin granules.

Topics: Blood Glucose; Boron Compounds; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipid Droplets

We aimed to explore the performance of detrended fluctuation function (DFF) in distinguishing patients with latent autoimmune diabetes in adults (LADA) from type 2 diabetes mellitus (T2DM) with glucose data derived from continuous glucose monitoring.. In total, 71 LADA and 152 T2DM patients were enrolled. Correlations between glucose parameters including time in range (TIR), mean glucose, standard deviation (SD), mean amplitude of glucose excursions (MAGE), coefficient of variation (CV), DFF and fasting and 2-hour postprandial C-peptide (FCP, 2hCP) were analyzed and compared. Receiver operating characteristics curve (ROC) analysis and 10-fold cross-validation were employed to explore and validate the performance of DFF in diabetes classification respectively.. Patients with LADA had a higher mean glucose, lower TIR, greater SD, MAGE and CV than those of T2DM (. A more violent glucose fluctuation pattern was marked in patients with LADA than T2DM. We first proposed the possible role of DFF in distinguishing patients with LADA from T2DM in our study population, which may assist in diabetes classification.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Latent Autoimmune Diabetes in Adults

Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population.. We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A), clinical and genetic characteristics, and progression (annual change in urine C-peptide-to-creatinine ratio [UCPCR]) in 722 adults (≥18 years old at diagnosis) with clinically diagnosed type 1 diabetes and diabetes duration <12 months. We also evaluated changes in treatment and glycemia over 2 years after informing participants and their clinicians of autoantibody results.. Of 722 participants diagnosed with type 1 diabetes, 24.8% (179) were autoantibody negative. This group had genetic and C-peptide characteristics suggestive of a high prevalence of nonautoimmune diabetes: lower mean type 1 diabetes genetic risk score (islet autoantibody negative vs. positive: 10.85 vs. 13.09 [P < 0.001] [type 2 diabetes 10.12]) and lower annual change in C-peptide (UCPCR), -24% vs. -43% (P < 0.001).After median 24 months of follow-up, treatment change occurred in 36.6% (60 of 164) of autoantibody-negative participants: 22.6% (37 of 164) discontinued insulin, with HbA1c similar to that of participants continuing insulin (57.5 vs. 60.8 mmol/mol [7.4 vs. 7.7%], P = 0.4), and 14.0% (23 of 164) added adjuvant agents to insulin.. In adult-onset clinically diagnosed type 1 diabetes, negative islet autoantibodies should prompt careful consideration of other diabetes subtypes. When routinely measured, negative antibodies are associated with successful insulin cessation. These findings support recent recommendations for routine islet autoantibody assessment in adult-onset type 1 diabetes.

Topics: Adolescent; Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Humans; Insulin; Insulin, Regular, Human

To investigate glycaemic variability (GV) patterns in patients with type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA).. A total of 842 subjects (510 T1D, 105 LADA, 227 T2D) were enrolled and underwent 1 week of continuous glucose monitoring (CGM). Clinical characteristics and CGM parameters were compared among T1D, LADA, and T2D. LADA patients were divided into two subgroups based on glutamic acid decarboxylase autoantibody titres (≥180 U/mL [LADA-1], <180 U/mL [LADA-2]) and compared. The C-peptide cut-offs for predicting a coefficient of variation (CV) of glucose ≥36% and a time in range (TIR) > 70% were determined using receiver operating characteristic analysis.. Twenty-seven patients (9 T1D, 18 T2D) were excluded due to insufficient CGM data. Sex, diabetes duration and HbA1c were comparable among the three groups. Fasting and 2-h postprandial C-peptide (FCP, 2hCP) increased sequentially across T1D, LADA, and T2D. T1D and LADA patients had comparable TIR and GV, whereas those with T2D had much higher TIR and lower GV (p < 0.001). The GV of LADA-1 was close to that of T1D, while the GV of LADA-2 was close to that of T2D. CP exhibited the strongest negative correlation with GV. The cut-offs of FCP/2hCP for predicting a CV ≥ 36% and TIR >70% were 121.6/243.1 and 128.9/252.8 pmol/L, respectively.. GV presented a continuous spectrum across T1D, LADA-1, LADA-2, and T2D. More frequent glucose monitoring is suggested for patients with impaired insulin secretion.. Chinese Clinical Trial Registration (ChiCTR) website approved by WHO; http://www.chictr.org.cn/ - ChiCTR2200065036.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Islets of Langerhans; Latent Autoimmune Diabetes in Adults

Females with a history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes mellitus (T2D) later in life.. This study prospectively examined whether greater habitual coffee consumption was related to a lower risk of T2D among females with a history of GDM.. We followed 4522 participants with a history of GDM in the NHS II for incident T2D between 1991 and 2017. Demographic, lifestyle factors including diet, and disease outcomes were updated every 2-4 y. Participants reported consumption of caffeinated and decaffeinated coffee on validated FFQs. Fasting blood samples were collected in 2012-2014 from a subset of participants free of diabetes to measure glucose metabolism biomarkers (HbA1c, insulin, C-peptide; n = 518). We used multivariable Cox regression models to calculate adjusted HRs and 95% CIs for the risk of T2D. We estimated the least squares mean of glucose metabolic biomarkers according to coffee consumption.. A total of 979 participants developed T2D. Caffeinated coffee consumption was inversely associated with the risk of T2D. Adjusted HR (95% CI) for ≤1 (nonzero), 2-3, and 4+ cups/d compared with 0 cup/d (reference) was 0.91 (0.78, 1.06), 0.83 (0.69, 1.01), and 0.46 (0.28, 0.76), respectively (P-trend = 0.004). Replacement of 1 serving/d of sugar-sweetened beverage and artificially sweetened beverage with 1 cup/d of caffeinated coffee was associated with a 17% (risk ratio [RR] = 0.83, 95% CI: 0.75, 0.93) and 9% (RR = 0.91, 95% CI: 0.84, 0.99) lower risk of T2D, respectively. Greater caffeinated coffee consumption was associated with lower fasting insulin and C-peptide concentrations (all P-trend <0.05). Decaffeinated coffee intake was not significantly related to T2D but was inversely associated with C-peptide concentrations (P-trend = 0.003).. Among predominantly Caucasian females with a history of GDM, greater consumption of caffeinated coffee was associated with a lower risk of T2D and a more favorable metabolic profile.

Topics: Biomarkers; C-Peptide; Coffee; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Pregnancy; Prospective Studies; Risk Factors; Sweetening Agents

This study aims to investigate the effect of single urine C peptide/creatinine (UCPCR) in assessing the islet β Cell function of type 2 diabetes mellitus (T2DM) patients with different renal function.. A total of 85 T2DM patients were recruited in this study, all the patients were assigned to one group with estimated glomerular filtration rate (eGFR)≤60 ml·min. UCPCR can be used to evaluate islets β Cell function in T2DM patients with different renal function status.

Topics: C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Kidney

While there is an emerging role of pancreatic fat in the aetiology of type 2 diabetes mellitus (T2DM), its impact on the associated decrease in insulin secretion remains controversial. We aimed to determine whether pancreatic fat negatively affects β-cell function and insulin secretion in women with overweight or obesity but without T2DM.. 20 women, with normo- or dysglycaemia based on fasting plasma glucose levels, and low (< 4.5%) vs high (≥ 4.5%) magnetic resonance (MR) quantified pancreatic fat, completed a 1-hr intravenous glucose tolerance test (ivGTT) which included two consecutive 30-min square-wave steps of hyperglycaemia generated by using 25% dextrose. Plasma glucose, insulin and C-peptide were measured, and insulin secretion rate (ISR) calculated using regularisation deconvolution method from C-peptide kinetics. Repeated measures linear mixed models, adjusted for ethnicity and baseline analyte concentrations, were used to compare changes during the ivGTT between high and low percentage pancreatic fat (PPF) groups.. No ethnic differences in anthropomorphic variables, body composition, visceral adipose tissue (MR-VAT) or PPF were measured and hence data were combined. Nine women (47%) were identified as having high PPF values. PPF was significantly associated with baseline C-peptide (p = 0.04) and ISR (p = 0.04) in all. During the 1-hr ivGTT, plasma glucose (p<0.0001), insulin (p<0.0001) and ISR (p = 0.02) increased significantly from baseline in both high and low PPF groups but did not differ between the two groups at any given time during the test (PPF x time, p > 0.05). Notably, the incremental areas under the curves for both first and second phase ISR were 0.04 units lower in the high than low PPF groups, but this was not significant (p > 0.05).. In women with overweight or obesity but without T2DM, PPF did not modify β-cell function as determined by ivGTT-assessed ISR. However, the salient feature in biphasic insulin secretion in those with ≥4.5% PPF may be of clinical importance, particularly in early stages of dysglycaemia may warrant further investigation.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Insulin Secretion; Obesity; Overweight

Type 2 diabetes mellitus (T2DM) is a metabolic disorder due to defects in insulin secretion or insulin resistance leading to the dysfunction and damage of various organs. To improve the clinical evaluation of short-term blood glycemic variability monitoring, it is critical to identify another blood cell status and nutritional status biomarker that is less susceptible to interference. This study identifies the significance of serum lactate dehydrogenase (LDH) level among T2DM patients treated in outpatient clinics and investigates the relationship of LDH level with other variables.. This study comprised 72 outpatients with T2DM over 20 years of age. Blood samples were collected followed by a hematological analysis of serum glycated albumin (GA), LDH, fasting blood glucose, glycosylated hemoglobin, C-peptide, and insulin antibodies (insulin Ab).. In conclusion, we suggested that LDH level was independent of long-term but associated with short-term blood glucose monitoring. The results indicated that changes in serum GA induced cell damage and the abnormal elevation of the serum level of LDH may occur simultaneously with glycemic variability. It has been reported that many biomarkers are being used to observe glucose variability in T2DM. However, LDH could provide a more convenient and faster evaluation of glycemic variability in T2DM.

Topics: Adult; Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Lactate Dehydrogenases; Serum Albumin; Thyrotropin

Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A

Topics: C-Peptide; Cohort Studies; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Hemoglobin A; Humans; Liver Neoplasms; Male

T2DM (Type 2 diabetes mellitus) is considered a disease that affects old age group. Recently, it has become common in children, adolescents and adults. Aim of the work - to highlight the challenges in differentiating T1DM (type1 diabetes mellitus) from T2DM (type2 diabetes mellitus) in early onset diabetes in youth depending on clinical and laboratory characteristics. Our cross-sectional study was performed on 200 newly diagnosed diabetic patients aged (18-30) years. All patients were subjected to detailed medical history and full clinical examination. Laboratory investigations included FBS, 2hPP, HbA1C, fasting C peptide and GADA. About 59% (118) of our patients were T2DM while (82) 41% were T1DM. T1DM was more dominant than T2DM in age group less than 25 years (T1DM 79% versus T2DM 21%, P<0.001), while T2DM was more than T1DM in age group more than 25 years (T2DM 93% versus T1DM 17%, P<0.001). GADA was detected in 73.2% of T1DM patient and it was high titer while GADA was detected in only 8% of T2DM with low titer, in addition GADA positive patients were significantly younger than negative patients, age (20.9±2.5 years vs. 26.4±3.5 years respectively) (P <0.001). About 8% of phenotypically type 2 diabetic youth had GADA positive antibodies which did not confer impact on c peptide level or glycemic control yet type 1 diabetics who were GADA negative had a better glycemic control.

Topics: Adolescent; Autoantibodies; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Egypt; Hepacivirus; Humans; Young Adult

Type 2 diabetes mellitus is a heterogeneous disease. Recently introduced new subclassifications promise more efficacious, tailored treatments which could complement current guidelines. In the differentiation of the new diabetes subphenotypes, assessment of insulin secretion is one of the essential components. Based on a large number of insulin secretion measurements, we propose fasting C-peptide/glucose ratio (CGR) as an adequate and practicable estimate of insulin secretion. CGR discriminates insulin deficiency from insulin hypersecretion. We suggest using insulin secretion, determined from CGR, as an essential input for therapeutic decisions at the beginning or modification of diabetes treatment. Furthermore, we propose 3 practical steps to guide decisions in the subtype-specific therapy of diabetes mellitus. The first step consists of detecting insulin deficiency indicated by a low CGR with the need for immediate insulin therapy. The second step is related to high CGR and aims at lowering cardiovascular risk associated with diabetes. The third step is the consideration of a de-escalation of glucose-lowering therapy in individuals with mild diabetes subphenotypes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glucose; Humans; Insulin; Insulin Secretion

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans

C-peptide is co-secreted with insulin and is not subject to hepatic clearance and thus reflects functional β-cell mass. Assessment of C-peptide levels can identify individuals at risk for or with type 1 diabetes with residual β-cell function in whom β cell-sparing interventions can be evaluated, and can aid in distinguishing type 2 diabetes from Latent Autoimmune Diabetes in Adults and late-onset type 1 diabetes. To facilitate C-peptide testing, we describe a quantitative point-of-care C-peptide test. C-peptide levels as low as 0.2 ng/ml were measurable in a fingerstick sample, and the test was accurate over a range of 0.17 to 12.0 ng/ml. This test exhibited a correlation of

Topics: Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Humans; Point-of-Care Testing

Nitrite stimulates insulin secretion from pancreatic β-cells; however, the underlying mechanisms have not been completely addressed. The aim of this study is to determine effect of nitrite on gene expression of SNARE proteins involved in insulin secretion from isolated pancreatic islets in Type 2 diabetic Wistar rats.. Three groups of rats were studied (n = 10/group): Control, diabetes, and diabetes + nitrite, which treated with sodium nitrite (50 mg/L) for 8 weeks. Type 2 diabetes was induced using a low-dose of streptozotocin (25 mg/kg) combined with high-fat diet. At the end of the study, pancreatic islets were isolated and mRNA expressions of interested genes were measured; in addition, protein expression of proinsulin and C-peptide in pancreatic tissue was assessed using immunofluorescence staining.. Compared with controls, in the isolated pancreatic islets of Type 2 diabetic rats, mRNA expression of glucokinase (59%), syntaxin1A (49%), SNAP25 (70%), Munc18b (48%), insulin1 (56%), and insulin2 (52%) as well as protein expression of proinsulin and C-peptide were lower. In diabetic rats, nitrite administration significantly increased gene expression of glucokinase, synaptotagmin III, syntaxin1A, SNAP25, Munc18b, and insulin genes as well as increased protein expression of proinsulin and C-peptide.. Stimulatory effect of nitrite on insulin secretion in Type 2 diabetic rats is at least in part due to increased gene expression of molecules involved in glucose sensing (glucokinase), calcium sensing (synaptotagmin III), and exocytosis of insulin vesicles (syntaxin1A, SNAP25, and Munc18b) as well as increased expression of insulin genes.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gene Expression; Glucokinase; Glucose; Humans; Insulin Secretion; Islets of Langerhans; Male; Nitrites; Proinsulin; Rats; Rats, Wistar; RNA, Messenger; Synaptotagmins

BACKGROUND We designed this study to develop and validate a prevalence model for latent autoimmune diabetes in adults (LADA) among people initially diagnosed with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The study recruited 930 patients aged ≥18 years who were diagnosed with T2DM within the past year. Demographic information, medical history, and clinical biochemistry records were collected. Logistic regression was used to develop a regression model to distinguish LADA from T2DM. Predictors of LADA were identified in a subgroup of patients (n=632) by univariate logistic regression analysis. From this we developed a prediction model using multivariate logistic regression analysis and tested its sensitivity and specificity among the remaining patients (n=298). RESULTS Among 930 recruited patients, 880 had T2DM (96.4%) and 50 had LADA (5.4%). Compared to T2DM patients, LADA patients had fewer surviving b cells and reduced insulin production. We identified age, ketosis, history of tobacco smoking, 1-hour plasma glucose (1hPG-AUC), and 2-hour C-peptide (2hCP-AUC) as the main predictive factors for LADA (P<0.05). Based on this, we developed a multivariable logistic regression model: Y=-8.249-0.035(X1)+1.755(X2)+1.008(X3)+0.321(X4)-0.126(X5), where Y is diabetes status (0=T2DM, 1=LADA), X1 is age, X2 is ketosis (1=no, 2=yes), X3 is history of tobacco smoking (1=no, 2=yes), X4 is 1hPG-AUC, and X5 is 2hCP-AUC. The model has high sensitivity (78.57%) and selectivity (67.96%). CONCLUSIONS This model can be applied to people newly diagnosed with T2DM. When Y ≥0.0472, total autoantibody screening is recommended to assess LADA.

Topics: Adult; Age Factors; Aged; Blood Glucose; C-Peptide; China; Diabetes Mellitus, Type 2; Female; Humans; Ketosis; Latent Autoimmune Diabetes in Adults; Male; Middle Aged; Prevalence; Reproducibility of Results; Sensitivity and Specificity; Tobacco Smoking; Young Adult

Melatonin (Mel) and its receptors are promising for glycaemic control in patients with type 2 diabetes mellitus (T2DM) and its complications, but there is significant heterogeneity among studies. This study aims to investigate the effects of Mel receptor agonist Neu-P11 on glucose metabolism, immunity, and islet function in T2DM rats.. In this study, SD rats were treated with a high-fat diet and streptozotocin (STZ) to establish a T2DM model. The glucose oxidase method was used to measure blood glucose levels. Glucose and insulin tolerance tests were used to assess glucose metabolism. Haematoxylin-eosin staining was used to observe pancreatic tissue injury. The apoptosis of isletβ cells was analysed by TUNEL and insulin staining. Reactive oxygen species (ROS) levels and immune cell expression were analysed by flow cytometry. IF was used to analyse the activation of microglia. The immunoglobulins: IgA, IgG, IgM, tumour necrosis factorα (TNF-α), interleukins IL-10 and IL-1β, interferonγ (IFN-γ), C-peptide, and insulin levels were determined by ELISA. The expression of CD11b, CD86, cleaved caspase 3, p21, and P16 proteins were analysed by western blot.. The results showed that the blood glucose level increased, insulin resistance occurred, spleen coefficient and ROS levels increased, humoral immunity in peripheral blood decreased, and inflammation increased in the model group compared to the control group. After Mel and Neu-P11 treatment, the blood glucose level decreased significantly, insulin sensitivity improved, spleen coefficient and ROS levels decreased, humoral immunity in peripheral blood was enhanced, and inflammation improved in T2DM rats. Brain functional analysis of T2DM rats showed that microglia cells were activated, TNF-α and IL-β levels were increased, and IL-10 levels were decreased. Mel and Neu-P11 treatment reversed these indexes. Functional analysis of islets in T2DM rats showed that islet structure inflammation was impaired, isletβ cells were apoptotic, p21 and p16 protein expressions were increased, and blood C-peptide and insulin were decreased. Mel and Neu-P11 treatment restored the function of pancreatic b cells and improved the damage of pancreatic tissue.. Melatonin and its receptor Neu-P11 can reduce the blood glucose level, enhance humoral and cellular immunity, inhibit microglia activation and inflammation, and repair isletβ cell function, and this improve the characterization of T2DM-related diseases.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Glycemic Control; Indoles; Insulin Resistance; Melatonin; Pyrans; Rats; Rats, Sprague-Dawley; Receptors, Melatonin; Streptozocin

Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccines against it could represent new environmental triggers for AIED. We report a patient, with history of vitiligo vulgaris and 8 years of type 2 diabetes, who came to our institution because of fever, weight loss, asthenia and thyrotoxicosis occurred 4 weeks later the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Clinical, biochemical and instrumental work-up demonstrated Graves' disease and autoimmune diabetes mellitus. The occurrence of these disorders could be explained through different mechanism such as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), mRNA "self-adjuvant" effect, molecular mimicry between human and viral proteins and immune disruption from external stimuli. However further studies are needed to better understand the underlying pathogenesis of AIED following SARS-CoV-2 vaccine.

Topics: Adjuvants, Immunologic; Autoantibodies; BNT162 Vaccine; C-Peptide; COVID-19; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Glycemic Control; Graves Disease; Humans; Male; Middle Aged; Molecular Mimicry; SARS-CoV-2; Thyrotoxicosis; Vitiligo

Type 2 diabetes mellitus (T2DM) and obesity are alarmingly increasing in children and adolescents. Hence, predictors for early metabolic abnormalities in childhood are urgently needed. We investigated glucose tolerance in children and adolescents with obesity, markers of insulin sensitivity between males and females and the potential association between the parameters measured during an OGTT (glucose, insulin, c-peptide) and prediabetes or stages of puberty.. Glucose tolerance in 89 children and adolescents with excess weight, aged 4-19 years, from Western Greece was studied. A 3-hour OGTT was performed and fasting glucose (FG), fasting insulin (FI), 1/FI, FG/FI, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Quantitative insulin sensitivity check index (QUICKI), ISI Matsuda index and Insulinogenic index (IGI30), were also calculated.. No significant differences were observed in glucose values between males and females. Insulin and c-peptide concentrations were higher in the girls at several time points. FG/FI was significantly higher in the boys. Girls with obesity may be at higher risk for future insulin resistance.. Better surveillance of pubertal girls with obesity is crucial and can be achieved using additional information provided by an OGTT, since they appear to be at a higher risk for beta-cell exhaustion. During the OGTT, not only are the baseline and 2-hour glucose and insulin measurements useful for predicting future metabolic risks and development of T2DM in children and adolescents with obesity, but additional time measurements may also be helpful.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Greece; Humans; Insulin; Insulin Resistance; Male; Pediatric Obesity; Puberty; Risk Factors; Sex Factors; Time Factors; Young Adult

Decreased insulin sensitivity occurs early in type 2 diabetes (T2D). T2D is highly prevalent in the Middle East and North Africa regions. This study assessed the variations in insulin sensitivity in normal apparently healthy subjects and the levels of adiponectin, adipsin and inflammatory markers.. The subjects showed wide variations in the whole-body glucose disposal rate (M value) from 2 to 20 mg/kg/min and were divided into three groups: most responsive (M>12 mg/kg/min, n=17), least responsive (M≤6 mg/kg/min, n=14) and intermediate responsive (M=6.1-12 mg/kg/min, n=29). Insulin and C peptide responses to OGTT were highest among the least insulin sensitive group. Triglycerides, cholesterol, alanine transaminase (ALT) and albumin levels were higher in the least responsive group compared with the other groups. Among the inflammatory markers, C reactive protein (CRP) was highest in the least sensitivity group compared with the other groups; however, there were no differences in the level of soluble receptor for advanced glycation end products and Tumor Necrosis Factor Receptor Superfamily 1B (TNFRS1B). Plasma levels of insulin sensitivity markers, adiponectin and adipsin, and oxidative stress markers, oxidized low-density lipoprotein, total antioxidant capacity and glutathione peroxidase 1, were similar between the groups.. A wide range in insulin sensitivity and significant differences in triglycerides, cholesterol, ALT and CRP concentrations were observed despite the fact that the study subjects were homogenous in terms of age, gender and ethnic background, and all had normal screening comprehensive chemistry and normal glucose response to OGTT. The striking differences in insulin sensitivity reflect differences in genetic predisposition and/or environmental exposure. The low insulin sensitivity status associated with increased insulin level may represent an early stage of metabolic abnormality.

Topics: Arabs; C-Peptide; Diabetes Mellitus, Type 2; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Male

Low C-peptide levels, indicating beta-cell dysfunction, are associated with increased within-day glucose variation and hypoglycemia. In advanced type 2 diabetes, severe hypoglycemia and increased glucose variation predict cardiovascular (CVD) risk. The present study examined the association between C-peptide levels and CVD risk and whether it can be explained by visit-to-visit glucose variation and severe hypoglycemia.. Fasting C-peptide levels at baseline, composite CVD outcome, severe hypoglycemia, and visit-to-visit fasting glucose coefficient of variation (CV) and average real variability (ARV) were assessed in 1565 Veterans Affairs Diabetes Trial participants.. There was a U-shaped relationship between C-peptide and CVD risk with increased risk with declining levels in the low range (< 0.50 nmol/l, HR 1.30 [95%CI 1.05-1.60], p = 0.02) and with rising levels in the high range (> 1.23 nmol/l, 1.27 [1.00-1.63], p = 0.05). C-peptide levels were inversely associated with the risk of severe hypoglycemia (OR 0.68 [0.60-0.77]) and visit-to-visit glucose variation (CV, standardized beta-estimate - 0.12 [SE 0.01]; ARV, - 0.10 [0.01]) (p < 0.0001 all). The association of low C-peptide levels with CVD risk was independent of cardiometabolic risk factors (1.48 [1.17-1.87, p = 0.001) and remained associated with CVD when tested in the same model with severe hypoglycemia and glucose CV.. Low C-peptide levels were associated with increased CVD risk in advanced type 2 diabetes. The association was independent of increases in glucose variation or severe hypoglycemia. C-peptide levels may predict future glucose control patterns and CVD risk, and identify phenotypes influencing clinical decision making in advanced type 2 diabetes.

Topics: Aged; Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fasting; Female; Glycemic Control; Heart Disease Risk Factors; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Time Factors; United States; United States Department of Veterans Affairs

The relationship between glycaemia and lipoprotein metabolism has not been completely clarified, and slight differences may be found between local authors, trials and evaluated parameters. Therefore this cross-sectional study investigated fasting cholesterol and glucose levels along with the determination of atherogenic index in a cohort of healthy individuals from the Czech Republic in relation to their fasting C-peptide levels. Data were collected between 2009 and 2018 and a total of 3189 individuals were stratified by C-peptide reference range (260-1730 pmol/l) into three groups - below (n = 111), within (n = 2952) and above (n = 126). Total, HDL, LDL cholesterol and atherogenic index were used to compare lipoprotein levels by relevant C-peptide concentrations. Participants using the supplements to affect lipid or glycaemia metabolism were excluded from this study. The evaluation of blood parameters in a fasting state included correlations between C-peptide and cholesterols, differences of variances (F-test) and the comparison of lipoprotein mean values (t-test) between the groups created by the C-peptide reference range. Mean values of total (4.9, 5.1, 5.3 mmol/l), LDL (2.6, 3.1, 3.4 mmol/l) cholesterol and atherogenic index (2.1, 2.8, 3.7) were higher with increasing C-peptide levels, whereas HDL was inversely associated with fasting C-peptide concentration. A positive and negative correlation between atherogenic index (rxy = 0.36) and HDL level (rxy = -0.36) with C-peptide values was found. Differences of HDL, LDL and atherogenic index were, in particular, recorded between the groups below and above the reference range of C-peptide (p ≤ 0.001). Considerable differences (p ≤ 0.001) were also observed for the same lipoprotein characteristics between the groups above and within the C-peptide reference. Generally, the type of cholesterol is crucial for the evaluation of specific changes concerning the C-peptide range. Lipoprotein concentrations differ in relation to C-peptide - not only below and above the physiological range, but also inside and outside of it. Conclusions: Fasting levels of cholesterol, plasma glucose, and atherogenic index were strongly associated with fasting C-peptide levels in healthy individuals. Our data suggest that fasting C-peptide could serve as a biomarker for the early detection of metabolic syndrome and/or insulin resistance prior to the manifestation of type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Cross-Sectional Studies; Czech Republic; Diabetes Mellitus, Type 2; Fasting; Glucose; Humans; Lipoproteins

To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).. Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.. Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.

Topics: Aged; Body Mass Index; C-Peptide; Case-Control Studies; Causality; Diabetes Mellitus, Type 2; Educational Status; Female; Glycated Hemoglobin; Humans; Male; Mediation Analysis; Middle Aged; Obesity; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Risk Factors; Sex Factors; Smoking

Maturity-onset diabetes of the young (MODY) is often misdiagnosed as other types of diabetes because it is overlooked due to atypical clinical presentations. This study aims to reveal the clinical and laboratory clues and examine their compatibility with MODY genotypes.. Participants consisted of 230 children with atypical presentations for type1(T1DM) and type2 diabetes mellitus (T2DM). MODY-causing mutations were screened in the following genes:GCK-HNF1A-HNF4A-HNF1B-PDX1-NEUROD1-KLF11-CEL-PAX4-INS-BLK. Clinical and laboratory features were compared between children with MODY and children without MODY.. The most common reasons for MODY screening were as follows (n/%):low daily dose of insulin (DDI) requirement (122/53%), absence of beta-cell antibodies(58/25.3%), coincidental hyperglycemia(26/11.3%), family history of diabetes (12/5.2%), hypoglycemia/hyperglycemia episodes(7/3%), hyperglycemia related to steroids(3/1.4%) and renal glycosuria(2/0.8%). The markers with the most likelihood to distinguish MODY from T1DM were determined as follows: measurable C-peptide in follow-up, family history of early-onset diabetes and low DDI requirement (odds ratio:12.55, 5.53 and 3.43, respectively). The distribution of the most common causative genes in children with MODY(n = 24) is as follows (n/%):GCK(15/62.5%), HNF4A(7/29.1%), HNF1A(1/9.2%) and PDX1(1/9.2%).All children(n = 12) with GCK-MODY(MODY2) were screened for low DDI requirement, while beta-cell negativity was more common in HNF4A-MODY(MODY1).. The study shows that measurable C-peptide in follow-up, family history of early-onset diabetes, and low DDI are still remarkable clues to predict MODY in children with misdiagnosed T1DM. In addition, the most common mutations were found in the GCK and HNF4A genes. Among children misdiagnosed with T1DM, a low DDI requirement was found more frequently in MODY2, whereas beta-cell antibody negativity was more common in MODY1.. 背景/目的: 由于青少年发病的成人型糖尿病(MODY)的非典型临床表现，该病经常被忽略。这项研究旨在揭示临床和实验室线索，并分析其与MODY基因型的匹配度。 方法: 受试者由230名非典型表现为1型(T1DM)和2型糖尿病(T2DM)的儿童组成。在以下基因中筛选引起MODY的突变:GCK-HNF1A-HNF4A-HNF1BPDX1-NEUROD1-KLF11-CEL-PAX4-INS-BLK。研究比较MODY患儿和非MODY患儿的临床和实验室特征。 结果: 进行MODY筛查的最常见原因如下(n /%):每日低剂量胰岛素(DDI)需求量(122/53%)、无β细胞抗体(58 / 25.3%)、偶发高血糖(26 / 11.3%)、糖尿病家族史(12 / 5.2%)、低血糖/高血糖发作(7/3%)、与类固醇有关的高血糖症(3 / 1.4%)和肾性糖尿(2 / 0.8%)。最有可能作为MODY与T1DM区分的标志物如下:随访中可测量的C肽、早发型糖尿病家族病史和DDI低需求(比值比分别为:12.55、5.53和3.43)。 儿童中MODY(n = 24)最常见的致病基因分布如下(n /%):GCK(15 / 62.5%)、HNF4A(7 / 29.1%)、HNF1A(1 / 9.2%)和PDX1(1 / 9.2%)。我们对所有儿童(n = 12)的GCK-MODY(MODY2)都进行了低DDI需求筛查，而β细胞抗体阴性在HNF4A-MODY(MODY1)中更为常见。 结论: 该研究表明，可检测的C肽、早期发病的糖尿病家族史和低DDI仍然是预测误诊为T1DM的儿童MODY的重要线索。此外，在GCK和HNF4A基因中发现了最常见的突变。在被误诊为T1DM的儿童中，MODY2的DDI需求较低更常见，而在MODY1中β细胞抗体阴性的情况则更为普遍。.

Topics: Adolescent; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Germinal Center Kinases; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4; Humans; Infant; Male; Mutation

Dysimmunity plays a key role in diabetes, especially type 1 diabetes mellitus. Islet-specific autoantibodies (ISAs) have been used as diagnostic markers for different phenotypic classifications of diabetes. This study was aimed to explore the relationships between ISA titers and the clinical characteristics of diabetic patients.. A total of 509 diabetic patients admitted to Department of Endocrinology and Metabolism at the Affiliated Hospital of Nantong University were recruited. Anthropometric parameters, serum biochemical index, glycosylated hemoglobin, urinary microalbumin/creatinine ratio, ISAs, fat mass, and islet β-cell function were measured. Multiple linear regression analysis was performed to identify relationships between ISA titers and clinical characteristics.. Compared with autoantibody negative group, blood pressure, weight, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), visceral fat mass, fasting C-peptide (FCP), 120 minutes C-peptide (120minCP) and area under C-peptide curve (AUCCP) of patients in either autoantibody positive or glutamate decarboxylase antibody (GADA) positive group were lower. Body mass index (BMI), waist circumference, triglycerides (TGs), body fat mass of patients in either autoantibody positive group were lower than autoantibody negative group. GADA titer negatively correlated with TC, LDL-C, FCP, 120minCP, and AUCCP. The islet cell antibody and insulin autoantibody titers both negatively correlated with body weight, BMI, TC, TG, and LDL-C. After adjusting confounders, multiple linear regression analysis showed that LDL-C and FCP negatively correlated with GADA titer.. Diabetic patients with a high ISA titer, especially GADA titer, have worse islet β-cell function, but less abdominal obesity and fewer features of the metabolic syndrome.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Humans; Metabolic Syndrome

We aimed to investigate the significance of the C-peptide levels on a glucagon stimulation test (GST) conducted soon after diagnosis as a predictive marker for residual β-cell function over time in Japanese children with type 1 diabetes (TD1).. We retrospectively enrolled 65 Japanese children (25 male, 40 female; age <16 years) with new-onset TD1. A GST was conducted within 1 month of diagnosis, when glucose toxicity improved. One- to 2-h postprandial serum C-peptide values were measured at 0, 3, 6, 12, 24, 36, 60, and 120 months after diagnosis.. Receiver operating characteristic analysis showed that the cutoff values of peak serum C-peptide levels used to predict the complete destruction of β-cells at 3, 6, and 12 months after diagnosis were all 0.20 ng/mL (area under the curve [AUC] 0.867, 95% confidence interval [CI] 0.745-0.990; AUC 0.774, 95% CI 0.634-0.914; and AUC 0.804, 95% CI 0.695-0.914, respectively); the values at 24, 36, and 60 months were 0.69 ng/mL (AUC 0.828, 95% CI 0.721-0.936), 0.60 ng/mL (AUC 0.777, 95% CI 0.636-0.918), and 0.70 ng/mL (AUC 0.848, 95% CI 0.715-0.982), respectively. On multivariate analysis, peak serum C-peptide level on a GST, diabetic ketoacidosis, age, and HbA1c level at diagnosis were associated with residual β-cell function over time.. Peak serum C-peptide levels on a GST conducted soon after diagnosis in Japanese children with TD1 could predict the time to decrease in postprandial serum C-peptide values to < 0.20 ng/mL.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Infant, Newborn; Insulin; Insulin-Secreting Cells; Male; Retrospective Studies

To identify the coefficient of variation (CV) threshold for unstable glucose variability (GV) and hypoglycemia, and to characterize a patient population with unstable GV and hypoglycemia.. This was an observational study that enrolled 284 Japanese outpatients with type 2 diabetes who underwent continuous glucose monitoring. The C-peptide index (CPI = [(fasting serum C-peptide) / (plasma glucose)] × 100) was used as a marker of endogenous insulin secretion. The CV threshold between stable and unstable GV was defined as the upper limit of the CV distribution in the subgroup of patients who did not receive insulin nor insulin secretagogues (relatively stable GV subgroup, n = 104). The optimal CV range corresponding to time below target range ≥4% was determined for all patients using receiver operating characteristic curve analysis. Various characteristics of patients with unstable GV and hypoglycemia were extracted using multivariate logistic regression analysis.. The upper limit of the CV in the relatively stable GV subgroup was 40. The optimal CV range corresponding to time below target range ≥4% was also defined as CV ≥40 (area under the curve 0.85) for all patients. The CPI was an independent risk for CV ≥40 (odds ratio 0.17, 95% confidence interval 0.04-0.50, P < 0.01). The optimal cut-off point for CPI to predict a CV cut-off value of 40 was equivalent to 0.81 (area under the curve 0.80).. A CV of 40 discriminates unstable GV and hypoglycemia from stable GV in Japanese outpatients with type 2 diabetes. Impaired insulin secretion might affect the stability of GV.

Topics: Aged; Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Secretion; Logistic Models; Male; Middle Aged; Reference Values; Risk Assessment; Risk Factors; ROC Curve; Time Factors

Topics: Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Humans; Latent Autoimmune Diabetes in Adults

Recent studies have suggested C-X-C motif chemokine ligand 14 (CXCL14), secreted from adipose tissue, to play an important role in the pathogenesis of metabolic syndrome. However, the clinical significance of CXCL14 in humans has not been elucidated. This study aimed to assess correlations between serum CXCL14 levels and clinical parameters in patients with type 2 diabetes mellitus.. In total, 176 individuals with type 2 diabetes mellitus were recruited. Serum CXCL14 concentrations were determined by enzyme-linked immunosorbent assay. We examined the associations of serum CXCL14 levels with laboratory values, abdominal computed tomography image information, surrogate markers used for evaluating the pathological states of diabetes, obesity and atherosclerosis.. Serum CXCL14 levels correlated positively with body mass index, waist circumference, subcutaneous and visceral fat areas, and serum alanine transaminase, uric acid, total cholesterol, low-density lipoprotein cholesterol, triglycerides and C-peptide (CPR) levels. In contrast, CXCL14 levels correlated inversely with age, pulse wave velocity and serum adiponectin levels. Multiple linear regression analysis showed serum levels of CPR (β = 0.227, P = 0.038) and the fatty liver index (β = 0.205, P = 0.049) to be the only parameters showing independent statistically significant associations with serum CXCL14 levels.. Serum CXCL14 levels were independently associated with serum CPR and fatty liver index in patients with type 2 diabetes mellitus. In these patients, a high serum CPR concentration might reflect insulin resistance rather than β-cell function, because CXCL14 showed simple correlations with obesity-related parameters. Collectively, these data suggested that serum CXCL14 levels in type 2 diabetes patients might be useful predictors of elevated serum CPR and hepatic steatosis.

Topics: Adiponectin; Age Factors; Aged; Alanine Transaminase; Biomarkers; Body Mass Index; C-Peptide; Chemokines, CXC; Cholesterol; Diabetes Mellitus, Type 2; Fatty Liver; Female; Humans; Insulin Resistance; Intra-Abdominal Fat; Linear Models; Lipoproteins, LDL; Liver Function Tests; Male; Middle Aged; Obesity; Pulse Wave Analysis; Triglycerides; Uric Acid; Waist Circumference

To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration.. We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months.. At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13-0.58), Subgroup 3 (β = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months.. Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Latent Class Analysis; Male; Middle Aged; Risk Assessment

The aim of this study was to determine the impact of the routine use of serum C-peptide in an out-patient clinic setting on individuals with a clinician-diagnosis of type 1 diabetes.. In this single-centre study, individuals with type 1 diabetes of at least 3 years duration were offered random serum C-peptide testing at routine clinic review. A C-peptide ≥200 pmol/L prompted further evaluation of the individual using a diagnostic algorithm that included measurement of islet cell antibodies and genetic testing. Where appropriate, a trial of anti-diabetic co-therapies was considered.. Serum C-peptide testing was performed in 859 individuals (90% of the eligible cohort), of whom 114 (13.2%) had C-peptide ≥200 pmol/L. The cause of diabetes was reclassified in 58 individuals (6.8% of the tested cohort). The majority of reclassifications were to type 2 diabetes (44 individuals; 5.1%), with a smaller proportion of monogenic diabetes (14 individuals; 1.6%). Overall, 13 individuals (1.5%) successfully discontinued insulin, while a further 16 individuals (1.9%) had improved glycaemic control following the addition of co-therapies. The estimated total cost of the testing programme was £23,262 (~€26,053), that is, £27 (~€30) per individual tested. In current terms, the cost of prior insulin therapy in the individuals with monogenic diabetes who successfully stopped insulin was approximately £57,000 (~€64,000).. Serum C-peptide testing can easily be incorporated into an out-patient clinic setting and could be a cost-effective intervention. C-peptide testing should be strongly considered in individuals with a clinician-diagnosis of type 1 diabetes of at least 3 years duration.

Topics: Adolescent; Adult; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Young Adult

PAX6 is a transcription factor involved in embryonic development of many organs, including the eyes and the pancreas. Mutations of PAX6 gene is the main cause of a rare disease, congenital aniridia (CA). This case-control study aims to investigate the effects of PAX6 mutations on glucose metabolism and insulin secretion in families with CA.. In all, 21 families with CA were screened by Sanger sequencing. Patients with PAX6 mutations and CA (cases) and age-matched healthy family members (controls) were enrolled. Oral glucose tolerance test (OGTT) was performed to detect diabetes or impaired glucose tolerance (IGT). Insulin and proinsulin secretion were evaluated.. Among 21 CA families, heterozygous PAX6 mutations were detected in five families. Among cases (n = 10) from the five families, two were diagnosed with newly identified diabetes and another two were diagnosed with IGT. Among controls (n = 12), two had IGT. The levels of haemoglobin A1c were 36 ± 4 mmol/mol (5.57 ± 0.46%) and 32 ± 5 mmol/L (5.21 ± 0.54%) in the cases and the controls, respectively (p = 0.049). More importantly, levels of proinsulin in the cases were significantly higher than that of the controls, despite similar levels of total insulin. The areas under the curve of proinsulin in the cases (6425 ± 4390) were significantly higher than that of the controls (3709 ± 1769) (p = 0.032).. PAX6 may participate in the production of proinsulin to insulin and heterozygous PAX6 mutations may be associated with glucose metabolism in CA patients.

Topics: Adult; Aniridia; C-Peptide; Case-Control Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glycated Hemoglobin; Heterozygote; Humans; Insulin; Male; Middle Aged; Mutation; PAX6 Transcription Factor; Proinsulin

We aimed at evaluating residual β-cell function in insulin-treated patients with type 2 diabetes (T2D) while determining for the first time the difference in C-peptide level between patients on basal-bolus compared to those on the basal insulin scheme, considered as an early stage of insulin treatment, together with assessing its correlation with the presence of complications.. A total of 93 candidates with T2D were enrolled in this cross-sectional study and were categorized into two groups based on the insulin regimen: Basal-Bolus (BB) if on both basal and rapid acting insulin, and Basal (B) if on basal insulin only, without rapid acting injections. HbA1c, fasting C-peptide concentration and other metabolic parameters were recorded, as well as the patient medical history.. The average fasting C-peptide was 1.81 ± 0.15 ng/mL, and its levels showed a significant inverse correlation with the duration of diabetes (r = -0.24, p = 0.03). Despite similar disease duration and metabolic control, BB participants displayed lower fasting C-peptide (p < 0.005) and higher fasting glucose (P = 0.01) compared with B patients. Concentrations below 1.09 ng/mL could predict the adoption of a basal-bolus treatment (Area 0.64, 95%CI:0.521-0.759, p = 0.038, sensitivity 45% and specificity 81%).. Insulin-treated patients with long-standing T2D showed detectable level of fasting C-peptide. Measuring the β-cell function may therefore guide toward effective therapeutic options when oral hypoglycemic agents prove unsuccessful.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Drug Dosage Calculations; Female; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Predictive Value of Tests; Prognosis; Treatment Outcome

The influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood.. We prospectively followed for cancer incidence 113 429 women in the Nurses' Health Study (1978-2014) and 45 604 men in the Health Professionals Follow-up Study (1988-2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records.. In the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1-6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1-8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1-10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years.. Incident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.

Topics: Adult; Aged; C-Peptide; Cohort Studies; Confidence Intervals; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Health Surveys; Humans; Incidence; Life Style; Male; Middle Aged; Neoplasms; Obesity; Proportional Hazards Models; Prospective Studies; Risk Factors; Time Factors; United States

To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression.. We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD.. Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 μmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant.. Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

Topics: Aged; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Inpatients; Insulin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Odds Ratio

Studies evaluating endocrine and exocrine functions in fibrocalculous pancreatic diabetes (FCPD) are scarce.. Insulin, C-peptide, glucagon, incretin hormones (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide [GIP]), and dipeptidyl peptidase IV (DPP-IV) were estimated in patients with FCPD (n = 20), type 2 diabetes mellitus (T2DM) (n = 20), and controls (n = 20) in fasting and 60 minutes after 75 g glucose.. Fasting and post-glucose C-peptide and insulin in FCPD were lower than that of T2DM and controls. Plasma glucagon decreased after glucose load in controls (3.72, 2.29), but increased in T2DM (4.01, 5.73), and remained unchanged in FCPD (3.44, 3.44). Active GLP-1 (pmol/L) after glucose load increased in FCPD (6.14 to 9.72, P = <.001), in T2DM (2.87 to 4.62, P < .001), and in controls (3.91 to 6.13, P < .001). Median active GLP-1 in FCPD, both in fasting and post-glucose state (6.14, 9.72), was twice that of T2DM (2.87, 4.62) and 1.5 times that of controls (3.91, 6.13) (P < .001 for all). Post-glucose GIP (pmol/L) increased in all: FCPD (15.83 to 94.14), T2DM (21.85 to 88.29), and control (13.00 to 74.65) (P < .001 for all). GIP was not different between groups. DPP-IV concentration (ng/mL) increased in controls (1578.54, 3012.00) and FCPD (1609.95, 1995.42), but not in T2DM (1204.50, 1939.50) (P = .131). DPP-IV between the three groups was not different. Fecal elastase was low in FCPD compared with T2DM controls.. In FCPD, basal C-peptide and glucagon are low, and glucagon does not increase after glucose load. GLP-1, but not GIP, in FCPD increases 1.5 to 2 times as compared with T2DM and controls (fasting and post glucose) without differences in DPP-IV.. 背景: 评价纤维结石性胰腺糖尿病(FCPD)内分泌和外分泌功能的研究很少。 方法: 测定FCPD组(n=20)、2型糖尿病(T2 DM)组(n=20)和对照组(n=20)空腹和75g葡萄糖后60min的胰岛素、C肽、胰高血糖素、肠泌素(胰高血糖素样肽1[GLP-1]和胃抑制肽[GIP])、二肽基肽酶IV(DPP-IV)水平。 结果: FCPD组空腹和糖负荷后C肽、胰岛素水平均低于T2 DM组和对照组。对照组糖负荷后胰高血糖素(pmol/L)降低(3.72; 2.29); T2 DM组升高(4.01; 5.73); FCPD组(3.44; 3.44)无明显变化。FCPD组(6.14~9.72; P=<0.001)、T2 DM组(2.87~4.62; P<0.001)和对照组(3.91~6.13; P<0.001)糖负荷后活性GLP-1(pmol/L)升高。FCPD组空腹和糖负荷后GLP-1(pmol/L)活性中位数(6.14; 9.72)是T2 DM组(2.87; 4.62)的两倍; 是对照组(3.91; 6.13)的1.5倍(P<0.001)。糖负荷后GIP(pmol/L)在所有组别中都升高:FCPD(15.83~94.14)、T2DM(21.85~88.29)、对照组(13.00~74.65), P<0.01。不同组间GIP差异无统计学意义。对照组(1578.54,3012.00)和FCPD组(1609.95,1995.42)的DPP-IV浓度(ng/mL)升高; 而T2 DM组(1204.50,1939.50)的DPP-IV浓度无明显变化(P=0.131)。DPP-IV于三组间差异无统计学意义。FCPD组中粪弹性蛋白酶低于T2 DM组对照组。 结论: FCPD患者糖负荷后基础C肽和胰高血糖素降低; 在糖负荷后胰高血糖素不升高。FCPD的GLP-1; 而不是GIP; 与T2 DM和对照组(空腹和糖负荷后)相比升高了1.5-2倍; 而DPP-IV没有差异.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Calcinosis; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Fibrosis; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic; Time Factors; Young Adult

We aimed to use data-driven glucose pattern analysis to unveil the correlation between the metrics reflecting glucose fluctuation and beta-cell function, and to identify the possible role of this metric in diabetes classification.. In total, 78 participants with type 1 diabetes and 59 with type 2 diabetes were enrolled in this study. All participants wore a flash glucose monitoring system, and glucose data were collected. A detrended fluctuation function (DFF) was utilized to extract glucose fluctuation information from flash glucose monitoring data and a DFF-based glucose fluctuation metric was proposed.. For the entire study population, a significant negative correlation between the DFF-based glucose fluctuation metric and fasting C-peptide was observed (r = -0.667; P <.001), which was larger than the correlation coefficient between the fasting C-peptide and mean amplitude of plasma glucose excursions (r = -0.639; P < .001), standard deviation (r = -0.649; P <.001), mean blood glucose (r = -0.519; P < .001) and time in range (r = 0.593; P < .001). As glucose data analysed by DFF revealed a clear bimodal distribution among the total participants, we randomly assigned the 137 participants into discovery cohorts (n = 100) and validation cohorts (n = 37) for 10 times to evaluate the consistency and effectiveness of the proposed metric for diabetes classification. The confidence interval for area under the curve according to the receiver operating characteristic analysis in the 10 discovery cohorts achieved (0.846, 0.868) and that for the 10 validation cohorts was (0.799, 0.862). In addition, the confidence intervals for sensitivity and specificity in the discovery cohorts were (75.5%, 83.0%), (81.3%, 88.5%) and (71.8%, 88.3%), (76.5%, 90.3%) in the validation cohorts, indicating the potential capacity of DFF in distinguishing type 1 and type 2 diabetes.. Our study first proposed the possible role of data-driven analysis acquired glucose metric in predicting beta-cell function and diabetes classification, and a large-scale, multicentre study will be needed in the future.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans

The fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β-cell health. However, its utility in discriminating between individuals with varying degrees of β-cell dysfunction is unclear. Proinsulin has a very different half-life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β-cell polypeptides (proinsulin, insulin and C-peptide) in people with normal and impaired glucose tolerance in differing metabolic environments.. Subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C-peptide ratios were calculated for the 0-, 30-, 60- and 240-minute time points. Insulin action (Si) and β-cell responsivity (Φ) indices were calculated using the oral minimal model.. The fasting proinsulin to c-peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β-cell responsivity to glucose during the glycerol or Intralipid study days in either group.. Among nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β-cell function.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Proinsulin

Controlling postprandial glucose levels in patients with type 1 diabetes is challenging even under the adequate treatment of insulin injection. Recent studies showed that dysregulated glucagon secretion exacerbates hyperglycemia in type 2 diabetes patients, but little is known in type 1 diabetes patients. We investigated whether the glucagon response to a meal ingestion could influence the postprandial glucose excursion in patients with type 1 diabetes.. We enrolled 34 patients with type 1 diabetes and 23 patients with type 2 diabetes as controls. All patients underwent a liquid mixed meal tolerance test. We measured levels of plasma glucose, C-peptide and glucagon at fasting (0 min), and 30, 60 and 120 min after meal ingestion. All type 1 diabetes patients received their usual basal insulin and two-thirds of the necessary dose of the premeal bolus insulin.. The levels of plasma glucagon were elevated and peaked 30 min after the mixed meal ingestion in both type 1 diabetes and type 2 diabetes patients. The glucagon increments from fasting to each time point (30, 60 and 120 min) in type 1 diabetes patients were comparable to those in type 2 diabetes patients. Among the type 1 diabetes patients, the glucagon response showed no differences between the subgroups based on diabetes duration (<5 vs ≥5 years) and fasting C-peptide levels (<0.10 vs ≥0.10 nmol/L). The changes in plasma glucose from fasting to 30 min were positively correlated with those in glucagon, but not C-peptide, irrespective of diabetes duration and fasting C-peptide levels in patients with type 1 diabetes.. The dysregulated glucagon likely contributes to postprandial hyperglycemia independent of the residual β-cell functions during the progression of type 1 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin-Secreting Cells; Male; Meals; Middle Aged; Prospective Studies

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans

Type 2 diabetes (T2D), the most common form of diabetes, is recognized as being a heterogenous disorder, and presents a universal threat to health. In T2D, the pathophysiology and phenotype differ significantly by ethnicity, particularly among Asian Indians, who are known to have the 'Asian Indian phenotype', which makes them more susceptible to develop T2D than white Caucasians. The recent subclassification of T2D into different subtypes or clusters, which behave differently with respect to clinical presentation and risk of developing complications is a remarkable development. Five unique "clusters" of individuals with diabetes were described in the Scandinavian population [Severe Autoimmune Diabetes (SAID), Severe Insulin Deficient Diabetes (SIDD), Severe Insulin Resistant Diabetes (SIRD), Mild Obesity-related Diabetes (MOD) and Mild Age-Related Diabetes (MARD)]. For the first time in India, identification of clusters of diabetes was done on 19,084 individuals with T2D, using 8 clinically relevant variables (age at diagnosis, BMI, waist circumference, HbA1c, triglycerides, HDL cholesterol and fasting and stimulated C-peptide). Four replicable clusters were identified [SIDD, MARD, IROD (Insulin Resistant Obese Diabetes) and CIRDD (Combined Insulin Resistant and Deficient Diabetes)], two of which were unique to the Indian population (IROD and CIRDD). Clustering of T2D helps i) to accurately subclassify diabetes into different subtypes, ii) plan therapies based on the pathophysiology, iii) predict prognosis and prevent diabetic complications and iv) helps in our approach to precision diabetes. Further studies would help us to refine the usefulness of these clusters of T2D particularly in the Indian population, with respect to selection of appropriate therapies and hopefully in the prevention of complications of diabetes.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; India; Insulin Resistance

We evaluated the utility of C peptide as an addition to the DiaRem score for predicting type 2 diabetes (T2D) remission 1 year after bariatric surgery in 175 patients. DiaRem score was significantly correlated with C peptide (r = - .43; p < .001). Both DiaRem and C peptide were significant predictors of remission of T2D (OR (95% CI) = .81 (.75-.86); p < 0001 and OR (95% CI) = 1.35 (1.15-1.60); p < .001, respectively). ROC analysis indicated that DiaRem was a significantly stronger predictor than C peptide (p < .001). Hierarchical regression indicated that C peptide failed to significantly improve the prediction of diabetes remission after accounting for DiaRem (OR (95% CI) = 1.079 (.87-1.26); p = .406). This study does not support the inclusion of C peptide in the DiaRem algorithm.

Topics: Algorithms; Bariatric Surgery; C-Peptide; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Obesity, Morbid; Remission Induction; Retrospective Studies; Treatment Outcome

Mesenchymal stem cells (MSCs) hold great potential in treating patients with diabetes, but the therapeutic effects are not always achieved. Particularly, the clinical factors regulating MSC therapy in this setting are largely unknown. In this study, 24 patients with type 2 diabetes mellitus (T2DM) treated with insulin were selected to receive three intravenous infusions of stem cells from human exfoliated deciduous teeth (SHED) over the course of 6 weeks and were followed up for 12 months. We observed a significant reduction of glycosylated serum albumin level (P < .05) and glycosylated hemoglobin level (P < .05) after SHED transplantation. The total effective rate was 86.36% and 68.18%, respectively, at the end of treatment and follow-up periods. Three patients ceased insulin injections after SHED transplantation. A steamed bread meal test showed that the serum levels of postprandial C-peptide at 2 hours were significantly higher than those at the baseline (P < .05). Further analysis showed that patients with a high level of blood cholesterol and a low baseline level of C-peptide had poor response to SHED transplantation. Some patients experienced a transient fever (11.11%), fatigue (4.17%), or rash (1.39%) after SHED transplantation, which were easily resolved. In summary, SHED infusion is a safe and effective therapy to improve glucose metabolism and islet function in patients with T2DM. Blood lipid levels and baseline islet function may serve as key factors contributing to the therapeutic outcome of MSC transplantation in patients with T2DM.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Insulin; Islets of Langerhans; Mesenchymal Stem Cell Transplantation; Stem Cells; Tooth, Deciduous

Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM.. Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration.. A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)].. Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gliclazide; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Proof of Concept Study

Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM).. This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes. A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-h oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-h glucose), measures of β-cell function and insulin sensitivity.. Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r - 0.22 to -0.35). Fasting and 2-h glucose were associated with early insulin and C-peptide responses (range: r - 0.37 to -0.40) as well as late insulin and total insulin and C-peptide responses (range: r - 0.50 to -0.60).. Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function. This Trial is registered in Clinicaltrials.gov as NCT01794143.

Topics: Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Metformin; Randomized Controlled Trials as Topic

Knowing the collective clinical factors that determine patient response to glucose-lowering medication would be beneficial in the treatment of type 2 diabetes. We carried out a retrospective cohort study to explore the combination of clinical factors involved in its therapeutic efficacy.. The results of cohort studies retrieved using the CoDiC. A logistic regression analysis showed that age at diagnosis, disease duration, hemoglobin A1c (HbA1c) and serum C-peptide reactivity (CPR) at medication commencement were associated with the probability of insulin treatment. Receiver operating characteristic curve showed that these clinical factors predicted insulin treatment positivity with an area under the curve of >0.600. The area under the curve increased to 0.674 and 0.720 for the disease duration-to-age at diagnosis ratio and HbA1c-to-CPR ratio, respectively. Furthermore, area under the curve increased to 0.727 and 0.750 in the indices (duration-to-age ratio at diagnosis × 43 + HbA1c) and (duration-to-age ration at diagnosis × 21 + HbA1c-to-CPR ratio), respectively. After stratification to three groups according to the indices, monthly HbA1c levels during 6 months of treatment were higher in the upper one-third than in the lower one-third of patients, and many patients did not achieve the target HbA1c level (53 mmol/mol) in the upper one-third, although greater than fourfold more patients were administered insulin in the upper one-third.. The combination of disease duration-to-age at diagnosis and HbA1c-to-CPR ratios is a collective risk factor that predicts response to the medications.

Topics: Age of Onset; Aged; Biomarkers, Pharmacological; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Japan; Logistic Models; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Risk Factors; ROC Curve; Time Factors

To explore the effects of glucose, insulin, and glycosylated hemoglobin (HbA1c) levels on the outcome of sarcopenia in patients with type 2 diabetes mellitus (T2DM).. A total of 482 T2DM patients were enrolled in the follow-up study. The median follow-up time was 36 months. Muscle mass and HbA1c were measured in all participants. And glucose, C-peptide and insulin levels were measured at 0 min, 30 min, and 120 min after glucose load. We subsequently analyzed daily glucose fluctuations and islet function before and after readmission as well as the influence of their changes on sarcopenia outcome.. After glucose load, incident sarcopenia patients showed greater glucose fluctuations and worse islet function than did non-sarcopenia patients. As HbA1c and standard deviation of blood glucose (SDBG) increased, readmitted non-sarcopenia patients showed a significantly increased odds ratio of incident sarcopenia; however, only patients with higher quartiles were statistically significant. Increased ΔAUC-C-peptide reduced the risk of incident sarcopenia (P < 0.05).. Patients with incident sarcopenia have poor glucose regulation and insufficient insulin secretion. Furthermore, as HbA1c and SDBG increased, AUC-C-peptide and AUC-insulin decreased in readmitted non-sarcopenia patients, the risk of incident sarcopenia increased.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Follow-Up Studies; Glycated Hemoglobin; Humans; Insulin; Sarcopenia

24-h average (IC) plasma concentrations of cortisol and growth hormone are lower in obese youth and adults without Type 2 diabetes (T2D) compared to lean subjects. Here we examined IC-cortisol and IC-growth hormone levels in obese youth with and without T2D.. We pooled ½-hourly samples from 20 to 24-hour sampling to create an IC for cortisol, cortisone, C-peptide, insulin, growth hormone and cortisol-binding-globulin in obese African-American youth with (n = 8) and without T2D (N = 9). Analytes were assayed by standard methods.. The groups were similar in age and sex, all participants had BMI% ≥94. T2D patients had slightly lower BMI z-score (2.25 ± 0.36 versus 2.58 ± 0.16, p = 0.0429). IC-cortisol (5.70 ± 1.8 μg/dl vs 4.18 ± 1.07 μg/dl, p = 0.0481) was higher and IC-C-peptide (2.33 ± 0.89 ng/ml vs 4.36 ± 1.12 ng/ml, p = 0.001) lower in T2D. There were no differences in cortisone/cortisol or for other analytes between groups. IC-cortisol was correlated with IC-cortisone (r = 0.46, p = 0.0471) but not with ICs of insulin, C-peptide, cortisol-binding-globulin, or growth hormone.. IC-cortisol levels are higher and IC-C-peptide lower in obese African-American youth with T2D. Higher levels of IC-cortisol in obese youth with T2D may indicate a change in hypothalamic-pituitary-adrenal regulation which may exacerbate hyperglycemia and other metabolic complications of obesity.

Topics: Adolescent; Black or African American; C-Peptide; Cortisone; Diabetes Mellitus, Type 2; Female; Globulins; Growth Hormone; Humans; Hydrocortisone; Insulin; Male; Obesity

In this study, we aimed to determine the frequency of and the clinical and metabolic features of patients with latent autoimmune diabetes in adults (LADA) at a single center in Turkey.. Patients over 30 years of age diagnosed with type 2 diabetes who did not require insulin for a minimum of 6 months following diagnosis were included. Data from 324 patients (163 women; 161 men), with a mean age of 54.97 ± 7.53 years, were analyzed in the study. Levels of antibodies to glutamate decarboxylase (anti-GAD) were measured in all patients, and LADA was diagnosed in patients testing positive for anti-GAD antibodies.. We observed a LADA frequency of 1.5% among Turkish patients followed for type 2 diabetes. The presence of obesity and metabolic syndrome did not exclude LADA, and patients with LADA had worse glycemic control than patients with type 2 diabetes did.

Topics: Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Infant; Latent Autoimmune Diabetes in Adults; Male; Middle Aged; Turkey

The urinary C-peptide/creatinine ratio (UCPCR) is low in patients with type 1 diabetes mellitus, but it has not been well characterized in patients with type 2 diabetes mellitus (T2DM). We aimed to measure the UCPCRs in patients with T2DM and explore the relationships among UCPCR, insulin resistance (IR), and chronic vascular complications of diabetes.. A cross-sectional study was performed of 1299 Chinese hospitalized patients with T2DM. Binary logistic regression was used to evaluate the relationships between the chronic vascular complications of diabetes and UCPCR. K-means analysis was used to allocate participants to subgroups with five to six variables (age at diagnosis, body mass index [BMI], glycosylated hemoglobin, homoeostasis model assessment 2-estimated beta-cell function (HOMA2-B), and HOMA2-insulin resistance (HOMA2-IR), with or without UCPCR).. UCPCR positively correlated with HOMA2-IR (r = 0.448, P < .001). After adjustment for sex, age, duration of diabetes, and other cardiovascular risk factors, UCPCR was positively associated with diabetic kidney disease (DKD) (odds ratio [OR] = 1.198, 95% CI 1.019-1.408, P = .029) and coronary heart disease (CHD) (OR = 1.312, 95% CI 1.079-1.594, P = .006). When UCPCR was added, cluster analysis using the six variables identified five subgroups of T2DM, characterized by differing age at diagnosis, BMI, beta-cell function, IR, and prevalence of vascular complications.. UCPCR is positively associated with IR, DKD, and CHD and represents a promising biomarker that could refine the classification of T2DM.. 背景: 1型糖尿病患者尿C肽/肌酐比值水平低。但尿C肽/肌酐比值在2型糖尿病患者中并没有被充分评估, 本研究拟测定2型糖尿病患者的尿C肽/肌酐比值水平, 探讨尿C肽/肌酐比值与胰岛素抵抗及糖尿病慢性血管并发症的相关性, 并评估尿C肽/肌酐比值改善2型糖尿病精准分型的可能性。 方法: 本研究共纳入北京大学人民医院内分泌科住院2型糖尿病患者1299名。采集所有患者的临床资料, 测定其空腹尿C肽/肌酐比, 通过二元Logistic回归分析尿C肽/肌酐比值与糖尿病血管并发症的相关性。并分别用传统的五个变量[诊断年龄, 体重指数, 糖化血红蛋白, 改良稳态模型计算的β细胞功能指数(HOMA2-B)及胰岛素抵抗指数(HOMR2-IR)]和加入尿C肽/肌酐比值后的六个变量, 通过相同的k-means聚类算法对2型糖尿病患者进行聚类分组, 比较不同亚组的临床特点。 结果: 尿C肽/肌酐比值与HOMA2-IR水平 (r=0.448, P<0.001)正相关。在调整了性别, 年龄, 病程及其他心血管疾病危险因素后, 尿C肽/肌酐比值水平与糖尿病肾病 [比值比(OR) =1.198, 95%CI (1.019, 1.408), P=0.029]及冠状动脉粥样硬化性心脏病的发生风险呈正相关 [OR=1.312, 95%CI (1.079, 1.594), P=0.006]。在五个传统临床变量基础上, 加入尿C肽/肌酐比值后再进行聚类分型, 可以清晰地将患者分为五组:两组具有早发糖尿病特征[早发胰岛素缺乏型糖尿病(n=350)和早发胰岛素抵抗型糖尿病(n=176)], 两组具有晚发糖尿病特征[晚发胰岛素缺乏型糖尿病(n=318)和晚发胰岛素抵抗型糖尿病(n=133)]及轻型糖尿病(n=299)。各组间诊断年龄, 体重指数, 胰岛β细胞功能, 胰岛素抵抗水平以及糖尿病血管并发症比例显著不同。 结论: 尿C肽/肌酐比值与胰岛素抵抗水平及糖尿病肾病, 冠状动脉粥样硬化性心脏病发生风险正相关。在传统临床变量基础上引入尿C肽/肌酐比值, 可以改善2型糖尿病的精准分型。.

Topics: Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Intolerance; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Prognosis

(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using

Topics: Adult; Amino Acids, Branched-Chain; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Humans; Insulin; Isoleucine; Leucine; Male; Middle Aged; Postprandial Period; Valine; Whey Proteins; Young Adult

Meal ingestion elicits a variety of neuronal, physiological and hormonal responses that differ in healthy, obese or diabetic individuals. The mixed meal tolerance test (MMTT) is a well-established method to evaluate pancreatic β-cell reserve and glucose homeostasis in both preclinical and clinical research in response to calorically defined meal. Nonhuman primates (NHPs) are highly valuable for diabetic research as they can naturally develop type 2 diabetes mellitus (T2DM) in a way similar to the onset and progression of human T2DM. The purpose of this study was to investigate the reproducibility and effects of a MMTT containing acetaminophen on plasma glucose, insulin, C-peptide, incretin hormones, lipids, acetaminophen appearance (a surrogate marker for gastric emptying) in 16 conscious obese cynomolgus monkeys (Macaca fascicularis). Plasma insulin, C-peptide, TG, aGLP-1, tGIP, PYY and acetaminophen significantly increased after meal/acetaminophen administration. A subsequent study in 6 animals showed that the changes of plasma glucose, insulin, C-peptide, lipids and acetaminophen were reproducible. There were no significant differences in responses to the MMTT among the obese NHPs with (n = 11) or without (n = 5) hyperglycemia. Our results demonstrate that mixed meal administration induces significant secretion of several incretins which are critical for maintaining glucose homeostasis. In addition, the responses to the MMTTs are reproducible in NHPs, which is important when the MMTT is used for evaluating post-meal glucose homeostasis in research.

Topics: Acetaminophen; Animal Feed; Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucose; Glucose Tolerance Test; Homeostasis; Incretins; Insulin; Insulin-Secreting Cells; Lipids; Macaca fascicularis; Male; Reproducibility of Results

Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic.. In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA. Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6-90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression.. Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance

Neonates at the highest and lowest percentiles of birth weight present an increased risk of developing metabolic diseases in adult life. While environmental events in utero may play an important role in this association, some genetic variants are associated both with birth weight and type 2 diabetes mellitus (T2DM), suggesting a genetic link between intrauterine growth and metabolism in adult life. Variants rs11708067 in ADCY5 and rs7754840 in CDKAL1 are associated with low birth weight, risk of T2DM, and lower insulin secretion in adults. We aimed to investigate whether, besides birth weight, these polymorphisms were related to insulin secretion at birth.. A cohort of 218 healthy term newborns from uncomplicated pregnancies were evaluated for anthropometric and biochemical variables. Cord blood insulin and C-peptide were analyzed by ELISA. Genotyping of rs11708067 in ADCY5 and rs7754840 in CDKAL1 was performed.. Newborns carrying the A allele of ADCY5 rs11708067 had lower cord blood insulin and C-peptide, even after adjusting by maternal glycemia, HbA1c, and pregestational BMI. Lower birth weight was found for AA-AG genotypes compared to GG, but no differences were seen in adjusted birth weight or z-score. Variant rs7754840 in CDKAL1 was not associated with birth weight, neonatal insulin, or C-peptide for any genotype or genetic model.. The variant rs11708067 in ADCY5 is associated with lower neonatal insulin and C-peptide concentrations. Our results suggest that the genetic influence on insulin secretion may be evident from birth, even in healthy newborns, independently of maternal glycemia and BMI.

Topics: Adenylyl Cyclases; Adult; Birth Weight; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Infant, Newborn; Insulin; Pregnancy; tRNA Methyltransferases

Patients with nonalcoholic fatty liver disease (NAFLD) are characterized by insulin resistance and hyperinsulinism. However, insulin resistance measurements have not been shown to be good diagnostic tools to predict NAFLD in prior studies.. We aimed to assess a newly validated method to measure intact molecules of insulin by mass spectrometry to predict NAFLD.. Patients underwent a 2-hour oral glucose tolerance test (OGTT), a liver magnetic resonance spectroscopy (1H-MRS), and a percutaneous liver biopsy if they had a diagnosis of NAFLD. Mass spectrometry was used to measure intact molecules of insulin and C-peptide.. A total of 180 patients were recruited (67% male; 52 ± 11 years of age; body mass index [BMI] 33.2 ± 5.7 kg/m2; 46% with diabetes and 65% with NAFLD). Intact fasting insulin was higher in patients with NAFLD, irrespective of diabetes status. Patients with NAFLD without diabetes showed ~4-fold increase in insulin secretion during the OGTT compared with all other subgroups (P = 0.008). Fasting intact insulin measurements predicted NAFLD in patients without diabetes (area under the receiver operating characteristic curve [AUC] of 0.90 [0.84-0.96]). This was significantly better than measuring insulin by radioimmunoassay (AUC 0.80 [0.71-0.89]; P = 0.007). Intact fasting insulin was better than other clinical variables (eg, aspartate transaminase, triglycerides, high-density lipoprotein, glucose, HbA1c, and BMI) to predict NAFLD. When combined with alanine transaminase (ALT) (intact insulin × ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and positive and negative predictive values of 93% and 88%, respectively. This newly described approach was significantly better than previously validated noninvasive scores such as NAFLD-LFS (P = 0.009), HSI (P < 0.001), and TyG index (P = 0.039).. In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and noninvasive strategy to predict presence of NAFLD.

Topics: Adult; Alanine Transaminase; Body Mass Index; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Middle Aged; Non-alcoholic Fatty Liver Disease; Reproducibility of Results

Evidence implicates tumor necrosis factor (TNF) in the pathophysiology of Type 2 Diabetes (T2D) through unclear mechanisms. We hypothesized that disordered glycemic control leads to TNF activation and increases in soluble-TNF (sTNF) and its receptors-1 (sTNFR1) and -2 (sTNFR2).. We characterized 265 T2D and non-diabetic Latin American subjects and assessed the relationship between the TNF system and fasting plasma glucose (FPG), hemoglobin-A1C (A1C), insulin (FPI), C-peptide and HOMA-Beta.. sTNF and sTNFR2 but not sTNFR1 levels were higher in T2D than non-diabetics (P<0.0001). In T2D, sTNFR2 was associated with A1C and C-peptide (R. Disordered glycemic control is associated with sTNF and sTNFR2. sTNFR2 levels were higher in T2D women than men. Thus, increased sTNFR2 levels may be an important biomarker for disordered glucose and inflammatory complications in T2D patients and women in particular.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycemic Control; Humans; Male; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha

The mixed meal tolerance test (MMTT) is a gold standard for evaluating beta-cell function. There is limited data on MMTT in monogenic diabetes (MD). Therefore, we aimed to analyze plasma C-peptide (CP) kinetics during MMTT in young MODY and neonatal diabetes patients as a biomarker for beta-cell function.. We included 41 patients with MD diagnosis (22 GCK, 8 HNF1A, 3 HNF4A, 4 KCNJ11, 2 ABCC8, 1 INS, 1 KLF11). Standardized 3-hour MMTT with glycemia and plasma CP measurements were performed for all individuals. Pancreatic beta-cell response was assessed by the area under the curve CP (AUC. A pretreatment challenge with MMTT might be used to guide the optimal treatment after molecular diagnosis of MD.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Kinetics; Meals

Chronic inflammation damaged the islet and resulted in dysfunction of T2D. Circular RNA is stable and better for biomarker in many diseases. Here, we aimed to identify potential circular RNA hsa_circ_0054633 that can be a biomarkers for the effects of insulin therapy in T2D.. In this retrospective case-control study, patients were from Li Huili Hospital, Ningbo, China, from February 10, 2019, to August 15, 2019. We included 47 healthy adults, 46 new-onset T2D with insulin resistance, and 51 patients with insulin therapy. Serum inflammation factors were tested by ELISA assays. We selected hsa_circ_0054633 as a candidate biomarker and measured its concentration in serum by qRT-PCR. The Pearson correlation test was used to evaluate the correlation between this circRNA and clinical variables.. Clinical data indicated that serum C peptide was increased in T2D treatment with insulin. Serum hsa_circ_0054633 was decreased in insulin treatment group. Hsa_circ_0054633 was negative correlated with C peptide (r = -0.2841, p = 0.0433,). IL-1 and IL-6, IL-17, and TNF-α were higher in T2D patients and decreased after insulin treatment, only IL-17 and TNF-α showed a positive correlation to hsa_circ_0054633 (r = 0.4825, p < 0.0001, and r = 0.6190, p < 0.0001). The area under ROC curve was 0.7432, 0.5839, and 0.7573 for Hsa_circ_0054633, C peptide, and their combination.. Hsa_circ_0054633 level was lower in T2D with insulin treatment than untreated and was a negative correlation with C peptide, and positively correlated with IL-17 and TNF-α, suggesting that hsa_circ_0054633 may be a potential early indicator of insulin treatment effect to improve inflammation condition.

Topics: Aged; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-1; Interleukin-17; Interleukin-6; Middle Aged; RNA, Circular; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Facies; Female; Histones; Humans; Intellectual Disability; Young Adult

We present a case of a 73-year-old woman who developed recurrent hypoglycaemia during a prolonged hospital stay following a mechanical fall. She had a complex history of insulin-treated diabetes mellitus, hypothyroidism, diffuse systemic cutaneous sclerosis, Raynaud's disease, previous breast cancer, Barrett's oesophagus and previous partial gastrectomy for a benign mass. Hypoglycaemia persisted despite weaning of insulin. She had no clinical features of adrenal or pituitary insufficiency with an acceptable cortisol on stopping prednisolone and had an optimal thyroid replacement. A 72-hour fast elicited hypoglycaemia with corresponding low insulin level. Although the C-peptide was detectable, there were no clinical, biochemical or radiological features suggestive of insulinoma. Reactive hypoglycaemia post partial gastrectomy was ruled out based on limited relation of the hypoglycaemia to meals and the low insulin levels. Hydroxychloroquine (HCQ)-induced hypoglycaemia was considered based on previous case reports and the recent literature, with a successful resolution of hypoglycaemia on discontinuation of HCQ.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Insulin; Pancreatic Neoplasms

To search for risk factors that could predict progression in latent autoimmune diabetes in adults (LADA) and compare them with those for type 2 diabetes.. This study included 175 participants with LADA (autoantibody positive, without insulin treatment ≥1 year after diagnosis) and 2331 participants with type 2 diabetes (autoantibody negative, without insulin treatment ≥1 year after diagnosis) from the HUNT2 and HUNT3 surveys. We used Cox regression models and receiver operating characteristic curve analysis to identify predictive factors for progression to insulin dependency within 10 years.. Low C-peptide levels (<0.3 nmol/L) predicted progression to insulin dependency within 10 years in both LADA (hazard ratio [HR] 6.40 [95% CI, 2.02-20.3]) and type 2 diabetes (HR 5.01 [95% CI, 3.53-7.10]). In addition, a high glutamic acid decarboxylase autoantibody (GADA) level (HR 5.37 [95% CI, 1.17-24.6]) predicted progression in LADA. Together, these two factors had a discriminatory power between non-progressors and progressors of area under the curve (AUC) of 0.86 (95% CI, 0.80-0.93). In type 2 diabetes, younger age at diagnosis (<50 years: HR 2.83 [95% CI, 1.56-5.15]; 50-69 years: HR 2.11 [95% CI, 1.19-3.74]), high HbA1c levels (≥53 mmol/mol, HR 2.44 [95% CI, 1.72-3.46]), central obesity (HR 1.65 [95% CI, 1.06-2.55]) and a body mass index of more than 30 kg/m. Factors predicting progression to insulin dependence are partly similar and partly dissimilar between LADA and type 2 diabetes. A constellation of low C-peptide and high GADA levels identifies LADA patients who are probable to progress to insulin dependence.

Topics: Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 2; Glutamate Decarboxylase; Humans; Insulin; Latent Autoimmune Diabetes in Adults

Several predictors of type 2 diabetes mellitus (T2DM) remission after metabolic surgery have been proposed and used to develop predictive scores. These scores may not be reproducible in diverse geographic regions with different baseline characteristics. This study aimed to identify predictive factors associated with T2DM remission after Roux-en-Y gastric bypass (RYGB) in patients with severe obesity. We hypothesized that the body composition alterations induced by bariatric surgery could also contribute to diabetes remission.. We retrospectively evaluated 100 patients with severe obesity and T2DM who underwent RYGB between 2014 and 2016 for preoperative factors (age, diabetes duration, insulin use, HbA1c, C-peptide plasma level, and basal insulinemia) to identify predictors of T2DM remission (glycemia<126 mg/dL and/or HbA1c<6.5%) at 3 years postoperatively. The potential preoperative predictors were prospectively applied to 20 other patients with obesity and T2DM who underwent RYGB for validation. In addition, 81 patients with severe obesity (33 with T2DM) underwent body composition evaluations by bioelectrical impedance analysis (InBody 770®) 1 year after RYGB for comparison of body composition changes between patients with and those without T2DM.. The retrospective analysis identified only a C-peptide level >3 ng/dL as a positive predictor of 3-year postoperative diabetes remission, which was validated in the prospective phase. There was a significant difference in the postoperative body composition changes between non-diabetic and diabetic patients only in trunk mass.. Preoperative C-peptide levels can be useful for predicting T2DM remission after RYGB. Trunk mass is the most important difference in postoperative body composition changes between non-diabetic and diabetic patients.

Topics: Body Composition; Body Mass Index; C-Peptide; Child, Preschool; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Obesity, Morbid; Prospective Studies; Remission Induction; Retrospective Studies; Treatment Outcome

Cluster analysis has identified distinct groups of type 2 diabetes (T2D) subjects with distinct metabolic characteristics. Thus, personalizing pharmacologic therapy to individual phenotypic and pathophysiologic characteristics has potential to improve metabolic control and reduce risk of microvascular and macrovascular complications.. The authors review the classification of T2D, genetic markers, pathophysiology and natural history of T2D, the ABCDE approach to therapy, the ADA/EASD stepwise approach to therapy, available antidiabetic agents, and provide a more rational therapeutic approach based upon pathophysiology and cardiovascular and renal outcome trials.. Although insulin resistance is the earliest detectable abnormality, overt T2D does not occur in the absence of progressive beta cell failure. Because of the complex etiology of T2D (Ominous Octet), initiation of therapy with combined agents that (i) target both insulin resistance and beta cell dysfunction and (ii) prevent macrovascular, as well as microvascular, complications will be required. The ratio of C-peptide at 120 minutes (OGTT) to baseline C-peptide predicts with high sensitivity who will respond to metformin, the response to glucose-lowering agents and provides a useful tool to guide optimal glucose lowering therapy.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells

Chemerin is an adipokine and a chemoattractant for leukocytes. Increased chemerin levels were observed in patients with coronary artery disease (CAD). We investigated associations between chemerin and biochemical measurements or body composition in CAD patients.. In the study, we included patients with stable CAD who had undergone percutaneous coronary intervention (PCI) in the past. All patients had routine blood tests, and their insulin and chemerin serum levels were routinely measured. Body composition was assessed with the DEXA method.. The study group comprised 163 patients (mean age 59.8 ± years, 26% of females, n = 43). There was no significant difference in serum chemerin concentrations between patients with diabetes and the remaining ones: 306.8 ± 121 vs. 274.15 ± 109 pg/mL,. In patients with CAD, serum chemerin levels are correlated with inflammation markers, insulin resistance, and an unfavorable lipid profile. Correlation with fat mass is dependent on glucose metabolism status. Depending on the presence of diabetes/prediabetes, the mechanisms regulating chemerin secretion may be different.

Topics: Aged; Blood Glucose; Blood Platelets; Body Composition; C-Peptide; C-Reactive Protein; Chemokines; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Inflammation; Insulin; Insulin Resistance; Lymphocytes; Male; Middle Aged; Neutrophils; Percutaneous Coronary Intervention; Pilot Projects; Triglycerides

To examine the relationship between baseline fasting C-peptide (FCP) and outcomes in insulin-naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla-100).. Post hoc pooled analysis of nine randomized, treat-to-target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once-daily Gla-100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40-1.20, >1.20-2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks.. At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla-100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c <7.0% versus FCP groups >0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla-100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia.. FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla-100. A low FCP identifies a markedly insulin-deficient, insulin-sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose-lowering therapy.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fasting; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine

To investigate the association between serum C-peptide level and cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes mellitus (DM) according to estimated glomerular filtration rate (eGFR) METHODS: In a cross-sectional study, we examined 939 individuals with type 2 DM. We measured fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) levels. The individuals were classified into 2 groups based on eGFR: individuals without impaired renal function (eGFR ≥60 ml∙min. Individuals with CAN had lower fasting C-peptide, postprandial C-peptide, and ΔC-peptide levels in patients both with and without impaired renal function. Multivariate logistic regression analyses adjusted for gender, age, and other confounders, including eGFR, showed that serum C-peptide level was significantly associated with CAN (odds ratio [OR] per standard deviation increase in the log-transformed value, 0.67; 95% confidence interval [CI], 0.52-0.87 for fasting C-peptide, P < 0.01; OR, 0.62; 95% CI, 0.47-0.83 for postprandial C-peptide, P < 0.01; OR, 0.71; 95% CI, 0.54-0.93 for ΔC-peptide, P < 0.05).. Serum C-peptide level was negatively associated with CAN in individuals with type 2 DM independent of eGFR.

Topics: Adult; Aged; Autonomic Nervous System; Autonomic Nervous System Diseases; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Risk Factors

The detection of glutamic acid decarboxylase 65 (GAD65) autoantibodies is essential for the prediction and diagnosis of latent autoimmune diabetes in adults (LADA). The aim of the current study was to compare a newly developed electrochemiluminescence (ECL)-GAD65 antibody assay with the established radiobinding assay, and to explore whether the new assay could be used to define LADA more precisely.. Serum samples were harvested from 141 patients with LADA, 95 with type 1 diabetes mellitus, and 99 with type 2 diabetes mellitus, and tested for GAD65 autoantibodies using both the radiobinding assay and ECL assay. A glutamic acid decarboxylase antibodies (GADA) competition assay was also performed to assess antibody affinity. Furthermore, the clinical features of these patients were compared.. Eighty-eight out of 141 serum samples (62.4%) from LADA patients were GAD65 antibody-positive by ECL assay. Compared with ECL-GAD65 antibody-negative patients, ECL-GAD65 antibody-positive patients were leaner (. Patients with ECL-GAD65 antibody-negative share a similar phenotype with type 2 diabetes mellitus patients, whereas patients with ECL-GAD65 antibody-positive resemble those with type 1 diabetes mellitus. Thus, the detection of GADA using ECL may help to identify the subtype of LADA.

Topics: Adolescent; Adult; Autoantibodies; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Islets of Langerhans; Latent Autoimmune Diabetes in Adults; Male; Middle Aged; Phenotype; Young Adult

Diabetic cardiomyopathy (DCM) is a nonischemic myocardial disorder characterized by metabolic disturbances and oxidative stress in diabetic patients. The present paper aims to determine the protective effect of the phlebotrophic drug, diosmin, on DCM in a model of high-fat diet-fed and streptozotocin-induced type 2 diabetes in the rat.. The animals were divided into 4 groups (8 rats/group) as follows: vehicle-treated nondiabetic control group, vehicle-treated diabetic group, diosmin (50 mg/kg)-treated diabetic group and diosmin (100 mg/kg)-treated diabetic group. Treatment was given once daily orally by gavage for 6 weeks. Oxidant and antioxidant stress markers, inflammatory markers and proapoptotic and antiapoptotic gene expression using quantified real-time polymerase chain reaction were investigated.. Diosmin treatment in diabetic rats lowered elevated blood glucose levels, homeostatic model assessment for insulin resistance, cardiac creatine kinase and lactate dehydrogenase enzymes, cardiac malondialdehyde and nitric oxide. Moreover, diosmin increased plasma insulin and c-peptide levels, cardiac glutathione content, superoxide dismutase, catalase and glutathione S-transferase activities. Also, diosmin treatment significantly (P < 0.05) lowered the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), down-regulated cardiac Bcl-2-associated X protein and caspase 3 and 9 and up-regulated B-cell lymphoma 2 mRNA expression levels.. Diosmin may have a sizeable therapeutic potential in the treatment of DCM due to antidiabetic, antioxidative stress, anti-inflammatory and antiapoptotic effects. Detailed studies are needed to disclose the precise mechanisms motivating the protective effect of diosmin‏.

Topics: Animals; Apoptosis; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diosmin; Dose-Response Relationship, Drug; Gene Expression Regulation; Homeostasis; Insulin; Insulin Resistance; Rats

The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China.. Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES.. Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels.. Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations.

Topics: Adolescent; C-Peptide; Child; Child, Preschool; China; Cohort Studies; Diabetes Mellitus, Type 2; DNA Mutational Analysis; Female; Genetic Testing; Glucokinase; Glycated Hemoglobin; Humans; Infant; Infant, Newborn; Insulin; Male; Molecular Diagnostic Techniques; Mutation

More and more studies focus on the relationship between the gastrointestinal microbiome and type 2 diabetes, but few of them have actually explored the relationship between enterotypes and type 2 diabetes.. Gut microbiota in type 2 diabetes group exhibited lower bacterial diversity compared with nondiabetic controls. The fecal communities from all subjects clustered into two enterotypes distinguished by the levels of. We identified two enterotypes,

Topics: Actinobacteria; Aged; Amine Oxidase (Copper-Containing); Bacteroides; Bacteroidetes; Biodiversity; Blood Glucose; C-Peptide; Case-Control Studies; Cholesterol, HDL; Diabetes Mellitus, Type 2; Female; Firmicutes; Fusobacteria; Gastrointestinal Microbiome; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lipopolysaccharides; Logistic Models; Male; Middle Aged; Pilot Projects; Postprandial Period; Prevotella; Proteobacteria; Risk Factors; RNA, Ribosomal, 16S; Triglycerides; Tumor Necrosis Factor-alpha; Verrucomicrobia

Circulating follistatin (Fst) binds activin A and thereby regulates biological functions such as muscle growth and β-cell survival. However, Fst and activin A's implication in metabolic regulation is unclear.. To investigate circulating Fst and activin A in obesity and type 2 diabetes (T2D) and determine their association with metabolic parameters. Further, to examine regulation of Fst and activin A by insulin and the influence of obesity and T2D hereon.. Plasma Fst and activin A levels were analyzed in obese T2D patients (N = 10) closely matched to glucose-tolerant lean (N = 12) and obese (N = 10) individuals in the fasted state and following a 4-h hyperinsulinemic-euglycemic clamp (40 mU·m-2·min-1) combined with indirect calorimetry.. Circulating Fst was ~30% higher in patients with T2D compared with both lean and obese nondiabetic individuals (P < .001), while plasma activin A was unaltered. In the total cohort, fasting plasma Fst correlated positively with fasting plasma glucose, serum insulin and C-peptide levels, homeostasis model assessment of insulin resistance, and hepatic and adipose tissue insulin resistance after adjusting for age, gender and group (all r > 0.47; P < .05). However, in the individual groups these correlations only achieved significance in patients with T2D (not plasma glucose). Acute hyperinsulinemia at euglycemia reduced circulating Fst by ~30% (P < .001) and this response was intact in patients with T2D. Insulin inhibited FST expression in human hepatocytes after 2 h and even further after 48 h.. Elevated circulating Fst, but not activin A, is strongly associated with measures of insulin resistance in patients with T2D. However, the ability of insulin to suppress circulating Fst is preserved in T2D.

Topics: Activins; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Follistatin; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity

The relationship between baseline fasting C-peptide (FCP) and glucose control was examined in insulin-naïve people with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs commencing basal insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) in the absence of sulfonylurea/glinides. Participants with FCP measurement from the EDITION 3 trial (n = 867) were stratified according to baseline FCP (≤0.40, >0.40-1.20, >1.20 nmol/L); 11.0%, 70.9% and 18.1% contributed to each group. Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 26 weeks. Glycaemic control (HbA1c, FPG) at 26 weeks was similar in each FCP group between insulins. However, end-of-study insulin dose was greater with higher FCP for both insulins. More people with lower baseline FCP experienced hypoglycaemia with both insulins, but with numerically lower incidence for Gla-300 versus Gla-100 across all FCP groups for all definitions (time periods and levels) of hypoglycaemia. This suggests that Gla-300 might be particularly advantageous for people who are at higher risk of hypoglycaemia.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fasting; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine

Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes. HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. However, hyperglycemia was suggested to enhance HIC, and it is not known whether poorly controlled diabetes increases HIC in patients with type 2 diabetes. We investigated whether HIC was increased in patients with poorly controlled diabetes, and whether HIC was associated with insulin resistance and incretins.. We performed a meal tolerance test and the hyperinsulinemic-euglycemic clamp in 21 patients with type 2 diabetes. We calculated the postprandial C-peptide area under the curve (AUC)-to-insulin AUC ratio as the HIC; measured fasting and postprandial glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon levels and analyzed serum adiponectin and zinc transporter-8 (ZnT8) gene polymorphism.. These results suggest that HIC was increased in patients with high HbA1c type 2 diabetes, low insulin secretion, low insulin resistance and high adiponectin conditions.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glycated Hemoglobin; Humans; Insulin

Diabetes is a growing epidemic worldwide and among our active duty population, posing a significant threat to maintaining military health and operational readiness. Latent autoimmune diabetes in adults (LADA) is a growing clinical phenotype of diabetes, with overlap between traditional type 1 diabetes mellitus and type 2 diabetes mellitus. In this case, a 27-year-old active duty male presented with polydipsia, polyuria, polyphagia, and recent weight loss. He was diagnosed with LADA, placed on a period of limited duty status and started on insulin. Eight months after diagnosis, he was transitioned from insulin to a glucagon-like peptide-1 receptor agonist in an effort to be returned to full duty status and worldwide deployable. Over 3 years after initial diagnosis, he has achieved partial clinical remission. He remains on active duty, serving on a medically limited platform with a single medication (a glucagon-like peptide-1 receptor agonist) and high compliance with a gluten-free, low-carbohydrate diet and regular exercise. One should consider the diagnosis of LADA and its unique management, especially in the younger active duty population. Not only is making the correct diagnosis regarding the type of diabetes critical in regard to prognosis and optimal medical management, but it can affect the ability of military members to remain on active duty.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Male; Military Personnel

The Disposition Index (DI) is widely used in clinical studies of β-cell function. However, direct physiologic interpretation of the DI value and the inverse exponential slope relating insulin secretion and insulin sensitivity terms is difficult. We evaluated a linearization of the relationship that allows separate evaluation of the DI term and the slope.. Insulin secretion and sensitivity indices were derived from standardized oral glucose tolerance testing, including commonly used terms and model-derived terms. The population included participants with normoglycemia, dysglycemia or Type 2 diabetes. Logarithmic transformation of the DI equation to linearize the secretion-sensitivity relationship was performed, and the resulting secretion-sensitivity relationships were evaluated using standard linear regression methods.. Simple logarithmic transformation linearized the secretion-sensitivity relationships available from a variety of OGTT-derived metrics. In normoglycemic subjects the slopes approximated -1 in insulin-basedsecretion-sensitivity pairs, and approximated -0.6 in C-peptide based secretion-sensitivity pairs. Group differences in DI terms were observed as expected. These analyses also revealed differing secretion-sensitivity slopes, with IGT and T2D demonstrating progressively impaired coupling.. Linearization of the secretion-sensitivity relationship provides simplified interpretation of the DI value and allows simple analysis and meaningful interpretation of the secretion-sensitivity slope. This linear relationship is amenable to standard statistical evaluations for comparisons of insulin secretion responses and of secretion-sensitivity coupling across groups.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance

Topics: Adult; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Prospective Studies

C-peptide is a reliable marker of beta cell reserve and is associated with diabetic complications. Furthermore, HbA1c level is associated with micro- and macro-vascular complications in diabetic patients. HbA1c measurement of diabetic patients with anemia may be misleading because HbA1c is calculated in percent by taking reference to hemoglobin measurements. We hypothesized that there may be a relationship between C-peptide index (CPI) and proteinuria in anemic patients with type 2 diabetes mellitus (T2DM). Therefore, the aim of the present study was to investigate the association between C-peptide levels and CPI in anemic patients with T2DM and proteinuria.. The patients over 18 years of age with T2DM whose C-peptide levels were analyzed in Endocrinology and Internal medicine clinics between 2014 and 2018 with normal kidney functions (GFR>60 ml/min) and who do not use any insulin secretagogue oral antidiabetic agent (i.e. sulfonylurea) were enrolled into the study.. Hemoglobin levels were present in 342 patients with T2DM. Among these 342 cases, 258 (75.4%) were non-anemic whereas 84 (24.6%) were anemic. The median DM duration of the anemic group was statistically significantly higher in T2DM (p=0.003). There was no statistically significant difference found in proteinuria prevalence between non-anemic and anemic patient groups (p=0.690 and p=0.748, respectively). Anemic T2DM cases were corrected according to the age, gender, and duration of DM. C-peptide and CPI levels were not statistically significant to predict proteinuria (p=0.449 and p=0.465, respectively).. The present study sheds light to the association between C-peptide, CPI, and anemic diabetic nephropathy in T2DM patients and indicates that further prospective studies are needed to clarify this issue.

Topics: Adult; Aged; Anemia; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Hemoglobins; Humans; Male; Middle Aged; Proteinuria; Retrospective Studies; Time Factors

Misclassification of diabetes is common due to an overlap in the clinical features of type 1 and type 2 diabetes. Combined diagnostic models incorporating clinical and biomarker information have recently been developed that can aid classification, but they have not been validated using pancreatic pathology. We evaluated a clinical diagnostic model against histologically defined type 1 diabetes.. We classified cases from the Network for Pancreatic Organ donors with Diabetes (nPOD) biobank as type 1 (n = 111) or non-type 1 (n = 42) diabetes using histopathology. Type 1 diabetes was defined by lobular loss of insulin-containing islets along with multiple insulin-deficient islets. We assessed the discriminative performance of previously described type 1 diabetes diagnostic models, based on clinical features (age at diagnosis, BMI) and biomarker data [autoantibodies, type 1 diabetes genetic risk score (T1D-GRS)], and singular features for identifying type 1 diabetes by the area under the curve of the receiver operator characteristic (AUC-ROC).. Diagnostic models validated well against histologically defined type 1 diabetes. The model combining clinical features, islet autoantibodies and T1D-GRS was strongly discriminative of type 1 diabetes, and performed better than clinical features alone (AUC-ROC 0.97 vs. 0.95; P = 0.03). Histological classification of type 1 diabetes was concordant with serum C-peptide [median < 17 pmol/l (limit of detection) vs. 1037 pmol/l in non-type 1 diabetes; P < 0.0001].. Our study provides robust histological evidence that a clinical diagnostic model, combining clinical features and biomarkers, could improve diabetes classification. Our study also provides reassurance that a C-peptide-based definition of type 1 diabetes is an appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible. Parts of this study were presented in abstract form at the Network for Pancreatic Organ Donors Conference, Florida, USA, 19-22 February 2019 and Diabetes UK Professional Conference, Liverpool, UK, 6-8 March 2019.

Topics: Adult; Age of Onset; Autoantibodies; Body Mass Index; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Genetic Predisposition to Disease; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Pancreas; Reproducibility of Results; Young Adult; Zinc Transporter 8

Type 2 diabetes (T2D) is characterized by islet β-cell dysfunction and impaired suppression of glucagon secretion of α-cells in response to oral hyperglycaemia. Bile acid (BA) metabolism plays a dominant role in maintaining glucose homeostasis. So we evaluated the association of fasting serum total bile acids (S-TBAs) with insulin sensitivity, islet β-cell function and glucagon levels in T2D. Total 2,952 T2D patients with fasting S-TBAs in the normal range were recruited and received oral glucose tolerance tests for determination of fasting and postchallenge glucose, C-peptide and glucagon. Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment (HOMA) and Matsuda index using C-peptide, i.e., IS

Topics: Adult; Bile Acids and Salts; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged

Clinical trials and animal studies have shown that sodium-glucose co-transporter type 2 (SGLT2) inhibitors improve pancreatic beta cell function. Our study aimed to investigate the effect of dapagliflozin on islet morphology and cell phenotype, and explore the origin and possible reason of the regenerated beta cells.. Two diabetic mouse models, db/db mice and pancreatic alpha cell lineage-tracing (glucagon-β-gal) mice whose diabetes was induced by high fat diet combined with streptozotocin, were used. Mice were treated by daily intragastric administration of dapagliflozin (1 mg/kg) or vehicle for 6 weeks. The plasma insulin, glucagon and glucagon-like peptide-1 (GLP-1) were determined by using ELISA. The evaluation of islet morphology and cell phenotype was performed with immunofluorescence. Primary rodent islets and αTC1.9, a mouse alpha cell line, were incubated with dapagliflozin (0.25-25 μmol/L) or vehicle in the presence or absence of GLP-1 receptor antagonist for 24 h in regular or high glucose medium. The expression of specific markers and hormone levels were determined.. Treatment with dapagliflozin significantly decreased blood glucose in the two diabetic models and upregulated plasma insulin and GLP-1 levels in db/db mice. The dapagliflozin treatment increased islet and beta cell numbers in the two diabetic mice. The beta cell proliferation as indicated by C-peptide and BrdU double-positive cells was boosted by dapagliflozin. The alpha to beta cell conversion, as evaluated by glucagon and insulin double-positive cells and confirmed by using alpha cell lineage-tracing, was facilitated by dapagliflozin. After the dapagliflozin treatment, some insulin-positive cells were located in the duct compartment or even co-localized with duct cell markers, suggestive of duct-derived beta cell neogenesis. In cultured primary rodent islets and αTC1.9 cells, dapagliflozin upregulated the expression of pancreatic endocrine progenitor and beta cell specific markers (including Pdx1) under high glucose condition. Moreover, dapagliflozin upregulated the expression of Pcsk1 (which encodes prohormone convertase 1/3, an important enzyme for processing proglucagon to GLP-1), and increased GLP-1 content and secretion in αTC1.9 cells. Importantly, the dapagliflozin-induced upregulation of Pdx1 expression was attenuated by GLP-1 receptor antagonist.. Except for glucose-lowering effect, dapagliflozin has extra protective effects on beta cells in type 2 diabetes. Dapagliflozin enhances beta cell self-replication, induces alpha to beta cell conversion, and promotes duct-derived beta cell neogenesis. The promoting effects of dapagliflozin on beta cell regeneration may be partially mediated via GLP-1 secreted from alpha cells.

Topics: Animals; Benzhydryl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Endocrine Cells; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Glucose; Glucosides; Insulin; Insulin-Secreting Cells; Male; Mice; Proprotein Convertase 1; Regeneration; Sodium-Glucose Transporter 2 Inhibitors

In view of the association of Ramadan intermittent fasting with profound changes in lifestyle both in nondiabetic and diabetic patients, the aim of this study was to investigate the effect of Ramadan fasting on adiponectin, leptin and leptin to adiponectin ratio (LAR), growth hormone (GH), human-sensitive C-reactive protein (hs-CRP), and diabetic and metabolic syndrome factors in patients with Type 2 Diabetes Mellitus (Type 2 DM), their first-degree relatives (FDRs), and healthy controls.. This cohort study involved 98 Yemeni male subjects aged 30-70 years old: 30 Type 2 DM, 37 FDRs of Type 2 diabetic patients, and 31 healthy control subjects. Subjects' body mass index (BMI), waist circumference (WC), and blood pressure (BP) were measured, and venous blood samples were collected twice: the first samples were collected a couple of days prior to Ramadan fasting (baseline) and the second samples after 3 weeks of fasting.. Ramadan fasting did not affect BMI, WC, and BP in Type 2 DM and their FDRs with respect to the baseline levels prior to Ramadan, whereas triglyceride and cholesterol were borderline significantly decreased in Type 2 DM with no effect in FDRs. Fasting blood glucose was not affected in Type 2 DM but was significantly increased in FDRs and control groups, whereas glycated haemoglobin (HbA1c) was slightly decreased in Type 2 DM, FDRs, and healthy controls. C-peptide, insulin, and insulin resistance (HOMA-IR) were significantly increased in Type 2 DM and FDRs, with no effect in the control group, whereas. Ramadan intermittent fasting decreased adiponectin and increased leptin, LAR, insulin, and insulin resistance in both Type 2 DM and FDRs as well as decreased GH in both FDRs and healthy controls and increased hs-CRP in healthy controls. Moreover, Ramadan intermittent fasting neither worsens a patient's glycemic parameters nor improves it, with the exception of a slight improvement in HbA1c in Type 2 DM, FDRs, and healthy controls.

Topics: Adipokines; Adiponectin; Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; C-Reactive Protein; Cohort Studies; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Triglycerides; Waist Circumference

Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage. Lowering blood sugar by the sodium-glucose co-transporter 2 inhibitor empagliflozin provides cardiac protection. We established a new rat model that develops both inducible diabetes and genetic hypertension and investigated the effect of empagliflozin treatment to test the hypothesis if empagliflozin will be protective in a heart failure model which is not based on a primary vascular event. The transgenic Tet29 rat model for inducible diabetes was crossed with the mRen27 hypertensive rat to create a novel model for heart failure with two stressors. The diabetic, hypertensive heart failure rat (mRen27/tetO-shIR) were treated with empagliflozin (10 mg/kg/d) or vehicle for 4 weeks. Cardiovascular alterations were monitored by advanced speckle tracking echocardiography, gene expression analysis and immunohistological staining. The novel model with increased blood pressure und higher blood sugar levels had a reduced survival compared to controls. The rats develop heart failure with reduced ejection fraction. Empagliflozin lowered blood sugar levels compared to vehicle treated animals (182.3 ± 10.4 mg/dl vs. 359.4 ± 35.8 mg/dl) but not blood pressure (135.7 ± 10.3 mmHg vs. 128.2 ± 3.8 mmHg). The cardiac function was improved in all three global strains (global longitudinal strain - 8.5 ± 0.5% vs. - 5.5 ± 0.6%, global radial strain 20.4 ± 2.7% vs. 8.8 ± 1.1%, global circumferential strain - 11.0 ± 0.7% vs. - 7.6 ± 0.8%) and by increased ejection fraction (42.8 ± 4.0% vs. 28.2 ± 3.0%). In addition, infiltration of macrophages was decreased by treatment (22.4 ± 1.7 vs. 32.3 ± 2.3 per field of view), despite mortality was not improved. Empagliflozin showed beneficial effects on cardiovascular dysfunction. In this novel rat model of combined hypertension and diabetes, the improvement in systolic and diastolic function was not secondary to a reduction in left ventricular mass or through modulation of the afterload, since blood pressure was not changed. The mRen27/tetO-shIR strain should provide utility in separating blood sugar from blood pressure-related treatment effects.

Topics: Animals; Benzhydryl Compounds; C-Peptide; Cardiotonic Agents; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucosides; Heart Failure; Humans; Hyperinsulinism; Hypertension; Male; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes (T2D) is defined by a single metabolite, glucose, but is increasingly recognized as a highly heterogeneous disease, including individuals with varying clinical characteristics, disease progression, drug response, and risk of complications. Identification of subtypes with differing risk profiles and disease etiologies at diagnosis could open up avenues for personalized medicine and allow clinical resources to be focused to the patients who would be most likely to develop diabetic complications, thereby both improving patient health and reducing costs for the health sector. More homogeneous populations also offer increased power in experimental, genetic, and clinical studies. Clinical parameters are easily available and reflect relevant disease pathways, including the effects of both genetic and environmental exposures. We used six clinical parameters (GAD autoantibodies, age at diabetes onset, HbA

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Insulin Resistance; Male

To examine whether proinflammatory and hyperinsulinemic diets are associated with increased risk of type 2 diabetes.. We prospectively followed 74,767 women from the Nurses' Health Study (1984-2016), 90,786 women from the Nurses' Health Study II (1989-2017), and 39,442 men from the Health Professionals Follow-up Study (1986-2016). Using repeated measures of food-frequency questionnaires, we calculated empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which are food-based indices that characterize dietary inflammatory or insulinemic potential based on circulating biomarkers of inflammation or C-peptide. Diagnoses of type 2 diabetes were confirmed by validated supplementary questionnaires.. We documented 19,666 incident type 2 diabetes cases over 4.9 million person-years of follow-up. In the pooled multivariable-adjusted analyses, individuals in the highest EDIP or EDIH quintile had 3.11 times (95% CI 2.96-3.27) and 3.40 times (95% CI 3.23-3.58) higher type 2 diabetes risk, respectively, compared with those in the lowest quintile. Additional adjustment for BMI attenuated the associations (hazard ratio 1.95 [95% CI 1.85-2.05] for EDIP and hazard ratio 1.87 [95% CI 1.78-1.98] for EDIH), suggesting adiposity partly mediates the observed associations. Moreover, individuals in both highest EDIP and EDIH quintiles had 2.34 times higher type 2 diabetes risk (95% CI 2.17-2.52), compared with those in both lowest quintiles, after adjustment for BMI.. Higher dietary inflammatory and insulinemic potential were associated with increased type 2 diabetes incidence. Findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking dietary patterns and type 2 diabetes development.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Diet; Female; Follow-Up Studies; Food; Humans; Hyperinsulinism; Incidence; Inflammation; Male; Middle Aged; Nurses; Obesity; Proportional Hazards Models; Prospective Studies; Risk; Self Report; United States

Objective The measurement of C-peptide immunoreactivity (CPR) is essential for evaluating the pancreatic β-cell function and selecting appropriate therapeutic agents in patients with diabetes mellitus. The meal tolerance test (MTT) is simple to administer physiological insulin-stimulating test. Previous studies have reported that several CPR-related indices are useful markers for predicting insulin requirement in type 2 diabetes. In the present study, we investigated the serum CPR response during the MTT in hospitalized patients with type 2 diabetes mellitus in order to clarify the clinical utility of the MTT. Methods We performed the MTT using a test meal with timed measurements of the serum CPR level based on the oral glucose tolerance test over 180 minutes and tested the correlation of various CPR-related indices and clinical factors in patients with type 2 diabetes mellitus. Patients The subjects were patients with type 2 diabetes mellitus who had been admitted to our hospital for diabetes management and education. The final study population consisted of 68 patients. Results The fasting CPR level was correlated with the 24-hour urinary CPR excretion and body mass index. The serum CPR level at 120 minutes in the MTT was strongly correlated with the area under the curve of CPR during the MTT. The patients who needed insulin therapy at 6 months after hospitalization showed a significant lower incremental CPR value from 0 to 120 minutes in the MTT than those who did not need insulin therapy. Conclusion The plasma C-peptide levels at 0 and 120 minutes in the MTT provide essential information for the clinical management of patients with type 2 diabetes mellitus.

Topics: Adult; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Meals; Meat; Middle Aged; Postprandial Period

The fructooligosaccharide 1-kestose cannot be hydrolyzed by gastrointestinal enzymes, and is instead fermented by the gut microbiota. Previous studies suggest that 1-kestose promotes increases in butyrate concentrations in vitro and in the ceca of rats. Low levels of butyrate-producing microbiota are frequently observed in the gut of patients and experimental animals with type 2 diabetes (T2D). However, little is known about the role of 1-kestose in increasing the butyrate-producing microbiota and improving the metabolic conditions in type 2 diabetic animals. Here, we demonstrate that supplementation with 1-kestose suppressed the development of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, possibly through improved glucose tolerance. We showed that the cecal contents of rats fed 1-kestose were high in butyrate and harbored a higher proportion of the butyrate-producing genus Anaerostipes compared to rats fed a control diet. These findings illustrate how 1-kestose modifications to the gut microbiota impact glucose metabolism of T2D, and provide a potential preventative strategy to control glucose metabolism associated with dysregulated insulin secretion.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cecum; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Drinking; Fasting; Gastrointestinal Microbiome; Glucose; Insulin; Organ Size; Rats; Trisaccharides

Vitamin D3 (vit. D3) deficiency is considered as one of the main factors involved in the development of type 2 diabetes (T2D). We assessed insulin resistance (IR), β-cell functional activity and metabolic profile according to 25(OH) vit. D3 status in patients with T2D.. The study included 109 patients with T2D, divided in 3 groups: group 1 (N.=11) with normal levels of vit. D3 (>30 ng/mL); group 2 (N.=38) with vit. D3 insufficiency (21-29 ng/mL); and group 3 (N.=60) with vit. D3 deficiency (<20 ng/mL). IR and β-cell functional activity were assessed as change in C-peptide concentration and homeostasis model assessment-estimated (HOMA) β-cell function which was calculated using HOMA2 calculator.. Patients with vit. D3 deficiency presented significantly higher C-peptide concentration compared to other groups. HOMA2 (3.29±1.89 vs. 2.12±0.71; P=0.049) and hemoglobin (H8b)A1c (9.11±1.63 vs. 7.75±1.06; P=0.016) levels changed significantly only in patients with vit. D3 deficiency compared to diabetics with normal vit. D3 levels. Furthermore, in univariate Pearson's correlation analysis, we observed significant association between vit. D3 levels and C-peptide, insulin sensitivity, HOMA2, triglyceride-glucose index, HbA1c and Body Mass Index, only in the vit. D3 deficiency group. In multivariate logistic regression analysis, poor glycemic control, as defined by HbA1c levels, was independent from metformin use while high density lipoprotein-cholesterol levels were associated with vit. D3 deficiency.. Our study demonstrated that vit. D3 deficiency in patients with T2D was associated with more severe IR, poor glycemic control and obesity compared to normal status or vit. D3 insufficiency.

Topics: Adolescent; Adult; Aged; Body Mass Index; C-Peptide; Cholecalciferol; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Ergocalciferols; Female; Glycemic Control; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Obesity; Vitamin D Deficiency; Young Adult

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies have suggested that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on 4 separate days, a liquid mixed-meal test preceded by single-dose administration of either

Topics: Benzhydryl Compounds; Biphenyl Compounds; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Energy Metabolism; Gastric Emptying; Glucagon; Glucosides; Glycerol; Half-Life; Humans; Sodium-Glucose Transporter 2 Inhibitors

At present, glycated hemoglobin (HbA1c) and glycated albumin (GA) are used to evaluate glycemic control in diabetic patients, but they cannot reflect insulin deficiency and/or insulin resistance.We investigated the feasibility of using estimated average glucose to fasting plasma glucose ratio (eAG/fPG ratio) to estimate insulin resistance in young adult diabetes. A total of 387 patients with type 2 diabetes were included and were stratified into 2 groups based on median values of the glycemic index ratio: the GA/A1c ratio <2.09 (n = 91) and ≥2.09 (n = 296); the eAG/fPG ratio <1.69 (n = 155) and ≥1.69 (n = 232). HbA1c, GA, fructosamine, insulin, and C-peptide levels were measured. The ratio of GA to HbA1c was calculated, and the homeostasis model assessment of β-cell function and insulin resistance were determined. The homeostasis model assessment of insulin resistance level was significantly associated with the eAG/fPG ratio, but not with the ratio of GA to HbA1c, GA, HbA1c, and fructosamine levels. The ratio of estimated average glucose to fasting plasma glucose level correlates with insulin resistance in young adult diabetes.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 2; Fasting; Female; Fructosamine; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Glycemic Index; Humans; Insulin; Insulin Resistance; Male; Serum Albumin; Young Adult

A number of studies have explored the association between depression and ghrelin, leptin, and cortisol; further, postprandial C-peptide levels have a therapeutic effect on type 2 diabetes mellitus (T2DM). However, the relationship between C-peptide and depression in patients with diabetes, remains unclear. The aim of this study was to explore the association between depression and ghrelin, leptin, cortisol, and C-peptide in patients with diabetes.. We enrolled 50 adults without T2DM, 77 non-depressed adults with T2DM (free of Axis-I psychiatric disorders as assessed using the Mental Illness Needs Index (MINI), Patient Health Questionnaire (PHQ-9 score ≤ 4)) and 59 patients with T2DM and depression (PHQ-9 ≥ 7 and positive by the Structured Clinical Interview for DSM-5). The age range of the participants was 45-59 years of age. We compared the above three groups and explored the association between ghrelin, leptin, cortisol, C-peptide, and depression in patients with diabetes. A post-hoc power-analysis was finished.. Compared with the non-depression T2DM group, the depression T2DM group had significantly higher blood glucose fluctuations. Further, compared with the non-depression T2DM and non-diabetic groups, the depression T2DM group had significantly lower levels of post-meal 2-h C-peptide and elevated evening cortisol (p < 0.01). Regression analysis revealed a significant negative correlation between depression severity and 2-h postprandial C-peptide in patients with diabetes (p < 0.01) and a significant positive correlation with midnight cortisol levels (p < 0.01). A post hoc power analysis showed that we had an adequate sample size and met the minimum requirement to attain 80% power. A post hoc power calculation also demonstrated that this study basically achieved power of 80% at 5% alpha level.. Our findings indicate a correlation of low fasting levels of 2-h C-peptide as well as higher midnight cortisol levels with higher depression severity in middle-aged patients with T2DM.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Depression; Diabetes Mellitus, Type 2; Ghrelin; Humans; Hydrocortisone; Middle Aged

Damage to corneal nerve fibers has been demonstrated in people with type 2 diabetes mellitus (T2DM) that further progresses with increasing severity of diabetic peripheral neuropathy. However, the role of C-peptide in corneal nerve damage has not been reported in T2DM. The present study investigated the relationship of fasting C-peptide levels with corneal neuropathy evaluated by corneal confocal microscopy (CCM) in patients with T2DM.. 160 T2DM patients (72 females) aged 34-78 with duration ranging from 0 to 40 years underwent CCM to measure corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), and corneal nerve branch density (CNBD). Pearson correlation analysis and multiple linear regression analysis were used to explore the association of fasting C-peptide levels with corneal nerve parameters. Partial correlation analysis (adjusted for age and gender) was also conducted to analyze the correlation of metabolic indexes with these three corneal nerve parameters. The relationship between fasting C-peptide levels and duration of diabetes was also explored by Pearson correlation analysis.. With an increase in fasting C-peptide levels, the values of CNFL, CNFD, and CNBD also showed a corresponding trend for an increase. Partial correlation analysis revealed that fasting C-peptide levels were positively associated with CNFL (. C-peptide was closely associated with corneal neuropathy and disease duration in T2DM. C-peptide levels might be both an indicator of beta-cell function and a marker of disease severity (such as diabetic corneal neuropathy) and duration.

Topics: Adult; Aged; Biomarkers; C-Peptide; Cornea; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Fasting; Female; Humans; Male; Microscopy, Confocal; Middle Aged; Nerve Fibers; Predictive Value of Tests; Severity of Illness Index; Time Factors

The aim of the study was to evaluate the association between C-peptide levels, glycaemic variability and hypoglycaemia in patients with insulin-treated type 2 diabetes (T2D).. A total of 98 patients with T2D treated with basal-bolus insulin were enrolled in a cross-sectional study. Glycaemic variability and hypoglycaemia were assessed from continuous glucose monitoring (CGM) data recorded over 6 days: Glycemic variability was assessed by calculating the mean coefficient of variation (CV), while hypoglycemia was defined as sensor glucose levels ≤ 3.9 mmol/L or < 3.0 mmol/L. Fasting C-peptide and fasting glucose were measured on day 1.. In patients with insulin-treated T2D, low levels of C-peptide are associated with greater glycaemic variability and higher risk of hypoglycaemia, suggesting that C-peptide levels should be taken into consideration when optimizing insulin treatment and assessing hypoglycaemia risk.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged

Fasting serum C-peptide is a biomarker of insulin production and insulin resistance, but its association with vascular complications in type 2 diabetes mellitus (T2DM) has never been fully elucidated. This study aimed to investigate whether C-peptide is associated with cardiovascular disease (CVD) and diabetic retinopathy (DR).. A total of 4793 diabetes patients were enrolled from seven communities in Shanghai, China, in 2018. CVD was defined as a self-reported combination of previous diagnoses, including coronary heart disease, myocardial infarction and stroke. DR was examined using fundus photographs. Logistic regression analyses were performed, and multiple imputed data were used to obtain stabilized estimates.. Prevalence of CVD increased with increasing C-peptide levels (Q1, Q2, Q3 and Q4: 33%, 34%, 37% and 44%, respectively; P. C-peptide was positively associated with CVD, but inversely associated with DR progression. The association between C-peptide and CVD could be due to associated metabolic risk factors.

Topics: Aged; C-Peptide; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Risk Factors

The relationship between pancreatic fatty infiltration and diabetes is widely known, whereas the causal relationship is not clear. Furthermore, it is uncertain whether pathogenesis of pancreatic fat is similar to that of liver fat. We aimed to clarify the contribution of this type of fat to glucose metabolism in type 2 diabetes patients by cross-sectional and longitudinal analyses.. A total of 56 patients with type 2 diabetes who had been hospitalized twice were analyzed. We evaluated the mean computed tomography values of the pancreas (P), liver (L) and spleen (S). Lower computed tomography values indicate a greater fat content. We defined indices of pancreatic or liver fat content as the differences between P or L and S. We assessed the associations among fat content for the two organs (P-S, L-S) and clinical parameters at the first hospitalization, and then analyzed the associations between these fat contents and changes in glycometabolic markers (the second data values minus the first).. In the cross-sectional study, P-S negatively correlated with the increment of C-peptide in the glucagon stimulation test (r = -0.71, P < 0.0001) and body mass index (r = -0.28, P = 0.034). L-S negatively correlated with homeostasis model assessment of insulin resistance (r = -0.73, P < 0.0001), body mass index (r = -0.62, P < 0.0001) and some other obesity-related indicators, but not with the increment of C-peptide in the glucagon stimulation test. In the longitudinal study, P-S positively correlated with the change of the increment of C-peptide in the glucagon stimulation test (r = 0.49, P = 0.021).. In type 2 diabetes patients, pancreatic fat was less associated with obesity-related indicators than liver fat, but was more strongly associated with the longitudinal decrease in endogenous insulin-secreting capacity.

Topics: Adipose Tissue; Aged; Biomarkers; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fatty Liver; Female; Follow-Up Studies; Gastrointestinal Agents; Glucagon; Glucose Tolerance Test; Humans; Longitudinal Studies; Male; Pancreatic Diseases; Prognosis

The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized β- and α-cell function, in cretin hormone release and insulin sensitivity in individuals with (remitters) or without (non-remitters) diabetes remission after RYGB.. This is a cross-sectional study of two distinct cohorts of individuals with or without diabetes remission at least 2 years after RYGB. Each individual underwent-either an oral glucose (remitters) or a mixed meal (non-remitters) test; glucose, proinsulin, insulin, C-peptide, glucagon, incretins and leptin were measured.. Compared to remitters (n = 23), non-remitters (n = 31) were older (mean [±SD] age 56.1 ± 8.2 vs. 46.0 ± 8.9 years, P < 0.001), had longer diabetes duration (13.1 ± 10.1 vs. 2.2 ± 2.4 years, P < 0.001), were further out from the surgery (5.6 ± 3.3 vs. 3.5 ± 1.7 years, P < 0.01), were more insulin resistant (HOMA-IR 4.01 ± 3.65 vs. 2.08 ± 1.22, P < 0.001), but did not differ for body weight. As predicted, remitters had higher β-cell glucose sensitivity (1.95 ± 1.23 vs. 0.86 ± 0.55 pmol/kg/min/mmol, P < 0.001) and disposition index (1.55 ± 1.75 vs 0.33 ± 0.27, P = 0.003), compared to non-remitters, who showed non-suppressibility of glucagon during the oral challenge (time × group P = 0.001). Higher proinsulin (16.55 ± 10.45 vs. 6.62 ± 3.50 PM, P < 0.0001), and proinsulin: C-peptide (40.83 ± 29.43 vs. 17.13 ± 7.16, P < 0.001) were strongly associated with non-remission status, while differences in incretins between remitters and non-remitters were minimal.. Individual without diabetes remission after gastric bypass have poorer β-cell response and lesser suppression of glucagon to an oral challenge; body weight and incretins differ minimally according to remission status.. 背景: 目前尚未完全明确2型糖尿病(T2D)患者接受胃旁路术(RYGB)后病情缓解或复发的决定因素。这项研究描述了RYGB术后糖尿病缓解或未缓解个体的β-与α-细胞功能、肠促胰岛素激素释放及胰岛素敏感性。 方法: 这是一项横断面研究, 对RYGB术后至少2年后糖尿病缓解或未缓解的不同队列个体进行了研究。每个个体均进行口服葡萄糖(缓解者)或者混合餐(非缓解者)耐量试验；测量血糖、胰岛素原、胰岛素、C肽、胰高血糖素、肠促胰岛素以及瘦素水平。 结果: 与缓解者(n=23)相比, 未缓解者(n=31)年龄更大(平均[±SD]年龄56.1±8.2 vs. 46.0±8.9岁, P<0.001)、糖尿病病程更长(13.1±10.1 vs. 2.2±2.4年, P<0.001)、距离手术时间更长(5.6±3.3 vs. 3.5±1.7年, P<0.01)、胰岛素抵抗更严重(HOMA-IR为4.01±3.65 vs. 2.08±1.22, P<0.001), 但体重无差异。正如预期, 与未缓解者相比, 缓解者具有较高的β细胞葡萄糖敏感性(1.95±1.23 vs. 0.86±0.55 pmol/kg/min/mmol, P<0.001)以及处置指数(1.55±1.75 vs. 0.33±0.27, P=0.003), 后者在口服耐量试验期间的胰高血糖素水平并未受到抑制(时间×分组, P=0.001)。较高水平的胰岛素原(16.55±10.45 vs. 6.62±3.50PM, P<0.0001)以及胰岛素原:C肽比值(40.83±29.43与17.13±7.16, P<0.001)与未缓解状态密切相关, 但是缓解者与未缓解者之间的肠促胰岛素差异非常小。 结论: 胃旁路术后糖尿病无缓解的个体对口服耐量试验中β细胞的应答较差, 对胰高血糖素的抑制也较小；根据糖尿病缓解状态进行分组, 发现体重与肠促胰岛素的差异非常小。.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Recurrence

A higher prevalence of nonalcoholic steatohepatitis (NASH) and advanced stages of fibrosis was observed in type 2 diabetes. We aim to investigate whether C-peptide is associated with nonalcoholic fatty liver disease (NAFLD) progression in type 2 diabetic adults.. A total of 4937 diabetic participants were enrolled from China in 2018. Liver steatosis was detected by ultrasound. Subjects with NAFLD were categorized into simple NAFLD and probable NASH by the concurrent presence of metabolic syndrome. NAFLD fibrosis score was used to identify patients with probable advanced fibrosis.. Individuals with a longer history of type 2 diabetes had a lower C-peptide level and a lower prevalence of probable NASH but a higher prevalence of advanced fibrosis. C-peptide was positively associated with simple NAFLD and probable NASH, with odds ratios (ORs) of 4.55 [95% confidence interval (CI) 3.16, 6.55] and 5.28 (95% CI 3.94, 7.09), respectively, comparing quartile 4 with quartile 1 (both p for trend <0.001). However, C-peptide quartiles were negatively associated with the probable presence of advanced fibrosis (Q4 vs. Q1, OR 0.59, 95% CI 0.36, 0.97, p for trend <0.05). A 1-SD increment of ln(C-peptide) was also significantly associated with inflammatory and fibrotic progression (OR 1.34, 95% CI 1.27, 1.41; OR 0.88, 95% CI 0.79, 0.98, respectively).. Significant but opposite associations between C-peptide and inflammatory and fibrotic progression of NAFLD were observed. Understanding islet hormone changes during type 2 diabetes and differentiating the stage of NAFLD may help to personalize treatment strategies for NAFLD patients with type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Disease Progression; Female; Follow-Up Studies; Humans; Inflammation; Liver Cirrhosis; Male; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease; Prognosis; Severity of Illness Index; Young Adult

In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools.. In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing.. Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients.. The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.

Topics: Adolescent; Adult; Age of Onset; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; India; Islets of Langerhans; Male; Pancreas; Prospective Studies; Young Adult

To explore the clinical features and complications of 545 hospitalized type 1 diabetic patients.
 Methods: All data of 545 patients with typical type 1 diabetes (T1DM) who were hospitalized in the Department of Endocrinology, the Second Xiangya Hospital, Central South University were collected. The data were analyzed retrospectively to explore the clinical features and complications. Clinical and biochemical characteristics were analyzed through comparison between different subgroups according to the onset age (≤13 years old, 14-29 years old, ≥30 years old).
 Results: The median onset age of T1DM patients was 27.0 (15.0, 40.0) years, and the middle-onset was 42.1%. Among the 3 groups, the proportion of female (58.0%) was the highest in the ≤13 years old group, concomitant with the lowest SBP and serum creatinine levels as well as the lowest incidence of all microvascular complications (21.0% of diabetic nephropathy, 23.3% of diabetic retinopathy, 34.1% of diabetic peripheral neuropathy; all P<0.05). Moreover, the fasting C peptide and peak C peptide levels were the lowest in ≥30 years old group compared with the other two groups, and the incidence of ketosis (33.5%) and all macrovascular complications were the highest among the three groups (all P<0.05).
 Conclusion: There are about half of the hospitalized patients with T1DM whose onset ages are ≥30 years. The incidence of ketosis at the onset and the risk for various microvascular and macrovascular complications after onset are higher than those with the onset age <30 years.. 目的：探讨1型糖尿病(type 1 diabetes，T1DM)住院患者的临床特征和并发症情况。方法：回顾性分析545例T1DM住院患者的临床资料，按照不同起病年龄(≤13岁、14~29岁、≥30岁)分析患者的临床特征和并发症情况。结果：545例T1DM患者的中位起病年龄为27.0(15.0，40.0)岁，≥30岁起病者占42.8%。与其他两组比较，≤13岁组女性比例(58.0%)较高，收缩压和血肌酐水平均最低，且所有微血管并发症的发生率(糖尿病肾病21.0%，糖尿病视网膜病变23.3%，糖尿病周围神经病变34.1%)均最低(均P<0.05)；与其他两组比较，≥30岁组空腹C肽及峰值C肽水平均最低，起病时酮症的发生率(33.5%)及大血管并发症的发生率均最高(均P<0.05)。结论：在T1DM住院患者中≥30岁起病者约占一半，起病时酮症的发生率及起病后各种微血管及大血管并发症的风险均较<30岁起病者更高。.

Topics: Adolescent; Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Retrospective Studies; Risk Factors; Young Adult

To explore clinical factors associated with bacterial translocation in Japanese patients with type 2 diabetes mellitus (T2DM).. The data of 118 patients with T2DM were obtained from two previous clinical studies, and were retrospectively analyzed regarding the clinical parameters associated with bacterial translocation defined as detection of bacteremia and levels of plasma lipopolysaccharide binding protein (LBP), the latter of which is thought to reflect inflammation caused by endotoxemia.. LBP level was not significantly different between patients with and without bacteremia. No clinical factors were significantly correlated with the detection of bacteremia. On the other hand, plasma LBP level was significantly correlated with HbA1c (r = 0.312), fasting blood glucose (r = 0.279), fasting C-peptide (r = 0.265), body mass index (r = 0.371), high-density lipoprotein cholesterol (r = -0.241), and inflammatory markers (high-sensitivity C-reactive protein, r = 0.543; and interleukin-6, r = 0.456). Multiple regression analysis identified body mass index, HbA1c, high-sensitivity C-reactive protein, and interleukin-6 as independent determinants of plasma LBP level.. The plasma LBP level was similar in patients with and without bacteremia. While both bacteremia and LBP are theoretically associated with bacterial translocation, the detection of bacteremia was not associated with LBP level in T2DM.

Topics: Acute-Phase Proteins; Asian People; Bacterial Translocation; Biomarkers; C-Peptide; C-Reactive Protein; Carrier Proteins; Diabetes Mellitus, Type 2; Endotoxemia; Female; Humans; Inflammation; Interleukin-6; Male; Membrane Glycoproteins; Middle Aged; Retrospective Studies

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin

Immune analytes have been widely tested in efforts to understand the heterogeneity of disease progression, risk, and therapeutic responses in type 1 diabetes (T1D). The future clinical utility of such analytes as biomarkers depends on their technical and biological variability, as well as their correlation with clinical outcomes. To assess the variability of a panel of 91 immune analytes, we conducted a prospective study of adults with T1D (<3 years from diagnosis), at 9-10 visits over 1 year. Autoantibodies and frequencies of T-cell, natural killer cell, and myeloid subsets were evaluated; autoreactive T-cell frequencies and function were also measured. We calculated an intraclass correlation coefficient (ICC) for each marker, which is a relative measure of between- and within-subject variability. Of the 91 analytes tested, we identified 35 with high between- and low within-subject variability, indicating their potential ability to be used to stratify subjects. We also provide extensive data regarding technical variability for 64 of the 91 analytes. To pilot the concept that ICC can be used to identify analytes that reflect biological outcomes, the association between each immune analyte and C-peptide was also evaluated using partial least squares modeling. CD8 effector memory T-cell (CD8 EM) frequency exhibited a high ICC and a positive correlation with C-peptide, which was also seen in an independent dataset of recent-onset T1D subjects. More work is needed to better understand the mechanisms underlying this relationship. Here we find that there are a limited number of technically reproducible immune analytes that also have a high ICC. We propose the use of ICC to define within- and between-subject variability and measurement of technical variability for future biomarker identification studies. Employing such a method is critical for selection of analytes to be tested in the context of future clinical trials aiming to understand heterogeneity in disease progression and response to therapy.

Topics: Adolescent; Adult; Autoantibodies; Biomarkers; C-Peptide; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Immunologic Memory; Killer Cells, Natural; Longitudinal Studies; Male; Middle Aged; Myeloid Cells; Prospective Studies; T-Lymphocytes; Young Adult

Little information is published on diabetes in young people in Bangladesh. We aimed to investigate the demographic, clinical, and biochemical features, and HLA-DRB1 alleles in new cases of diabetes affecting Bangladeshi children and adolescents <22 years of age.. The study was conducted at Bangladesh Institute of Research and Rehabilitation of Diabetes, Endocrine and Metabolic Disorders (BIRDEM) in Dhaka. One hundred subjects aged <22 years at diagnosis were enrolled. Demographic characteristics, clinical information, biochemical parameters (blood glucose, HbA1c, C-peptide, and autoantibodies against glutamic acid decarboxylase 65 (GADA) and islet antigen-2 (IA-2A) were measured. High-resolution DNA genotyping was performed for HLA-DRB1.. Eighty-four subjects were clinically diagnosed as type 1 diabetes (T1D), seven as type 2 diabetes (T2D), and nine as fibrocalculous pancreatic disease (FCPD). Of the 84 with T1D, 37 (44%) were males and 47 (56%) females, with median age at diagnosis 13 years (y) (range 1.6-21.7) and peak age at onset 12-15 years. 85% of subjects were assessed within one month of diagnosis and all within eleven months. For subjects diagnosed with T1D, mean C-peptide was 0.46 ± 0.22 nmol/L (1.40 ± 0.59 ng/mL), with 9 (10.7%) IA-2A positive, 22 (26%) GADA positive, and 5 (6%) positive for both autoantibodies. Analysis of HLA-DRB1 genotypes revealed locus-level T1D association (p = 6.0E-05); DRB1*04:01 appeared predisposing (p < 3.0E-06), and DRB1*14:01 appeared protective (p = 1.7E-02).. Atypical forms of T1D appear to be more common in young people in Bangladesh than in European populations. This will be helpful in guiding more specific assessment at onset and potentially, expanding treatment options.

Topics: Adolescent; Adult; Bangladesh; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 2; Female; HLA-DRB1 Chains; Humans; Infant; Male; Young Adult

Maturity Onset Diabetes of the Young (MODY) is a type of diabetes that results from mutations in 13 known genes that play a role in the development and maturation of pancreatic beta cells. It represents 5% of all individuals diagnosed with diabetes before the age of 45 years and it is misdiagnosed as type 1 or type 2 diabetes in 80% of the cases.. We present the case of a 21-year old female, initially diagnosed with type 1 diabetes when she was 19 years, and glycemic dyscontrol despite adequate use of long-acting insulin. She had family history of diabetes and persisting glycosuria. Due to high suspicions of MODY diabetes we requested an oral glucose tolerance test (basal 130 mg/dL, 2 hours post-glucose load 240 mg/dL) and serum concentrations of C-peptide (1.83 ng/mL) that confirmed our diagnosis. The patient improved after treatment with sulfonylurea with discontinuation of insulin treatment.. Prompt identification of MODY allows patients to have effective and safe treatments and prevent the development of premature complications; in addition, its identification allows genetic counseling and can guide the management of other first-degree relatives who also suffer from it.. la diabetes del adulto de inicio juvenil (MODY, por sus siglas en inglés: maturity onset diabetes of the young) es un tipo de diabetes que resulta de mutaciones en 13 genes conocidos que desempeñan un papel en el desarrollo y la maduración de las células beta pancreáticas. Representa el 5% de todas las personas diagnosticadas con diabetes antes de los 45 años y se diagnostica erróneamente como diabetes tipo 1 o tipo 2 hasta en el 80% de los casos.. presentamos el caso de una mujer de 21 años, inicialmente diagnosticada con diabetes tipo 1 a los 19 años y con descontrol glucémico a pesar del uso adecuado de insulina de acción prolongada. Tenía antecedentes familiares de diabetes y glucosuria persistente. Debido a la alta sospecha de diabetes MODY, solicitamos una prueba oral de tolerancia a la glucosa (basal 130 mg/dL y dos horas después de la carga de glucosa: 240 mg/dL) y de concentraciones séricas de péptido C (1.83 ng/mL), que confirmaron el diagnóstico. La paciente mejoró después del tratamiento con sulfonilurea y se logró la interrupción del tratamiento con insulina.. la identificación temprana de la diabetes tipo MODY permite a los pacientes tener tratamientos efectivos y seguros, y prevenir el desarrollo de complicaciones prematuras; además, su identificación permite el asesoramiento genético y puede orientar el manejo de otros parientes de primer grado que también la padecen.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Young Adult

Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is implicated in the pathogenesis of both type 1 diabetes (T1D) as well as type 2 diabetes (T2D) and has been postulated to be increased in these diseases due to hyperglycemia. We have examined the serum and tissue distribution of HA in human subjects with T1D and T2D and in mouse models of these diseases and evaluated the relationship between HA levels and glycemic control. We found that serum HA levels are increased in T2D but not T1D independently of hemoglobin-A1c, C-peptide, body mass index, or time since diabetes diagnosis. HA is likewise increased in skeletal muscle in T2D subjects relative to non-diabetic controls. Analogous increases in serum and muscle HA are seen in diabetic db/db mice (T2D), but not in diabetic DORmO mice (T1D). Diabetes induced by the β-cell toxin streptozotozin (STZ) lead to an increase in blood glucose but not to an increase in serum HA. These data indicate that HA levels are increased in multiple tissue compartments in T2D but not T1D independently of glycemic control. Given that T2D but not T1D is associated with systemic inflammation, these patterns are consistent with inflammatory factors and not hyperglycemia driving increased HA. Serum HA may have value as a biomarker of systemic inflammation in T2D.

Topics: Adult; Animals; Body Mass Index; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyaluronic Acid; Male; Mice; Muscle, Skeletal; Streptozocin; Young Adult

C-peptide level is recognized as an important indicator of diabetes diagnosis. A sensitive and specific double-antibody sandwich enzyme-linked immunosorbent assay for the detection of C-peptide based on double antibody sandwich method was studied in this paper. The rabbit and hen were innunized with PLL-C-peptide and BSA-C-peptide respectively to obtain specific Yolk antibody (IgY) and polyclonal antibody used to construct the sandwich ELISA for the measurement of C-peptide. The limit of detection was 0.51 μg/mL and the half maximal inhibitory concentration (IC50) was 3.26 μg/mL. The method developed in the study showed no evident cross-reactivity with other similar analogs. The detection standard curve of C-peptide exhibited a good linearity (R

Topics: Adult; Aged; Antibodies; Antibody Specificity; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Humans; Limit of Detection; Male; Middle Aged; Predictive Value of Tests; Reproducibility of Results; Time Factors; Urinalysis; Workflow; Young Adult

The aim of this study was to observe the clinical features of type 2 diabetes mellitus (T2DM) patients with ketosis as the initial symptom, and investigate its differences from clinical features of non-ketotic T2DM patients.. A total of 385 T2DM patients treated in our hospital from 2014 to 2017 were selected and divided into ketosis-prone T2DM group and non-ketotic T2DM group. Ketosis-prone T2DM patients refer to DM patients with the urine ketone body++ or above or the blood ketone body ≥1.0 mmol/L when treated. Fasting venous blood was collected from all patients in the early morning at 2 d after admission to detect the liver function, renal function, blood glucose, triglyceride, total cholesterol, glycosylated hemoglobin and fasting C-peptide, glutamic acid decarboxylase antibody (GAD-Ab) and islet cell antibody (ICA) were also detected, and the 24 h urine specimen was retained to detect the 24 h urine microalbumin excretion rate.. The proportion of male in ketosis-prone T2DM group was significantly higher than that in non-ketotic T2DM group (P<0.01). Patients in ketosis-prone T2DM group was younger than those in non-ketotic T2DM group (P<0.05). The number of days from initial symptom to treatment in ketosis-prone T2DM group was smaller than that in non-ketotic T2DM group (P<0.05). The fasting C-peptide level in ketosis-prone T2DM group was significantly lower than that in non-ketotic T2DM group (P<0.05). The degree of weight loss and level of glycosylated hemoglobin in ketosis-prone T2DM group were significantly higher than those in non-ketotic T2DM group (P<0.05).. Ketosis-prone T2DM patients are characterized by lower age at onset, higher proportion of male, shorter duration of disease, poorer islet function, higher blood glucose and more significant weight loss than non-ketotic T2DM patients.

Topics: Adult; Age Factors; Autoantibodies; Body Mass Index; C-Peptide; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Disease Susceptibility; Female; Glycated Hemoglobin; Humans; Ketosis; Lipids; Male; Middle Aged; Risk Factors; Sex Factors; Weight Loss

Pancreas transplant improves quality of life and survival of patients irrespective of pretransplant C-peptide levels. Our objectives were to examine complications and outcomes in patients without measureable C-peptide (insulin-dependent type 1 diabetes mellitus) and carefully selected patients with measurable C-peptide (insulin-dependent type 2 diabetes mellitus) after pancreas transplant.. We conducted a retrospective analysis to examine the demographic, transplant factors, complications, and outcomes in patients with nondetectable pretransplant C-peptide (insulin-dependent type 1 diabetes mellitus) and patients with detectable pretransplant C-peptide (insulin-dependent type 2 diabetes mellitus).. Of 214 consecutive pancreas transplant procedures over a 12-year period, 112 had pretransplant C-peptide level testing (63 patients with type 1 and 49 with type 2 diabetes mellitus). Patients with type 1 disease were more likely to be female (P = .048), and patients with type 2 disease were more likely to be African American (P < .001) and have undergone previous pancreas transplant (P = .042). We observed no differences in donor factors or posttransplant factors (C-peptide after year 2, glucose, and hemoglobin A1C, except that patients with type 2 disease had more pancreatitis) (P = .036). There were no differences in posttransplant complications; however, patients with type 2 disease had significantly higher BK virus nephropathy (P = .006). There were no differences in outcomes between cohorts (rejection, graft loss, or death; P = not significant).. Pancreas transplant can be performed with excellent and equivalent outcomes in patients with type 1 and carefully selected type 2 diabetes mellitus. Patients with type 2 disease are more likely to have posttransplant pancreatitis and BK virus nephropathy, affecting the net benefit for transplant.

Topics: Adolescent; Adult; Biomarkers; BK Virus; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Immunocompromised Host; Kidney Diseases; Male; Opportunistic Infections; Pancreas Transplantation; Pancreatitis; Polyomavirus Infections; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tumor Virus Infections; Young Adult

It remains widely perceived that early-onset Type 2 Diabetes (T2D) in children and adolescents is rare and clinically distinct from Type 1 Diabetes (T1D). We studied the challenges of classifying subtypes of early-onset diabetes using clinical features and biomarkers, and management of these patients. We reviewed retrospectively the record of patients < 25 years old who attended the diabetes clinic in Penang General Hospital, Malaysia between 1st December 2012 and 30th June 2015. We examined their clinical features, C-peptide and pancreatic autoantibodies. Comparisons were made between T1D and T2D for magnitude, demographics, metabolic status and complications. We studied 176 patients with a mean age of 20 ± 3.7 years, 43.2% had T1D, 13.6% had T2D, and 13.6% had mixed features of both. When tested, pancreatic autoantibodies were positive in 59.4% of the T1D. T2D presented two years later than T1D at 14.3 years, 20% were asymptomatic at presentation, and 50% required insulin supplementation despite fasting c-peptide of > 250 pmol/L. HbA1C of ≤ 8.0% (64 mmol/mol) was achieved in 30.3% of T1D, 58.3% of T2D on OAD and 16.7% of T2D on insulin. The T2D had greater cardiovascular risk with higher body mass index, more dyslipidaemia, higher blood pressure and earlier onset of nephropathy. The overlapping clinical features, variable autoimmunity, and beta-cell loss complicate classification of young diabetes. Pancreatic autoantibodies and C-peptide did not always predict diabetes subtypes nor respond to insulin. The poor metabolic control and high cardiovascular risk burden among the T2D highlight the need for population-based study and focused intervention.

Topics: Adolescent; Age of Onset; Autoantibodies; C-Peptide; Cardiovascular Diseases; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Malaysia; Male; Pancreas; Retrospective Studies; Young Adult

Type 2 diabetic patients are becoming younger and having a tendency to family aggregation, they are easily suspected as maturity-onset diabetes of young (MODY) in the outpatient clinic and send to genetic testing. 9 diabetic families were compared in our outpatient clinic who met the primary diagnosis criteria of MODY. Detailed clinical features and laboratory data including gene sequence were collected and analyzed. The patients met the primary clinical diagnostic criteria of MODY for genetic testing at the first look. However, members of families A1 to A3 had normal Body mass index (BMI) and a lower C-peptide level which indicated impaired pancreatic islet function. In contrast, the members with diabetes of families B1 to B6 had normal or increased C-peptide level which indicated insulin resistance and were overweight with BMI. Genetic testing showed that the mutations in HNF1A, INS, KCNJ11 and so on in families A were consistent with the diagnosis of MODY. No pathogenic mutation was found in the members of families B which were diagnosed with familial T2D. Before the clinical laboratory testing and the further gene test, BMI and the concentration of C-peptide are important for the promptly differential diagnosis of MODY from familial type 2 diabetes and medication instruction in the outpatient clinic which could help to alleviate the burden of genetic testing for them.

Topics: Adolescent; Adult; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Genetic Testing; Hepatocyte Nuclear Factor 1-alpha; Humans; Male; Middle Aged; Pedigree; Young Adult

Some studies have suggested that blood glucose fluctuation and C-peptide level were considered as predictive factors for carotid artery intima-media thickness (CIMT). However, the relationships of these variables are unclear. This research was aimed to identify the potential effects of blood glucose fluctuation, C-peptide level and conventional risk factors on CIMT.. A total of 280 type 2 diabetes mellitus (T2DM) patients were enrolled into this study. Population characteristics were obtained through medical history and clinical parameters. The patients were divided into two groups according to the critical value of CIMT (0.9). Research data were analyzed to identify risk factors of CIMT between the two groups.. The comparison results of basic information showed that differences in age and illness years between the two groups were statistically significant (p = 0.0002 and p = 0.0063). Logistic regression analysis results indicated that smoking, uric acid (UA) levels, 2 h C-peptide and standard deviation of blood glucose (SDBG) were the influence factors for CIMT thickening (p = 0.032, p = 0.047, p = 0.049 and p = 0.042, respectively). Blood glucose fluctuation could affect the risk of some complications. In largest amplitude of glycemic excursions (LAGE) > 4.4 group, the CIMT abnormal rate was 27.10%, which was significantly higher than 12.12% in the LAGE ≤ 4.4 group (p = 0.012). The CIMT abnormal rate of SDBG > 2.0 group was 27.81%, which was significantly higher than that of the SDBG ≤ 2.0 group (p = 0.018).. Blood glucose fluctuation is an independent risk factor associated with CIMT in T2DM patients, in addition to conventional risk factors, such as smoking, high UA level and 2 h C-peptide. Therefore, more attention should be given to the change of CIMT and the complications.

Topics: Asian People; Blood Glucose; C-Peptide; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Ethnicity; Female; Humans; Male; Middle Aged; Risk Factors

Accurate dosing of medications for glycemic control is a challenge for clinicians in diabetic patients with kidney disease. Diminishing glomerular filtration rates are associated with decreased renal clearance of insulin and increased prevalence of hypoglycemic episodes. Measurement of glucose/C peptide ratios may be useful to guide dosing in those patients who receive powerful insulin secretogogues as glomerular function decreases with age and disease.. In order to determine the relationship between glucose, C-peptide and renal function, we reviewed the records of patients with type 2 diabetes followed in our kidney hypertension clinic who met the following criteria: age 35-90 years, requirement of medications to control glycemia, at least 4 simultaneous measurements of C peptide, HbA1c, creatinine and blood glucose.. 87 patients (67 males, 20 females), ages 67.1 ± 10.6 years, BMI 32.5 ± 5.2, A1c 8.2 ± 1.2%, eGFR 73 ± 27.2 ml/min, had glucose/C-peptide ratios 60.7 ± 46.4. 59% of the total group were taking insulin secretogogues. Patients were divided into groups based upon mean eGFR and use or absence of insulin secretogogues. Glucose C-peptide ratios were lowest in the quartile of patients with the lowest eGFR (<50 ml/min).. Diminished renal function and advanced age are associated with the lowest glucose/C-peptide ratios, independent of achieved glycemic control. With similar use of secretogogues, glucose/C-peptide ratio were lower when eGFR was ≤49 ml/min compared to >50-80 ml/min. Use of secretogogues was associated with decreased glucose/C-peptide levels. In patients with reduced renal function (eGFR < 50 ml/min), use of insulin secretogogues may be associated with lower glucose/C-peptide ratios associated with higher risks for hypoglycemic reactions.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Prognosis

To investigate prognostic factors for complete remission in type 2 diabetes mellitus (T2DM) patients who underwent gastric bypass (GBP) and to establish a prognostic model for risk stratification.. We evaluated the baseline clinical features of patients with T2DM who received at Beijing Tian Tan Hospital from April 2012 to December 2015. Complete remission of T2DM was defined as meeting the following criteria: HbA1c < 6.5%, fasting plasma glucose (FPG) < 100 mg/dL, and absence of hypoglycemic drugs for 1 year following GBP.. A total of 101 patients were enrolled in our study, and the complete remission rate of T2DM was 70.3% (71/101). Compared with patients with incomplete remission, patients with complete remission of T2DM had higher C-peptide levels, lower HbA1c, shorter disease duration, better β cell function, and an absence of insulin therapy. HbA1c level, fasting C-peptide, duration of T2DM, and history of medical therapy were important prognostic factors for complete remission of T2DM (P = 0.001, 0.002, 0.01, 0.028, respectively). Patients with HbA1c lower than 7.5%, a history of T2DM shorter than 9.5 years, fasting C-peptide higher than 1.2 ng/mL, and absence of insulin therapy before GBP achieved a higher complete remission rate of T2DM after GBP (AUC of the model was 0.825, 95% CI, 0.741-0.910; P = 0.001).. The duration of T2DM, history of medical therapy, and levels of HbA1c and fasting C-peptide are independent predictors for the prognosis of T2DM patients undergoing GBP. Patients with HbA1c lower than 7.5%, a history of T2DM shorter than 9.5 years, a fasting C-peptide higher than 1.2 ng/mL, and an absence of insulin therapy may have a higher complete remission rate of T2DM after GBP.

Topics: Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; China; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity, Morbid; Prognosis; Time Factors

The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.

Topics: Adult; C-Peptide; Computer Simulation; Diabetes Mellitus, Type 2; Female; Glucose; Healthy Volunteers; Hepatic Veins; Humans; Hyperglycemia; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Statistics, Nonparametric

We performed this study to identify factors related to intact incretin levels in patients with type 2 diabetes mellitus (T2DM).. We cross-sectionally analyzed 336 patients with T2DM. Intact glucagon-like peptide 1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 minutes after ingestion of a standard mixed meal. The differences between 30 and 0 minute iGLP-1 and iGIP levels were indicated as ΔiGLP-1 and ΔiGIP.. In simple correlation analyses, fasting iGLP-1 was positively correlated with glucose, C-peptide, creatinine, and triglyceride levels, and negatively correlated with estimated glomerular filtration rate. ΔiGLP-1 was positively correlated only with ΔC-peptide levels. Fasting iGIP showed positive correlations with glycosylated hemoglobin (HbA1c) and fasting glucose levels, and negative correlations with ΔC-peptide levels. ΔiGIP was negatively correlated with diabetes duration and HbA1c levels, and positively correlated with Δglucose and ΔC-peptide levels. In multivariate analyses adjusting for age, sex, and covariates, fasting iGLP-1 levels were significantly related to fasting glucose levels, ΔiGLP-1 levels were positively related to ΔC-peptide levels, fasting iGIP levels were related to fasting C-peptide levels, and ΔiGIP levels were positively related to ΔC-peptide and Δglucose levels.. Taken together, intact incretin levels are primarily related to C-peptide and glucose levels. This result suggests that glycemia and insulin secretion are the main factors associated with intact incretin levels in T2DM patients.

Topics: Aged; Blood Glucose; C-Peptide; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eating; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Secretion; Male; Middle Aged; Multivariate Analysis; Triglycerides

To study the association between baseline level of C-peptide and all-cause death, cardiovascular death and cardiovascular complications among persons with newly diagnosed type 2 diabetes.. The Skaraborg Diabetes Register contains data on baseline C-peptide concentrations among 398 persons <65 years with newly diagnosed type 2 diabetes 1996-1998. National registries were used to determine all-cause death, cardiovascular death and incidence of myocardial infarction and ischemic stroke until 31 December 2014. The association between baseline C-peptide and outcomes were evaluated with adjustment for multiple confounders by Cox regression analysis. Missing data were handled by multiple imputation.. In the imputed and fully adjusted model there was a significant association between 1 nmol/l increase in C-peptide concentration and all-cause death (HR 2.20, 95% CI 1.49-3.25, p < 0.001, number of events = 104), underlying cardiovascular death (HR 2.69, 1.49-4.85, p = 0.001, n = 35) and the composite outcome of underlying cardiovascular death, myocardial infarction or ischemic stroke (HR 1.61, 1.06-2.45, p = 0.027, n = 90).. Elevated C-peptide levels at baseline in persons with newly diagnosed type 2 diabetes are associated with increased risk of all-cause and cardiovascular mortality. C-peptide might be used to identify persons at high risk of cardiovascular complications and premature death.