c-peptide and Hyperglycemia

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

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

The incidence and prevalence of diabetes are increasing worldwide. According to the International Diabetes Federation, more than 55 million people in the European region have diabetes, and this number is expected to rise to 64 million in 2030, with most of the cases being due to type 2 diabetes. Diabetes is associated with potentially serious microvascular and macrovascular complications such as nephropathy, neuropathy, and retinopathy as well as coronary artery disease. The pathophysiological mechanism behind this phenomenon is complex. In recent years the impact of proinsulin C-peptide in the development of vascular disease has been highlighted, but it displays differential function in type 1 and type 2 diabetes. In type 1 diabetes, which is characterized by a lack of insulin and C-peptide, supplementation of C-peptide has been shown to improve microvascular complications. In type 2 diabetes, however, C-peptide levels are increased above normal levels and correlate with the occurrence of macrovascular complications and cardiovascular deaths. This review focuses on the impact of C-peptide in the atherogenic process.

Topics: Animals; Atherosclerosis; C-Peptide; Diabetic Angiopathies; Disease Models, Animal; Endothelium, Vascular; Humans; Hyperglycemia; Inflammation; NF-kappa B

Postmortem chemistry is becoming increasingly essential in the forensic pathology routine and considerable progress has been made over the past years. Biochemical analyses of vitreous humor, cerebrospinal fluid, blood and urine may provide significant information in determining the cause of death or in elucidating forensic cases. Postmortem chemistry may essentially contribute in the determination of the cause of death when the pathophysiological changes involved in the death process cannot be detected by morphological methods (e.g. diabetes mellitus, alcoholic ketoacidosis and electrolytic disorders). It can also provide significant information and useful support in other forensic situations, including anaphylaxis, hypothermia, sepsis and hormonal disturbances. In this article, we present a review of the literature that covers this vast topic and we report the results of our observations. We have focused our attention on glucose metabolism, renal function and electrolytic disorders.

Topics: Biomarkers; Bodily Secretions; Body Fluids; C-Peptide; Diabetes Mellitus; Diabetic Ketoacidosis; Electrolytes; Forensic Pathology; Fructosamine; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Ketone Bodies; Kidney Function Tests; Postmortem Changes

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

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

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

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

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

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

Topics: C-Peptide; Humans; Hyperglycemia; Hypoglycemia; Insulin

Appropriate use of test strategies requires not only an appreciation of analytic considerations and the ability of the tests to confirm or exclude the hypotheses, but also an understanding of the underlying pathophysiology and clinical features of the problems to be addressed. This discussion covers disease definition, pathophysiology, analytic considerations, and strategies for diagnosis and management.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Insulin; Male; Pregnancy; Proinsulin

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

Late preterm steroid administration can induce transient maternal and thus fetal hyperglycemia, which can increase production of fetal insulin and C-peptide. Infants delivered in this setting are subsequently at increased risk for hypoglycemia. Although maternal glycemic control before delivery is a key component of care for parturients with diabetes, this intervention has not been studied in the setting of late preterm steroid administration.. This study aimed to determine the effect of maternal screening for and treatment of hyperglycemia after late preterm steroid administration on fetal C-peptide levels and other metabolic markers.. This was a multicenter, randomized trial (NCT03076775) of nondiabetic parturients with a singleton gestation receiving betamethasone at 34 0/7 weeks to 36 5/7 weeks for anticipated preterm birth. Participants randomized to maternal glycemic control received fasting and 1-hour postprandial or serial intrapartum capillary blood glucose screening with insulin treatment as indicated. Those randomized to expectant management did not receive any glucose screening or treatment. The primary outcome was fetal C-peptide level measured from umbilical cord blood at delivery. Secondary outcomes included other fetal metabolic markers and neonatal hypoglycemia (glucose level <40 mg/dL). Baseline characteristics and outcomes were compared between the groups. We estimated that we would need a sample size of 144 to provide >90% power to show a 1 ng/mL decrease in C-peptide concentration (±1.5 ng/mL) at ⍺=0.05 using a 2-sample t test and 1 interim analysis. After the interim analysis, the trial was stopped for futility.. Of 491 screened parturients, 163 (33%) were deemed eligible and 86 (53%) were randomized to 1 of the treatment groups (June 2017 to February 2021). One person was lost to follow-up because of delivery at another hospital. Baseline characteristics were similar between groups. The median interval from betamethasone administration to delivery was 24 hours (interquartile range, 13-96 hours) and did not differ between groups (P=.82). Most (82%) randomized to maternal glycemic control had hyperglycemia: 80% had at least 1 fasting glucose level >95 mg/dL, 75% had at least one 1-hour postprandial glucose level >140 mg/dL, and 80% had at least 1 intrapartum glucose level >110 mg/dL. In addition, 15% had at least 1 glucose level >180 mg/dL. None had maternal hypoglycemia after insulin treatment. Compared with expectant management, maternal glycemic control did not affect the median fetal C-peptide level (1.02; interquartile range, 0.52-1.85 vs 1.09; interquartile range, 0.61-1.65; P=.97) or other metabolic markers. Maternal glycemic control also did not affect neonatal hypoglycemia (49% vs 51%; P=.83) or other secondary neonatal or maternal outcomes. There was no evidence of effect modification by gestational age or body mass index at randomization, indication for betamethasone, duration from betamethasone to delivery, maternal race or ethnicity, or neonatal sex. In addition, the results were unchanged in a sensitivity analysis using a per-protocol approach.. Maternal hyperglycemia was observed in most nondiabetic parturients after receiving late preterm betamethasone. However, there was no improvement in fetal metabolic status, neonatal hypoglycemia, or other neonatal or maternal outcomes with maternal glycemic control. Therefore, maternal glucose surveillance and treatment does not seem to be beneficial in nondiabetic parturients receiving late preterm steroids.

Topics: Betamethasone; C-Peptide; Female; Glucose; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Parturition; Pregnancy; Premature Birth

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

Dietary fat and protein impact postprandial hyperglycemia in people with type 1 diabetes, but the underlying mechanisms are poorly understood. Glucoregulatory hormones are also known to modulate gastric emptying and may contribute to this effect.. Investigate the effects of fat and protein on glucagon-like peptide (GLP-1), glucagon-dependent insulinotropic polypeptide (GIP) and glucagon secretion.. 2 crossover euglycemic insulin clamp clinical trials at 2 Australian pediatric diabetes centers. Participants were 12-21 years (n = 21) with type 1 diabetes for ≥1 year. Participants consumed a low-protein (LP) or high-protein (HP) meal in Study 1, and low-protein/low-fat (LPLF) or high-protein/high-fat (HPHF) meal in Study 2, all containing 30 g of carbohydrate. An insulin clamp was used to maintain postprandial euglycemia and plasma glucoregulatory hormones were measured every 30 minutes for 5 hours. Data from both cohorts (n = 11, 10) were analyzed separately. The main outcome measure was area under the curve of GLP-1, GIP, and glucagon.. Meals low in fat and protein had minimal effect on GLP-1, while there was sustained elevation after HP (80.3 ± 16.8 pmol/L) vs LP (56.9 ± 18.6), P = .016, and HPHF (103.0 ± 26.9) vs LPLF (69.5 ± 31.9) meals, P = .002. The prompt rise in GIP after all meals was greater after HP (190.2 ± 35.7 pmol/L) vs LP (152.3 ± 23.3), P = .003, and HPHF (258.6 ± 31.0) vs LPLF (151.7 ± 29.4), P < .001. A rise in glucagon was also seen in response to protein, and HP (292.5 ± 88.1 pg/mL) vs LP (182.8 ± 48.5), P = .010.. The impact of fat and protein on postprandial glucose excursions may be mediated by the differential secretion of glucoregulatory hormones. Further studies to better understand these mechanisms may lead to improved personalized postprandial glucose management.

Topics: Adult; Australia; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Dietary Fats; Dietary Proteins; Female; Follow-Up Studies; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Male; Meals; Prognosis

Treating women with gestational diabetes mellitus in the third trimester improves perinatal outcomes. It is unknown whether treating women with mild glucose intolerance earlier in pregnancy would be beneficial in the reduction of maternal and neonatal morbidities.. In women with hyperglycemia (hemoglobin A1c ≥5.7% and/or fasting glucose ≥92 mg/dL) in early pregnancy, we sought to determine whether immediate treatment improved maternal and neonatal outcomes.. This unblinded randomized controlled trial enrolled women with hyperglycemia at ≤15+0 weeks gestation between 2013 and 2015. Participants were assigned randomly to early pregnancy or third-trimester treatment of hyperglycemia that included nutrition counseling, glucose monitoring, and medications as needed. Participants underwent a blinded 2-hour glucose tolerance test at 24-28 weeks gestation. Exclusion criteria were pregestational diabetes mellitus and multiple gestations. The primary outcome was the proportion of infants with neonatal umbilical cord C-peptide >1.77 nmoL (90th percentile). Secondary outcomes were neonatal fat mass, infant World Health Organization weight-for-length percentile at birth, maternal gestational weight gain, and diagnosis of gestational diabetes mellitus on glucose tolerance test. Mann-Whitney-Wilcoxon test and Fisher's exact test were used, as appropriate.. A total of 202 women were assigned randomly; 45 women dropped out before delivery, which left cases 157 for analysis (82 with early pregnancy and 75 with third-trimester treatment). The trial was terminated early because of low enrollment. Baseline characteristics were similar between groups. There was no difference in C-peptide >90th percentile between groups (1 [1.5%] vs 4 [6.7%]; P=.19) in the early pregnancy and third-trimester groups, respectively). There was also no difference in fat mass (0.37±0.16 vs 0.36±0.17 kg; P=.91), weight-for-length percentile at birth (25% vs 25%; P=.46), or macrosomia (1.5 vs 5.0%; P=.84). Maternal gestational weight gain was 22.6±12.9 lb and 23.9±11.2 lb in the early pregnancy and third-trimester groups, respectively (P=.88). Gestational diabetes mellitus was diagnosed in 19.0% of the cohort and did not differ between groups (14.2% vs 25.8%; P=.17).. In this population of women with hyperglycemia, treatment in early pregnancy did not appear to improve maternal or neonatal outcomes significantly. Given comparable results in both groups, caution should be used in the initiation of an intensive diabetes mellitus treatment protocol for women with the diagnosis of hyperglycemia in early gestation.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes, Gestational; Female; Humans; Hyperglycemia; Infant, Newborn; Pregnancy

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) causes postprandial insulin release and inhibits bone resorption assessed by carboxy-terminal collagen crosslinks (CTX).. To study if GIP affects bone homeostasis biomarkers independently of insulin release and glycemic level.. Randomized, double-blinded, crossover study with 5 study days.. Ten male C-peptide-negative patients with type 1 diabetes.. On 3 matched days with "low glycemia" (plasma glucose in the interval 3 to 7 mmol/L for 120 minutes), we administered intravenous (IV) GIP (4 pmol × kg-1 × min-1), glucagon-like peptide 1 (1 pmol × kg-1 × min-1), or placebo (saline), and on 2 matched days with "high glycemia" (plasma glucose 12 mmol/L for 90 minutes), we administered either GIP or saline.. CTX, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone (PTH).. During low glycemia: GIP progressively suppressed CTX from baseline by up to 59 ± 18% compared with 24 ± 10% during saline infusion (P < 0.0001). Absolute values of P1NP and PTH did not differ between days. During high glycemia: GIP suppressed CTX from baseline by up to 59 ± 19% compared with 7 ± 9% during saline infusion (P < 0.0001). P1NP did not differ between days. GIP suppressed PTH after 60 minutes compared with saline (P < 0.01), but this difference disappeared after 90 minutes.. Short-term GIP infusions robustly reduce bone resorption independently of endogenous insulin secretion and during both elevated and low plasma glucose, but have no effect on P1NP or PTH after 90 minutes.

Topics: Adult; Biomarkers; Blood Glucose; Bone Resorption; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Follow-Up Studies; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Humans; Hyperglycemia; Hypoglycemia; Male; Postprandial Period; Prognosis

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

To evaluate the effect of a single preoperative dose of 125 mg methylprednisolone (MP) on glycemic homeostasis early after fast-track total hip and knee arthroplasty.. One-hundred thirty-four patients undergoing elective unilateral total hip arthroplasty and total knee arthroplasty were randomized (1:1) to preoperative intravenous MP 125 mg (group MP) or isotonic saline intravenous (group C). All procedures were performed under spinal anesthesia, using a standardized multimodal analgesic regime. The primary outcome was the change in plasma glucose 2 hours postoperatively, and secondary outcomes included plasma C-peptide concentrations, homeostatic model assessment (HOMA), HOMA-IR (insulin resistance), and HOMA-B (β-cell function). Fasting blood samples were collected at baseline and 2, 6 (nonfasting), 24, and 48 hours after surgery with complete samples from 122 patients (group MP = 62, group C = 60) for analyses.. MP patients had increased plasma glucose levels at 2 hours (adjusted mean [95% CI], 7.4 mmol·L [7.2-7.5] vs 6.0 mmol·L [5.9-6.2]; P = .023) and 6 hours (13.9 mmol·L [13.3-14.5] vs 8.4 mmol·L [7.8-9.0]; P < .001), and in plasma C-peptide 24 hours postoperatively (1675 pmol·L [1573-1778] vs 1248 pmol·L [1145-1351]; P < .001). An impaired insulin response was also observed in group MP as reflected by HOMA-B (P < .001). Additionally, HOMA-IR increased 24 hours postoperatively in group MP compared to group C (P < .001). Parameters were normalized 48 hours postoperatively.. Preoperative administration of MP 125 mg resulted in a transient postoperative increase in plasma glucose and insulin resistance and impaired insulin secretion in response to hyperglycemia.

Topics: Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Biomarkers; Blood Glucose; C-Peptide; Denmark; Double-Blind Method; Drug Administration Schedule; Female; Glucocorticoids; Humans; Hyperglycemia; Insulin Resistance; Male; Methylprednisolone; Middle Aged; Preoperative Care; Risk Factors; Time Factors; Treatment Outcome

Type-1 diabetes mellitus (T1DM) is caused by autoimmune insulitis. There are evidences that pregnancy and n-3 fatty acids exhibit suppressive effect on human inflammatory system.. Ninety pregnant women with T1DM were included in the prospective randomized placebo controlled clinical trial. Forty-seven of them were put on standard diabetic diet enriched with EPA and DHA twice a day (EPA 120 mg and DHA 616 mg; Study group) and 43 pregnant diabetic women were on standard diabetic diet with placebo (Control group). Duration of T1DM in all participants was between 5 to 30 years. Blood samples were analyzed from all pregnant women for fasting C-peptide (FC-peptide), fasting plasma glucose (FPG) and HbA1c in each trimester throughout pregnancy and after delivery. Umbilical vein blood was analyzed for fetal C-peptide level, glucose concentration and insulin resistance.. In the Study group FC-peptide concentration raised from 59.6±103.9 pmol/l in first trimester, to 67.7±101.3 pmol/l in the second trimester and to 95.1±152.7 pmol/l in the third trimester. Comparing the FC-peptide values during first and third trimester a statistically significant increase in third trimester was found (P<0.001). In the Control group FC-peptide concentration ranged from 41.7±91.6 pmol/l in the first trimester to 41.2±70.9 mmol/l in the second trimester while in the third trimester it reached 52.4±95.3 pmol/l. Comparing the FC-peptide values during first and third trimester the statistical difference was not significant.. Combining of LC n-3 PUFAs and pregnancy yields immunological tolerance and stimulates the production of endogenous insulin in women with T1DM.

Topics: Adult; Biomarkers; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diet, Diabetic; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Fetal Blood; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Maternal Nutritional Physiological Phenomena; Pregnancy; Pregnancy in Diabetics; Young Adult

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

To investigate the effect of initial insulin dosage on blood glucose (BG) dynamics, β-cell protection, and oxidative stress in type 1 diabetes mellitus.. Sixty newly diagnosed type 1 diabetes mellitus patients were randomly assigned to continuous subcutaneous insulin infusions of 0.6 ± 0.2 IU/kg/d (group 1), 1.0 ± 0.2 IU/kg/d (group 2), or 1.4 ± 0.2 IU/kg/d (group 3) for 3 wk. BG was monitored continuously for the first 10 d and the last 2 d of wk 2 and 3. A total of 24-hour urinary 8-iso-PGF2α was assayed on days 8, 9, and 10. The occurrence and duration of the honeymoon period were recorded. Fasting C-peptide and glycosylated hemoglobin (HbA1c) were assayed after 1, 6, and 12 months of insulin treatment.. BG decreased to the target range by the end of wk 3 (group 1), wk 2 (group 2), or wk 1 (group 3). The actual insulin dosage over the 3 wk, frequency of hypoglycemia on wk 1 and 2, and median BG at the end of wk 1 differed significantly, but not 8-iso-PGF2α and the honeymoon period in the three groups. No severe hypoglycemia event was observed in any patient, but there was significant difference in the first occurrence of hypoglycemia.. Differences in initial insulin dosage produced different BG dynamics in wk 1, equivalent BG dynamics on wk 2 and 3, but had no influence on short- and long-term BG control and honeymoon phase. The wide range of initial insulin dosage could be chosen if guided by BG monitoring.

Topics: Biomarkers; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Dinoprost; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Insulin Secretion; Insulin-Secreting Cells; Male; Monitoring, Ambulatory; Oxidative Stress

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 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

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

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

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

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

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

Hyperglycaemia is a common complication of prematurity and is associated with neonatal mortality and morbidity, yet the aetiology is incompletely understood. C-peptide has been used in adults to estimate endogenous insulin secretion due to its simple clearance kinetics.. To determine insulin secretion calculated from plasma C-peptide concentrations in hyperglycaemic preterm babies.. This is a retrospective analysis of a cohort of 41 very preterm babies with a median gestational age of 27.2 weeks (26.2-28.7) enrolled in a randomised controlled trial of tight glycaemic control when they developed hyperglycaemia (2 consecutive blood glucose concentrations, BGC, > 8.5 mmol·l(-1)). Insulin secretion was determined using a steady state analysis of a 2-compartment C-peptide kinetic model.. BGC, plasma insulin concentration, plasma C-peptide concentrations, and insulin secretion were higher at randomisation than 1-2 weeks following randomisation (p ≤ 0.02). Insulin secretion was higher in girls at 11.7 mU·l(-1)·kg(-1)·min(-1) (5.3-18.7) vs. 4.7 mU·l(-1)·kg(-1)·min(-1) (2.1-8.3; p < 0.005), with no difference in clinical characteristics, BGC, plasma insulin concentration, or nutrition between the sexes (p > 0.25). Insulin secretion was lower in samples taken during exogenous insulin delivery at 3.7 mU·l(-1)·kg(-1)·min(-1) (1.8-6.9) vs. 9.8 mU·l(-1)·kg(-1)·min(-1) (4.7-17.8; p = 0.02).. Insulin secretion was higher when babies had higher BGC, indicating that endogenous insulin secretion is sensitive to BGC. Girls had higher insulin secretion, at similar blood glucose and plasma insulin concentrations, than boys.

Topics: Australia; Blood Glucose; C-Peptide; Female; Gestational Age; Humans; Hyperglycemia; Infant, Extremely Premature; Infant, Newborn; Insulin; Insulin Secretion; Male; Retrospective Studies; Sex Factors

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

Surgical stress response, results in elevated levels of anti-insulin hormones and reduced insulin secretion. This hormonal state may be detrimental for surgical patients due to the presence of insulin resistance and hyperglycemia. Additionally, pre-operative fasting favors this conditions. The aim of this study is to analyze the impact of pre-operative caloric load, with 440kJ from amino acid infusions on the levels of glucose, cortisol and insulin resistance in surgical patients.. The study included 20 female patients scheduled for mastectomy, aged 30-60 years without diabetes and BMI < 30 m(2), divided into two groups. The study group A, the evening before the surgery, received 1000 ml amino acid infusions, while the control group B didn't receive any infusion. In both groups glucose, C-peptide and cortisol levels were determinate preoperatively and postoperatively. From the obtained C-peptide and glucose values, with the help of computer model (HOMA2*), the insulin resistance (IR), functionality of beta cells (BETA) and insulin sensitivity (IS) were calculated.. Postoperative values of insulin resistance (0.94 ± 0.12 vs 1.13 ± 0.2; p = 0.02) and glucose (4.79 ± 0.5 vs 5.77 ± 0.6; p = 0.002) were lower in the study group compared to control group. Postoperative cortisol levels in both groups were higher than the preoperative, but no significant difference was found. The study group showed higher values for BETA and IS. Percentage changes between the groups were significant for all parameters.. Pre-operative caloric load (amino acids) reduces the level of insulin resistance and glucose in the presence of elevated cortisol levels.

Topics: Adult; Amino Acids; Biomarkers; Blood Glucose; C-Peptide; Energy Intake; Female; Humans; Hydrocortisone; Hyperglycemia; Infusions, Parenteral; Insulin Resistance; Mastectomy; Middle Aged; Pilot Projects; Preoperative Care; Prospective Studies; Republic of North Macedonia; Time Factors; 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

To evaluate whether clinically relevant concentrations of stimulated C-peptide in response to a mixed-meal tolerance test can be detected after almost 30 years of diabetes in people included in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort.. Mixed-meal tolerance tests were performed in a sample of 58 people. C-peptide levels were measured using a chemiluminescent immunoassay. This sample size assured a high probability of detecting C-peptide response if the true prevalence was at least 5%, a level that would justify the subsequent assessment of C-peptide in the entire cohort.. Of the 58 participants, 17% showed a definite response, defined as one or more post-stimulus concentrations of C-peptide > 0.03 nmol/l, and measurable concentrations were found in all participants.. These results show that a stimulated C-peptide response can be measured in some people with long-term Type 1 diabetes. Further investigation of all participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study will help relate long-term residual C-peptide response to glycaemia over time and provide insight into the relevance of this response in terms of insulin dose, severe hypoglycaemia, retinopathy, nephropathy and macrovascular disease. Establishing the clinical relevance of long-term C-peptide responses is important in understanding the impact that therapy to preserve or improve β-cell function may have in patients with long-term Type 1 diabetes.

Topics: C-Peptide; Canada; Cohort Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Disease Progression; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incidence; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Pilot Projects; Postprandial Period; United States

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

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

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

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

Our study examines the hypothesis that in addition to sugar starch-type diet, a fat-protein meal elevates postprandial glycemia as well, and it should be included in calculated prandial insulin dose accordingly. The goal was to determine the impact of the inclusion of fat-protein nutrients in the general algorithm for the mealtime insulin dose calculator on 6-h postprandial glycemia.. Of 26 screened type 1 diabetes patients using an insulin pump, 24 were randomly assigned to an experimental Group A and to a control Group B. Group A received dual-wave insulin boluses for their pizza dinner, consisting of 45 g/180 kcal of carbohydrates and 400 kcal from fat-protein where the insulin dose was calculated using the following algorithm: n Carbohydrate Units×ICR+n Fat-Protein Units×ICR/6 h (standard+extended insulin boluses), where ICR represents the insulin-to-carbohydrate ratio. For the control Group B, the algorithm used was n Carbohydrate Units×ICR. The glucose, C-peptide, and glucagon concentrations were evaluated before the meal and at 30, 60, 120, 240, and 360 min postprandial.. There were no statistically significant differences involving patients' metabolic control, C-peptide, glucagon secretion, or duration of diabetes between Group A and B. In Group A the significant glucose increment occurred at 120-360 min, with its maximum at 240 min: 60.2 versus -3.0 mg/dL (P=0.04), respectively. There were no significant differences in glucagon and C-peptide concentrations postprandial.. A mixed meal effectively elevates postprandial glycemia after 4-6 h. Dual-wave insulin bolus, in which insulin is calculated for both the carbohydrates and fat proteins, is effective in controlling postprandial glycemia.

Topics: Adolescent; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Child; Diabetes Mellitus, Type 1; Dietary Fats; Dietary Proteins; Female; Glucagon; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Male; Postprandial Period

Postoperative insulin resistance and the consequent hyperglycemia affects clinical outcome. Insulin sensitivity may be modulated by preoperative nutrition, adequate pain management and minimal invasive surgery. This study aims to disclose the impact of perioperative glucose control on postoperative insulin resistance.. Twenty patients scheduled for elective open hepatectomy were enrolled in this prospective, randomized study. In the treatment group (n = 9) insulin was administered intravenously to keep blood glucose between 6 and 8 mmol/l during surgery. The control group (n = 8) received insulin if blood glucose >14 mmol/l. Insulin sensitivity was measured by a hyperinsulinemic normoglycemic clamp (0.8 mU/kg/min), performed on all patients both on the day before surgery and immediately postoperatively. Plasma cortisol, insulin and C-peptide were measured.. There was a significant difference in mean glucose value during surgery. In the control group 8.8 mmol/l (SD 1.5) vs. 6.9 mmol/l (SD 0.4) in the treated group, p = 0.003. In the control group insulin sensitivity decreased to 21.9% ± 16.2% of the preoperative value and in the insulin treated group to 46.8 ± 15.5%, p < 0.005. Insulin levels were significantly higher in the treatment group as well as consequently lower C-peptide levels.. This trial revealed a significant difference in postoperative insulin resistance in the group treated with insulin during surgery.

Topics: Administration, Intravenous; Aged; Blood Glucose; C-Peptide; Female; Glucose Clamp Technique; Hepatectomy; Humans; Hydrocortisone; Hyperglycemia; Insulin; Insulin Resistance; Male; Middle Aged; Perioperative Care; Postoperative Period; Prospective Studies

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

Hyperglycemia during hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine, with methylprednisolone premedication) chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL). To examine whether intensive insulin therapy could improve outcomes, a randomized trial was conducted that compared glargine plus aspart vs. conventional therapy. Intensive insulin did not improve ALL clinical outcomes despite improved glycemic control. Secondary analysis suggests that the choice of antidiabetic pharmacotherapy may influence ALL outcomes.. Hyperglycemia during hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine, with methylprednisolone premedication) chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL).. To examine whether an intensive insulin regimen could improve outcomes compared with conventional antidiabetic pharmacotherapy, a randomized trial was conducted that compared glargine plus aspart vs. conventional therapy (control). Between April 2004 and July 2008, 52 patients newly diagnosed with ALL, Burkitt lymphoma, or lymphoblastic lymphoma who were on hyper-CVAD in the inpatient setting and had a random serum glucose level >180 mg/dL on ≥2 occasions during chemotherapy were enrolled.. The trial was terminated early due to futility regarding ALL clinical outcomes despite improved glycemic control. Secondary analysis revealed that molar insulin-to-C-peptide ratio (I/C) > 0.175 (a surrogate measure of exogenous insulin usage) was associated with decreased overall survival, complete remission duration and progression-free survival (PFS), whereas metformin and/or thiazolidinedione usage were associated with increased PFS. In multivariate analyses, factors that significantly predicted short overall survival included age ≥ 60 years (P = .0002), I/C ≥ 0.175 (P = .0016), and average glucose level ≥ 180 mg/dL (P = .0236). Factors that significantly predicted short PFS included age ≥ 60 years (P = .0008), I/C ≥ 0.175 (P = .0002), high systemic risk (P = .0173) and average glucose level ≥ 180 mg/dL (P = .0249). I/C ≥ 0.175 was the only significant (P = .0042) factor that predicted short complete remission duration.. A glargine-plus-aspart intensive insulin regimen did not improve ALL outcomes in patients with hyperglycemia. Exogenous insulin may be associated with poor outcomes, whereas metformin and thiazolidinediones may be associated with improved outcomes. Analysis of these results suggests that the choice of antidiabetic pharmacotherapy may influence ALL outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blood Glucose; Burkitt Lymphoma; C-Peptide; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Thiazolidinediones; Treatment Outcome; Vincristine; Young Adult

For the last 10 yr, continuous glucose monitoring (CGM) has brought up new insights into the accuracy of blood glucose analysis.. Our objective was to determine how islet graft function was able to influence the various components of dysglycemia after islet transplantation (IT).. We conducted a single-arm open-labeled study with a 3-yr follow-up in a referral center (ClinicalTrial.gov identifiers NCT00446264 and NCT01123187).. Twenty-three consecutive patients with type 1 diabetes (14 islet alone, nine islet after kidney) received IT within 3 months using the Edmonton protocol.. INTERVENTION included 72-h CGM before and 3, 6, 9, 12, 24, and 36 months after transplantation.. Graft function was estimated via β-score, a previously validated index (range 0-8) based on treatment requirements, C-peptide, blood glucose, and glycated hemoglobin.. At the 3-yr visit, graft function persisted in 19 patients (82%), and 10 (43%) remained insulin independent. Glycated hemoglobin decreased in the whole cohort from 8.3% (7.3-9.0%) at baseline to 6.7% (5.9-7.7%) at 3 yr [median (interquartile range), P < 0.01]. Mean glucose, glucose sd, and time spent with glycemia above 10 mmol/liter (hyperglycemia) and below 3 mmol/liter (hypoglycemia) were significantly lower after IT (P < 0.05 vs. baseline). The four CGM outcomes were related to β-score (P < 0.001). However, partial function (β-score >3) was sufficient to abrogate hypoglycemia; suboptimal function (β-score >5) was necessary to significantly improve mean glucose, glucose sd, and hyperglycemia; and optimal function (β score >7) was necessary to normalize them.. The four components of dysglycemia were not equally affected by the degree of islet graft function, which could have important implications for future development of β-cell replacement. A β-score above 3 dramatically reduced the occurrence of hypoglycemia.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Islets of Langerhans Transplantation; Male; Middle Aged; Treatment Outcome

Glucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance.. A randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0-28.3] years; BMI: 26.4 [24.3-28.0] kg/m(2)) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity.. PRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively).. The GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Exenatide; Glucagon-Like Peptide 1; Glucocorticoids; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Peptides; Prednisone; Venoms; Young Adult

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

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

OBJECTIVE To determine if glucose and C-peptide values obtained as part of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study could be used to estimate insulin sensitivity during late pregnancy. RESEARCH DESIGN AND METHODS A total of 78 women enrolled in the HAPO study were recruited for this ancillary study. Venous plasma samples were drawn after an 8- to 10-h fast (time 0) and at 30, 60, 90, and 120 min after a 75-g glucose challenge, which was performed at 24-32 weeks' gestation. Samples were analyzed for plasma glucose, insulin, and C-peptide. Insulin sensitivity was estimated using the established Matsuda and DeFronzo insulin sensitivity index for oral glucose tolerance tests (IS(OGTT)). Insulin sensitivity was also calculated from two other commonly used indexes of insulin sensitivity (that for homeostasis model assessment [IS(HOMA)] and that for quantitative insulin sensitivity check index [IS(QUICKI)]). A new insulin sensitivity index was calculated using the glucose and C-peptide concentrations at 0 and 60 min to derive IS(HOMA C-pep), IS(QUICKI C-pep), and IS(OGTT C-pep). These indexes were then correlated with insulin sensitivity estimated from the IS(OGTT). RESULTS The strongest correlation with the IS(OGTT) was obtained for IS(OGTT C-pep) (r = 0.792, P < 0.001). Further, the correlations of IS(HOMA) (C-pep) and IS(QUICKI C-pep) with IS(OGTT) were also significant (r = 0.676, P < 0.001 and r = 0.707, P < 0.001, respectively). CONCLUSIONS These data suggest that calculated IS(OGTT C-pep) is an excellent predictor of insulin sensitivity in pregnancy and can be used to estimate insulin sensitivity in over 25,000 women participating in the HAPO study.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes, Gestational; Female; Glucose Tolerance Test; Health Status Indicators; Humans; Hyperglycemia; Insulin; Insulin Resistance; Pregnancy; Pregnancy Outcome; Young Adult

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

To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG).. People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6-(2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration.. EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group.. Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG.

Topics: Aged; Blood Glucose; Body Mass Index; C-Peptide; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Male; Middle Aged; Pyrazines; Severity of Illness Index; Sitagliptin Phosphate; Triazoles

We examined whether parenteral regular insulin can prevent diabetes in IA-2 antibody-positive (IA-2A+) relatives of type 1 diabetic patients, using a trial protocol that differed substantially from that of the Diabetes Prevention Trial-1.. Twenty-five IA-2A+ relatives received regular human insulin twice a day for 36 months, during which time they were followed (median [interquartile range; IQR]: 47 [19-66] months) for glucose tolerance, HbA(1c) and islet autoantibodies, together with 25 IA-2A+ relatives (observation/control group) who fulfilled the same inclusion criteria, but were observed for 52 [27-67] months (P=0.58).. Twelve (48%) insulin-treated relatives and 15 (60%) relatives in the control group developed diabetes. There was no difference in diabetes-free survival between the two groups (P=0.97). Five-year progression (95% confidence interval) was 44% (25-69) in the insulin-treated group and 49% (29-70) in the observation group. At inclusion, progressors tended to have a higher pro-insulin/C-peptide ratio than non-progressors when measured 2 hours after a standardized glucose load (median [IQR]: 2.7% [1.8-4.3] vs. 1.6% [1.1-2.1]; P=0.01). No major hypoglycaemic episodes or significant increases in body mass index or diabetes autoantibodies were observed.. Prophylactic injections of regular human insulin were well tolerated, but failed to prevent type 1 diabetes onset in IA-2A+ relatives.

Topics: Adolescent; Adult; Autoantibodies; Belgium; Body Mass Index; C-Peptide; Child; Confidence Intervals; Diabetes Mellitus, Type 1; Female; Genetic Predisposition to Disease; Genotype; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Male; Pedigree; Proinsulin; Time Factors; Young Adult

The initial success of islet transplantation (ITx) is followed by graft dysfunction (GDF) and insulin reintroduction. Exenatide, a GLP-1 agonist, increases insulin and decreases glucagon secretion and has potential for beta-cell regeneration. To improve functional islet mass, exenatide treatment was given to ITx recipients with GDF. The objective of this study was to assess metabolic and hormonal effects of exenatide in GDF. In this prospective, single-arm, nonrandomized study, 11 type 1 diabetes recipients of ITx with GDF had HbA1c, weight, insulin requirements, and 5-h mixed meal tolerance test (MMTT; with/without exenatide given before test) at baseline, 3, 6, and 12 months after initiating exenatide treatment. Baseline MMTT showed postprandial hyperglycemia and hyperglucagonemia. Daily exenatide treatment resulted in improved glucose, increased amylin/insulin ratio, and decreased proinsulin/insulin ratio as assessed by MMTT. Glucagon responses remained unchanged. Exenatide administration 1 h before MMTT showed decreased glucagon and glucose at 0 min and attenuation in their postprandial rise. Time-to-peak glucose was delayed, followed by insulin, proinsulin, amylin, and C-peptide, indicating glucose-driven insulin secretion. Five subjects completed 12-month follow-up. Glucose and glucagon suppression responses after MMTT with exenatide were no longer observed. Retrospective 3-month analysis of these subjects revealed higher and sustained glucagon levels that did not suppress as profoundly with exenatide administration, associated with higher glucose levels and increased C-peptide responses. In conclusion, Exenatide suppresses the abnormal postprandial hyperglucagonemia and hyperglycemia observed in GDF. Changes in amylin and proinsulin secretion may reflect more efficient insulin processing. Different degrees of responsiveness to exenatide were identified. These may help guide the clinical management of ITx recipients.

Topics: Adult; Amyloid; Area Under Curve; C-Peptide; Demography; Diabetes Mellitus, Type 1; Exenatide; Female; Glucagon; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Islet Amyloid Polypeptide; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Peptides; Primary Graft Dysfunction; Prospective Studies; Transplantation, Homologous; Venoms

Topics: Benzodiazepines; Blood Glucose; C-Peptide; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Olanzapine; Reference Values; Risperidone; Selective Serotonin Reuptake Inhibitors

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

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

Hyperglycemia and hyperinsulinemia are common in intensive care unit (ICU) patients and relate to illness severity. Intensive insulin therapy (IIT) to maintain normoglycemia reduces morbidity and mortality. Blood glucose control explains this benefit because a high insulin dose is associated with adverse outcome. Mitogenic insulin effects could theoretically explain this link.. To investigate further the association between insulin dose and adverse outcome, we studied the effect of IIT on circulating insulin levels, markers of insulin sensitivity, and the metabolic and mitogenic insulin signaling molecules in key tissues.. This is a subanalysis of a large randomized, controlled study.. The study was performed in a university hospital surgical ICU.. A total of 339 critically ill patients, treated in ICU for at least a week, were included in this subanalysis.. Strict normoglycemia with IIT compared with conventional insulin therapy was performed.. Severalfold higher insulin doses than with conventional insulin therapy were required to maintain normoglycemia with IIT. However, serum insulin levels were only transiently higher with IIT, despite the much lower blood glucose levels. IIT normalized the elevated serum C-peptide levels and increased circulating adiponectin levels. The metabolic insulin signal was increased by IIT in muscle, but not in liver. The mitogenic insulin signal in either tissue was not affected by IIT.. Normoglycemia can be maintained in ICU patients without a sustained further elevation of insulinemia. Together with the increased adiponectin levels, this finding suggests that IIT may improve insulin sensitivity. Skeletal muscle, but not liver, revealed an increased metabolic insulin signal. The therapy did not impose mitogenic risk in these tissues.

Topics: Adiponectin; Aged; Blood Glucose; C-Peptide; Critical Illness; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Liver; Male; Middle Aged; Muscle, Skeletal; Receptors, Adiponectin; Signal Transduction

The plasma glucose excursion may influence the metabolic responses after oral glucose ingestion. Although previous studies addressed the effects of hyperglycemia in conditions of hyperinsulinemia, it has not been evaluated whether the route of glucose administration (oral vs. intravenous) plays a role. Our aim was to determine the effects of moderately controlled hyperglycemia on glucose metabolism before and after oral glucose ingestion. Eight normal men underwent two oral glucose clamps at 6 and 10 mmol/l plasma glucose. Glucose turnover and cycling rates were measured by infusion of [2H7]glucose. The oral glucose load was labeled by D-[6,6-2H2]glucose to monitor exogenous glucose appearance, and respiratory exchanges were measured by indirect calorimetry. Sixty percent of the oral glucose load appeared in the systemic circulation during both the 6 and 10 mmol/l plasma glucose tests, although less endogenous glucose appeared during the 10 mmol/l tests before glucose ingestion (P < 0.05). This inhibitory effect of hyperglycemia was not detectable after oral glucose ingestion, although glucose utilization was increased (+28%, P < 0.05) due to increased nonoxidative glucose disposal [10 vs. 6 mmol/l: +20%, not significant (NS) before oral glucose ingestion; +40%, P < 0.05 after oral glucose ingestion]. Glucose cycling rates were increased by hyperglycemia (+13% before oral glucose ingestion, P < 0.001; +31% after oral glucose ingestion, P < 0.05) and oral glucose ingestion during both the 6 (+10%, P < 0.05) and 10 mmol/l (+26%, P < 0.005) tests. A moderate hyperglycemia inhibits endogenous glucose production and contributes to glucose tolerance by enhancing nonoxidative glucose disposal. Hyperglycemia and oral glucose ingestion both stimulate glucose cycling.

Topics: Administration, Oral; Blood Glucose; C-Peptide; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Time Factors

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

Low birth weight (LBW) is associated with increased risk of type 2 diabetes mellitus. An impaired incretin effect was reported previously in type 2 diabetic patients.. We studied the secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in young LBW men (n = 24) and matched normal birth weight controls (NBW) (n = 25).. LBW subjects were 5 cm shorter but had a body mass index similar to NBW. LBW subjects had significantly elevated fasting and postprandial plasma glucose, as well as postprandial (standard meal test) plasma insulin and C-peptide concentrations, suggestive of insulin resistance. Insulin secretion in response to changes in glucose concentration ("beta-cell responsiveness") during the meal test was similar in LBW and NBW but inappropriate in LBW relative to insulin sensitivity. Fasting and postprandial plasma GLP-1 and GIP levels were similar in the groups. First- and second-phase insulin responses were similar in LBW and NBW during a hyperglycemic clamp (7 mm) with infusion of GLP-1 or GIP, respectively, demonstrating normal action of these hormones on insulin secretion.. Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young LBW men.

Topics: Adult; Blood Glucose; C-Peptide; Eating; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Infant, Low Birth Weight; Infant, Newborn; Insulin; Insulin Secretion; Islets of Langerhans; Male; Peptide Fragments; Protein Precursors

The vascular endothelium is a site of pathological changes in patients with diabetes mellitus that may be related to severe chronic hyperglycemia. However, it is unclear whether transient hyperglycemia alters vascular function in an otherwise healthy human forearm. To test the hypothesis that acute, moderate hyperglycemia impairs endothelium-dependent forearm vasodilation, we measured vasodilator responses in 25 healthy volunteers (11 F, 14 M) assigned to one of three protocols. In protocol 1, glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance. Protocol 2 involved 6 h of mild hyperglycemia (approximately 7 mmol/l). Protocol 3 involved 6 h of euglycemia. Glucose concentration was maintained with a variable systemic glucose infusion. Insulin concentrations were maintained at approximately 65 pmol/l by means of a somatostatin and "basal" insulin infusion. Glucagon and growth hormone were replaced at basal concentrations. Forearm blood flow (FBF) was calculated from Doppler ultrasound measurements at the brachial artery. In each protocol, FBF dose responses to intrabrachial acetylcholine (ACh) and sodium nitroprusside (NTP) were assessed at baseline and at 60, 180, and 360 min of glucose infusion. Peak endothelium-dependent vasodilator responses to ACh were not diminished by hyperglycemia in any trial. For example, peak responses to ACh during protocol 2 were 307 +/- 47 ml/min at euglycemic baseline and 325 +/- 52, 353 +/- 65, and 370 +/- 70 ml/min during three subsequent hyperglycemic trials (P = 0.46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm.

Topics: Adaptation, Physiological; Adolescent; Adult; Blood Flow Velocity; Blood Glucose; Brachial Artery; C-Peptide; Chronic Disease; Female; Forearm; Glucose Clamp Technique; Hemostasis; Humans; Hyperglycemia; Insulin; Male; Metabolic Clearance Rate; Regional Blood Flow; Ultrasonography

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 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

Although it is well established that severe chronic hyperglycemia is associated with microvascular disease, it is not known whether transient hyperglycemia similar to that observed with impaired glucose tolerance or early Type 2 diabetes contributes to this pathology by altering microvascular function. To test the hypothesis that acute hyperglycemia decreases microvascular vasodilator responsiveness in human skin, we measured the cutaneous vasodilator response to local warming. This response can be divided into two phases, an initial peak that relies predominantly on local sensory nerves and a second slower phase that is largely dependent on endothelial nitric oxide. We reasoned that a change in one or both phases would indicate a change in the corresponding mechanism(s) with hyperglycemia. Twenty-eight healthy volunteers (14 women, 14 men) were randomly divided into three groups, corresponding to 6 h of euglycemia (n = 8), 6 h when glucose was clamped at approximately 7 mmol/l (n = 10), or 6 h when glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance (n = 10). Insulin concentrations in all instances were maintained at approximately 65 pmol/l by means of continuous infusions of somatostatin and insulin. Glucagon and growth hormone were also continuously infused to maintain their basal concentrations. Despite substantial differences in both the level and pattern of glucose concentrations, neither maximum cutaneous vasodilation nor the pattern of the vasodilator response to local warming differed over the 6 h of study. We conclude that acute hyperglycemia similar to levels commonly observed in people with either early Type 2 diabetes or impaired glucose tolerance does not alter the vasodilator response to local warming of the skin in humans.

Topics: Acute Disease; Adult; Blood Glucose; Blood Vessels; C-Peptide; Female; Glucose Intolerance; Hemodynamics; Hot Temperature; Humans; Hyperglycemia; Insulin; Male; Osmolar Concentration; Reference Values; Regional Blood Flow; Skin; Time Factors

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Dietary Carbohydrates; Dietary Fiber; Glucose Intolerance; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Pilot Projects; Postprandial Period

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

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

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

Changes in tumor necrosis factor-alpha (TNF-alpha) may provide a mechanism to explain impaired glucose metabolism with advancing age. Hyperglycemic clamps (180 min, 10 mM) were performed on seven older [67 +/- 2 yr; body mass index (BMI) 24.7 +/- 1.0 kg/m(2)] and seven younger (22 +/- 1 yr; BMI 21.8 +/- 1.3 kg/m(2)) healthy sedentary males with normal glucose tolerance. TNF-alpha production at basal and at the end of 180 min of hyperglycemia and hyperinsulinemia was measured ex vivo from lipopolysaccharide-stimulated (1 ng/ml) peripheral blood mononuclear cells. Plasma glucose, insulin, and C-peptide levels were similar in both groups at basal and during the last 30 min of the hyperglycemic clamp. Glucose infusion rates were lower (P < 0.004) in the older group compared with the young, indicating decreased insulin action among the older subjects. Basal TNF-alpha secretion was similar in older and younger subjects. TNF-alpha was suppressed (P < 0.02) in the younger group (230 +/- 46 vs. 126 +/- 49 pg/ml; basal vs. clamp) but not in the older group (153 +/- 37 vs. 182 +/- 42 pg/ml), with significant group differences in response (P < 0.05). A significant correlation was observed between the level of suppression in TNF-alpha production and insulin action (Kendall's rank, tau = 0.40, P < 0.05). Furthermore, the TNF-alpha response during the clamp was related to fat mass (r = 0.88, P < 0.001) and abdominal fat (r = 0.81, P < 0.003). In conclusion, these findings suggest a possible mechanism by which TNF-alpha may modulate glucose metabolism in younger people. Aging and modest increases in adiposity prevent the "normal" suppression of TNF-alpha production after a sustained postprandial-like hyperglycemic-hyperinsulinemic stimulus, which may contribute in part to the decline in insulin sensitivity in older men.

Topics: Adult; Aged; Aging; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Islets of Langerhans; Male; Monocytes; Tumor Necrosis Factor-alpha

Elevated plasma non-esterified fatty acid (NEFA) levels in obese subjects may contribute to their higher insulin secretory rates by direct effects on the islet B-cells. This may involve short-term metabolic effects, or long-term effects on islet B-cell mass, which is characteristically increased in obesity. We examined the effects of elevating plasma NEFA levels for 5.5 to 7 h on insulin secretion after an overnight fast and during a 90 min 12 mmol/l hyperglycemic clamp in 9 normal women (40.1 +/- 9.5 years [mean +/- SD]; BMI: 25.2 +/- 3.72 kg/m(2) ). Subjects were studied twice. In one study plasma NEFA levels were increased approximately 2-fold by infusion of 20% Intralipid (60 ml/h) and heparin (900 U/h) for 5.5 h before and throughout the glucose clamp. Elevated NEFA levels were associated with a small increase in fasting plasma glucose (5.0 +/- 0.1 vs 4.7 +/- 0.1 mmol/l, P <0.05) and C-peptide levels (0.54 +/- 0.09 vs 0.41 +/- 0.06 nmol/l, P <0.05). The increase in fasting insulin levels did not, however, reach statistical significance (9.0 +/- 2.5 vs 5.3 +/- 1.4 mU/l, NS). During the glucose clamp, plasma NEFA levels were suppressed to very low levels in the saline control study. Although plasma NEFA levels also fell in the lipid/heparin study, they remained significantly higher than on the control day, and somewhat higher than might be expected postprandially in obese subjects. During the glucose clamps, plasma glucose, insulin, and C-peptide profiles were similar on the two study days. No difference in either first or second phase insulin secretion was observed between the two studies. In conclusion, our findings do not support the idea that the exaggerated insulin secretion in obesity is mediated by short-term effects of plasma NEFA levels on islet B-cell metabolism, independent of plasma glucose levels.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Heparin; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Lipids; Triglycerides

The role of the pattern, quantity and site of insulin secretion in the tolerance to a glucose challenge is not fully evaluated in humans because it is difficult to obtain appropriate clinical models.. To address this issue, we studied subjects with reduced pancreatic mass (hemipancreatectomized, HEMI), systemic insulin delivery (pancreas transplant recipients, PTX), and two control groups (healthy, CON; and with uveitis on the same immunosuppression as PTX, UVE), with an hyperglycaemic clamp (study 1, + 4.2 mmol L-1), using a repeat experiment (study 2) with a fixed glucose infusion, calculated to increase by 35% that in study 1.. In study 1, CON increased glucose uptake to 20 +/- 3 micromol kg-1 min-1 after a biphasic insulin response. In study 2, CON further increased the glucose uptake via an increment in prehepatic insulin secretion that stimulated insulin sensitivity without changes in peripheral insulin and glucose concentrations. HEMI and PTX had 35% less glucose uptake in study 1, compared to CON, and increased glucose concentrations (+ 1.6 mmol L-1) in study 2. UVE had an intermediate defect. The causes of intolerance were different: HEMI had a defective first-phase insulin secretion (50% peripheral insulin concentrations) but maintained insulin sensitivity; PTX had normal peripheral insulin but only one-third of the insulin sensitivity of CON.. Hemipancreatectomy and systemic insulin delivery impair first-phase insulin secretion; second-phase peripheral insulinization (HEMI); insulin sensitivity (PTX); and a mechanism evidentiated in study 2 of CON that increases insulin sensitivity in response to prehepatic insulin secretion (both groups). Failure of these mechanisms is largely compensated by hyperglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Feedback; Female; Glucagon; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hydrocortisone; Hyperglycemia; Immunosuppression Therapy; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Pancreas Transplantation; Pancreatectomy

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 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 address the question whether there are simple clinical predictors of need for insulin in the first 18 months of treatment of diabetes presenting in young adult subjects, a prospective study of 24 patients with diabetes mellitus (age: 18-40 years) was designed. At diagnosis of diabetes, age, sex, body mass index (BMI), glycemia, ketonuria, C-peptide, insulin autoantibodies, islet cell antibodies and glutamic acid decarboxylase antibodies were recorded before starting any treatment. At the end of the follow-up (18 +/- 4 months), they were divided into two groups according to their need for insulin therapy: group 1 (n=15; 62%), who needed insulin therapy, and group 2 (n=9; 38%), who did not. Each marker was related to actual need for therapy necessity. Multivariate analysis showed that BMI and age were the variables with greatest predictive value regarding need for insulin. These data reveal that the need for insulin therapy in young adult diabetic patients may be supported by the clinical criteria of age and BMI, which are both easily and quickly determined.

Topics: Adolescent; Adult; Age Factors; Autoantibodies; Biomarkers; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glutamate Decarboxylase; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Ketones; Male; Predictive Value of Tests

Insulin is secreted in a high frequency pulsatile manner. These pulses are delivered directly into the portal vein and then undergo extraction and dilution before delivery into the systemic circulation. The reported frequency of these insulin pulses estimated in peripheral blood varies from an interpulse interval of 4-20 min. We postulated that this discrepancy is due to the attenuation of the pulse signal in the systemic circulation vs. the portal circulation. In the present study we measured pulsatile insulin release directly in the portal circulation of human subjects who had indwelling transjugular intrahepatic portasystemic stent shunts (TIPSS) to decompress portal hypertension. We quantitated pulsatile insulin secretion in both the overnight fasted state (fasting) and during a hyperglycemic clamp (8 mmol/L). Direct portal vein sampling established that pulsatile insulin secretion in humans has an interval (periodicity) of approximately 5 min. The amplitude (and mass) of the insulin concentration oscillations observed in the portal vein was approximately 5-fold greater than that observed in the arterialized vein and was similar to that observed in the dog. Increased insulin release during hyperglycemia was achieved through amplification of the insulin pulse mass. In conclusion, direct portal vein sampling in humans revealed that the interpulse interval of insulin pulses in humans is about 5 min, and this frequency is also observed when sampling from the systemic circulation using a highly specific insulin assay and 1-min sampling, but is about 4-fold greater than the frequency observed at this site using single site RIAs. We confirm that enhanced insulin release in response to hyperglycemia is achieved by amplification of these high frequency pulses.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Insulin; Liver; Liver Function Tests; Male; Middle Aged; Portal Pressure; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic

Acute hyperglycaemia is known to inhibit jejunal interdigestive motility. This study was undertaken to establish the effects of hyperglycaemia on fed jejunal motility and small intestinal transit time, and to establish if the effects of hyperglycaemia are mediated in part by hyperinsulinaemia.. Nine healthy male volunteers were studied in random order using three experimental conditions: (a) euglycaemic clamp [glucose 5 mmol L(-1)]; (b) hyperglycaemic clamp [glucose 15 mmol L(-1)]; and (c) euglycaemic hyperinsulinaemic clamp [glucose 5 mmol L(-l)]. Fed jejunal motility was induced by an intrajejunal perfusion of lipid (Lipofundin medium-chained triglyceride 10%) at 1.5 mL min(-1) [1.5 kcal min(-1)] for 180 min through the most proximal port of a manometry catheter (eight ports spaced at 2-cm intervals) located just distal to the ligament of Treitz. One minute after starting the lipid perfusion, 15 g of lactulose dissolved in 20 mL of tap water was infused. Small intestinal transit time was measured by the hydrogen breath test.. Acute hyperglycaemia reduced the total number of jejunal contractions and progradely propagated contractions, the motility index (P < 0.05) and the mean amplitude of contractions and delayed intestinal transit time. Hyperinsulinaemia reduced the total number of jejunal contractions, motility index (P < 0.05) and intestinal transit time.. Thus, hyperinsulinaemia may contribute to the inhibitory effects of hyperglycaemia on jejunal motility. In addition, this study demonstrated that intrajejunal infusion of lipid stimulates sustained glucagon-like peptide-1 release. In contrast to fat-induced gastric inhibitory polypeptide release, this glucagon-like peptide-1 release is not inhibited by exogenous or endogenous hyperinsulinaemia (P = 0.59).

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Drug Combinations; Gastrointestinal Motility; Gastrointestinal Transit; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Jejunum; Male; Pancreatic Polypeptide; Peptide Fragments; Perfusion; Phospholipids; Protein Precursors; Sorbitol

Oral glucose induces a greater insulin response than i.v. glucose, a difference apparently due to the secretion of gut factors ("incretins"). Studies examining the mechanisms of this finding in human subjects are limited, however, because of differences in glucose profiles. To overcome this obstacle, we studied eight young nonobese subjects using the hyperglycemic clamp with and without superimposed ingestion of oral glucose. In both studies, glucose was acutely raised by 12.5 mg/dL above fasting values by the infusion of i.v. glucose and maintained at this level for 180 min. During the experimental study, but not the control, each subject ingested oral glucose (30 g) at 120 min, and the glucose infusion was adjusted to maintain the plasma glucose plateau. Plasma insulin responses were nearly identical during both studies until oral glucose was added. After oral glucose, both plasma insulin and C-peptide levels sharply increased by 45-55% above control values (p < 0.001), indicating a potentiation of insulin secretion rather than decreased hepatic extraction of insulin. Plasma gastric inhibitory polypeptide (GIP) levels increased significantly in response to oral glucose, whereas plasma levels of glucagon-like peptide-1 (7-37) were not affected. The time course of the rise in plasma GIP and insulin was nearly identical. We conclude that the GIP response to a modest oral glucose load may play an important physiologic role in glucose-stimulated insulin secretion in healthy young subjects.

Topics: Administration, Oral; Adolescent; Adult; C-Peptide; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Peptide Fragments; Peptides; Secretory Rate; Stimulation, Chemical

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

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

The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Central Nervous System; Denervation; Glucagon; Glucose Clamp Technique; Growth Hormone; Homeostasis; Humans; Hydrocortisone; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Resistance; Liver; Liver Transplantation; Middle Aged; Models, Biological; Somatostatin; 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

To determine the respective roles of insulin and glucagon for hepatic glycogen synthesis and turnover, hyperglycemic clamps were performed with somatostatin [0.1 micrograms/(kg.min)] in healthy young men under conditions of: (I) basal fasting) portal vein insulinemia-hypoglucagonemia, (II) basal portal vein insulinemia-basal glucagonemia, and (III) basal peripheral insulinemia-hypoglucagonemia. Synthetic rates, pathway (direct versus indirect) contributions, and percent turnover of hepatic glycogen were assessed by in vivo 13C nuclear magnetic resonance spectroscopy during [1-13C]glucose infusion followed by a natural abundance glucose chase in conjunction with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. In the presence of hyperglycemia (10.4 +/- 0.1 mM) and basal portal vein insulinemia (192 +/- 6 pM), suppression of glucagon secretion (plasma glucagon, I:31 +/- 4, II: 63 +/- 8 pg/ml) doubled the hepatic accumulation of glycogen (Vsyn) compared with conditions of basal glucagonemia [I: 0.40 +/- 0.06, II: 0.19 +/- 0.03 mumol/(liter.min): P < 0.0025]. Glycogen turnover was markedly reduced (I: 19 +/- 7%, II: 69 +/- 12%; P < 0.005), so that net rate of glycogen synthesis increased approximately fivefold (P < 0.001) by inhibition of glucagon secretion. The relative contribution of gluconeogenesis (indirect pathway) to glycogen synthesis was lower during hypoglucagonemia (42 +/- 6%) than during basal glucagonemia (54 +/- 5%; P < 0.005). Under conditions of basal peripheral insulinemia (54 +/- 2 pM) and hypoglucagonemia (III) there was negligible hepatic glycogen synthesis and turnover. In conclusion, small changes in portal vein concentrations of insulin and glucagon independently affect hepatic glycogen synthesis and turnover. Inhibition of glucagon secretion under conditions of hyperglycemia and basal concentrations of insulin results in: (a) twofold increase in rate of hepatic glycogen synthesis, (b) reduction of glycogen turnover by approximately 73%, and (c) augmented percent contribution of the direct pathway to glycogen synthesis compared with conditions of basal glucagonemia.

Topics: Adult; Amino Acids; C-Peptide; Fatty Acids, Nonesterified; Gastrointestinal Agents; Glucagon; Glucose; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Lactates; Lactic Acid; Liver; Male; Models, Biological

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

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

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

Animal studies suggest that hyperglycaemia directly affects local blood flow and vascular reactivity. We studied the effects of 7 h of local forearm hyperglycaemia, on forearm (muscle) and skin microcirculatory blood flow in 12 healthy men. Furthermore, the effects of this local hyperglycaemia on forearm vasoreactivity to noradrenaline were studied. Using the perfused forearm technique, a local hyperglycaemia of approximately 16 mmol/l was induced by continuous intraarterial infusion of 5% glucose. All subjects received both glucose and placebo (0.9% NaCl) infusions on two different occasions, in random order and blinded for the subjects. Forearm (muscle) blood flow and vascular reactivity to noradrenaline were measured using venous occlusion plethysmography. Skin microcirculatory blood flow was evaluated using intravital capillary microscopy (nutritive blood flow) and laser-Doppler fluxmetry (thermoregulatory blood flow). Measurements were performed at baseline, after 4 h, and after 7 h of intraarterial glucose or placebo infusion. During local glucose infusion there was a slight increase in the levels of insulin, C-peptide, systemic glucose, and blood pressure, compared to the placebo experiments. No differences were observed in forearm blood flow and laser-Doppler flux ratio (infused: contralateral arm), as well as in capillary blood cell velocity between glucose and placebo experiments. Noradrenaline produced similar reductions in forearm blood flow ratio during glucose and placebo experiments. We conclude that in contrast to animal studies, local hyperglycaemia (approximately 16 mmol/l) for 7 h does not affect forearm macro and microcirculatory blood flow or vascular reactivity to noradrenaline in man.

Topics: Adult; Animals; Blood Glucose; Blood Pressure; C-Peptide; Epinephrine; Forearm; Glucose; Glucose Clamp Technique; Heart Rate; Humans; Hyperglycemia; Infusions, Intra-Arterial; Insulin; Lactates; Male; Microcirculation; Muscles; Norepinephrine; Pyruvates; Reference Values; Regional Blood Flow; Single-Blind Method; Skin; Time Factors

To assess the influence of enteric factors on insulin action, seven lean healthy subjects were studied under conditions of hyperinsulinemic euglycemic glucose clamp, double isotope administration, and enteral vs. parenteral glucose infusion. In random order, glucose and mannitol radiolabeled with [2-3H]glucose were infused intraduodenally for 4 h while the systemic rate of glucose turnover was assessed by [6-14C]glucose. During the final hour of the study, plasma glucose, insulin, C-peptide, glucagon, cholecystokinin, and neurotensin were similar under both experimental conditions. Despite an increase in gastric inhibitory polypeptide concentration during combined enteral and iv glucose infusion to levels that mimicked meal ingestion, total glucose infusion rate, insulin-induced stimulation of glucose uptake, and insulin-induced suppression of hepatic glucose release were comparable to those observed during iv glucose administration. These data indicate that under conditions of modest hyperinsulinemia and euglycemia, gastric inhibitory polypeptide did not influence hepatic or extrahepatic insulin action.

Topics: Adult; Blood Glucose; C-Peptide; Cholecystokinin; Duodenum; Female; Gastric Inhibitory Polypeptide; Glucose; Humans; Hyperglycemia; Hyperinsulinism; Infusions, Parenteral; Insulin; Liver; Male; Mannitol; Spleen

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

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

Thirty-eight patients with insulin dependent diabetes mellitus who had background retinopathy and no residual endogenous insulin secretion as assessed by plasma C-peptide determinations, were randomized to either conventional insulin treatment or to more intensive glucose control using ultralente insulin as basal cover and soluble insulin at mealtimes and were followed for five years. Plasma glucose profile and glycosylated hemoglobin were determined every eight weeks. Eye examinations were performed at the start of the study and after one, three and five years. Age, duration of diabetes, insulin dosage, glycemic control were comparable in the two groups. The mean plasma glucose profile was similar at entry in both groups and did not change in the conventionally-treated group. Mean plasma glucose profile 11.2 +/- 1 mmol/l with glycosylated hemoglobin level 10.7 +/- 0.3% fell to 7.9 +/- 0.4 mmol/l and 8.7 +/- 0.5% respectively during intensive treatment. Retinal morphology deteriorated during the follow-up with no significant differences between patients under unchanged conventional treatment and intensive insulin regimen. Proliferative retinopathy developed in six patients--three of these were under intensive insulin treatment. These data suggest that substantial long-term improvement of glycemic control does not affect progression of background retinopathy even when it is mild. The evolution of established retinopathy in insulin dependent diabetic patients is not only a function of poor glycemic control; other factors, either intrinsic or environmental, must also be important.

Topics: Adult; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin, Long-Acting; Male; Middle Aged; Prospective Studies; Random Allocation

1 The effects of oral doses of pindolol (15 mg), metoprolol (200 mg) and propranolol (160 mg) on the response to insulin-induced hypoglycaemia and an oral glucose load were investigated. 2 Serum insulin and serum C-peptide secretion in response to a glucose load were inhibited (2P less than 0.01) by metoprolol and propranolol but not by pindolol. 3 During hypoglycaemia metoprolol and propranolol inhibited the clearance of insulin (2P less than 0.01) and caused a delay of glucose nadirs. 4 Adrenaline secretion during hypoglycaemia was markedly increased by metoprolol and propranolol but not by pindolol. 5 The counterregulatory response of growth hormone, ACTH and cortisol was increased following metoprolol and propranolol but not after pindolol. 6 The hypoglycaemic symptoms and signs showed a prevalence of sweating and prolonged changes in skin conductivity whereas palpitations were not observed during beta-adrenoceptor blockade. Asymptomatic hypoglycaemia did not occur. 7 The absence of unphysiological rises in adrenaline, growth hormone, ACTH and cortisol supports the use of a beta-adrenoceptor blocker with intrinsic sympathomimetic activity.

Topics: Adrenergic beta-Antagonists; Adult; Blood Glucose; C-Peptide; Catecholamines; Glucose Tolerance Test; Heart Rate; Hormones; Humans; Hyperglycemia; Hypoglycemia; Insulin; Male; Sympathomimetics

A peak period of hyperglycaemia in insulin-dependent diabetics occurs after breakfast. A randomised crossover study was performed on nine diabetic children at home to study the effect of varying the time of their morning mixed injection of Monotard and Actrapid insulin on this hyperglycaemic peak. Performing the study at home minimised the children's stress.After diabetic control had been improved children injected their insulin 30 minutes (early injection) or five minutes (late injection) before breakfast on two consecutive Saturday mornings. Blood samples were taken at 30-minute intervals over 3(1/2) hours and analysed for concentrations of glucose, insulin, C-peptide, pyruvate, lactate, alanine, and ketones. Diet, insulin dose, and exercise were kept the same on both test days.The mean blood glucose concentration at breakfast (0 minutes) was 11 mmol/l after the early injection and 10 mmol/l after the late injection. Subsequent concentrations were consistently lower with the early injection regimen than the late regimen. The greatest difference between values in the two groups was 3.7 mmol/l at 150 minutes. Mean plasma insulin concentrations were lower in the children on the early regimen than in those on the late regimen at 30 minutes before breakfast but higher at 0 minutes and thereafter. There were no significant differences in mean concentration of intermediary metabolites between the two injection regimens. These were mainly within the normal range for healthy young adults except for the ketone concentrations, which were raised with both injection regimens until 180 minutes after breakfast.These results suggest that the timing of the morning injection of insulin is important in the control of postprandial hyperglycaemia in diabetic children.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Drug Administration Schedule; Food; Humans; Hyperglycemia; Insulin; Ketones; Time Factors

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

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

Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C-peptide supplementation using osmotic pumps or biopolymer-conjugated C-peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor-induced pathological events, but not hyperglycemia-induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C-peptide inhibited hyperglycemia-induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C-peptide supplementation alleviates hyperglycemia-induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dietary Supplements; Hyperglycemia; Mice; Reactive Oxygen Species; Retina; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Type 1 diabetes mellitus (T1DM) is a common chronic systemic disease that threatens the health of children worldwide. Diabetic ketoacidosis (DKA) is the most severe acute complication of diabetes and can lead to death. This study aimed to explore the epidemiological features, clinical manifestations, and risk factors for DKA in children and adolescents newly diagnosed with T1DM in the Department of Endocrinology of the Children's Hospital of Henan Province.. Medical records of 683 children and adolescents newly diagnosed with T1DM in our center from March 2014 to November 2021 were retrospectively analyzed. The data included the general condition, laboratory indexes, and clinical symptoms. The patients were divided into three groups according to age: Group I, 0-3 years; Group II, 4-9 years; and Group III, 10-18 years.. The incidence of DKA was 62.96% and was highest in Group I. Group I had the lowest C-peptide and hemoglobin A1c, but the highest blood glucose at first diagnosis, and 25-hydroxyvitamin D3 levels, hospitalization lengths, and medical costs. 25.5% of the children were delayed in diagnosis. Logistic regression analysis showed that elevated HbA1c levels and hyperglycemia were independent risk factors for DKA. On the other hand, C-peptide and 25- hydroxyvitamin D were protective factors for DKA.. The incidence of DKA among children and adolescents in the Henan Province is very high. Moreover, DKA can be easily delayed in diagnosis. Newly diagnosed infants with T1DM are more likely to present with DKA, suffer more severe metabolic disorders, endure longer hospital stays, and accrue higher medical costs.

Topics: Adolescent; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Glycated Hemoglobin; Humans; Hyperglycemia; Infant; Infant, Newborn; Retrospective Studies; Risk Factors

Topics: Animals; C-Peptide; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Humans; Hyperglycemia; Mice; Neovascularization, Pathologic; Retinal Neovascularization

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [-59.1% to -91.6%]; ΔC-peptide:glucose, -76.3% [-49.2% to -90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.

Topics: Allografts; C-Peptide; Humans; Hyperglycemia; Islets of Langerhans Transplantation; Peptides

Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death.. In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated.. Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)].. In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients.

Topics: Brain Death; C-Peptide; Cell Death; Cell-Free Nucleic Acids; Humans; Hyperglycemia; Insulin; Islets of Langerhans Transplantation; MicroRNAs; Tissue Donors

Over the last 13 years, the Immune Tolerance Network (ITN), has conducted trials of agents to abrogate the autoimmunity underlying type 1 diabetes. Primary endpoints center on the change of C-peptide production during mixed meal tolerance tests (MMTT), measured as the area under the curve (AUC) or AUC mean over 2-3 years. Studies permit rapid-acting insulin until a few hours before the MMTT, and thus do not exclude overnight hyperglycemia prior to testing. We hypothesize that overnight or fasting hyperglycemia will deplete pre-formed insulin and impact measurements of first-phase insulin secretion and C-peptide AUC.. Publicly available, deidentified, subject-level data were obtained from ITN TrialShare. We developed several graphical analyses to reexamine results from each MMTT including combined glucose and C-peptide response curves, the centroids of polygons of MMTT timepoints, and ratios comparing extents of excursions of glucose and c-peptide production.. We have applied these graphical analyses to 1161 MMTT from 245 subjects in 8 studies. Graphical analyses of MMTT results for individuals over the course of the follow-up period reflect the expected loss of c-peptide and higher blood glucose during MMTT; centroids move accordingly, upwards and leftwards.. We were able to analyze MMTT data from ITN studies with several graphical analyses. We are poised to apply these approaches to test our central hypothesis by comparing how deviations from modeled rates of predicted changes for an individual over time correlate with blood glucose levels in the hours before a MMTT. This may lead to refinement of future trial protocols to ensure tighter regulation of glycemic excursions ahead of provocative testing.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucose; Humans; Hyperglycemia

Proinsulin C-peptide has a protective effect against diabetic complications; however, its role in hyperglycemia-induced pulmonary fibrosis is unknown. In this study, we investigated the inhibitory effect of C-peptide on hyperglycemia-induced pulmonary fibrosis and the molecular mechanism of C-peptide action in the lungs of diabetic mice and in human pulmonary microvascular endothelial cells (HPMVECs). We found that, in the lungs of diabetic mice, C-peptide supplementation using osmotic pumps attenuated hyperglycemia-induced pulmonary fibrosis and expression of fibrosis-related proteins. In HPMVECs, C-peptide inhibited vascular endothelial growth factor-induced adherens junction disruption and endothelial cell permeability by inhibiting reactive oxygen species generation and transglutaminase (TGase) activation. In the lungs, C-peptide supplementation suppressed hyperglycemia-induced reactive oxygen species generation, TGase activation, and microvascular leakage. C-peptide inhibited hyperglycemia-induced inflammation and apoptosis, which are involved in the pathological process of pulmonary fibrosis. We also demonstrated the role of TGase2 in hyperglycemia-induced vascular leakage, inflammation, apoptosis, and pulmonary fibrosis in the lungs of diabetic TGase2-null (Tgm2-/-) mice. Furthermore, we demonstrated a long-term inhibitory effect of systemic delivery of C-peptide using K9-C-peptide hydrogels on hyperglycemia-induced fibrosis in diabetic lungs. Overall, our findings suggest that C-peptide alleviates hyperglycemia-induced pulmonary fibrosis by inhibiting TGase2-mediated microvascular leakage, inflammation, and apoptosis in diabetes.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Endothelial Cells; Hyperglycemia; Inflammation; Mice; Mice, Inbred C57BL; Protein Glutamine gamma Glutamyltransferase 2; Pulmonary Fibrosis; Reactive Oxygen Species; Transglutaminases; Vascular Endothelial Growth Factor A

The role of executive functions (EF) is to maintain particular behaviours in order to achieve intended goals. EF are crucial in management of pre-diabetes, diabetes and obesity which are grievous diseases and can lead to severe complications. The aims of our study were to: assess EF in group of obese subject with carbohydrate disorders, evaluate whether biochemical factors and comorbidities related to metabolic disorders have adverse effect on EF in this group of patients.. The study included 185 obese patients (146 women; 39 men) who were divided on three groups: pre-diabetic, diabetic and control subgroup. Patient underwent Wisconsin Card Sorting Test (WCST) to evaluate EF. Assessed biochemical factors included C-peptide, fasting plasma glucose (FPG) and glycosylated hemoglobin A1c (HbA1c).. Diabetic patients showed the worst WCST scores among the rest of groups. Pre-diabetic individuals did not differ in EF performance from control subgroup. We observed significant correlations between FPG and HbA1c and worse WCST scores in pre-diabetic subgroup. In diabetic patients C-peptide correlated with poorer EF. Depressive symptoms and hypertension significantly correlated with non-perseverative errors in WCST.. The subgroup of diabetic patients were the most obese and had the worst glycemia parameters. They also showed the worst EF in WCST. According to obtained results, hyperglycemia positively correlated with poor EF in pre-diabetes. However, in diabetic subjects cognitive deterioration may results from insulin resistance rather than hyperglycemia. In obese individuals with carbohydrate disorders both hypertension and depressive symptoms significantly contributed to EF dysfunction.

Topics: C-Peptide; Carbohydrate Metabolism; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Male; Obesity; Prediabetic State; Prefrontal Cortex

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

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

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 examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity.. Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study.. In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30 min and 1 h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30 min, 1 h and 2 h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (β = 1.388; 95% CI 0.870, 1.906; p < 0.001; β = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (β = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (β = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model.. This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

Topics: Adiposity; Adult; Age Factors; Biomarkers; Birth Weight; Blood Glucose; C-Peptide; Child; Female; Fetal Blood; Follow-Up Studies; Humans; Hyperglycemia; Infant, Newborn; Insulin Resistance; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Risk Assessment; Risk Factors; Skinfold Thickness; Young Adult

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

Currently, there is a lack of data relating to glycemic parameters and their relationship with C-peptide (CP) and proinsulin (PI) during the partial remission period (PRP) in type 1 diabetes mellitus (T1D). The aim of this study was to evaluate glycemic parameters in children with T1D who are in the PRP using intermittently scanned continuous glucose monitoring systems (isCGMS) and to investigate any relationships between CP and PI levels.. The study included 21 children who were in the PRP and 31 children who were not. A cross-sectional, non-randomized study was performed. Demographic, clinical data were collected and 2 week- isCGMS data were retrieved.. The Serum CP showed a positive correlation with time-in-range in the PRP (p:0.03), however PI showed no correlations with glycemic parameters in both periods. The Serum CP and PI levels and the PI:CP ratio were significantly higher in the PRP group than in the non-PRP group. In the non-PRP group, the PI level was below 0.1 pmol/L (which is the detectable limit) in only 2 of the 17 cases as compared with none in the PRP group. Similarly, only 2 of the 17 children in the non-PRP group had CP levels of less than 0.2 nmol / L, although both had detectable PI levels. Overall time-in-range (3. 9-1.0 mmol/L) was significantly high in the PRP group. In contrast, the mean sensor glucose levels, time spent in hyperglycemia, and coefficient of variation levels (32.2vs 40.5%) were significantly lower in the PRP group.. Although the mean glucose and time in range during the PRP was better than that in the non-PRP group, the glycemic variability during this period was not as low as expected. While the CP levels showed an association with TIR during the PRP, there was no correlation between PI levels and glycemic parameters. Further studies are needed to determine if PI might prove to be a useful parameter in clinical follow-up.

Topics: Adolescent; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Child; Child, Preschool; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Proinsulin; Remission, Spontaneous

Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity.. Data on mother/offspring pairs (. In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI,. Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity.

Topics: Adiposity; Blood Glucose; Body Mass Index; C-Peptide; Child; Female; Fetal Blood; Follow-Up Studies; Humans; Hyperglycemia; Pediatric Obesity; Pregnancy; Pregnancy Outcome

Medicinal uses and applications of metals and their complexes are of increasing clinical and commercial importance. The ligation behavior of quercetin (Q), which is a flavonoid, and its Zn (II) (Q/Zn) complex were studied and characterized based on elemental analysis, molar conductance, Fourier-transform infrared (FTIR) spectra, electronic spectra, proton nuclear magnetic resonance (1H-NMR), thermogravimetric analysis, and transmission electron microscopy (TEM). FTIR spectral data revealed that Q acts as a bidentate ligand (chelating ligand) through carbonyl C(4) = O oxygen and phenolic C(3)-OH oxygen in conjugation with Zn. Electronic, FTIR, and 1H-NMR spectral data revealed that the Q/Zn complex has a distorted octahedral geometry, with the following chemical formula: [Zn(Q)(NO3)(H2O)2].5H2O. Diabetes was induced by streptozotocin (STZ) injection. A total of 70 male albino rats were divided into seven groups: control, diabetic untreated group and diabetic groups treated with either MSCs and/or Q and/or Q/Zn or their combination. Serum insulin, glucose, C-peptide, glycosylated hemoglobin, lipid profile, and enzymatic and non-enzymatic antioxidant levels were determined. Pancreatic and lung histology and TEM for pancreatic tissues in addition to gene expression of both SOD and CAT in pulmonary tissues were evaluated. MSCs in combination with Q/Zn therapy exhibited potent protective effects against STZ induced hyperglycemia and suppressed oxidative stress, genotoxicity, glycometabolic disturbances, and structural alterations. Engrafted MSCs were found inside pancreatic tissue at the end of the experiment. In conclusion, Q/Zn with MSC therapy produced a synergistic effect against oxidative stress and genotoxicity and can be considered potential ameliorative therapy against diabetes with pulmonary dysfunction, which may benefit against COVID-19.

Topics: Animals; Blood Glucose; C-Peptide; Cells, Cultured; Coordination Complexes; Diabetes Mellitus, Experimental; Glycated Hemoglobin; Hyperglycemia; Hypoglycemic Agents; Insulin; Lung; Male; Mesenchymal Stem Cell Transplantation; Oxidative Stress; Quercetin; Rats; Zinc

Topics: Acute Disease; Aged; Blood Glucose; C-Peptide; ChAdOx1 nCoV-19; Comorbidity; COVID-19; COVID-19 Vaccines; Emergencies; Humans; Hyperglycemia; Hypertension; Male; Metabolic Syndrome; Middle Aged; Prediabetic State; SARS-CoV-2

BACKGROUNDResidual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known.METHODSWe studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017-0.200; n = 16), intermediate (>0.200-0.400; n = 15), or high (>0.400; n = 17). We compared the groups' glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp.RESULTSLow and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group.CONCLUSIONThese results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control.FUNDINGFunding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon-Secreting Cells; Humans; Hyperglycemia; Insulin-Secreting Cells; Male; Middle Aged

Energy balance-related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear.. We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A. The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA. These results further support hypotheses that systemic biomarkers of metabolic health-inflammation and abnormal glucose homeostasis-mediate part of the relationship between several energy balance-related modifiable factors and colorectal cancer risk.. Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors.

Topics: Aged; Biomarkers; Body Mass Index; C-Peptide; Colorectal Neoplasms; Energy Metabolism; Exercise; Feeding Behavior; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperinsulinism; Incidence; Inflammation; Male; Middle Aged; Prospective Studies; Receptors, Immunologic; Risk Assessment

We investigated the impact of postreperfusion syndrome (PRS) on hyperglycemia occurrence and connecting (C) peptide release, which acts as a surrogate marker for insulin resistance, during the intraoperative period after graft reperfusion in patients undergoing living donor liver transplantation (LDLT) using propensity score (PS)-matching analysis.. Medical records from 324 adult patients who underwent elective LDLT were retrospectively reviewed, and their data were analyzed according to PRS occurrence (PRS vs. non-PRS groups) using the PS-matching method. Intraoperative levels of blood glucose and C-peptide were measured through the arterial or venous line at each surgical phase. Hyperglycemia was defined as a peak glucose level >200 mg/dL, and normal plasma concentrations of C-peptide in the fasting state were taken to range between 0.5 and 2.0 ng/mL.. After PS matching, there were no significant differences in pre- and intra-operative recipient findings and donor-graft findings between groups. Although glucose and C-peptide levels continuously increased through the surgical phases in both groups, glucose and C-peptide levels during the neohepatic phase were significantly higher in the PRS group than in the non-PRS group, and larger changes in levels were observed between the preanhepatic and neohepatic phases. There were higher incidences of C-peptide levels >2.0 ng/mL and peak glucose levels >200 mg/dL in the neohepatic phase in patients with PRS than in those without. PRS adjusted for PS with or without exogenous insulin infusion was significantly associated with hyperglycemia occurrence during the neohepatic phase.. Elucidating the association between PRS and hyperglycemia occurrence will help with establishing a standard protocol for intraoperative glycemic control in patients undergoing LDLT.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Insulin Infusion Systems; Insulin Resistance; Liver Transplantation; Living Donors; Male; Middle Aged; Propensity Score; Reperfusion; Stress, Physiological; Syndrome

To investigate the incretin axis in people with cystic fibrosis.. Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min.. Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

Topics: Adult; C-Peptide; Cystic Fibrosis; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Incretins; Infusions, Intravenous; Insulin; Male

Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance.. To determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns.. Cross-sectional, observational study.. Hyperglycemia and Adverse Pregnancy Outcome study.. One thousand six hundred multiethnic mother-newborn pairs.. Cord blood C-peptide, birthweight, and newborn sum of skinfolds.. Meta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes.. Cord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.

Topics: Adiposity; Adult; Anthropometry; Biomarkers; Birth Weight; C-Peptide; Cross-Sectional Studies; Ethnicity; Female; Fetal Blood; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Infant, Newborn; Male; Metabolomics; Native Hawaiian or Other Pacific Islander; Obesity; Pregnancy; Pregnancy Outcome; Severity of Illness Index

C-peptide has a beneficial effect against diabetic complications, but its role in hyperglycemia-induced metastasis is unknown. We investigated hyperglycemia-mediated pulmonary vascular leakage and metastasis and C-peptide inhibition of these molecular events using human pulmonary microvascular endothelial cells (HPMVECs) and streptozotocin-induced diabetic mice. VEGF, which is elevated in the lungs of diabetic mice, activated transglutaminase 2 (TGase2) in HPMVECs by sequential elevation of intracellular Ca

Topics: Animals; Apoptosis; C-Peptide; Diabetes Mellitus, Experimental; Female; GTP-Binding Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Protein Glutamine gamma Glutamyltransferase 2; Reactive Oxygen Species; Transglutaminases; Vascular Endothelial Growth Factor A

A potential therapeutic strategy for diabetes is the transplantation of induced-insulin secreting cells. Based on the common embryonic origin of liver and pancreas, we studied the potential of adult human liver stem-like cells (HLSC) to generate in vitro insulin-producing 3D spheroid structures (HLSC-ILS). HLSC-ILS were generated by a one-step protocol based on charge dependent aggregation of HLSC induced by protamine. 3D aggregation promoted the spontaneous differentiation into cells expressing insulin and several key markers of pancreatic β cells. HLSC-ILS showed endocrine granules similar to those seen in human β cells. In static and dynamic in vitro conditions, such structures produced C-peptide after stimulation with high glucose. HLSC-ILS significantly reduced hyperglycemia and restored a normo-glycemic profile when implanted in streptozotocin-diabetic SCID mice. Diabetic mice expressed human C-peptide and very low or undetectable levels of murine C-peptide. Hyperglycemia and a diabetic profile were restored after HLSC-ISL explant. The gene expression profile of in vitro generated HLSC-ILS showed a differentiation from HLSC profile and an endocrine commitment with the enhanced expression of several markers of β cell differentiation. The comparative analysis of gene expression profiles after 2 and 4 weeks of in vivo implantation showed a further β-cell differentiation, with a genetic profile still immature but closer to that of human islets. In conclusion, protamine-induced spheroid aggregation of HLSC triggers a spontaneous differentiation to an endocrine phenotype. Although the in vitro differentiated HLSC-ILS were immature, they responded to high glucose with insulin secretion and in vivo reversed hyperglycemia in diabetic SCID mice.

Topics: Adult; Animals; Biomarkers; C-Peptide; Cell Differentiation; Diabetes Mellitus, Experimental; Gene Expression Regulation; Glucose; Humans; Hyperglycemia; Insulin-Secreting Cells; Islets of Langerhans; Liver; Male; Mice, SCID; Phenotype; Protamines; Spheroids, Cellular; Stem Cells

(1) Examine associations of a branched-chain amino acid (BCAA) metabolite pattern with metabolic risk across adolescence; (2) use Least Absolute Shrinkage and Selection Operator (LASSO) to identify novel metabolites of metabolic risk.. We used linear regression to examine associations of a BCAA score with change (∆) in metabolic biomarkers over 5-year follow-up in 179 adolescents 8-14 years at baseline. Next, we applied LASSO, a regularized regression technique well suited for reduction of high-dimensional data, to identify metabolite predictors of ∆biomarkers.. In boys, the BCAA score corresponded with decreasing C-peptide, C-peptide-based insulin resistance (CP-IR), total cholesterol (TC), and low-density-lipoprotein cholesterol (LDL). In pubertal girls, the BCAA pattern corresponded with increasing C-peptide and leptin. LASSO identified asparagine as a predictor of decreasing C-peptide (β = -0.33) and CP-IR (β = -0.012), and acetyl-carnitine (β = 2.098), 4-hydroxyproline (β = -0.050), ornithine (β = -0.353), and α-aminoisobutyric acid (β = -0.793) as determinants of TC in boys. In girls, histidine was a negative determinant of TC (β = -0.033).. The BCAA pattern was associated with ∆glycemia and ∆lipids in a sex-specific manner. LASSO identified asparagine, which influences growth hormone secretion, as a determinant of decreasing C-peptide and CP-IR in boys, and metabolites on lipid metabolism pathways as determinants of decreasing cholesterol in both sexes.

Topics: Acetylcarnitine; Adolescent; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Asparagine; Biomarkers; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Carnitine; Child; Cholesterol; Female; Humans; Hydroxyproline; Hyperglycemia; Insulin Resistance; Leptin; Male; Metabolome; Ornithine; Prospective Studies; Puberty; Regression Analysis; Risk Factors

Explore the maternal body mass index (BMI) relationship with peripheral deiodinase activity further. Examine associations between deiodinase activity, glucose, and C-peptide. Consider findings in the historical context of related existing literature.. Identify fasting plasma samples and selected demographic, biophysical, and biochemical data from a subset of 600 randomly selected non-Hispanic white women recruited in the Hyperglycemia Adverse Pregnancy Outcomes (HAPO) study, all with glucose tolerance testing [545 samples sufficient to measure TSH, free T4 (fT4), and T3]. Exclude highest and lowest 1% TSH values (535 available for analysis). Assess deiodinase activity by using T3/fT4 ratios. Among women with and without gestational diabetes mellitus (GDM), compare thyroid measurements, C-peptide, and other selected data. Examine relationships independent of GDM status between BMI and thyroid hormones and between thyroid hormones and glucose and C-peptide.. Levels of BMI, T3/fT4 ratio, and T3 were significantly higher among women with GDM (P = 0.01, 0.005, and 0.001, respectively). Irrespective of GDM status, maternal BMI was associated directly with both T3/fT4 ratio (r = 0.40, P < 0.001) and T3 (r = 0.34, P < 0.001) but inversely with fT4 (r = -0.21, P < 0.001). In turn, fasting thyroid hormone levels (most notably T3/fT4 ratio) were directly associated with maternal glucose [z score sum (fasting, 1, 2 hours); r = 0.24, P < 0.001] and with C-peptide [z score sum (fasting, 1 hour); r = 0.27, P < 0.001].. Higher BMI was associated with increased deiodinase activity, consistent with reports from elsewhere. Increased deiodinase activity, in turn, was associated with higher glucose. Deiodinase activity accounts for a small percentage of z score sum glucose.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes, Gestational; Fasting; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Iodide Peroxidase; Pregnancy; Pregnancy Outcome; Retrospective Studies; White People; Young Adult

Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear.. To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals.. Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion.. Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study.. EGP.. Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects.. Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucagon; Gluconeogenesis; Glucose; Glucose Clamp Technique; Glycogenolysis; Healthy Volunteers; Humans; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Middle Aged; Tritium

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

In type 1 diabetes, a renewable source of human pancreatic β cells, in particular from human induced pluripotent stem cell (hiPSC) origin, would greatly benefit cell therapy. Earlier work showed that pancreatic progenitors differentiated from human embryonic stem cells in vitro can further mature to become glucose responsive following macroencapsulation and transplantation in mice. Here we took a similar approach optimizing the generation of pancreatic progenitors from hiPSCs. This work demonstrates that hiPSCs differentiated to pancreatic endoderm in vitro can be efficiently and robustly generated under large-scale conditions. The hiPSC-derived pancreatic endoderm cells (HiPECs) can further differentiate into glucose-responsive islet-like cells following macroencapsulation and in vivo implantation. The HiPECs can protect mice from streptozotocin-induced hyperglycemia and maintain normal glucose homeostasis and equilibrated plasma glucose concentrations at levels similar to the human set point. These results further validate the potential use of hiPSC-derived islet cells for application in clinical settings.

Topics: Animals; Biomarkers; Blood Glucose; C-Peptide; Cell Differentiation; Diabetes Mellitus, Experimental; Disease Models, Animal; Endoderm; Fluorescent Antibody Technique; Humans; Hyperglycemia; Immunophenotyping; Induced Pluripotent Stem Cells; Insulin; Insulin-Secreting Cells; Mice; Models, Biological; Stem Cell Transplantation; Treatment Outcome

A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission. Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Blood Glucose; C-Peptide; Carcinoma, Renal Cell; Diabetes Mellitus, Type 1; Humans; Hyperglycemia; Insulin; Kidney Neoplasms; Male; Nivolumab

Anti-programmed cell death-1 (PD-1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute-onset insulin-dependent diabetes after anti-PD-1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti-PD-1 therapy. We describe an atypical case of hyperglycemia after anti-PD-1 antibody administration. A 68-year-old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA-A*24:02 and -DRB1*09:01) and resistant (HLA-DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti-PD-1 antibody-induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; HLA Antigens; Humans; Hyperglycemia; Insulin; Insulin Secretion; Lung Neoplasms; Male; Nivolumab

Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear.. We sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance.. This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance.. An inpatient clinical research unit at an academic medical center.. A total of 310 nondiabetic persons participated in this study.. Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control.. We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants.. Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of β-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations.. In nondiabetic participants, glucagon secretion was altered by changes in insulin action.

Topics: Biomarkers; Blood Glucose; C-Peptide; Cross-Sectional Studies; Female; Follow-Up Studies; Glucagon; Glucagon-Secreting Cells; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Prediabetic State; Prognosis

Adipose stem cell (ASC) transplantation is a promising therapeutic strategy for diabetic renal fibrosis. Hypoxia-inducible factor 1α (HIF1α) is a negative regulatory factor of mitochondrial function. In the current study, we aimed to explore if HIF1α deletion protects against hyperglycemia-induced ASC damage and enhances the therapeutic efficiency of ASCs in diabetic renal fibrosis. Our data indicated that HIF1α was upregulated in ASCs in response to high glucose stimulation. Higher HIF1α expression was associated with ASC apoptosis and proliferation arrest. Loss of HIF1α activated mitophagy protecting ASCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting HIF1α-deleted ASCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c, and inflammatory markers. In addition, the engraftment of HIF1α-modified ASCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that HIF1α-modified ASCs reduced renal fibrosis. Collectively, our results demonstrate that ASCs may be a promising therapeutic treatment for ameliorating diabetes and the development of renal fibrosis and that the loss of HIF1α in ASCs may further increase the efficiency of stem cell-based therapy. These findings provide a new understanding about the protective effects of HIF1α silencing on ASCs and offer a new strategy for promoting the therapeutic efficacy of ASCs in diabetic renal fibrosis.

Topics: Adipocytes; Animals; Apoptosis; Blood Glucose; C-Peptide; Cell Proliferation; Diabetes Complications; Diabetes Mellitus, Experimental; Fibrosis; Gene Deletion; Glucose; Glycated Hemoglobin; Hyperglycemia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Kidney; Mice; Mitophagy; Stem Cells; Up-Regulation

We aim to investigate the relationship between serum somatostatin (SST) levels and glucose-lipid metabolism at various stages of glucose tolerance in the Jino ethnic minority (n=111) and Han population (n=113) of Yunnan Province, southwest China. Anthropometric parameters and biochemical traits were measured. Serum SST and plasma glucagon levels were tested. Participants were divided into three subgroups: isolated fasting hyperglycemia (IFH), isolated post challenge hyperglycemia (IPH) and normal glucose tolerance (NGT). SST levels were found lower while glucagon levels were significantly higher in the Jino ethnic with IPH (P=0.0026 and P=0.0069, respectively). Fasting glucose and high density lipoprotein-cholesterol (HDL-C) levels were higher (P=0.0055 and P=0.0021, respectively) and fasting insulin levels and homeostasis model assessments β-cell function were lower (P=0.0479 and P=0.0007, respectively) in the Jino population. After adjusting for confounding factors, the serum SST level was associated with glucagon (P<0.0001) in both populations. The SST level was correlated with fasting Cpeptide (P=0.0267) in Jino and HDL-C levels in Han (P=0.0079). Our findings suggest that serum SST levels and plasma glucagon levels may vary in subjects with IPH between two ethnics.

Topics: Adult; Asian People; C-Peptide; China; Cholesterol, HDL; Fasting; Female; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Lipid Metabolism; Middle Aged; Somatostatin

The present study has been aimed to identify molecular dynamics of pancreatic transcription factors (pTFs) during events of directed trans-differentiation of human hepatic progenitor cells (hHPCs) into insulin producing cells (InPCs) within bioengineered humanized neoorgan. The study demonstrates applicability of acellularized whole splenic scaffold (ASOS) to generate insulin producing humanized transplantable neoorgan through activation of pancreatic transcription factors.. An efficient acellularization process was developed for xenogeneic rat spleen using change in different gradients of reagents perfusion through splenic artery for varying time points. The acellularized xenogeneic spleen scaffold was characterized thoroughly for preservation of extra-cellular matrix and retention of organ specific vasculature and mechanical properties. Further scaffolds were sterilized and repopulated with hHPCs which were triggered using a stage wise induction with growth factors and hyperglycemic challenge for trans-differentiation into InPCs. Dynamics of pTFs alone or simultaneously during induction process was identified using gene expression analysis and immunological staining.. The cells within the engineered neoorgan respond to growth factors and extrinsic hyperglycemic challenge and generate large number of InPCs under controlled dynamic regulation of pTFs. Highly controlled regulation of pTFs generates higher percentage of Nkx-6.1+/C-peptide+ cells within the engineered splenic scaffolds. Generation of high percentage of insulin and C-peptide positive cells in three-dimensional organ architecture responded better to hyperglycemic stimuli and produced higher quantity of insulin than 2D-culture system.. The present study provides a novel platform for designing effective regenerative strategies using whole organ scaffolds to control hyperglycemia under tight regulation of pTFs using humanized neoorgan system.

Topics: Animals; C-Peptide; Cell Differentiation; Homeodomain Proteins; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Molecular Dynamics Simulation; Rats; Spleen; Stem Cell Transplantation; Stem Cells; Tissue Culture Techniques; Tissue Engineering; Tissue Scaffolds; Trans-Activators; Transcription Factors

The hemoglobin glycation index (HGI) is an index of differences in the glycation of hemoglobin according to blood glucose level. The glycation gap (G-gap) is an empiric measure of the extent of disagreement between hemoglobin A1C (HbA1C) and glycated albumin (GA). The aim of this study was to investigate the extent of agreement between the HGI and G-gap with respect to GA level, and to elucidate factors related to a high HGI.. Data were obtained from 105 patients with type 2 diabetes, and fasting blood glucose (FBG), HbA1c, and GA values were measured simultaneously. The G-gap was calculated as the difference between the measured and GA-based predicted HbA1c levels. HGI was calculated as the difference between measured and FBG-based predicted HbA1c levels.. The HGI and G-gap were highly correlated according GA (r=0.722, P<0.001). In general, the two indices were similar in terms of both direction and magnitude. The classification of patients as high, moderate, or low glycators based on HGI versus G-gap was consistent for the majority of the population and only 5% of patients were reclassified from high to low or low to high. Fasting C-peptide levels decreased linearly, and the percentage of patients using insulin increased linearly, between the lowest and highest HGI tertile (both P<0.05).. There was 95% agreement between the HGI and G-gap using GA among type 2 diabetes patients. Furthermore, a high HGI was associated with a higher prevalence of insulin use among type 2 diabetes patients.

Topics: Algorithms; Blood Glucose; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Models, Biological; Reproducibility of Results; Republic of Korea; Retrospective Studies; Serum Albumin; Severity of Illness Index; Up-Regulation

There is little information regarding β cell mass in individuals at early stages of type 1 diabetes (T1D).. To investigate both acute insulin response to arginine at hyperglycemia (AIRmax), as a correlate of β cell mass, and β cell function by the intravenous glucose tolerance test (IVGTT) in subjects at early stages of T1D.. Forty subjects were enrolled: (1) low-risk group: relatives of patients with T1D with 0 to 1 antibody (n = 21) and (2) high-risk group: relatives with ≥2 antibodies (n = 19).. Acute insulin and C-peptide responses to IVGTT and to AIRmax. Participants underwent two IVGTT and AIRmax procedures on different days.. AIRmax was reproducible, well tolerated, and correlated to first-phase insulin response (FPIR) from IVGTT (r = 0.779). The high-risk group had greater impaired β cell function compared with the low-risk group, determined both by lower mean FPIR and a greater number of subjects below an established threshold for abnormal function [10 of 19 (52.6%) versus 4 of 21 (19%)]. There was a heterogeneous AIRmax response in these subjects with low FPIR, ranging from 38 to 250 μU/mL.. There is significant variation in insulin secretory reserve as assessed by AIRmax in family members with low β cell function assessed by FPIR. As AIRmax is a functional measure of β cell mass, these data suggest heterogeneity in disease pathogenesis in which mass is preserved in relation to function in some individuals. The tolerability and reproducibility of AIRmax suggest it could be a useful stratification measure in clinical trials of disease-modifying therapy.

Topics: Adult; Arginine; C-Peptide; Cell Count; Diabetes Mellitus, Type 1; Female; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Male; Pancreatic Function Tests; Reproducibility of Results; Risk

The aim of this study was to investigate whether insulin sensitivity, beta-cell function or glycaemic control at diagnosis predict initiation of second-line treatment in newly diagnosed type 2 diabetes.. Type 2 diabetes patients (n = 138) undergoing initial metformin monotherapy (age [mean ± SD], 52 ± 10 years; 67% males; BMI, 32 ± 6 kg/m. Second-line treatment was initiated in 26% of newly diagnosed type 2 diabetes patients within the first 3.3 years after diagnosis, using mostly DPP-4 inhibitors or GLP-1 receptor agonists (64%). In age-, sex- and BMI-adjusted survival models, higher baseline HbA1c and fasting glucose values were associated with earlier treatment intensification. Lower baseline M value and C-peptide secretion (CP iAUC) were also related to an earlier initiation of second-line treatment. In the best multivariable model, baseline HbA1c ≥ 7% (hazard ratio, HR; 95% CI: 3.18; 1.35-7.50) and fasting glucose ≥140 mg/dL (HR, 2.45; 95% CI, 1.04-5.78) were associated with shorter time to second-line therapy, adjusting for age, sex and BMI.. Baseline hyperglycaemia is a strong predictor of requirement of early intensification of glucose-lowering therapy in newly diagnosed type 2 diabetes.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Fasting; Female; Germany; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Liraglutide; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Time Factors

Gastric bypass surgery produces clear antidiabetic effects in a substantial proportion of morbidly obese patients. In view of the recent trend away from 'bariatric' surgery and toward 'metabolic' surgery, it is important to elucidate the enhancing effect of bypass surgery on pancreatic β-cell mass, which is related to diabetes remission in non-obese patients. We investigated the effects of gastric bypass surgery on glycemic control and other pancreatic changes in a spontaneous non-obese type 2 diabetes Goto-Kakizaki rat model. Significant improvements in postprandial hyperglycemia and plasma c-peptide level were observed when glucose was administered orally post-surgery. Other important events observed after surgery were enhanced first phase insulin secretion in a in site pancreatic perfusion experiment, pancreatic hyperplasia, improved islet structure (revealed by immunohistochemical analysis), striking increase in β-cell mass, slight increase in ratio of β-cell area to total pancreas area, and increased number of small islets closely related to exocrine ducts. No notable changes were observed in ratio of β-cell to non-β endocrine cell area, β-cell apoptosis, or β-cell proliferation. These findings demonstrate that gastric bypass surgery in this rat model increases endocrine cells and pancreatic hyperplasia, and reflect the important role of the gastrointestinal system in regulation of metabolism.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Disease Models, Animal; Fasting; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucose Tolerance Test; Hyperglycemia; Hyperplasia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Pancreas; Rats; Rats, Wistar

Herein, we investigated the hypoglycemic effect of plant gallic acid (GA) on glucose uptake in an insulin-resistant cell culture model and on hepatic carbohydrate metabolism in rats with a high-fructose diet (HFD)-induced diabetes. Our hypothesis is that GA ameliorates hyperglycemia via alleviating hepatic insulin resistance by suppressing hepatic inflammation and improves abnormal hepatic carbohydrate metabolism by suppressing hepatic gluconeogenesis and enhancing the hepatic glycogenesis and glycolysis pathways in HFD-induced diabetic rats. Gallic acid increased glucose uptake activity by 19.2% at a concentration of 6.25 μg/mL in insulin-resistant FL83B mouse hepatocytes. In HFD-induced diabetic rats, GA significantly alleviated hyperglycemia, reduced the values of the area under the curve for glucose in an oral glucose tolerance test, and reduced the scores of the homeostasis model assessment of insulin resistance index. The levels of serum C-peptide and fructosamine and cardiovascular risk index scores were also significantly decreased in HFD rats treated with GA. Moreover, GA up-regulated the expression of hepatic insulin signal transduction-related proteins, including insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3 kinase, Akt/protein kinase B, and glucose transporter 2, in HFD rats. Gallic acid also down-regulated the expression of hepatic gluconeogenesis-related proteins, such as fructose-1,6-bisphosphatase, and up-regulated expression of hepatic glycogen synthase and glycolysis-related proteins, including hexokinase, phosphofructokinase, and aldolase, in HFD rats. Our findings indicate that GA has potential as a health food ingredient to prevent diabetes mellitus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; C-Peptide; Carbohydrate Metabolism; Cell Line; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Supplements; Fructosamine; Fructose; Gallic Acid; Gene Expression Regulation; Hepatitis; Hepatocytes; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Mice; Oxidative Stress; Rats, Wistar

Bone-marrow-derived stem cells can regenerate pancreatic tissue in a model of type 1 diabetes mellitus. Mesenchymal stem cells (MSCs) form the main part of bone marrow. We show that the intrapancreatic transplantation of MSCs elevates serum insulin and C-peptide, while decreasing blood glucose. MSCs engrafted into the damaged rat pancreas become distributed into the blood vessels, acini, ducts, and islets. Renascent islets, islet-like clusters, and a small number of MSCs expressing insulin protein have been observed in the pancreas of diabetic rats. Intrapancreatic transplantation of MSCs triggers a series of molecular and cellular events, including differentiation towards the pancreas directly and the provision of a niche to start endogenous pancreatic regeneration, which ameliorates hypoinsulinemia and hyperglycemia caused by streptozotocin. These data establish the many roles of MSCs in the restoration of the function of an injured organ.

Topics: Animals; Blood Glucose; Bone Marrow Cells; C-Peptide; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Glucose Tolerance Test; Hyperglycemia; Insulin; Islets of Langerhans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pancreas; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Regeneration

We report the correction of hyperglycemia of STZ induced diabetic mice using one intravenous systemic administration of a single stranded serotype 8 pseudotyped adeno-associated virus (ssAAV2/8) vector encoding the human proinsulin gene under a constitutive liver specific promoter. In vivo dose titration experiments were carried out and we identified an optimal range that achieved maintenance of euglycaemia or a mild diabetic condition for at least 9 months and ongoing to beyond 1 year for some animals, accompanied by human C-peptide secretion and weight gain. Further DNA codon optimization of the insulin gene construct resulted in approximately 3-10 times more human C-peptide secreted in the blood of codon optimized treated animals thereby reducing the number of vector particles required to achieve the same extent of reduction in blood glucose levels as the non-codon optimized vector. The constitutive secretion of insulin achieved with a single administration of the vector could be of therapeutic value for some diabetic patients.

Topics: Animals; C-Peptide; Codon; Dependovirus; Diabetes Mellitus, Experimental; Genetic Vectors; Humans; Hyperglycemia; Insulin; Liver; Mice, Inbred NOD; Pancreas; Recombinant Proteins

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia and impaired insulin secretion with onset within 6 months of birth. While rare, NDM presents complex challenges regarding the management of glycemic control. The availability of continuous subcutaneous insulin infusion pumps (CSII) in combination with continuous glucose monitoring systems (CGM) provides an opportunity to monitor glucose levels more closely and deliver insulin more safely.. We report four cases of young infants with NDM successfully treated with CSII and CGM. Moreover, in two cases with Kir 6.2 mutation, we describe the use of CSII in switching therapy from insulin to sulfonylurea treatment.. Insulin pump requirement for the 4 neonatal diabetes cases was the same regardless of disease pathogenesis and c-peptide levels. No dilution of insulin was needed. The use of an integrated CGM system helped in a more precise control of BG levels with the possibility of several modifications of insulin basal rates. Moreover, as showed in the first two case-reports, when the treatment was switched from insulin to glibenclamide, according to identification of Kir 6.2 mutation and diagnosis of NPDM, the CSII therapy demonstrated to be helpful in allowing gradual insulin suspension and progressive introduction of sulfonylurea.. During the neonatal period, the use of CSII therapy is safe, more physiological, accurate and easier for the insulin administration management. Furthermore, CSII therapy is safe during the switch of therapy from insulin to glibenclamide for infants with permanent neonatal diabetes mellitus.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glyburide; Humans; Hyperglycemia; Infant; Infant, Newborn; Insulin; Insulin Infusion Systems; Male; Monitoring, Physiologic; Sulfonylurea Compounds

Metabolic alterations after burn injury have been well described in children; however, in adult patients, glucose metabolism and insulin sensitivity are essentially unknown. We sought to characterize metabolic alterations and insulin resistance after burn injury and determine their magnitude and persistence at discharge.. Prospective, cohort study.. Tertiary burn centre.. Nondiabetic adults with an acute burn involving greater than or equal to 20% total body surface area.. An oral glucose tolerance test was administered at discharge.. Glucose, insulin, and C-peptide levels were measured to derive surrogate measures of insulin resistance and β-cell function, including quantitative insulin sensitivity check index, homeostasis model assessment of β-cell function, homeostasis model assessment of insulin sensitivity, homeostasis model assessment of insulin resistance, and the composite whole-body insulin sensitivity index. Patients were grouped according to the degree of glucose tolerance: normal glucose tolerance, impaired fasting glucose/impaired glucose tolerance, or diabetes. Forty-five adults, 44 ± 15 years old and with 38% ± 14% total body surface area burned, underwent an oral glucose tolerance test at discharge. Median quantitative insulin sensitivity check index (0.348 [0.332-0.375]) and median homeostasis model assessment of insulin resistance (1.13 [0.69-1.45]) were abnormal, indicating insulin resistance and impaired insulin production at discharge. Two-thirds of patients (n = 28) met criteria for impaired fasting glucose/impaired glucose tolerance or diabetes.. We have demonstrated that burn-injured adults remain hyperglycemic, are insulin resistant, and express defects in insulin secretion at discharge. Patients with lower burn severity (total body surface area, 20-30%) express similar metabolic alterations as patients with larger burns (total body surface area, ≥ 30%). Glucose tolerance testing at discharge offers an opportunity for early identification of burn patients who may be at high risk of prediabetes and diabetes. Our findings demonstrated that two-thirds of burn patients had some degree of glucose intolerance. With this in mind, surveillance of glucose intolerance post discharge should be considered. As hyperglycemia and insulin resistance are associated with poor outcomes, studies should focus on how long these profound alterations persist.

Topics: Adult; Aged; Blood Glucose; Body Surface Area; Burns; C-Peptide; Female; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Patient Discharge; Prospective Studies; Young Adult

A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency.

Topics: Autoantibodies; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Disease Progression; Female; Glutamate Decarboxylase; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Middle Aged; Pancreas; Predictive Value of Tests; Treatment Outcome

C-peptide exerts protective effects against diabetic complications; however, its role in inhibiting hyperglycemic memory (HGM) has not been elucidated. We investigated the beneficial effect of C-peptide on HGM-induced vascular damage in vitro and in vivo using human umbilical vein endothelial cells and diabetic mice. HGM induced apoptosis by persistent generation of intracellular ROS and sustained formation of ONOO(-) and nitrotyrosine. These HGM-induced intracellular events were normalized by treatment with C-peptide, but not insulin, in endothelial cells. C-peptide also inhibited persistent upregulation of p53 and activation of mitochondrial adaptor p66(shc) after glucose normalization. Further, C-peptide replacement therapy prevented persistent generation of ROS and ONOO(-) in the aorta of diabetic mice whose glucose levels were normalized by the administration of insulin. C-peptide, but not insulin, also prevented HGM-induced endothelial apoptosis in the murine diabetic aorta. This study highlights a promising role for C-peptide in preventing HGM-induced intracellular events and diabetic vascular damage.

Topics: Animals; Apoptosis; C-Peptide; Diabetes Mellitus, Experimental; Endothelium, Vascular; Genes, p53; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Mice; Peroxynitrous Acid; Protective Agents; Reactive Oxygen Species; Src Homology 2 Domain-Containing, Transforming Protein 1

The hyperglycemic clamp test, the gold standard of beta cell function, predicts impending type 1 diabetes in islet autoantibody-positive individuals, but the latter may benefit from less invasive function tests such as the proinsulin:C-peptide ratio (PI:C). The present study aims to optimize precision of PI:C measurements by automating a dual-label trefoil-type time-resolved fluorescence immunoassay (TT-TRFIA), and to compare its diagnostic performance for predicting type 1 diabetes with that of clamp-derived C-peptide release.. Between-day imprecision (n = 20) and split-sample analysis (n = 95) were used to compare TT-TRFIA (AutoDelfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche). High-risk multiple autoantibody-positive first-degree relatives (n = 49; age 5-39) were tested for fasting PI:C, HOMA2-IR and hyperglycemic clamp and followed for 20-57 months (interquartile range).. TT-TRFIA values for proinsulin, C-peptide and PI:C correlated significantly (r2 = 0.96-0.99; P<0.001) with results obtained with separate methods. TT-TRFIA achieved better between-day %CV for PI:C at three different levels (4.5-7.1 vs 6.7-9.5 for separate methods). In high-risk relatives fasting PI:C was significantly and inversely correlated (rs = -0.596; P<0.001) with first-phase C-peptide release during clamp (also with second phase release, only available for age 12-39 years; n = 31), but only after normalization for HOMA2-IR. In ROC- and Cox regression analysis, HOMA2-IR-corrected PI:C predicted 2-year progression to diabetes equally well as clamp-derived C-peptide release.. The reproducibility of PI:C benefits from the automated simultaneous determination of both hormones. HOMA2-IR-corrected PI:C may serve as a minimally invasive alternative to the more tedious hyperglycemic clamp test.

Topics: Adolescent; Adult; Autoantibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Fasting; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Prognosis; Proinsulin; Regression Analysis

We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D.. The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors.. The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all).. The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers.

Topics: Adolescent; Autoantibodies; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Disease Progression; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Male; Patient Acuity; Risk Factors; Severity of Illness Index

Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20μg/kg/day) or high (200μg/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.

Topics: Animals; Apoptosis; Blood Glucose; C-Peptide; Cell Count; Diabetes Mellitus, Experimental; Exenatide; Fasting; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Graft Survival; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Mice, Inbred BALB C; Models, Animal; Peptides; Venoms

Hyperglycemia represents one of possible mediators for activation of immune system and may contribute to worsening of inflammatory state associated with obesity. The aim of our study was to investigate the effect of a short-term hyperglycemia (HG) on the phenotype and relative content of immune cells in circulation and subcutaneous abdominal adipose tissue (SAAT) in obese women without metabolic complications.. Three hour HG clamp with infusion of octreotide and control investigations with infusion of octreotide or saline were performed in three groups of obese women (Group1: HG, Group 2: Octreotide, Group 3: Saline, n=10 per group). Before and at the end of the interventions, samples of SAAT and blood were obtained. The relative content of immune cells in blood and SAAT was determined by flow cytometry. Gene expression analysis of immunity-related markers in SAAT was performed by quantitative real-time PCR.. In blood, no changes in analysed immune cell population were observed in response to HG. In SAAT, HG induced an increase in the content of CD206 negative monocytes/macrophages (p<0.05) and T lymphocytes (both T helper and T cytotoxic lymphocytes, p<0.01). Further, HG promoted an increase of mRNA levels of immune response markers (CCL2, TLR4, TNFα) and lymphocyte markers (CD3g, CD4, CD8a, TBX21, GATA3, FoxP3) in SAAT (p<0.05 and 0.01). Under both control infusions, none of these changes were observed.. Acute HG significantly increased the content of monocytes and lymphocytes in SAAT of healthy obese women. This result suggests that the short-term HG can modulate an immune status of AT in obese subjects.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Cell Count; Female; Gene Expression Regulation; Health; Humans; Hyperglycemia; Insulin; Macrophages; Monocytes; Obesity; Octreotide; Phenotype; RNA, Messenger; Subcutaneous Fat, Abdominal; T-Lymphocytes

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Allografts; Blood Glucose; Body Mass Index; C-Peptide; Cytokines; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hyperglycemia; Inflammation; Insulin; Insulin Resistance; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Time Factors; Transplantation Conditioning; Young Adult

An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4+ T cells, CD8+ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.

Topics: Animals; Antilymphocyte Serum; C-Peptide; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Hyperglycemia; Insulin; Mice; Mice, Inbred NOD; Pancreas; Proton Pump Inhibitors; Treatment Outcome

We examined whether measures of glycaemic variability (GV), assessed by continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG), can complement or replace measures of beta cell function and insulin action in detecting the progression of preclinical disease to type 1 diabetes.. Twenty-two autoantibody-positive (autoAb(+)) first-degree relatives (FDRs) of patients with type 1 diabetes who were themselves at high 5-year risk (50%) for type 1 diabetes underwent CGM, a hyperglycaemic clamp test and OGTT, and were followed for up to 31 months. Clamp variables were used to estimate beta cell function (first-phase [AUC5-10 min] and second-phase [AUC120-150 min] C-peptide release) combined with insulin resistance (glucose disposal rate; M 120-150 min). Age-matched healthy volunteers (n = 20) and individuals with recent-onset type 1 diabetes (n = 9) served as control groups.. In autoAb(+) FDRs, M 120-150 min below the 10th percentile (P10) of controls achieved 86% diagnostic efficiency in discriminating between normoglycaemic FDRs and individuals with (impending) dysglycaemia. M 120-150 min outperformed AUC5-10 min and AUC120-150 min C-peptide below P10 of controls, which were only 59-68% effective. Among GV variables, CGM above the reference range was better at detecting (impending) dysglycaemia than elevated SMBG (77-82% vs 73% efficiency). Combined CGM measures were equally efficient as M 120-150 min (86%). Daytime GV variables were inversely correlated with clamp variables, and more strongly with M 120-150 min than with AUC5-10 min or AUC120-150 min C-peptide.. CGM-derived GV and the glucose disposal rate, reflecting both insulin secretion and action, outperformed SMBG and first- or second-phase AUC C-peptide in identifying FDRs with (impending) dysglycaemia or diabetes. Our results indicate the feasibility of developing minimally invasive CGM-based criteria for close metabolic monitoring and as outcome measures in trials.

Topics: Adolescent; Adult; Area Under Curve; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Healthy Volunteers; Humans; Hyperglycemia; Insulin-Secreting Cells; Male; Young Adult

Hyperglycaemia is a common complication in the intensive care unit (ICU), and is associated with worsened outcomes. Model-based insulin therapy protocols have been shown to be safe and effective in intensive care. Such protocols rely on correct modeling of glucose-insulin dynamics. In particular, model-based control typically relies on insulin sensitivity (SI) metrics, which are heavily influenced by plasma insulin kinetics. Plasma insulin samples were taken as part of a sepsis study and compared to modeled plasma insulin. Samples were taken in septic patients at the onset of glycaemic control, and once the patient consistently met less than two of the SIRs criteria that help define sepsis. It was found that inter-patient insulin dynamics were more variable at the onset of insulin therapy, than in the later samples after sepsis abated. Overall, the model adequately captured crucial steady state dynamics. Transient dynamics in plasma insulin following a bolus were faster than modeled, indicating greater clearance of insulin than currently modeled.

Topics: Aged; C-Peptide; Female; Half-Life; Hospital Mortality; Humans; Hyperglycemia; Insulin; Intensive Care Units; Male; Middle Aged; Models, Theoretical; Sepsis

OBJECTIVE To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS We compared fasting serum from an oral glucose tolerance test at ∼28 weeks' gestation from 67 Northern European ancestry mothers from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with high (>90th percentile) FPG with 50 mothers with low (<10th percentile) FPG but comparable BMI. Metabolic data from biochemical analyses of conventional clinical metabolites, targeted mass spectrometry (MS)-based measurement of amino acids, and nontargeted gas chromatography/MS were subjected to per-metabolite analyses and collective pathway analyses using Unipathway annotation. RESULTS High-FPG mothers had a metabolic profile consistent with insulin resistance including higher triglycerides, 3-hydroxybutyrate, and amino acids including alanine, proline, and branched-chain amino acids (false discovery rate [FDR]-adjusted P < 0.05). Lower 1,5-anhydroglucitol in high-FPG mothers suggested recent hyperglycemic excursions (FDR-adjusted P < 0.05). Pathway analyses indicated differences in amino acid degradation pathways for the two groups (FDR-adjusted P < 0.05), consistent with population-based findings in nonpregnant populations. Exploratory analyses with newborn outcomes indicated positive associations for maternal triglycerides with neonatal sum of skinfolds and cord C-peptide and a negative association between maternal glycine and cord C-peptide (P < 0.05). CONCLUSIONS Metabolomics reveals perturbations in metabolism of major macronutrients and amino acid degradation pathways in high- versus low-FPG mothers.

Topics: 3-Hydroxybutyric Acid; Adult; Amino Acids; Blood Glucose; C-Peptide; Female; Food; Glucose Tolerance Test; Humans; Hyperglycemia; Infant, Newborn; Metabolomics; Mothers; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Triglycerides

Previously we reported studies of XMetA, an agonist antibody to the insulin receptor (INSR). We have now utilized phage display to identify XMetS, a novel monoclonal antibody to the INSR. Biophysical studies demonstrated that XMetS bound to the human and mouse INSR with picomolar affinity. Unlike monoclonal antibody XMetA, XMetS alone had little or no agonist effect on the INSR. However, XMetS was a strong positive allosteric modulator of the INSR that increased the binding affinity for insulin nearly 20-fold. XMetS potentiated insulin-stimulated INSR signaling ∼15-fold or greater including; autophosphorylation of the INSR, phosphorylation of Akt, a major enzyme in the metabolic pathway, and phosphorylation of Erk, a major enzyme in the growth pathway. The enhanced signaling effects of XMetS were more pronounced with Akt than with Erk. In cultured cells, XMetS also enhanced insulin-stimulated glucose transport. In contrast to its effects on the INSR, XMetS did not potentiate IGF-1 activation of the IGF-1 receptor. We studied the effect of XMetS treatment in two mouse models of insulin resistance and diabetes. The first was the diet induced obesity mouse, a hyperinsulinemic, insulin resistant animal, and the second was the multi-low dose streptozotocin/high-fat diet mouse, an insulinopenic, insulin resistant animal. In both models, XMetS normalized fasting blood glucose levels and glucose tolerance. In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in both mouse models. XMetS improved the response to exogenous insulin without causing hypoglycemia. These data indicate that an allosteric monoclonal antibody can be generated that markedly enhances the binding affinity of insulin to the INSR. These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory hyperinsulinism in insulin resistant conditions.

Topics: Allosteric Site; Animals; Antibodies, Monoclonal; Antigens, CD; C-Peptide; Cell Separation; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Type 2; Flow Cytometry; Glucose; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Mice; Mice, Inbred C57BL; Obesity; Peptide Library; Phosphorylation; Protein Structure, Tertiary; Receptor, Insulin; Signal Transduction

To examine the associations between gestational weight gain (GWG) exceeding Institute of Medicine (IOM) guidelines and neonatal adiposity in the five North American field centers of the Hyperglycemia and Adverse Pregnancy Outcome study.. GWG was categorized as less than, within, or greater than 2009 IOM guidelines. Birthweight, body fat percentage, cord serum C-peptide, and sum of neonatal flank, subscapular, and triceps skin fold thicknesses were dichotomized as >90th percentile or ≤90th percentile obtained by quantile regression. Logistic regression analysis was used.. Of the 5297 participants, 11.6% gained less, 31.9% gained within, and 56.5% gained more than the recommendation. With adjustment for glucose tolerance levels, normal and overweight women who gained more than the recommendation had increased odds of delivering infants with sum of skin folds >90th percentile (OR = 1.75 and 4.77, respectively) and percentage body fat >90th percentile (OR = 2.41 and 2.59, respectively), and normal weight and obese women who gained more than the recommendation had increased odds of delivering infants with birthweight >90th percentile (OR = 2.80 and 1.93, respectively) compared to women who gained within the recommendation.. This analysis showed independent associations between exceeding IOM GWG recommendations and neonatal adiposity in normal and overweight women, controlling for glucose tolerance levels.

Topics: Adiposity; Adult; Birth Weight; Blood Glucose; Body Mass Index; C-Peptide; Female; Gestational Age; Glucose Tolerance Test; Humans; Hyperglycemia; Infant, Newborn; Male; North America; Obesity; Overweight; Pregnancy; Pregnancy Complications; Pregnancy Outcome; United States; Weight Gain

Diabetic ketosis had been identified as a characteristic of type 1 diabetes mellitus (T1DM), but now emerging evidence has identified that they were diagnosed as T2DM after long time follow up. This case control study was aimed at comparing the clinical characteristic, β-cell function, and insulin resistance of ketosis and nonketotic onset T2DM and providing evidence for treatment selection. 140 cases of newly diagnosed T2DM patients were divided into ketosis (62 cases) and nonketotic onset group (78 cases). After correction of hyperglycemia and ketosis with insulin therapy, plasma C-peptide concentrations were measured at 0, 0.5, 1, 2, and 3 hours after 75 g glucose oral administration. Area under the curve (AUC) of C-peptide was calculated. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β) and insulin resistance (HOMA-IR). Our results showed that ketosis onset group had higher prevalence of nonalcoholic fatty liver disease (NAFLD) than nonketotic group (P = 0.04). Ketosis onset group had increased plasma C-peptide levels at 0 h, 0.5 h, and 3 h and higher AUC(0-0.5), AUC₀₋₁, AUC₀₋₃ (P < 0.05). Moreover, this group also had higher HOMA-β and HOMA-IR than nonketotic group (P < 0.05). From these data, we concluded that ketosis onset T2DM had better islet β-cell function and more serious insulin resistance than nonketotic onset T2DM.

Topics: Adolescent; Adult; Aged; C-Peptide; Case-Control Studies; China; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Fatty Liver; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Ketone Bodies; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Prevalence; Retrospective Studies; Young Adult

Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes.

Topics: Adolescent; Adult; Algorithms; Blood Glucose; C-Peptide; Female; Food; Gastric Emptying; Glucagon; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Kinetics; Male; Middle Aged; Young Adult

A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess β-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) μU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) μU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of β-cell function.

Topics: Adult; Aged; Arginine; Blood Glucose; Body Mass Index; C-Peptide; Female; Glucagon; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Insulin-Secreting Cells; Kinetics; Male; Middle Aged; Mouth Mucosa; Nausea; Obesity; Paresthesia; Reproducibility of Results

We evaluated the effect of sitagliptin on glycemic control, endogenous insulin secretion, and beta cell function in Japanese patients with type 2 diabetes mellitus (T2DM) receiving a combination of oral antidiabetics and basal insulin analog glargine (basal-supported oral therapy [BOT]). Twenty-one patients showing inadequate glycemic control with BOT were given dipeptidylpeptidase-4 inhibitor (DPP-4I) sitagliptin at 50 mg/day for 12 weeks. Clinical markers of glycemic control, HbA1c, glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG), were measured before and 4 and 12 weeks after the start of sitagliptin. A 2-hour morning meal test was performed upon enrollment and at 12 weeks, and plasma glucose (PG), serum C-peptide, and plasma intact proinsulin (PI) were measured. HbA1c, GA, and 1,5-AG at 4 and 12 weeks were significantly improved over enrollment levels. The area under the PG concentration curve (AUC-PG) during the meal test at 12 weeks was significantly reduced (from 350 ± 17 mg ･ hr/dL before sitagliptin treatment to 338 ± 21 mg ･ hr/dL [mean ± SE], P < 0.05,); the AUC-C-peptide was unchanged (from 3.4 ± 0.4 ng ･ hr/mL to 3.6 ± 0.5 ng ･ hr/mL). However, both fasting and 2-hour PI/C-peptide ratios at 12 weeks were significantly decreased (from 13.3 ± 2.3 to 11.1 ± 2.0 [P < 0 .05] and from 9.5 ± 1.6 to 5.3 ± 0.9 [P < 0.01], respectively). Adding sitagliptin to BOT in Japanese T2DM patients appears to improve glycemic control without increasing endogenous insulin secretion and to reduce fasting and 2-hour postprandial PI/C-peptide ratios.

Topics: Administration, Oral; Aged; Algorithms; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin-Secreting Cells; Insulin, Long-Acting; Japan; Male; Proinsulin; Pyrazines; Sitagliptin Phosphate; Triazoles

To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c).. The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset of type 1 diabetes (T1D). Receiver operating characteristic curve (ROC) analysis was used to evaluate the predictive value of IDAA1c and age on partial C-peptide remission (stimulated C-peptide, SCP > 300 pmol/L).. PR (IDAA1c ≤ 9) in the Danish and Hvidoere cohorts occurred in 62 vs. 61% (3 months, p = 0.80), 47 vs. 44% (6 months, p = 0.57), 26 vs. 32% (9 months, p = 0.32) and 19 vs. 18% (12 months, p = 0.69). The effect of age on SCP was significantly higher in the Danish cohort compared with the Hvidoere cohort (p < 0.0001), likely due to higher attained Boost SCP, so the sensitivity and specificity of those in PR by IDAA1c ≤ 9, SCP > 300 pmol/L was 0.85 and 0.62 at 6 months and 0.62 vs. 0.38 at 12 months, respectively. IDAA1c with age significantly improved the ROC analyses and the AUC reached 0.89 ± 0.04 (age) vs. 0.94 ± 0.02 (age + IDAA1c) at 6 months (p < 0.0004) and 0.76 ± 0.04 (age) vs. 0.90 ± 0.03 (age + IDAA1c) at 12 months (p < 0.0001).. The diagnostic and prognostic power of the IDAA1c measure is kept but due to the higher Boost stimulation in the Danish cohort, the specificity of the formula is lower with the chosen limits for SCP (300 pmol/L) and IDAA1c ≤9, respectively.

Topics: Adolescent; Age Factors; C-Peptide; Child; Child, Preschool; Cohort Studies; Denmark; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Infant; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Prediabetic State; Remission Induction; Sensitivity and Specificity

Defining responders to glucose lowering therapy can be important for both clinical care and for the development of a stratified approach to diabetes management. Response is commonly defined by either HbA1c change after treatment or whether a target HbA1c is achieved. We aimed to determine the extent to which the individuals identified as responders and non-responders to glucose lowering therapy, and their characteristics, depend on the response definition chosen.. We prospectively studied 230 participants commencing GLP-1 agonist therapy. We assessed participant characteristics at baseline and repeated HbA1c after 3 months treatment. We defined responders (best quartile of response) based on HbA1c change or HbA1c achieved. We assessed the extent to which these methods identified the same individuals and how this affected the baseline characteristics associated with treatment response.. Different definitions of response identified different participants. Only 39% of responders by one definition were also good responders by the other. Characteristics associated with good response depend on the response definition chosen: good response by HbA1c achieved was associated with low baseline HbA1c (p<0.001), high C-peptide (p<0.001) and shorter diabetes duration (p = 0.01) whereas response defined by HbA1c change was associated with high HbA1c (p<0.001) only. We describe a simple novel method of defining treatment response based on a combination of HbA1c change and HbA1c achieved that defines response groups with similar baseline glycaemia.. The outcome of studies aiming to identify predictors of treatment response to glucose lowering therapy may depend on how response is defined. Alternative definitions of response should be considered which minimise influence of baseline glycaemia.

Topics: Blood Glucose; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Triglycerides

Administering steroids before cardiopulmonary bypass in pediatric heart surgery modulates systemic inflammatory response syndrome and improves postoperative recovery. However, the use of steroids aggravates hyperglycemia, which is associated with a poor prognosis. Adult patients with systemic inflammatory response syndrome usually evolve with hyperglycemia and high insulin levels, whereas >90% of pediatric patients exhibit hyperglycemia and low insulin levels. This study aims to determine: A) the metabolic and inflammatory factors that are associated with hyperglycemia and low insulin levels in children who underwent cardiac surgery with cardiopulmonary bypass and who received a single high dose of methylprednisolone and B) the best predictors of insulin variation using a mathematical model.. This preliminary study recruited 20 children who underwent heart surgery with cardiopulmonary bypass and received methylprednisolone (30 mg/kg) immediately after anesthesia. Among the 20 patients initially recruited, one was excluded because of the absence of hyperglycemia and lower insulin levels after surgery. However, these abnormalities were confirmed in the remaining 19 children. The C-peptide, CRP, IL-6, and adrenomedullin levels were measured before surgery, immediately after cardiopulmonary bypass, and on the first, second, and third days after cardiac surgery.. IL-6, CRP, and adrenomedullin increments were observed, whereas the C-peptide levels remained within reference intervals.. The multiple regression model demonstrated that in addition to age and glycemia (two well-known factors that are directly involved in glucose metabolism), adrenomedullin and IL-6 levels were independent factors associated with lower insulin concentrations. These four parameters were responsible for 64.7% of the observed insulin variances. In addition, the fact that C-peptide levels did not fall together with insulin could have grounded the medical decision not to administer insulin to patients.

Topics: Adrenomedullin; Age Factors; Anti-Inflammatory Agents; Blood Glucose; C-Peptide; C-Reactive Protein; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child, Preschool; Female; Humans; Hyperglycemia; Infant; Insulin; Interleukin-6; Male; Methylprednisolone; Models, Biological; Postoperative Period; Reference Values; Regression Analysis

An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7-8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving β-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid β-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS.

Topics: Adaptor Proteins, Signal Transducing; Adenoviridae; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Genetic Therapy; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Vasoconstrictor Agents

Alloxan generates hydrogen peroxide in the body, and a small amount of alloxan administered to acatalasemic mice results in diabetes. D-α-Tocopherol (vitamin E) is an antioxidant which helps prevent excess oxidation in the body. In this study, we examined the effect of vitamin E on diabetes caused by alloxan administration in mice.. Mice were maintained on a vitamin E-deprived diet and supplemented diet, respectively, for 14 weeks. Alloxan was then intraperitoneally administered, and blood glucose, glucose tolerance and the insulin level in mouse blood were examined.. Hyperglycemia was observed in the mice maintained on the vitamin E-deprived diet. The incidence of hyperglycemia in the mice maintained on the vitamin E-deprived diet was significantly higher than that in the mice maintained on the supplemented diet. The abnormal glucose metabolism caused by alloxan administration was ameliorated by the vitamin E-supplemented diet.. It is deduced that vitamin E can prevent a decrease of insulin concentration in the blood in this mouse model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Alloxan; alpha-Tocopherol; Animals; Antioxidants; Biomarkers; Blood Glucose; C-Peptide; Catalase; Deoxyguanosine; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Hyperglycemia; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C3H; Oxidative Stress; Pancreas

Causes of hyperglycemia in critically ill non-diabetic children may differ from those in adults. The objective of this study was to investigate the pathogenesis of critical illness hyperglycemia (CIH) in terms of insulin resistance and β-cell dysfunction. Critically ill children with blood glucose (BG) levels of >150 mg/dL (8.3 mmol/L) were enrolled in the study. Insulin sensitivity and β-cell function in the hyperglycemic and euglycemic periods were analyzed with BG/insulin and BG/C-peptide ratios, and utilizing homeostasis model assessment (HOMA). A total of 40 patients were enrolled in the study. BG/insulin and BG/C-peptide ratios were significantly higher in the hyperglycemic period. The HOMA-B and S scores for the hyperglycemic period revealed that out of all the patients who survived (n=30), 20 had β-cell dysfunction, while the remaining (n=11) had insulin resistance. β-cell dysfunction was significantly higher in the hyperglycemic period (p<0.001). As in adults, β-cell dysfunction may play a major role in the pathophysiology of CIH in children.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child, Preschool; Critical Illness; Female; Humans; Hyperglycemia; Infant; Insulin Resistance; Insulin-Secreting Cells; Male

Diabetes mellitus is a metabolic disorder that affects millions of people worldwide. Present study highlights the antidiabetogenic property of Linum usitassimum active fraction (LU6) in streptozotocin (STZ) induced diabetic Swiss mice. Treatment with LU6 fraction showed improved glucose utilization with increase in liver glucose-6-phosphate dehydrogenase enzyme activity and normal glycogenesis in hepatic and muscle tissues. Reduction in pancreatic and intestinal glucosidase inhibitory activity was observed with LU6 treatment, indicating beneficial effects in reducing postprandial hyperglycemia (PPHG). Normalization of plasma insulin and C-peptide levels were observed in diabetic mice, indicating endogenous insulin secretion after the treatment with LU6. The histochemical and immunohistochemical analysis on pancreatic islets suggests the role of LU6 fraction in islet regeneration and insulin secretion as evident in increase functional pancreatic islets producing insulin. Furthermore, significant insulin producing islet formation was also observed in in vitro PANC-1 cells after LU6 treatment, indicating the cellular aggregates to be newly formed islets. This suggests the potential of LU6 fraction in the formation of new islets in vitro, as well as in vivo. Thus, LU6 can be used as a neutraceutical-based first-line treatment for diabetes.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Flax; Glucose; Glucosephosphate Dehydrogenase; Glucosidases; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Liver; Male; Mice; Phytotherapy; Regeneration

β-cell replacement may efficiently cure type 1 diabetic (T1D) patients whose insulin-secreting β-cells have been selectively destroyed by autoantigen-reactive T cells. To generate insulin-secreting cells we used two cell sources: rat multipotent adult progenitor cells (rMAPC) and the highly similar rat extra-embryonic endoderm precursor (rXEN-P) cells isolated under rMAPC conditions from blastocysts (rHypoSC). rMAPC/rHypoSC were sequentially committed to definitive endoderm, pancreatic endoderm, and β-cell like cells. On day 21, 20% of rMAPC/rHypoSC progeny expressed Pdx1 and C-peptide. rMAPCr/HypoSC progeny secreted C-peptide under the stimulus of insulin agonist carbachol, and was inhibited by the L-type voltage-dependent calcium channel blocker nifedipine. When rMAPC or rHypoSC differentiated d21 progeny were grafted under the kidney capsule of streptozotocin-induced diabetic nude mice, hyperglycemia reversed after 4 weeks in 6/10 rMAPC- and 5/10 rHypoSC-transplanted mice. Hyperglycemia recurred within 24 hours of graft removal and the histological analysis of the retrieved grafts revealed presence of Pdx1-, Nkx6.1- and C-peptide-positive cells. The ability of both rMAPC and HypoSC to differentiate to functional β-cell like cells may serve to gain insight into signals that govern β-cell differentiation and aid in developing culture systems to commit other (pluripotent) stem cells to clinically useful β-cells for cell therapy of T1D.

Topics: Animals; Blastocyst; Blotting, Western; Bone Marrow Cells; C-Peptide; Cell Differentiation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Embryonic Stem Cells; Endoderm; Gene Expression; Germ Layers; Homeodomain Proteins; Humans; Hyperglycemia; Insulin-Secreting Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Multipotent Stem Cells; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Stem Cell Transplantation; Time Factors; Trans-Activators

Altered sex hormone levels are thought to play an important role in adult-onset diseases including obesity, cardiovascular disease, and diabetes. They contribute to these complex diseases through changes in their availability, which is influenced, in part, by binding proteins. Insulin resistance, which is characteristic of these diseases, along with increased insulin secretion, is a physiologic change that occurs normally during pregnancy. To determine the relationship between insulin resistance and sex hormone levels, we examined the associations of sex hormone-binding globulin (SHBG) and testosterone with measures of glycemia and insulinemia in a healthy pregnant population. We measured fasting serum SHBG and testosterone levels in 215 Hispanic mothers of Mexican ancestry from the HAPO Study cohort and tested for associations between SHBG and testosterone levels and maternal plasma glucose and C-peptide. After adjusting for confounding variables, serum total testosterone (TT) was positively associated with fasting C-peptide (0.18 μg/l higher for TT higher by 1 SD, p=0.001) and 1-h C-peptide (0.79 μg/l higher for TT higher by 1 SD, p<0.001). Free testosterone (FT) was also positively associated with fasting C-peptide (0.19 μg/l higher for FT higher by 1 SD, p<0.001), and 1-h C-peptide (0.83 μg/l higher for FT higher by 1 SD, p<0.001). Although these findings are from a single cohort, this study provides evidence for an association between testosterone and C-peptide during pregnancy in a nondiabetic Hispanic obstetric population.

Topics: Blood Glucose; C-Peptide; Cohort Studies; Female; Humans; Hyperglycemia; Insulin; Mexican Americans; Mexico; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Sex Hormone-Binding Globulin; Testosterone; United States

The worldwide rapid increase in diabetes poses a significant challenge to current therapeutic approaches. Single-dose mesenchymal stem cell (MSC) infusion ameliorates hyperglycemia but fails to restore normoglycemia in diabetic animals. We therefore hypothesized that multiple intravenous MSC infusions may reverse hyperglycemia in type 2 diabetes (T2D) rats. We administered serial allogenous bone-marrow derived MSC infusions (1 × 10(6)cells/infusion) via the tail vein once every 2 weeks to T2D rats, induced by high-fat diet and streptozocin (STZ) administration. Hyperglycemia decreased only transiently after a single infusion in early-phase (1 week) T2D rats, but approximated normal levels after at least three-time infusions. This normal blood level was maintained for at least 9 weeks. Serum concentrations of both insulin and C-peptide were dramatically increased after serial MSC infusions. Oral glucose tolerance tests revealed that glucose metabolism was significantly ameliorated. Immunofluorescence analysis of insulin/glucagon staining revealed the restoration of islet structure and number after multiple MSC treatments. When multiple-MSC treatment was initiated in late-phase (5 week) T2D rats, the results were slightly different. The results of this study suggested that a multiple-MSC infusion strategy offers a viable clinical option for T2D patients.

Topics: Administration, Intravenous; Animals; Blood Glucose; Bone Marrow; C-Peptide; Culture Media, Conditioned; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucagon; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Streptozocin

North American ginseng (NAG) has received increasing attention as an alternative medicine for the treatment of diabetes. Extract of the NAG root has been reported to possess antidiabetic properties, but the underlying mechanisms for such effects have not been identified. Here we investigated the effects of NAG root extract on type 1 and 2 diabetes and the underlying mechanisms involved for such effects. Type 1 [C57BL/6 mice with streptozotocin (STZ)-induction] and type 2 (db/db) diabetic models were examined. Groups of diabetic mice (both type 1 and 2) were treated with alcoholic extract of the NAG root (200 mg/kg BW/day, oral gavage) for 1 or 2 months following onset of diabetes. Ginseng treatment significantly increased the body weight in type 1 diabetic animals in contrast to the type 2 model, where it caused diminution of body weight. Blood glucose and glycated hemoglobin levels diminished in the diabetic groups of both models with NAG treatment. Interestingly, plasma insulin and C-peptide levels were significantly increased in the STZ-diabetic mice, whereas they were reduced in the db/db mice following NAG treatment. Histological and morphometric analyses (islet/pancreas ratio) of the pancreas revealed an increase in the islet area following the treatment compared to both the untreated diabetic groups. These data indicate that NAG possibly causes regeneration of β-cells resulting in enhanced insulin secretion. On the other hand, in type 2 diabetes, the additional effects of NAG on body weight might have also resulted in improved glucose control.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Panax; Pancreas; Phytotherapy; Plant Extracts

Topics: C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Intestinal Mucosa; Male; Receptors, G-Protein-Coupled

Impairment of the incretin effect is one of the hallmarks of type 2 diabetes mellitus (T2DM). However, it is unknown whether this abnormality is specific to incretin-stimulated insulin secretion or a manifestation of generalized β-cell dysfunction. The aim of this study was to determine whether improved glycemic control restores the incretin effect.. Fifteen T2DM subjects were studied before and after 8 weeks of intensified treatment with insulin. The incretin effect was determined by comparing plasma insulin and C-peptide levels at clamped hyperglycemia from iv glucose, and iv glucose plus glucose ingestion.. Long-acting insulin, titrated to reduce fasting glucose to 7 mM, lowered hemoglobin A1c from 8.6% ± 0.2% to 7.1% ± 0.2% over 8 weeks. The incremental C-peptide responses and insulin secretion rates to iv glucose did not differ before and after insulin treatment (5.6 ± 1.0 and 6.0 ± 0.9 nmol/L·min and 0.75 ± 0.10 and 0.76 ± 0.11 pmol/min), but the C-peptide response to glucose ingestion was greater after treatment than before (10.9 ± 2.2 and 7.1 ± 0.9 nmol/L·min; P = .03) as were the insulin secretion rates (1.11 ± 0.22 and 0.67 ± 0.07 pmol/min; P = .04). The incretin effect computed from plasma C-peptide was 21.8% ± 6.5% before insulin treatment and increased 40.9% ± 3.9% after insulin treatment (P < .02).. Intensified insulin treatment to improve glycemic control led to a disproportionate improvement of insulin secretion in response to oral compared with iv glucose stimulation in patients with type 2 diabetes. This suggests that in T2DM the impaired incretin effect is independent of abnormal glucose-stimulated insulin secretion.

Topics: Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Drug Monitoring; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Glargine; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Insulin, Long-Acting; Male; Middle Aged; Overweight

The aim of the study was to analyse the prevalence and characteristics of secondary diabetes induced by 5-fluorouracil (5-FU) based chemotherapy in non-diabetic patients with colorectal cancer (CRC).. A total of 422 consecutive CRC patients who received 5-FU-based chemotherapy were retrospectively analysed. Fasting plasma glucose (FPG) levels were determined before each cycle of chemotherapy during active treatment and regular follow-up. The prevalence and characteristics of secondary hyperglycaemia were investigated, with special focus on the clinical outcome.. Among the 422 CRC patients, 60 had pre-existing hyperglycaemia. In the remaining 362 with normal FPG levels before chemotherapy, 42 (11.6%) and 41 (11.3%) patients developed diabetes and impaired fasting glucose during the study period. Among the 42 secondary diabetic patients, 22 (52.4%) received anti-diabetes drug therapy, in 7 (16.7%) cases the FPG level returned to normal without any active intervention, and 13 (30.9%) cases received diet control and physiotherapy. Thirty-one (8.6%) patients developed diabetes. Based on the Common Terminology Criteria for Adverse Events, an adverse event over Grade 3 occurred in seven cases during follow-up. Diabetes-related adverse events had a serious negative impact on chemotherapy in six cases. Diabetes-related death occurred in three patients.. Secondary diabetes associated with 5-FU-based chemotherapy occurs in around 10% of CRC patients, with a significant negative impact on treatment and clinical outcome. 5-FU-related diabetes should be regarded as a common side effect of 5-FU treatment.

Topics: Aged; Analysis of Variance; Antimetabolites, Antineoplastic; C-Peptide; Colorectal Neoplasms; Diabetes Mellitus; Feeding Behavior; Female; Fluorouracil; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Physical Therapy Modalities; Retrospective Studies; Statistics, Nonparametric; Treatment Outcome

C-peptide is a bioactive peptide with a potentially protective role in diabetes complications; however, its molecular mechanism of protection against cardiovascular damage caused by hyperglycemia-induced apoptosis remains unclear. We investigated the protective mechanism of C-peptide against hyperglycemia-induced apoptosis using human umbilical vein endothelial cells and streptozotocin diabetic mice. High glucose (33 mmol/L) induced apoptotic cell death in endothelial cells via sequential elevation of intracellular Ca(2+) and reactive oxygen species (ROS) as well as subsequent activation of transglutaminase 2 (TG2). C-peptide (1 nmol/L) prevented endothelial cell death by inhibiting protein kinase C- and NADPH oxidase-dependent intracellular ROS generation and by abolishing high glucose-induced TG2 activation, without affecting intracellular Ca(2+) levels. Consistently, in the aorta of streptozotocin diabetic mice, hyperglycemia stimulated transamidating activity and endothelial cell apoptosis that was inhibited by C-peptide replacement therapy (35 pmol/min/kg) using osmotic pumps (control and diabetes, n = 8; diabetes + C-peptide, n = 7). In addition, C-peptide prevented hyperglycemia-induced activation of transamidation activity and apoptosis in the heart and renal cortex of streptozotocin diabetic mice. Thus, C-peptide protects endothelial cells from hyperglycemia-induced apoptotic cell death by inhibiting intracellular ROS-mediated activation of TG2. Furthermore, TG2 may be a promising avenue of therapeutic investigation to treat diabetic vasculopathies.

Topics: Animals; Apoptosis; C-Peptide; Calcium; Cells, Cultured; Diabetes Mellitus, Experimental; Enzyme Activation; GTP-Binding Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Kidney Cortex; Male; Mice; Mice, Inbred C57BL; Myocardium; Protein Glutamine gamma Glutamyltransferase 2; Reactive Oxygen Species; Streptozocin; Transglutaminases

Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion?. Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis.. Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031).. Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous β-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Insulin; Insulin Glargine; Insulin Secretion; Insulin, Long-Acting; Male; Middle Aged; Postprandial Period; Treatment Outcome

Topics: Animals; Apoptosis; C-Peptide; GTP-Binding Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Male; Protein Glutamine gamma Glutamyltransferase 2; Reactive Oxygen Species; Transglutaminases

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

Topics: Aged; Algorithms; Biomarkers; Blood Glucose; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Insulin-Secreting Cells; Logistic Models; Male; Medical Records; Middle Aged; Postprandial Period; Retrospective Studies

People with prediabetes are at high risk of developing diabetes.. The objective of this study was to determine the pathogenesis of fasting and postprandial hyperglycemia in prediabetes.. Glucose production, gluconeogenesis, glycogenolysis, and glucose disappearance were measured before and during a hyperinsulinemic clamp using [6,6-(2)H2]glucose and the deuterated water method corrected for transaldolase exchange.. The study was conducted at the Mayo Clinic Clinical Research Unit.. Subjects with impaired fasting glucose (IFG)/normal glucose tolerance (NGT) (n = 14), IFG/impaired glucose tolerance (IGT) (n = 18), and normal fasting glucose (NFG)/NGT (n = 16) were studied.. A hyperinsulinemic clamp was used.. Glucose production, glucose disappearance, gluconeogenesis, and glycogenolysis were measured.. Fasting glucose production was higher (P < .0001) in subjects with IFG/NGT than in those with NFG/NGT because of increased rates of gluconeogenesis (P = .003). On the other hand, insulin-induced suppression of glucose production, gluconeogenesis, glycogenolysis, and stimulation of glucose disappearance all were normal. Although fasting glucose production also was increased (P = .0002) in subjects with IFG/IGT, insulin-induced suppression of glucose production, gluconeogenesis, and glycogenolysis and stimulation of glucose disappearance were impaired (P = .005).. Fasting hyperglycemia is due to excessive glucose production in people with either IFG/NGT or IFG/IGT. Both insulin action and postprandial glucose concentrations are normal in IFG/NGT but abnormal in IFG/IGT. This finding suggests that hepatic and extrahepatic insulin resistance causes or exacerbates postprandial glucose intolerance in IFG/IGT. Elevated gluconeogenesis in the fasting state in IFG/NGT and impaired insulin-induced suppression of both gluconeogenesis and glycogenolysis in IFG/IGT suggest that alteration in the regulation of these pathways occurs early in the evolution of type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbon Isotopes; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Gluconeogenesis; Glucose Clamp Technique; Glucose Intolerance; Glycogenolysis; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Liver; Male; Middle Aged; Prediabetic State

No data is so far available on the relation between glucose values and insulin resistance and mortality, both at short- and long-term, in patients with acute heart failure syndromes (AHF). We prospectively assessed in 100 consecutive non-diabetic AHF patients whether acute glucose metabolism, as indicated by fasting glycemia and insulin resistance (HOMA index) was able to affect short- and long-term mortality. In the overall population, 51 patients showed admission glucose values >140 mg/dl. No significant difference was observed in admission and peak glycemia, insulin and C-peptide values and in HOMA-index between dead and survived patients. At multivariate logistic backward stepwise analysis the following variables were independent predictors for in-ICCU mortality (when adjusted for left ventricular ejection fraction): Fibrinogen (1 mg/dl increase) [OR (95% CI) 0.991 (0.984-0.997); p = 0.004]; NT-pro BNP (100 UI increase) [OR (95%CI) 1.005 (1.002-1.009); p = 0.004]; leukocyte count (1,000/μl increase) [OR (95%CI) 1.252 (1.070-1.464); p = 0.005]. eGFR was independently correlated with long-term mortality (HR 0.96, 95%CI 0.94-0.98, p < 0.001). In consecutive patients with acute heart failure without previously known diabetes, we documented, for the first time, that fasting glucose and insulin values and insulin resistance do not affect mortality at short- and long-term. Inflammatory activation (as indicated by the leukocyte count and the fibrinogen) and NT-pro BNP levels are independent predictors for early death while the eGFR affects the long-term mortality.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glomerular Filtration Rate; Heart Failure; Humans; Hyperglycemia; Insulin; Insulin Resistance; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies

Epidemiological evidence suggests that whole grain intake is associated with reduced risk of type 2 diabetes. However, studies of individual whole grains on the prevention of type 2 diabetes are lacking. The objective of the present study was to examine the effect of different whole grains on type 2 diabetes in an animal model of type 2 diabetes, the Goto-Kakisaki (GK) rat. GK rats were fed either a basal diet or a whole grain-containing diet for 5 months. Whole grain diets contained 65 % whole grain flours of wheat, barley, oats or maize. After 2 months of feeding, fasting plasma glucose concentrations were lower in the wheat, barley and oats groups, compared with the basal group, whereas glycated Hb was significantly greater in the wheat group compared with other groups. Feeding of whole barley and maize increased plasma C-peptide concentrations compared with whole wheat at 2 months. There was a trend in the improvement of insulin resistance with a consumption of barley and oats diets at 2 months (P = 0·06) compared with the basal diet. Oxidative stress markers, urinary thiobarbituric acid-reactive substances and 8-isoprostane, did not improve with whole grain intake at 2 months. At 5 months, whole grain diets did not differ from the basal diet in glycaemic control, insulin secretion, oxidative stress and preservation of pancreatic β-cell mass. These results suggest that the consumption of whole grains may offer modest benefit early in the development of type 2 diabetes, but this benefit is lost with further development of the disease.

Topics: Animals; Antioxidants; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Dietary Fiber; Dinoprost; Disease Progression; Edible Grain; Food Handling; Functional Food; Glycated Hemoglobin; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Oxidative Stress; Random Allocation; Rats; Rats, Mutant Strains; Rats, Wistar; Thiobarbituric Acid Reactive Substances

We investigated C-peptide effects on inflammatory cytokine release and adhesion of monocytes exposed to high glucose and lipopolysaccharide (LPS) in vitro.. Monocytic cells (U-937) were cultured in the presence of 30 mmol/L glucose and stimulated with 0.5 ng/μL LPS in the presence or absence of C-peptide (1 μmol/L) for 24 h to induce inflammatory cytokine secretion. Adhesion of U-937 monocytes to human aortic endothelial cells (HAEC) was also studied in the presence or absence of C-peptide. Concentrations of IL-6, IL-8, macrophage inflammatory protein(MIP)-1α, and MIP-1β in supernatants from LPS-stimulated U-937 monocytes were assessed by Luminex. To gain insights into potential intracellular signaling pathways affected by C-peptide, we investigated nuclear translocation of nuclear factor(NF)-κB p65/p50 subunits by western blot in LPS-treated U-937 cells. The effect of C-peptide on LPS-induced phosphorylation of the cytoplasmic protein IκB-α was also investigated by immunoblotting.. Addition of C-peptide significantly reduced cytokine secretion from LPS-stimulated U-937 monocytes. Adhesion of U-937 cells to HAEC was also significantly reduced by C-peptide. These effects were accompanied by reduced NF-κB p65/p50 nuclear translocation and decreased phosphorylation of IκB-α.. We conclude that, in conditions of hyperglycemia, C-peptide reduces monocytes activation via inhibition of the NF-κB pathway.

Topics: Aorta; C-Peptide; Chemokine CCL3; Chemokine CCL4; Endothelial Cells; Humans; Hyperglycemia; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Monocytes; Phosphorylation; U937 Cells

During myocardial infarction (MI), a transient decrease of both insulin sensitivity and secretion triggers stress hyperglycemia, which is followed by a substantial increase in mortality. Recent findings in cellular models indicate that HDL may act on glucose homeostasis by improving insulin sensitivity and secretion. In this study, we explored this potential effect in patients during the acute phase of MI.. Plasma glucose, insulin and C-peptide were measured at admission in the first 24h and on the fifth day after MI with ST-segment elevation in 183 consecutive non-diabetic patients. Patients were divided into HDL-C quartiles for the analyses (Q1: <31, Q2: 31-38, Q3: 38-47 and Q4: >47mg/dL). The Homeostasis Model Assessment version 2 was used to assess insulin sensitivity (HOMA2S) and beta-cell function (HOMA2B).. On admission, no difference was found between the quartiles in glucose (p=0.6), insulin (p=0.6) or C-peptide (p=0.5) levels, HOMA2S (p=0.9) or HOMA2B (p=1.0). On the fifth day there was a reduction in glucose levels whose intensity was directly proportional to the HDL-C quartile (p<0.001). At the same time, there was a reduction in plasma insulin (p<0.001) and C-peptides (p<0.001) whose magnitude was inversely proportional to the HDL-C quartile. Consistently, the increase of HOMA2S (p<0.001) and HOMA2B (p=0.01) were also positively associated with HDL-C levels. Furthermore, plasma HDL-C levels were inversely and independently associated with blood glucose change during the acute phase.. This study demonstrates the association between low plasma HDL-C levels and increased duration of stress hyperglycemia during MI and suggests in humans the interaction between HDL and insulin secretion and sensitivity.

Topics: Aged; Analysis of Variance; Biomarkers; Blood Glucose; Brazil; C-Peptide; Cholesterol, HDL; Female; Homeostasis; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Prospective Studies; Stress, Physiological; Time Factors; Up-Regulation

The aim of this study was to investigate whether combined epidermal growth factor (EGF) and gastrin can correct the hyperglycemia induced by streptozotocin (STZ) in rats and to determine the involvement of the transcription factor pancreatic and duodenal homeobox 1 (PDX1) in this process.. Rat diabetes was induced by intraperitoneal injection of STZ. The mRNA and protein levels of insulin and PDX1 were determined by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Serum levels of C-peptide and insulin were analyzed using radioimmunoassay kits.. The combined administration of EGF and gastrin efficiently reversed the hyperglycemia induced by STZ. Elevated insulin concentration was detected in diabetic rats treated with EGF plus gastrin. The authors also found that both insulin and PDX1 expression were reduced in STZ-treated rats. Interestingly, the combination treatment also significantly enhanced the mRNA levels of insulin and PDX1, and that of their protein products.. Therapy with EGF plus gastrin corrected hyperglycemia and maintained insulin content in STZ-induced diabetic rats via up-regulation of PDX1 expression, suggesting that this combination treatment may provide a valuable approach for pancreatic islet neogenesis in vivo.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Combinations; Epidermal Growth Factor; Gastrins; Homeodomain Proteins; Humans; Hyperglycemia; Injections, Subcutaneous; Insulin; Islets of Langerhans; Male; Radioimmunoassay; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trans-Activators

The aim of this study was to examine whether percutaneous electrical muscle stimulation (EMS) attenuates postprandial hyperglycemia in type 2 diabetes.. Eleven patients with type 2 diabetes participated in two experimental sessions; one was a 30-min EMS 30 min after a breakfast (EMS trial) and the other was a complete rest after a breakfast (Control trial). In each trial, blood was sampled before and at 30, 60, 90, and 120 min after the meal.. Postprandial glucose level was significantly attenuated in EMS trial at 60, 90, and 120 min after a meal (p<0.05). The C-peptide concentration was also significantly lowered in EMS trial (p<0.01). On the other hand, there was no significant increase in creatine phosphokinase (CPK) concentration in each trial.. The present results provide first evidence indicating that EMS is a new exercise method for treating postprandial hyperglycemia in individuals with type 2 diabetes, especially who cannot perform adequate voluntary exercise because of excessive obesity, orthopedic diseases, or severe diabetic complications.

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Electric Stimulation; Humans; Hyperglycemia; Japan; Lactic Acid; Male; Middle Aged; Muscle, Skeletal; Postprandial Period; Pulmonary Gas Exchange; Sedentary Behavior; Time Factors

Insulinoma is a tumour of insulin-producing cells of the pancreas and is known to be one of the causes of hypoglycaemia. Usually, appropriate removal of the insulinoma results in normalization of blood glucose levels. However, we found novel cases of insulinoma, in which hyperglycaemia developed soon after resection of the insulinoma.. We encountered two patients with repeated hypoglycaemia caused by insulinoma. Following removal of the insulinoma, unanticipated hyperglycaemia was observed in both patients. Thereafter, their blood tests revealed low levels of serum C-peptide and high titres of anti-glutamic acid decarboxylase antibody, indicating concomitant Type 1 diabetes. Indeed, histological examination of the resected specimen revealed that one patient showed insulitis in non-tumorous pancreatic tissue in which β-cells had already disappeared. Moreover, inflammatory cells infiltrated the insulinoma, as if it were insulitis of Type 1 diabetes, suggesting the existence of anti-islet autoimmunity.. These are first cases of insulinoma associated with underlying Type 1 diabetes. Physicians should be aware of the possibility that insulinoma may mask Type 1 diabetes, and measurement of anti-islet autoantibodies may be helpful to find underlying Type 1 diabetes, such as in these cases. It is pathologically interesting that the immune cell infiltration into insulinoma may be suggestive of anti-islet autoimmunity.

Topics: Adult; Aged; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Humans; Hyperglycemia; Insulinoma; Islets of Langerhans; Male; Pancreatic Neoplasms

Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3(+) enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins(+)) cells that express markers of mature β cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins(+) cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins(+) cells. Following ablation by the β-cell toxin streptozotocin, gut Ins(+) cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3(+) enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins(+) cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; C-Peptide; Cell Differentiation; Diabetes Mellitus, Experimental; Enteroendocrine Cells; Forkhead Box Protein O1; Forkhead Transcription Factors; Gastrointestinal Tract; Glucose; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuroendocrine Cells; Stem Cells; Streptozocin; Sulfonylurea Compounds; Wnt Signaling Pathway

The mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test.. Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin.. The 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥ 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test (r = 0.97, P < 0.0001). A fasting serum C-peptide ≥ 0.07 nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥ 0.2 nmol/l).. Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients.

Topics: Adolescent; Adult; Age of Onset; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; England; Fasting; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Meals; Middle Aged; Young Adult

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on β-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; KCNQ1 Potassium Channel; Membrane Proteins; Transcription Factor 7-Like 2 Protein

Since mediators of inflammation are associated with insulin resistance, and the risk of developing diabetes mellitus and gestational diabetes, we hypothesized that genetic variation in members of the inflammatory gene pathway impact glucose levels and related phenotypes in pregnancy. We evaluated this hypothesis by testing for association between genetic variants in 31 inflammatory pathway genes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort, a large multiethnic multicenter study designed to address the impact of glycemia less than overt diabetes on pregnancy outcome.. Fasting, 1-hour, and 2-hour glucose, fasting and 1-hour C-peptide, and HbA1c levels were measured in blood samples obtained from HAPO participants during an oral glucose tolerance test at 24-32 weeks gestation. We tested for association between 458 SNPs mapping to 31 genes in the inflammatory pathway and metabolic phenotypes in 3836 European ancestry and 1713 Thai pregnant women. The strongest evidence for association was observed with TNF alpha and HbA1c (rs1052248; 0.04% increase per allele C; p-value = 4.4×10(-5)), RETN and fasting plasma glucose (rs1423096; 0.7 mg/dl decrease per allele A; p-value = 1.1×10(-4)), IL8 and 1 hr plasma glucose (rs2886920; 2.6 mg/dl decrease per allele T; p-value = 1.3×10(-4)), ADIPOR2 and fasting C-peptide (rs2041139; 0.55 ug/L decrease per allele A; p-value = 1.4×10(-4)), LEPR and 1-hour C-peptide (rs1171278; 0.62 ug/L decrease per allele T; p-value = 2.4×10(-4)), and IL6 and 1-hour plasma glucose (rs6954897; -2.29 mg/dl decrease per allele G, p-value = 4.3×10(-4)).. Based on the genes surveyed in this study the inflammatory pathway is unlikely to have a strong impact on maternal metabolic phenotypes in pregnancy although variation in individual members of the pathway (e.g. RETN, IL8, ADIPOR2, LEPR, IL6, and TNF alpha,) may contribute to metabolic phenotypes in pregnant women.

Topics: Asian People; Blood Glucose; C-Peptide; Cohort Studies; Fasting; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Inflammation; Interleukin-6; Interleukin-8; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Receptors, Adiponectin; Receptors, Leptin; Resistin; Signal Transduction; Thailand; Tumor Necrosis Factor-alpha; White People

In the present study, we examined the therapeutic potential of human amnion-derived insulin-secreting cells for type 1 diabetes. Human amniotic mesenchymal stem cells (hAMs) were isolated from amnion and cultivated to differentiate into insulin-secreting cells in vitro. After culture in vitro, the differentiated cells (hAM-ISCs) were intensively stained with dithizone and secreted insulin and c-peptide in a high-glucose-dependent manner. They expressed mRNAs of pancreatic cell-related genes, including INS, PDX1, Nkx6-1, NEUROG3, ISL1, NEUROD1, GLUT1, GLUT2, PC1/3, PC2, GCK, PPY, SST, and GC, and were positive for human insulin and c-peptide. Transplantation of hAM-ISCs into the kidneys of mice with streptozotocin-induced diabetes restored body weight and normalized the blood glucose levels, which lasted for 210 days. Only human insulin and c-peptide were detected in the blood of normalized mice after 2 months of transplantation, but little mouse insulin and c-peptide. Removal of graft-bearing kidneys from these mice resulted in causing hyperglycemia again. Human cell-specific gene, hAlu, and human pancreatic cell-specific genes, insulin, PDX1, GLUT1, GLP1R, Nkx6-1, NEUROD1, and NEUROG3, were detected in the graft-bearing kidneys. Colocalization of human insulin and human nuclei antigen was also observed. These results demonstrate that hAMs could differentiate into functional insulin-secreting cells in vitro, and human insulin secreted from hAM-ISCs following transplantation into type 1 diabetic mice could normalize hyperglycemia, overcoming immune rejection for a long period.

Topics: Animals; Blood Glucose; C-Peptide; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Humans; Hyperglycemia; Immunohistochemistry; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Transplantation, Heterologous

Juvenile (2-23 years old) cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin (STZ), and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile (2-3 years old) cynomolgus monkeys were separated into three groups and administered with different doses of STZ (100, 68 or 60 mg kg(-1)). Basal and glucose-stimulated blood glucose, insulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immunohistochemistry were performed before and after STZ treatment. Monkeys treated with both 100 and 68 mg kg(-1) of STZ exhibited continuous hyperglycemia, which coincided with a nearly complete loss of islet β-cells. Two monkeys received 60 mg kg(-1) of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal function slightly increased in these three groups. However, 24 hours post-STZ, serum total bile acid levels were significantly increased in monkeys treated with 100 mg kg(-1) than those treated with 68 mg kg(-1) of STZ (P<0.05). These data suggest that 100 mg kg(-1) and 68 mg kg(-1) of STZ can safely induce diabetes in cynomolgus monkeys aged 2-3 years, but 68 mg kg(-1) of STZ, rather than 100 mg kg(-1) of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m(-2) of STZ should be the lower limit for inducing diabetes in juvenile monkeys.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperglycemia; Immunohistochemistry; Islets of Langerhans; Kidney; Liver; Macaca fascicularis; Male; Streptozocin; Time Factors

To correctly evaluate the glucose control system, it is crucial to account for both insulin sensitivity and secretion. The disposition index (DI) is the most widely accepted method to do so. The original paradigm (hyperbolic law) consists of the multiplicative product of indices related to insulin sensitivity and secretion, but more recently, an alternative formula has been proposed with the exponent α (power function law). Traditionally, curve-fitting approaches have been used to evaluate the DI in a population: the algorithmic implementations often introduce some critical issues, such as the assumption that one of the two indices is error free or the effects of the log transformation on the measurement errors. In this work, we review the commonly used approaches and show that they provide biased estimates. Then we propose a novel nonlinear total least square (NLTLS) approach, which does not need to use the approximations built in the previously proposed alternatives, and show its superiority. All of the traditional fit procedures, including NLTLS, account only for uncertainty affecting insulin sensitivity and secretion indices when they are estimated from noisy data. Thus, they fail when part of the observed variability is due to inherent differences in DI values between individuals. To handle this inevitable source of variability, we propose a nonlinear mixed-effects approach that describes the DI using population hyperparameters such as the population typical values and covariance matrix. On simulated data, this novel technique is much more reliable than the curve-fitting approaches, and it proves robust even when no or small population variability is present in the DI values. Applying this new approach to the analysis of real IVGTT data suggests a value of α significantly smaller than 1, supporting the importance of testing the power function law as an alternative to the simpler hyperbolic law.

Topics: Adult; Aged; Aging; Algorithms; Blood Glucose; C-Peptide; Computer Simulation; Glucose Tolerance Test; Homeostasis; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Least-Squares Analysis; Middle Aged; Models, Biological; Nonlinear Dynamics; Young Adult

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemia; Immune Tolerance; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Middle Aged; Tacrolimus

Hyperglycemia following major trauma is a well know phenomenon related to stress-induced systemic reaction. Reports on glucose level management in patients with head trauma have been published, but the development of insulin resistance in trauma patients without head injury has not been extensively studied. The aim of this study was therefore to investigate the prognostic role of acute insulin-resistance, assessed by the HOMA model, in patients with severe trauma without head injury.. All patients consecutively admitted to the Intensive Care Unit (ICU) of a tertiary referral center (Careggi Teaching Hospital, Florence, IT) for major trauma without head injury (Jan-Dec 2010) were enrolled. Patients with a previous diagnosis of diabetes mellitus requiring insulin therapy or metabolism alteration were excluded from the analysis. Patients were divided into "insulin resistant" and "non-insulin resistant" based on the Homeostasis Model Assessment index (HOMA IR). Results are expressed as medians.. Out of 175 trauma patients admitted to the ICU during the study period, a total of 54 patients without head trauma were considered for the study, 37 of whom met the inclusion criteria. In total, 23 patients (62.2%) resulted insulin resistant, whereas 14 patients (37.8%) were non-insulin resistant. Groups were comparable in demographic, clinical/laboratory characteristics, and severity of injury. Insulin resistant patients had a significantly higher BMI (P=0.0416), C-reactive protein (P=0.0265), and leukocytes count (0.0301), compared to non-insulin resistant patients. Also ICU length of stay was longer in insulin resistant patients (P=0.0381).. Our data suggest that admission insulin resistance might be used as an early outcome predictor.

Topics: Adult; Body Mass Index; C-Peptide; C-Reactive Protein; Female; Humans; Hyperglycemia; Infections; Insulin Resistance; Intensive Care Units; Length of Stay; Leukocyte Count; Logistic Models; Male; Middle Aged; Pilot Projects; Prognosis; Prospective Studies; Respiration, Artificial; Wounds and Injuries

Immunoassays are susceptible to analytical interferences including from endogenous immunoglobulin antibodies at a rate of ∼0.4% to 4%. Hundreds of millions of immunoassay tests (>10 millions in the UK alone) are performed yearly worldwide for measurements of an array of large and small moieties such as proteins, hormones, tumour markers, rheumatoid factor, troponin, small peptides, steroids and drugs.. Interference in these tests can lead to false results which when suspected, or surmised, can be analytically confirmed in most cases. Suspecting false laboratory data in the first place is not difficult when results are gross and without clinical correlates. However, when false results are subtle and/or plausible, it can be difficult to suspect with adverse clinical sequelae. This problem can be ameliorated by using a probabilistic Bayesian reasoning to flag up potentially suspect results even when laboratory data appear "not-unreasonable".. Essentially, in disorders with low prevalence, the majority of positive results caused by analytical interference are likely to be false positives. On the other hand, when the disease prevalence is high, false negative results increase and become more significant. To illustrate the scope and utility of this approach, six different examples covering wide range of analytes are given, each highlighting specific aspect/nature of interference and suggested options to reduce it.. Bayesian reasoning would allow laboratorians and/or clinicians to extract information about potentially false results, thus seeking follow-up confirmatory tests prior to the initiation of more expensive/invasive procedures or concluding a potentially wrong diagnosis.

Topics: Acute Coronary Syndrome; Aged; Bayes Theorem; C-Peptide; Chorionic Gonadotropin; Data Interpretation, Statistical; False Positive Reactions; Female; Humans; Hyperglycemia; Hypothyroidism; Immunoassay; Insulin; Myocardial Infarction; Proinsulin; Prostate-Specific Antigen; Rheumatoid Factor; Thyrotropin; Troponin

Although islet transplantation holds promise for the treatment of diabetes, the scarcity of donor tissue remains a major drawback. The aim of this study is to generate insulin-producing cells from adult human pancreatic cells isolated from surgically resected pancreatic tissue. To isolate pancreatic endocrine precursor cells from 57 surgically resected pancreases, the cells were cultured and propagated in conditioned medium after which they were differentiated in Matrigel. The resultant cells were characterized using morphology, immunofluorescent studies, expression of differentiated pancreatic islet-specific genes using quantitative reverse transcription-PCR, and glucose-induced insulin secretion through analysis of C-peptide secretion. The relationships between propagation of insulin-producing cells and clinical variables of the donor were also analyzed. Finally, insulin-producing cell function was examined in streptozotocin-induced diabetic rats. Pancreatic endocrine precursor cells were successfully cultured; insulin-producing cells cultured from soft pancreas parenchyma had a significantly higher success rate. Morphological examination revealed islet-like cluster formation upon transfer to Matrigel. The presence of the neural stem cell marker nestin, duct cell marker cytokeratin 19, and endocrine cell markers C-peptide and pancreatic and duodenal homeobox 1, was also observed. In addition, glucose-stimulated C-peptide release was significantly increased in the insulin-producing cells. Furthermore, in diabetic rats, transplantation of insulin-producing cells reduced hyperglycemia. Isolated pancreatic endocrine precursor cells from surgically resected pancreatic tissue differentiated into insulin-producing cells and showed characteristics of functional endocrine cells. Thus, surgically resected pancreatic tissue may represent an alternative source of functional insulin-producing cells.

Topics: Adult; Aged; Animals; C-Peptide; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Homeodomain Proteins; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Intermediate Filament Proteins; Keratin-19; Male; Middle Aged; Nerve Tissue Proteins; Nestin; Pancreas; Pancreatic Diseases; Rats; Tissue Donors; Transplantation, Heterologous; Treatment Outcome

Islet replacement therapy is limited by shortage of donor islet cells. Usage of islet cells derived from porcine pancreatic stem cells (PSCs) is currently viewed as the most promising alternative for human islet transplantation. However, PSCs are rare and have a finite proliferative lifespan. In this study, we isolated and established an immortalized mesenchymal stem cell (MSC) line derived from foetal porcine pancreas, by transfecting human telomerase reverse transcriptase (hTERT) and called these immortalized pancreatic mesenchymal stem cells (iPMSCs). The iPMSCs have been cultured for more than 80 passages and have capacity to differentiate into neurons, cardiomyocytes, germ cells and islet-like cells, analysed by morphology, RT-PCR, western blotting, immunofluorescence, immunocytochemistry and transplantation assay. Islets derived from iPMSCs reversed hyperglycaemia in streptozotocin-induced diabetic mice and secreted insulin and C-peptide in vitro. These results demonstrated that iPMSCs might provide unlimited resources for islet replacement therapy and models for functional cell differentiation.

Topics: Animals; C-Peptide; Cell Differentiation; Cell Line, Transformed; Diabetes Mellitus, Experimental; Fetus; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Mesenchymal Stem Cells; Mice; Mice, Nude; Pancreas; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Swine; Telomerase; Transfection

We evaluated the relationship between insulin resistance (IR) and insulin secretion with the metabolic syndrome (MS) in 885 subjects (377 men/508 women, age 49±11 years, BMI 29±5.2kgm(-2)) at risk of diabetes enrolled in the genetics, pathophysiology and evolution of type 2 diabetes (GENFIEV) study.. All subjects underwent a 75-g oral glucose tolerance test (OGTT) for the estimation of plasma levels of glucose and C-peptide, as well as fasting insulin and lipid profile. IR was arbitrarily defined as HOMA-IR value above the 75th centile of normal glucose tolerance (NGT) subjects. Overall MS prevalence (National Cholesterol Treatment Panel-Adult Treatment Panel (NCEP-ATPIII) criteria) was 33%, 19% in subjects with NGT, 42% in impaired fasting glucose (IFG), 34% in impaired glucose tolerance (IGT), 74% in IFG+IGT subjects, and 56% in newly diagnosed diabetic patients. Prevalence was slightly higher with IDF criteria. MS prevalence was >50% in subjects with 2h glucose >7.8mmoll(-1), independently of fasting plasma glucose. IR prevalence was higher in subjects with MS than in those without (63% vs. 23%; p<0.0001) and increased from 54% to 73% and 88% in the presence of three, four or five traits, respectively. IR occurred in 42% of subjects with non-diabetic alterations of glucose homeostasis, being the highest in those with IFG+IGT (IFG+IGT 53%, IFG 45%, IGT 38%; p<0.0001). Individuals with MS were more IR irrespective of glucose tolerance (p<0.0001) with no difference in insulinogenic index. Hypertriglyceridaemia (OR: 3.38; Confidence Interval, CI: 2.294.99), abdominal obesity (3.26; CI: 2.18-4.89), hyperglycaemia (3.02; CI: 1.80-5.07) and hypertension (1.69; CI: 1.12-2.55) were all associated with IR.. These results show that in subjects with altered glucose tolerance (in particular IFG+IGT) MS prevalence is high and is generally associated to IR. Some combinations of traits of MS may significantly contribute to identify subjects with IR.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Insulin Resistance; Italy; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Prediabetic State; Prevalence; Risk Factors

Intrauterine exposure to elevated glucose concentrations may be a mediating factor in prenatal programming of offspring diabetes risk. However, studies examining the effects of maternal glucose concentration on measures of insulin sensitivity and β-cell response in prepubertal children are limited.. We tested the hypothesis that maternal gestational glucose concentration would be inversely associated with children's insulin sensitivity independent of adiposity and positively associated with children's β-cell response independent of adiposity and insulin sensitivity.. This was a cross-sectional study of 21 children aged 5-10 yr in a clinical research setting.. Children's insulin sensitivity index and basal, static, dynamic, and total β-cell response to glucose were determined by mathematical modeling using insulin, glucose, and C-peptide values after a liquid meal tolerance test. Children's percent body fat was determined by dual-energy x-ray absorptiometry. Maternal gestational glucose concentration for the target pregnancy was determined after a 50-g, 1-h oral glucose challenge test at 24-28 wk gestation.. Maternal glucose concentration was significantly, inversely associated with children's insulin sensitivity, independent of percent fat and ethnicity (P <0.05). A significant, positive association was observed for maternal glucose concentration with static β-cell response, independent of percent fat and insulin sensitivity (P < 0.05).. Maternal gestational glucose concentration was significantly associated with offspring insulin sensitivity and β-cell response independent of adiposity. These results suggest that maternal glucose may program the fetus both at the pancreas and at the level of insulin target tissues such as skeletal muscle and liver.

Topics: Absorptiometry, Photon; Adiposity; Adult; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Child; Child, Preschool; Data Interpretation, Statistical; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Pancreatic Function Tests; Pregnancy; Pregnancy Complications

To observe the relationship between inflammatory response and the constituents of islet β cell secretion during stress hyperglycemia (SHG) in critically ill patients, in order to study the impact of inflammatory response on insulin resistance and the secretion function of islet β cells.. According to the state of inflammatory response, 45 critical patients with SHG were divided into two groups: stress and the convalescence period. Twenty five healthy individuals were enrolled as control group. The blood levels of tumour necrosis factor β (TNF-β), blood glucose (BG), and insulin components including proinsulin (PI), immunoreactive insulin (IRI), true insulin (TI), C-peptide (C-P) were measured respectively. The levels of BG, TNF-β, insulin components, insulin resistance index (HOMA-IR) and the secretion index (HOMA-β) were compared among groups. The relationship between TNF-β and BG, insulin components, HOMA-IR, HOMA-β were analyzed.. (1)There was no difference in concentrations of TI among stress period, convalescence stage and control group [3.68 (1.57, 7.70), 3.42 (2.41, 7.40), 1.46 (0.35, 4.90) mU/L, all P >0.05], whereas the concentration of BG [(10.04 ± 2.43) mmol/L], TNF-β [13.70 (11.77, 20.00) ng/L], PI [6.20 (3.22, 9.27) pmol/L], IRI [13.45 (9.88, 19.88) mU/L] and C-P [3.01 (2.37, 4.00) μg/L]in stress period were significantly higher than those in the convalescence stage[BG: (6.09 ± 0.84) mmol/L, TNF-β: 11.58 (8.80, 13.22) ng/L,PI: 1.54 (0.36, 11.82) pmol/L, IRI: 10.80 (5.35, 12.60) mU/L, C-P: 2.42 (1.17, 3.56) μg/L] and control group [BG: (4.87 ± 0.56) mmol/L,TNF-β: 9.27 (7.48, 12.16) ng/L, PI: 2.20 (1.88, 4.54) pmol/L, IRI: 5.50 (4.00, 8.00) mU/L, C-P: 1.15 (0.87, 1.76) μg/L, P <0.05 or P <0.01]. (2)The HOMA-IR [5.17 (3.41, 11.51)] in stress period was significantly higher than that in the convalescence[3.24 (1.51, 6.95)] and control group [1.14 (0.81, 1.79), P <0.05 and P<0.01]. The HOMA-β [10.80 (3.72, 31.40)] of isletβ cell in stress period was significantly lower than that in the convalescence [28.42 (6.46, 125.01)] and control group [21.94 (7.77, 62.01), P <0.01 and P <0.05]. (3)There were positive correlations between the concentration of TNF-β and PI, IRI, C-P and HOMA-IR ( r 1=0.292, r 2=0.344, r 3=0.397, r 4=0.324, P <0.05 or P <0.01). There were negative correlation between concentration of TNF-β and HOMA-β ( r =-0.235 , P <0.05) .. The severer the inflammatory response, the higher PI, IRI and C-P, while the secretion of TI is relatively deficient.Inflammatory response could affect insulin resistance and the secretion function of islet βcell during SHG in critically ill patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Case-Control Studies; Critical Illness; Female; Humans; Hyperglycemia; Inflammation; Insulin; Insulin Resistance; Islets of Langerhans; Lymphotoxin-alpha; Male; Middle Aged; Young Adult

Hyperglycaemia in acutely ill patients is well described and correcting this hyperglycaemia improves outcomes. It has been generally attributed to endogenous factors, specifically decreased secretion of insulin or increased secretion of anti-insulin hormones, and cytokines, or both. Norepinephrine is the most commonly used vasopressor in critically ill patients. When titrated, it has anecdotally been found to cause wide swings in blood glucose levels. We tested the hypothesis that norepinephrine, a plausible exogenous, iatrogenic cause of hyperglycaemia, causes resistance to insulin action with the hyperinsulinaemic-euglycaemic clamp method.. Hyperinsulinaemic-euglycaemic (about 100 mg dL(-1) ) clamps were performed before and during infusion of norepinephrine, in doses of 110 ng kg(-1) min(-1) , which raised mean arterial pressure from 82 ± 7 to 94 ± 8 mmHg (p < 0.01) in 11 healthy adults.. The glucose infusion rate required to maintain euglycaemia during the clamps, a marker of whole-body insulin sensitivity, decreased from 11.2 ± 3.7 mg kg(-1) min(-1) at baseline to 9.0 ± 2.6 mg kg(-1) min(-1) (p = 0.015) during the norepinephrine infusion. Steady-state insulin and C-peptide levels did not significantly change. Cortisol levels showed diurnal variation in the beginning and were also different at steady state.. Infusion of pressor doses of norepinephrine causes resistance to insulin action in humans.

Topics: Adult; C-Peptide; Female; Glucose Clamp Technique; Humans; Hydrocortisone; Hyperglycemia; Insulin; Insulin Resistance; Male; Norepinephrine; Vasoconstrictor Agents

The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n=10), a selective M(3) muscarinic antagonist; ketanserin 2mg/kg (n=10), a 5HT(2A) antagonist; raclopride 0.3mg/kg (n=11) a selective D(2)/D(3) antagonist; terfenadine 20mg/kg (n=9) a selective H(1) antagonist; or, vehicle (n=11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic β-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H(1) blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M(3)) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D(2)-like receptors in β-cells, which mediate inhibition of insulin secretion, we propose that prolonged D(2) blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation.

Topics: Animals; Antipsychotic Agents; Blood Glucose; C-Peptide; Disease Models, Animal; Glucose; Hyperglycemia; Insulin; Insulin Resistance; Male; Protein Binding; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Histamine

Transdifferentiation of stem cells into insulin-producing cells for the treatment of diabetes have shown promising but inconsistent results. We examined the potential for attracting bone marrow stem cells (BMSCs) to the pancreas using a chemokine, stromal cell-derived factor 1 (SDF-1). SDF-1 treatment markedly increased the number of GFP labeled BMSCs in the pancreas, but surprisingly, the majority was observed in liver. The liver cells had typical pancreatic endocrine cell gene expression including insulin I, insulin II, PDX-1, somatostatin, and glucagon. Combined treatment with SDF-1 and BMSC transplant reduced hyperglycemia and prolonged the long-term survival of diabetic mice, and a sub group had complete normoglycemia (<150 mg/dl), restored blood insulin levels, and normal glucose tolerance. Our results suggest that SDF-1 could potentially be used to improve the homing of stem cells and β-cell regeneration. The mechanism appears to involve an increase in insulin producing cells mainly in the liver.

Topics: Animals; Body Weight; Bone Marrow Cells; C-Peptide; Cell Differentiation; Chemokine CXCL12; Diabetes Mellitus, Experimental; Gene Expression Regulation; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Organ Specificity; Stem Cell Transplantation; Stem Cells; Survival Analysis

Replacement of proinsulin C-peptide in type 1 diabetes ameliorates nerve and kidney dysfunction, conditions which are associated with a decrease in Na,K-ATPase activity. We determined the molecular mechanism by which long term exposure to C-peptide stimulates Na,K-ATPase expression and activity in primary human renal tubular cells (HRTC) in control and hyperglycemic conditions.. HRTC were cultured from the outer cortex obtained from patients undergoing elective nephrectomy. Ouabain-sensitive rubidium ((86)Rb(+)) uptake and Na,K-ATPase activity were determined. Abundance of Na,K-ATPase was determined by Western blotting in intact cells or isolated basolateral membranes (BLM). DNA binding activity was determined by electrical mobility shift assay (EMSA). Culturing of HRTCs for 5 days with 1 nM, but not 10 nM of human C-peptide leads to increase in Na,K-ATPase α(1)-subunit protein expression, accompanied with increase in (86)Rb(+) uptake, both in normal- and hyperglycemic conditions. Na,K-ATPase α(1)-subunit expression and Na,K-ATPase activity were reduced in BLM isolated from cells cultured in presence of high glucose. Exposure to1 nM, but not 10 nM of C-peptide increased PKCε phosphorylation as well as phosphorylation and abundance of nuclear ERK1/2 regardless of glucose concentration. Exposure to 1 nM of C-peptide increased DNA binding activity of transcription factor ZEB (AREB6), concomitant with Na,K-ATPase α(1)-subunit mRNA expression. Effects of 1 nM C-peptide on Na,K-ATPase α(1)-subunit expression and/or ZEB DNA binding activity in HRTC were abolished by incubation with PKC or MEK1/2 inhibitors and ZEB siRNA silencing.. Despite activation of ERK1/2 and PKC by hyperglycemia, a distinct pool of PKCs and ERK1/2 is involved in regulation of Na,K-ATPase expression and activity by C-peptide. Most likely C-peptide stimulates sodium pump expression via activation of ZEB, a transcription factor that has not been previously implicated in C-peptide-mediated signaling. Importantly, only physiological concentrations of C-peptide elicit this effect.

Topics: C-Peptide; Cell Nucleus; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Enzymologic; Gene Silencing; Homeodomain Proteins; Humans; Hyperglycemia; Kidney Tubules; MAP Kinase Signaling System; Models, Biological; Ouabain; Peptides; Phosphorylation; Protein Isoforms; Protein Kinase C; Protein Kinase C-alpha; Protein Kinase C-delta; Protein Kinase C-epsilon; Signal Transduction; Sodium; Sodium-Potassium-Exchanging ATPase; Transcription Factors; Zinc Finger E-box-Binding Homeobox 1

Insulin-dependent diabetes mellitus (IDDM) is characterized by the rapid development of potentially severe metabolic abnormalities resulting from insulin deficiency. The transplantation of insulin-producing cells is a promising approach for the treatment of IDDM. The transcription factor pancreatic duodenal homeobox 1 (Pdx1) plays an important role in the differentiation of pancreatic beta cells. In this study, the human Pdx1 gene was transduced and expressed in murine adipose tissue-derived stem cells (ASCs). To evaluate pancreatic repair, we used a mouse model of pancreatic damage resulting in hyperglycemia, which involves injection of mice with streptozotocin (STZ). STZ-treated mice transplanted with Pdx1-transduced ASCs (Pdx1-ASCs) showed significantly decreased blood glucose levels and increased survival, when compared with control mice. While stable expression of Pdx1 in ASCs did not induce the pancreatic phenotype in vitro in our experiment, the transplanted stem cells became engrafted in the pancreas, wherein they expressed insulin and C-peptide, which is a marker of insulin-producing cells. These results suggest that Pdx1-ASCs are stably engrafted in the pancreas, acquire a functional beta-cell phenotype, and partially restore pancreatic function in vivo. The ease and safety associated with extirpating high numbers of cells from adipose tissues support the applicability of this system to developing a new cell therapy for IDDM.

Topics: Adipose Tissue; Animals; C-Peptide; Cell Differentiation; Diabetes Mellitus; Diabetes Mellitus, Type 1; Homeodomain Proteins; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Mice; Pancreas; Stem Cell Transplantation; Stem Cells; Streptozocin; Trans-Activators

Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.. We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes.. We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 x 10(-10)), which was also associated with mean glucose (P = 2 x 10(-5)). This was confirmed using A1C in the intensive treatment group (P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.. A major locus for A1C and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.

Topics: Blood Glucose; C-Peptide; Diabetes Complications; Diabetes Mellitus, Type 1; Drug Administration Schedule; Ethnicity; Genome-Wide Association Study; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Meta-Analysis as Topic; Patient Selection; Polymorphism, Single Nucleotide; Racial Groups; Receptors, Cell Surface; Reference Values; Siblings

The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A(+) FDRs) of type 1 diabetic patients.. Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A(+) FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT.. Seven (41%) FDRs developed diabetes 3-63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p < 0.05) and HVs (p < 0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3-21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp.. Clamp-derived functional variables stratify risk of diabetes in IA-2A(+) FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage.. ClinicalTrials.gov NCT00654121. The insulin trial was financially supported by Novo Nordisk Pharma nv.

Topics: Adolescent; Adult; Autoantibodies; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Family; Glucose Clamp Technique; HLA-DQ Antigens; Humans; Hyperglycemia; Insulin; Medical History Taking; Reference Values; Risk Assessment; Young Adult

Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and beta-cell function contribute to the progression to the disease.. In 328 islet cell autoantibody-positive, nondiabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range 8], sequential OGTTs (2,143 in total) were performed at baseline, every 6 months, and 2.7 years [2.7] later, when 115 subjects became diabetic. Beta-cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses.. In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas beta-cell glucose sensitivity was impaired (median 48 pmol/min per m2 per mmol/l [interquartile range 36] vs. 87 pmol/min per m2 per mmol/l [67]; P < 0.0001) and predicted incident diabetes (P < 0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-h glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (approximately 13 mmol x l(-1) x year(-1)); glucose sensitivity began to decline significantly (P < 0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable.. In high-risk relatives, beta-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, with a slow linear increase followed by a rapid surge, and are anticipated by a further deterioration of beta-cell glucose sensitivity.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Disease Progression; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Kaplan-Meier Estimate; Male; Models, Biological; Predictive Value of Tests; Risk Factors

Recent studies reported that bone marrow cavity offers a widely distributed and well-vascularized microenvironment which is a considerable implantation site for bioartificial pancreas (BAP). In this study, the in vivo performance of BAPs in bone marrow was further demonstrated in a spontaneous diabetes animal. Mouse insulinoma cells encapsulating in agarose gel were enclosed in a calcium phosphate cement chamber to create a BAP. Ten BAPs were implanted into the femur bone marrow cavity of a diabetic feline. The preprandial blood glucose level, 2 h glucose curve, serum C-peptide level and physiological conditions of the recipient were recorded perioperatively. Results showed that the cat still suffered from hyperglycemia postoperatively. However, the physiological conditions of feline were improved with an increase of serum C-peptide level. The peak point of 2 h glucose curve decreased from 400 to 165-290 mg/dl. The efficiency of exogenous insulin extended from 2 to 10-14 h postoperatively which reveals that the implanted BAPs had partial function. This case report revealed that BAPs implanted in the bone marrow cavity for the spontaneous diabetic is effective. The implanted BAPs provided therapeutic benefit despite sustained hyperglycemia. Further study shall be considered to improve the outcomes of BAPs transplantation.

Topics: Animals; Blood Glucose; Bone Marrow; C-Peptide; Cats; Cell Line, Tumor; Diabetes Mellitus, Type 1; Disease Models, Animal; Hyperglycemia; Insulin; Islets of Langerhans Transplantation; Mice; Pancreas, Artificial

The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide.. Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept.. SII was performed 49.3+/-4.8 months (mean+/-SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076+/-492 vs. 9071+/-796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4+/-0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8+/-2.2 vs. 14.2+/-2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%+/-0.2% pre-SII vs. 6.1%+/-0.2% post-SII, P=0.005) and did not become immunosensitized.. Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Topics: Antilymphocyte Serum; Blood Glucose; C-Peptide; Drug Therapy, Combination; Etanercept; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Male; Postoperative Complications; Receptors, Tumor Necrosis Factor; Sirolimus; Tacrolimus

To probe into the effects of different doses of FK506 on endocrine function of pancreatic islets in Wistar rats.. Wistar rats were randomly divide into control group A (0mg/kg/d) and experimental group B (1mg/kg/d), C (3mg/kg/d), D (10mg/kg/d) treated with FK506. In an intraperitoneal glucose tolerance test, plasma glucose, insulin and C-peptide were measured with a glucose analyzer and ELISA. The ultra-structure of beta cells of pancreatic islets were assayed with an electric microscope.. In the intraperitoneal glucose tolerance test, the level of plasma glucose increased with an increasing of dose of FK506 and the level of plasma insulin and C-peptide decreased with an increasing of dose of FK506. The result of the plasma glucose level showed no significant difference among groups A, B, C, and D at 0 and 120 min P>or=0.05, and result of plasma glucose level show significant differences among groups A, B, C, D at 30, 60 and 90 min, P<0.05. The result of the plasma insulin level showed significant difference among groups A, B, C, and D at 0, 30, 60, 90 min P<0.05.The result of the plasma C-peptide level showed no significant difference among groups A, B, C, and D at 0 min P> 0.05, and the result of plasma C-peptide level showed significant differences in groups A, B, C, and D at 30, 60, 90 and 120 min, P<0.05.With electric microscope assay, the endocrine secretory granules decreased in experiment group. There is some vacuolization in the beta cells of pancreatic islets in group D.. It was shown in the study that disorders of glucose metabolism induced by FK506 were related to the dosage of FK506.

Topics: Animals; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Hyperglycemia; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Microscopy, Electron, Transmission; Rats; Rats, Wistar; Tacrolimus

The purpose of this study was to examine associations of fasting C-peptide, body mass index (BMI), and maternal glucose with the risk of preeclampsia in a multicenter multinational study.. We conducted a secondary analysis of a blinded observational cohort study. Subjects underwent a 75-g oral glucose tolerance test at 24-32 weeks' gestation. Associations of preeclampsia with fasting C-peptide, BMI, and maternal glucose were assessed with the use of multiple logistic regression analyses and adjustment for potential confounders.. Of 21,364 women who were included in the analyses, 5.2% had preeclampsia. Adjusted odds ratios for preeclampsia for 1 SD higher fasting C-peptide (0.87 ug/L), BMI (5.1 kg/m(2)), and fasting (6.9 mg/dL), 1-hour (30.9 mg/dL), and 2-hour plasma glucose (23.5 mg/dL) were 1.28 (95% confidence interval [CI], 1.20-1.36), 1.60 (95% CI, 1.60-1.71), 1.08 (95% CI, 1.00-1.16), 1.19 (95% CI, 1.11-1.28), and 1.21 (95% CI,1.13-1.30), respectively.. Results indicate strong, independent associations of fasting C-peptide and BMI with preeclampsia. Maternal glucose levels (below diabetes mellitus) had weaker associations with preeclampsia, particularly after adjustment for fasting C-peptide and BMI.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Cohort Studies; Fasting; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Logistic Models; Pre-Eclampsia; Pregnancy

The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect.. To characterize the alpha- and beta-cell responses to GLP-1 in type 1 diabetic patients without residual beta-cell function.. Nine type 1 diabetic patients, classified as C-peptide negative by a glucagon test, were clamped at plasma glucose of 20 mmol/liter for 90 min with arginine infusion at time 45 min and concomitant infusion of GLP-1 (1.2 pmol/kg x min) or saline.. Infusion with GLP-1 increased C-peptide concentration just above the detection limit of 33 pmol/liter in one patient, but C-peptide remained immeasurable in all other patients. In the eight remaining patients, total area under the curve of glucagon was significantly decreased with GLP-1 compared with saline: 485 +/- 72 vs. 760 +/- 97 pmol/liter x min (P < 0.001). In addition, GLP-1 decreased the arginine-stimulated glucagon release (incremental AUC of 103 +/- 21 and 137 +/- 16 pmol/liter x min, with GLP-1 and saline, respectively, P < 0.05).. In type 1 diabetic patients without endogenous insulin secretion, GLP-1 decreases the glucagon secretion as well as the arginine-induced glucagon response during hyperglycemia. GLP-1 induced endogenous insulin secretion in one of nine type 1 diabetic patients previously classified as being without endogenous insulin secretion.

Topics: Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Hyperglycemia; Insulin-Secreting Cells; Serum Albumin

It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose.. In men and women with NGT (n=1,123) or IGR(n=156) (age 44 +/- 8 years, BMI 25+/-4 kg/m2, mean +/- SD)we measured: (1) IS by clamp; (2) insulin secretion rates(ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose-response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose.. After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups,whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. InIGR vs NGT, IS was impaired (92 [75] vs 133 [86] micromol min(-1)[kg fat-free mass](-1) [nmol/l](-1), median [interquartile range],p<0.0001) as was beta cell glucose sensitivity (69 [46] vs 119[83] pmol min(-1) m(-2) [nmol/l](-1), p<0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p<0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels.. Insulin resistance normally upregulates the secretory tone, with no evidence of defective compensation in IGR. In contrast, beta cell glucose sensitivity is independent of insulin resistance, but a key determinant of glucose tolerance. This suggests that hyperglycaemia results from an intrinsic beta cell defect rather than from inadequate compensation for insulin resistance.

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Patch-Clamp Techniques

This study aimed to determine how insufficiently suppressed endogenous glucose production vs. reduced peripheral glucose uptake contribute to postprandial hyperglycaemia in type 2 diabetes (T2D).. Eight men with T2D (age: 52+/-7 years; BMI: 26.6+/-2.3 kg/m(2); fasting glycaemia: 7.1+/-1.5 mmol/L) were compared with eight non-diabetic controls (age: 51+/-5 years; BMI: 24.6+/-2.9 kg/m(2); fasting glycaemia: 4.9+/-0.4 mmol/L). Their glucose turnover rates and hepatic glucose cycles were measured by monitoring [2H7]glucose infusion, with m+7 and m+6 enrichment, 3 h before and 4 h after the ingestion of [6,6-2H2]-labelled glucose, while maintaining glycaemia at 10 mmol/L using the pancreatic clamp technique.. Of the 700 mg/kg oral glucose load, 71% appeared in the systemic circulation of the T2D patients vs. 63% in the controls (NS). Endogenous glucose production and hepatic glucose cycles did not differ from normal either before or after oral glucose ingestion, while peripheral glucose uptake was reduced by 40% in the T2D group both before (P<0.01) and after (P<0.05) ingestion of oral glucose.. When T2D patients were compared with non-diabetic subjects with similarly controlled levels of hyperglycaemia after oral glucose ingestion, they essentially differed only in peripheral glucose uptake, whereas endogenous glucose production was apparently unaltered.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Statistics, Nonparametric

Regenerative medicine aims at producing new cells for repair or replacement of diseased and damaged tissues. Embryonic and adult stem cells have been suggested as attractive sources of cells for generating the new cells needed. The leading dogma was that adult cells in mammals, once committed to a specific lineage, become "terminally differentiated" and can no longer change their fate. However, in recent years increasing evidence has accumulated demonstrating the remarkable ability of some differentiated cells to be converted into a different cell type via a process termed developmental redirection or adult cells reprogramming. For example, abundant human cell types, such as dermal fibroblasts and adipocytes, could potentially be harvested and converted into other, medically important cell types, such as neurons, cardiomyocytes, or pancreatic beta cells. In this chapter, we describe a method of activating the pancreatic lineage and beta-cells function in adult human liver cells by ectopic expression of pancreatic transcription factors. This approach aims to generate custom-made autologous surrogate beta cells for treatment of diabetes, and possibly bypass both the shortage of cadaveric human donor tissues and the need for life-long immune-suppression.

Topics: Adult; Animals; C-Peptide; Cell Culture Techniques; Cell Differentiation; Cell Lineage; Cells, Cultured; Gene Expression Regulation, Developmental; Glucose; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Liver; Mice; Mice, Inbred NOD; Mice, SCID; Transcription Factors

Maintenance of normal glucose homeostasis is crucial for survival during the perinatal period. Acylated ghrelin (AG) but not unacylated ghrelin (UAG) inhibits insulin release from pancreatic islets in adult rats. Circulating AG concentrations are low in the fetus and progressively increase in the postnatal period. We tested the hypothesis that AG has insulinostatic effects in vitro and in vivo during the perinatal period. In vitro, AG (10(-10)-10(-8) M) caused a 25-53% decrease in insulin secretion by islets from 5-d-old rat pups under normo- and hyperglycemic conditions, an effect that was mediated through the growth hormone secretagogue receptor (GHSR- 1a). Ghrelin (1-5) amide, [Dap3]-octanoyl, a pentapeptide that is resistant to deacylation and binds the GHSR-1a, had similar effects at 10(-8) M. In vivo, AG, UAG, or GHRP-6 [D-Lys3], a GHSR-1a antagonist, did not affect insulin or glucagon concentrations during the first 3 h of life. In 6-d-old pups, AG, UAG, or ghrelin (1-5) amide, [Dap3]-octanoyl did not affect glucose-induced insulin or C-peptide concentrations. In summary, AG has insulinostatic effects in vitro as early as during the perinatal period. These effects could not be confirmed in vivo, possibly due to the short half-life of AG in rat neonates.

Topics: Acylation; Animals; Animals, Newborn; Blood Glucose; C-Peptide; Cesarean Section; Dose-Response Relationship, Drug; Female; Ghrelin; Glucose; Homeostasis; Hyperglycemia; Insulin; Islets of Langerhans; Male; Oligopeptides; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Tissue Culture Techniques

Glucose-dependent insulinotropic polypeptide (GIP) has been implicated in lipid metabolism in animals. In humans, however, there is no clear evidence of GIP effecting lipid metabolism. The present experiments were performed in order to elucidate the effects of GIP on regional adipose tissue metabolism.. Eight healthy subjects were studied on four different occasions. Abdominal subcutaneous adipose tissue metabolism was assessed by measuring arterio-venous concentration differences and regional adipose tissue blood flow during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperinsulinemic-hyperglycemic (HI-HG) clamp.. During GIP and HI-HG clamp, abdominal subcutaneous adipose tissue blood flow, hydrolysis of circulating triacylglycerol (TAG) (P = 0.009), and glucose uptake (P = 0.03) increased significantly while free fatty acid (FFA) output (P = 0.04) and FFA/glycerol release ratio (P = 0.02) decreased compared with saline and HI-HG clamp.. In conclusion, GIP in combination with hyperinsulinemia and slight hyperglycemia increased adipose tissue blood flow, glucose uptake, and FFA re-esterification, thus resulting in increased TAG deposition in abdominal subcutaneous adipose tissue.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids; Gastric Inhibitory Polypeptide; Glucose Clamp Technique; Glycerol; Humans; Hyperglycemia; Hyperinsulinism; Male; Subcutaneous Fat, Abdominal; Thinness; Triglycerides

The goal was to describe the temporal pattern of neonatal plasma glucose levels and associations with maternal glucose levels, cord serum C-peptide levels, and neonatal size and adiposity.. A total of 17,094 mothers and infants were included in the Hyperglycemia and Adverse Pregnancy Outcome Study (15 centers in 9 countries). Mothers underwent a 75-g, 2-hour, oral glucose tolerance test (OGTT) at 24 to 32 weeks of gestation. Cord blood and neonatal blood samples were collected. Biochemical neonatal hypoglycemia was defined as glucose levels of <10th percentile (2.2 mmol/L). Clinically identified hypoglycemia was ascertained through medical record review and associations were assessed.. Plasma glucose concentrations were stable during the first 5 hours after birth. Maternal glucose levels were weakly positively associated with biochemical neonatal hypoglycemia (odds ratios: 1.07-1.14 for 1-SD higher OGTT glucose levels). Frequency of neonatal hypoglycemia was higher with higher cord C-peptide levels (odds ratio: 11.6 for highest versus lowest C-peptide category). Larger and/or fatter infants were more likely to have hypoglycemia (P < .001), and infants with hypoglycemia tended to have a higher frequency of cord C-peptide levels of >90th percentile.. Mean neonatal plasma glucose concentrations varied little in the first 5 hours after birth, which suggests normal postnatal adjustment. Biochemical and clinical hypoglycemia were weakly related to maternal OGTT glucose measurements but were strongly associated with elevated cord serum C-peptide levels. Larger and/or fatter infants were more likely to develop hypoglycemia and hyperinsulinemia. These relationships suggest physiologic relationships between maternal glycemia and fetal insulin production.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Factors

To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity.. Eligible pregnant women underwent a standard 75-g oral glucose tolerance test between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skin folds >90th percentile or percent body fat >90th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the baby's sex.. Among 23,316 HAPO Study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity, there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-h, and 2-h plasma glucose higher by 1 SD.. These findings confirm the link between maternal glucose and neonatal adiposity and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biological relationship influencing fetal growth.

Topics: Adiposity; Adult; Blood Glucose; Body Mass Index; C-Peptide; Female; Gestational Age; Glucose Tolerance Test; Humans; Hyperglycemia; Infant, Newborn; Logistic Models; Maternal Age; Pregnancy; Pregnancy Outcome; Risk Factors

This study investigated the effects of ursolic acid on immunoregulation and pancreatic beta-cell function in type 1 diabetes fed a high-fat diet for 4 weeks. Male mice were divided into non-diabetic, diabetic control, and diabetic-ursolic acid (0.05%, w/w) groups, which were fed a high-fat (37% calories from fat). Diabetes was induced by injection of streptozotocin (200 mg/kg B.W., i.p.). Ursolic acid significantly improved blood glucose levels, glucose intolerance, and insulin sensitivity compared to the diabetic group. The plasma insulin and C-peptide concentrations were significantly higher in the diabetic-ursolic acid group than in the diabetic group. Ursolic acid significantly elevated the insulin levels with preservation of insulin staining of beta-cells in the pancreas. In splenocytes, concanavalin (Con) A-induced T-cell proliferation was significantly higher in the diabetic-ursolic acid group compared to the diabetic group, but liposaccharide (LPS)-induced B-cell proliferation did not differ between groups. Ursolic acid enhanced IL-2 and IFN-gamma production in response to Con A stimulation, whereas it inhibited TNF-alpha production in response to LPS stimulation. In this study, neither streptozotocin nor ursolic acid had effects on lymphocyte subsets. These results indicate that ursolic acid exhibits potential anti-diabetic and immunomodulatory properties by increasing insulin levels with preservation of pancreatic beta-cells and modulating blood glucose levels, T-cell proliferation and cytokines production by lymphocytes in type 1 diabetic mice fed a high-fat diet.

Topics: Adjuvants, Immunologic; Animals; Antigens, Surface; Blood Glucose; C-Peptide; Cytokines; Diabetes Mellitus, Experimental; Diet; Dietary Fats; Dietary Supplements; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Immunity, Cellular; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Lymphocytes; Male; Mice; Mice, Inbred ICR; Pancreas; Pancreatic Function Tests; Triterpenes; Ursolic Acid

Topics: Adiposity; Adult; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Infant, Newborn; Pregnancy; Pregnancy Outcome

Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes. It is unclear whether this is a primary defect or a consequence of the hyperglycemia in type 2 diabetes. We examined whether acute hyperglycemia reduces the postprandial excursions of gastric inhibitory polypeptide (GIP) and GLP-1, and if so, whether this can be attributed to changes in gastric emptying.. Fifteen nondiabetic individuals participated in a euglycemic clamp and a hyperglycemic clamp experiment, carried out over 285 min. A mixed meal was ingested after 45 min. Plasma concentrations of glucose, insulin, C-peptide, glucagon, triglycerides, GIP, and GLP-1 were determined, and gastric emptying was assessed using a (13)C-octanoate breath test.. Glucose levels were 160 +/- 1 mg/dl during the hyperglycemic clamp experiments and 83 +/- 3 mg/dl during the euglycemia (P < 0.0001). Glucose infusion rates were higher during hyperglycemia, but meal ingestion led to a decline in glucose requirements in both experiments (P < 0.0001). Insulin and C-peptide levels were higher during the hyperglycemic clamp experiments (P < 0.0001), whereas glucagon levels were higher during euglycemia (P < 0.0001). The postprandial increases in GIP and GLP-1 concentrations were 46 and 52% lower during the experiments with hyperglycemia (P = 0.0017 and P = 0.021). Hyperglycemia also elicited a significant delay in gastric emptying (P < 0.0001).. Hyperglycemia acutely reduces the postprandial levels of GIP and GLP-1, possibly through a deceleration of gastric emptying. This supports the concept that reduced incretin levels in some patients with type 2 diabetes are a consequence rather than a cause of type 2 diabetes.

Topics: Adult; Body Mass Index; C-Peptide; Cholesterol, HDL; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Kidney Function Tests; Liver Function Tests; Male; Postprandial Period; Reference Values; Young Adult

Streptozotocin (STZ) given intravenously destroys pancreatic beta cells and is widely used in animal models to mimic type 1 diabetes. The effects of STZ on the clinical state of health and metabolism were studied in six high health certified domestic pigs weighing 19+/-1.3 kg at the start of the experiment. A single STZ dose of 150 mg/kg of body weight successfully induced hyperglycaemia and alterations in amino acid metabolism. Within 9 h after STZ administration, the blood glucose values fell from 5.4-7.5 mmol/L to 0.8-2.2 mmol/L. Hypoglycaemia was treated with 0.5 g glucose/kg body weight. In all pigs, hyperglycaemia was produced 24 h after STZ treatment, and 3 days after STZ injection, the glucose concentration was >25 mmol/L. Mean C-peptide concentration was 0.25+/-0.16 microg/L since 2 days after STZ injection until the end of the study. The serum concentration of the branched-chain amino acids (BCAA) increased four-fold, and alanine and taurine decreased by approximately 70% and 50%, respectively, after STZ treatment. All but one pig remained brisk and the physical examination was normal except for a retarded growth rate and a reduction of the skeletal muscle. At the end of the study, the pigs were moderately emaciated. Postmortem examination confirmed muscle wasting and a reduction of abdominal and subcutaneous fat. In conclusion, STZ-induced diabetes in pigs fulfils the requirements for a good animal model for type 1 diabetes with respect to clinical signs of the disease and alterations in the carbohydrate and amino acid metabolism.

Topics: Alanine; Amino Acids; Amino Acids, Branched-Chain; Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Hyperglycemia; Insulin; Muscle, Skeletal; Swine; Taurine

We investigated the impact of olmesartan and temocapril on pancreatic islet beta-cells during the development of diabetes mellitus using Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats. Four-week-old male OLETF rats were fed standard chow (untreated:n5), or chow containing either 0.005% olmesartan(n5) or 0.01% temocapril (n5) until being sacrificed at 35 weeks of age. Pancreas sections were double-stained with anti-insulin and anti-glucagon antibodies. The percent areas of beta-cells, alpha-cells and non-alpha-non-beta-cells were compared among groups. In untreated OLETF rats, the fasting plasma glucose (FPG) level was elevated at the 18th week and remained elevated until the 35th week. On the other hand, no significant elevation in FPG levels was observed in olmesartan- or temocapril-treated rats. Pancreatic islets from olmesartan-treated rats were significantly smaller in size as compared with those from untreated OLETF rats. Furthermore, the average area occupied by beta-cells as a fraction of the total area of an individual islet was significantly higher in olmesartan- or temocapril-treated rats than that in untreated OLETF rats. Olmesartan and temocapril both prevented the development of hyperglycemia, possibly through the prevention of islet beta-cell loss in spontaneously diabetic OLETF rats.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; C-Peptide; Fructosamine; Hyperglycemia; Imidazoles; Insulin; Insulin-Secreting Cells; Male; Rats; Rats, Inbred OLETF; Receptor, Angiotensin, Type 1; Tetrazoles; Thiazepines

We have previously described the derivation of insulin-producing cell lines from mouse embryonic stem cells (mESCs) by differentiation of an intermediate lineage-restricted E-RoSH cell line through nutrient depletion in the presence of nicotinamide followed by limiting dilution. Here we investigated whether insulin-producing cell lines could be similarly derived directly from mouse embryo cells or tissues. Using a similar approach, we generated the RoSH2.K and MEPI-1 to -14 insulin-producing cell lines from the 5.5-dpc embryo-derived E-RoSH-analogous RoSH2 cell line and a 6.0-dpc mouse embryo culture, respectively. Insulin content was approximately 8 microg/10(6) MEPI-1 cells and 0.5 microg/10(6) RoSH2.K cells. Like insulin-producing mESC-derived ERoSHK cell lines, both MEPI and RoSH2.K lines were amenable to repeated cycles of freeze and thaw, replicated for months with a doubling time of 3-4 days, and exhibited genomic, structural, biochemical, and pharmacological properties of pancreatic beta-cells, including storage and release of insulin and C-peptide in an equimolar ratio. Transplantation of these cells also reversed hyperglycemia in streptozotocin-treated SCID mice and did not induce teratoma. Like ERoSHK cells, both RoSH2.K and MEPI-1 cells also induced hypoglycemia in the mice. Therefore, our protocol is robust and could reproducibly generate insulin-producing cell lines from different embryonic cell sources.

Topics: Animals; C-Peptide; Cell Culture Techniques; Cell Differentiation; Cell Line; Cell Transplantation; Embryo, Mammalian; Hyperglycemia; Insulin; Insulin-Secreting Cells; Mice; Mice, SCID; Streptozocin; Treatment Outcome

Generating surrogate insulin-producing cells from embryonic stem cells (ESCs) through in vitro replication of successive steps during pancreatic development has been challenging . Here we describe a novel reproducible protocol to establish homogeneous and scalable insulin-producing cell lines from mouse (m) ESCs via differentiation of the previously described lineage-restricted clonal mESC-derived E-RoSH cells. Unlike their parental mESCs, E-RoSH cells expressed high levels of mesodermal and endodermal genes. Nutrient depletion in the presence of nicotinamide inhibited proliferation of E-RoSH cells and induced differentiation into heterogeneous cultures comprising vascular-like structures that produced detectable levels of insulin and C-peptide in an equimolar ratio. Limiting dilution of these cultures resulted in the isolation of eight independent insulin-producing cell lines in five experiments. All these lines were cloned and shown to be amenable to repeated cycles of freeze and thaw and to replicate for months with a doubling time of 3-4 days. Under such conditions, the cultured cells exhibited genomic, structural, biochemical, and pharmacological properties of pancreatic beta cells, including storage of an equimolar ratio of insulin and C-peptide in granules and release of the contents of these organelles through a glucose-sensitive machinery. After transplantation, these cells reversed hyperglycemia in streptozotocin-treated SCID mice and did not form teratomas.

Topics: Animals; C-Peptide; Cell Culture Techniques; Cell Differentiation; Cell Lineage; Cell Transplantation; Embryonic Stem Cells; Endoderm; Hyperglycemia; Insulin; Insulin-Secreting Cells; Mesoderm; Mice; Mice, SCID; Treatment Outcome

Loss of pancreatic beta cell mass and function leads to the development of diabetes mellitus. Currently there is no technical way to non-invasively image islet function and mass. Murine models suggest that islets are highly vascularised organs that make a significant contribution to the total pancreatic blood flow. The current study was undertaken to test with arterial spin labelling (ASL) magnetic resonance imaging if islet mass and/or stimulation of human pancreatic islets by hyperglycaemia can differentially increase whole-pancreas perfusion, thereby distinguishing non-diabetic from type 1 diabetic patients.. We assessed pancreatic blood flow using ASL at baseline, during a hyperglycaemia clamp study (glucose at 11 mmol/l) and during recovery to euglycaemia.. Seventeen healthy volunteers and seven type 1 diabetic patients were studied. In healthy volunteers we observed no change in pancreatic blood flow during the three phases of the study. A trend for an increase in blood flow was observed in the two control tissues, the liver and kidney. Similarly, there was no significant difference in blood flow during the three stages (baseline, hyperglycaemia and recovery) in diabetic patients and there was no significant difference observed between diabetic patients and normal volunteers.. Our data suggest that in humans neither increased demand nor islet mass has a substantial influence on pancreatic perfusion. It is possible, however, that the current state-of-the art imaging technology employed in this study might not be sensitive enough to distinguish between a true effect and noise.. ClinicalTrials.gov NCT00280085.

Topics: Adult; Blood Flow Velocity; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Insulin-Secreting Cells; Magnetic Resonance Imaging; Male; Middle Aged; Pancreas; Reference Values; Young Adult

Insulin resistance can broadly be defined as the diminished ability of cells to respond to the action of insulin in transporting glucose from the bloodstream into cells and tissues. Here, we report that erythrocytes (ERYs) obtained from type 2 diabetic rats display an apparent resistance to Zn(2+)-activated C-peptide. Thus, the aims of this study were to demonstrate that Zn(2+)-activated C-peptide exerts potentially beneficial effects on healthy ERYs and that these same effects on type 2 diabetic ERYs are enhanced in the presence of metformin. Incubation of ERYs (obtained from type 2 diabetic BBZDR/Wor-rats) with Zn(2+)-activated C-peptide followed by chemiluminescence measurements of ATP resulted in a 31.2 +/- 4.0% increase in ATP release from these ERYs compared to a 78.4 +/- 4.9% increase from control ERYs. Glucose accumulation in diabetic ERYs, measured by scintillation counting of (14)C-labeled glucose, increased by 35.8 +/- 1.3% in the presence of the Zn(2+)-activated C-peptide, a value significantly lower than results obtained from control ERYs (64.3 +/- 5.1%). When Zn(2+)-activated C-peptide was exogenously added to diabetic ERYs, immunoassays revealed a 32.5 +/- 8.2% increase in C-peptide absorbance compared to a 64.4 +/- 10.3% increase in control ERYs. Phosphatidylserine (PS) externalization and metformin sensitization of Zn(2+)-activated C-peptide were examined spectrofluorometrically by measuring the binding of FITC-labeled annexin to PS. The incubation of diabetic ERYs with metformin prior to the addition of Zn(2+)-activated C-peptide resulted in values that were statistically equivalent to those of controls. Summarily, data obtained here demonstrate an apparent resistance to Zn(2+)-activated C-peptide by the ERY that is corrected by metformin.

Topics: Adenosine Triphosphate; Animals; Antibodies; C-Peptide; Diabetes Mellitus, Type 2; Erythrocytes; Exocytosis; Glucose; Humans; Hyperglycemia; Metformin; Phosphatidylserines; Rats; Spectrometry, Mass, Electrospray Ionization; Zinc

Pancreatic islet transplantation has demonstrated that long-term insulin independence may be achieved in patients suffering from diabetes mellitus type 1. However, limited availability of islet tissue means that new sources of insulin-producing cells that are responsive to glucose are required. Here, we show that human amnion epithelial cells (HAEC) can be induced to differentiate into functional insulin-producing cells in vitro. After induction of differentiation, HAEC expressed multiple pancreatic beta-cell genes, including insulin, pancreas duodenum homeobox-1, paired box gene 6, NK2 transcription factor-related locus 2, Islet 1, glucokinase, and glucose transporter-2, and released C-peptide in a glucose-regulated manner in response to other extracellular stimulations. The transplantation of induced HAEC into streptozotocin-induced diabetic C57 mice reversed hyperglycemia, restored body weight, and maintained euglycemia for 30 d. These findings indicated that HAEC may be a new source for cell replacement therapy in type 1 diabetes.

Topics: Amnion; Animals; C-Peptide; Cell Differentiation; Cells, Cultured; Culture Media, Serum-Free; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Epithelial Cells; Glucose; Humans; Hyperglycemia; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Radioimmunoassay; Time Factors

The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp.Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; C-Peptide; Disease Models, Animal; Glucose; Glucose Clamp Technique; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Time Factors

Although patients with type 2 diabetes show no bone mineral density (BMD) reduction, fracture risks are known to increase. It is unclear why the patients have an increased risk of fracture despite sufficient BMD. We investigated the relationships of body mass index (BMI), HbA(1c), and urinary C-peptide (uC-peptide) versus BMD, bone metabolic markers, serum adiponectin, and prevalent vertebral fracture (VF). A total of 163 Japanese type 2 diabetic men were consecutively recruited, and radiographic and biochemical data were collected. BMI was positively correlated with BMD at the whole body, lumbar spine, and femoral neck (P < 0.05) and negatively correlated with osteocalcin and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) (P < 0.01). HbA(1c) was negatively correlated with osteocalcin (P < 0.01) but not BMD at any site. Subjects were classified into four groups based on BMI and HbA(1c) (group LL BMI < 24 and HbA(1c) < 9, group LH BMI < 24 and HbA(1c) > or = 9, group HL BMI > or = 24 and HbA(1c) < 9, group HH BMI > or = 24 and HbA(1c) > or = 9). Serum adiponectin, osteocalcin, and uNTX were lower and the incidence of VF was higher despite sufficient BMD in the HH group. Multivariate logistic regression analysis adjusted for age, duration of diabetes, uC-peptide, and estimated glomerular filtration rate showed that the HH group was associated with the presence of a VF and multiple VFs (odds ratio [OR] = 3.056, 95% confidence interval [CI] 1.031-9.056, P = 0.0439, and OR = 5.415, 95% CI 1.126-26.040, P = 0.0350, respectively). Combination of obesity with hyperglycemia was a risk factor for VF despite sufficient BMD in diabetic men.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Bone Density; C-Peptide; Collagen Type I; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Logistic Models; Male; Middle Aged; Obesity; Osteocalcin; Peptides; Radiography; Risk Factors; Spinal Fractures

To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.. We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m(-2)), hypertension (blood pressure > or =140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose > or =6.1 mmol l(-1) or post-load glucose in capillary plasma > or =8.9 mmol l(-1)).. None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20-5.52; P (trend)=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1-9 were 1.56 (95% CI 0.93-2.62; P=0.090), 1.83 (95% CI 1.00-3.36; P=0.051) and 1.50 (95% CI 0.83-2.71; P=0.18), respectively.. Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Colorectal Neoplasms; Epidemiologic Methods; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Sweden

Metabolic syndrome (MetS) is known to increase the risk of cardiovascular disease. C-reactive protein (CRP) has been reported to be elevated in subjects with MetS. However, which component of MetS contributes mostly to the elevation has not been studied in detail.. We studied 628 apparently healthy Japanese subjects (men 262, women 366, age 19-85 years). Body mass index, waist circumference (WC), blood pressure, lipids, glucose, insulin and CRP were measured. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report.. In partial correlation analysis, WC showed the strongest correlation with CRP among the variables related to MetS. CRP increased as the number of MetS components increased. The mean CRP value adjusted for demographic variables was higher in subjects with MetS than those without MetS, and further adjustments with variables related to MetS revealed that the significant difference between the two groups disappeared only when further adjustment was made for WC. In multiple linear regression analysis, the independent variable that most strongly explained the CRP level was WC, which was followed by HDL-cholesterol. Finally, comparison of the CRP levels in groups stratified by abdominal obesity and the number of MetS components revealed that those with abdominal obesity tended to show higher CRP levels compared with those without abdominal obesity regardless of the number of MetS components other than WC.. Subjects with MetS showed higher levels of CRP and the main determinant of the CRP elevation was WC.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Exercise; Female; Humans; Hyperglycemia; Hypertension; Insulin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Patient Selection; Waist-Hip Ratio

Prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo.. Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and beta-cell mass was quantified by morphometric analysis.. Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and beta-cell mass and proliferation were unchanged.. Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or beta-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to beta-cell failure in type 2 diabetes.

Topics: Animals; Blood Glucose; C-Peptide; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Homeodomain Proteins; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Male; Rats; Rats, Wistar; RNA, Messenger; Trans-Activators

Exercise improves glucose tolerance in obese rodent models and humans; however, effects with respect to mechanisms of beta-cell compensation remain unexplained. We examined exercise's effects during the progression of hyperglycemia in male Zucker diabetic fatty (ZDF) rats until 19 wk of age. At 6 wk old, rats were assigned to 1) basal--euthanized for baseline values; 2) exercise--swam individually for 1 h/day, 5 days/wk; and 3) controls (n = 8-10/group). Exercise (13 wk) resulted in maintenance of fasted hyperinsulinemia and prevented increases in fed and fasted glucose (P < 0.05) compared with sham-exercised and sedentary controls (P < 0.05). Beta-cell function calculations indicate prolonged beta-cell adaptation in exercised animals alone. During an intraperitoneal glucose tolerance test (IPGTT), exercised rats had lower 2-h glucose (P < 0.05) vs. controls. Area-under-the-curve analyses from baseline for IPGTT glucose and insulin indicate improved glucose tolerance with exercise was associated with increased insulin production and/or secretion. Beta-cell mass increased in exercised vs. basal animals; however, mass expansion was absent at 19 wk in controls (P < 0.05). Hypertrophy and replication contributed to expansion of beta-cell mass; exercised animals had increased beta-cell size and bromodeoxyuridine incorporation rates vs. controls (P < 0.05). The relative area of GLUT2 and protein kinase B was significantly elevated in exercised vs. sedentary controls (P < 0.05). Last, we show formation of ubiquitinated protein aggregates, a response to cellular/oxidative stress, occurred in nonexercised 19 wk-old ZDF rats but not in lean, 6 wk-old basal, or exercised rats. In conclusion, improved beta-cell compensation through increased beta-cell function and mass occurs in exercised but not sedentary ZDF rats and may be in part responsible for improved glucoregulation.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cell Count; Cell Proliferation; Eating; Fluorescent Antibody Technique; Glucose Tolerance Test; Glucose Transporter Type 2; Hyperglycemia; Image Processing, Computer-Assisted; In Situ Nick-End Labeling; Insulin; Insulin-Secreting Cells; Male; Obesity; Oncogene Protein v-akt; Physical Conditioning, Animal; Postprandial Period; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Swimming

A 64-years-old man referred to a hospital because of high-grade fever. He was diagnosed as having influenza B by "POCTEM Influenza A/B", a rapid influenza diagnostic kit which detect some antigens of influenza virus. Six days after medication of oseltamivir phosphate, his flu-symptoms disappeared, but he complained sever thirsty. And after 2days, he suffered from loss of consciousness and was admitted to the hospital. Laboratory data on admission showed diabetes ketoacidosis, slight elevation of HbA1c level despite sever hyperglycemia, and increase of serum amylase concentration. Anti GAD antibody and anti IA-2 antibody were not detected. Urinary C-peptide excretion was undetectable and serum C-peptide levels were also undetectable after glucagon and arginin load, suggesting disappearance of endogeneous insulin secretion. Class II HLA was susceptible to fulminant type1 diabetes. Based on these findings, we diagnosed him with fulminant type1 diabetes. In Japan, only three viruses in three cases have been reported to be the trigger in the development of fulminant type 1 diabetes. They were human herpes virus 6, herpes simplex virus and Coxsackie B3 virus. This is the fourth report of fulminant type 1 diabetes developed after the established diagnosis of viral infection and the first after influenza B virus infection. The fact that fulminant type 1 diabetes developed after the infection of such a common virus suggest that factors within host will play more important roles than virus itself in the etiology of fulminant type 1 diabetes.

Topics: Amylases; Antiviral Agents; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Glycated Hemoglobin; Humans; Hyperglycemia; Influenza B virus; Influenza, Human; Male; Middle Aged; Oseltamivir

It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes.. A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.. For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker.. Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.

Topics: Adult; Blood Glucose; C-Peptide; Cesarean Section; Female; Fetal Blood; Fetal Macrosomia; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Odds Ratio; Pregnancy; Pregnancy Complications; Pregnancy Outcome

The aim of our study was to establish whether the well-known defective or absent secretion of glucagon in type 1 diabetes in response to hypoglycaemia is selective or includes lack of responses to other stimuli, such as amino acids.. Responses of glucagon to hypoglycaemia were measured in eight patients with type 1 diabetes and six non-diabetic subjects during hyperinsulinaemic (insulin infusion 0.5 mU kg(-1) min(-1)) and eu-, hypo- and hyperglycaemic clamp studies (sequential steps of plasma glucose 5.0, 2.9, 5.0, 10 mmol/l). Subjects were studied on three randomised occasions with infusion of low- or high-dose alanine, or saline.. With saline, glucagon increased in hypoglycaemia in non-diabetic subjects but not in diabetic subjects. Glucagon increased further with low-dose (181 +/- 16 ng l(-1) min(-1)) and high-dose alanine (238 +/- 20 ng l(-1) min(-1)) in non-diabetic subjects, but only with high-dose alanine in diabetic subjects (area under curve 112 +/- 5 ng l(-1) min(-1)). The alanine-induced glucagon increase in diabetic subjects paralleled the spontaneous glucagon response to hypoglycaemia in non-diabetic subjects not receiving alanine. The greater responses of glucagon to hypoglycaemia with alanine infusion were offset by recovery of eu- or hyperglycaemia.. In type 1 diabetes, the usually deficient responses of glucagon to hypoglycaemia may improve after increasing the concentration of plasma amino acids. Amino acid-enhanced secretion of glucagon in response to hypoglycaemia remains under physiological control since it is regulated primarily by the ambient plasma glucose concentration. These findings might be relevant to improving counter-regulatory defences against insulin-induced hypoglycaemia in type 1 diabetes.

Topics: Adolescent; Adult; Alanine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Homeostasis; Humans; Hyperglycemia; Hypoglycemia; Male; Middle Aged; Norepinephrine; Reference Values

Islet cell replacement is considered as the optimal treatment for type I diabetes. However, the availability of human pancreatic islets for transplantation is limited. Here, we show that human bone marrow-derived mesenchymal stem cells (hMSCs) could be induced to differentiate into functional insulin-producing cells by introduction of the pancreatic duodenal homeobox-1 (PDX-1). Recombinant adenoviral vector was used to deliver PDX-1 gene into hMSCs. After being infected with Ad-PDX-1, hMSCs were successfully induced to differentiate into insulin-secreting cells. The differentiated PDX-1+ hMSCs expressed multiple islet-cell genes including neurogenin3 (Ngn3), insulin, GK, Glut2, and glucagon, produced and released insulin/C-peptide in a weak glucose-regulated manner. After the differentiated PDX-1+ hMSCs were transplanted into STZ-induced diabetic mice, euglycemia can be obtained within 2 weeks and maintained for at least 42 days. These findings validate the hMSCs model system as a potential basis for enrichment of human beta cells or their precursors, and a possible source for cell replacement therapy in diabetes.

Topics: Adenoviridae; Adult; Animals; C-Peptide; Cell Differentiation; Diabetes Mellitus, Experimental; Gene Expression Regulation; Glucose; Homeodomain Proteins; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Potassium Channels; Streptozocin; Trans-Activators

The intra-islet insulin hypothesis proposes that the decrement in beta-cell insulin secretion during hypoglycemia provides an activation signal for alpha-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open alpha-cell ATP-sensitive K(+) channels. Since insulin binds zinc, and zinc is co-secreted with insulin, we tested whether decreased zinc delivery to the alpha-cell activates glucagon secretion. In streptozotocin-induced diabetic Wistar rats, we observed that switching off intrapancreatic artery insulin infusions in vivo during hypoglycemia greatly improved glucagon secretion (area under the curve [AUC]: control group 240 +/- 261 and experimental group 4,346 +/- 1,259 pg x ml(-1) x 90 min(-1); n = 5, P < 0.02). Switching off pancreatic artery infusions of zinc chloride during hypoglycemia also improved the glucagon response (AUC: control group 817 +/- 107 and experimental group 3,445 +/- 573 pg x ml(-1) x 90 min(-1); n = 6, P < 0.01). However, switching off zinc-free insulin infusions had no effect. Studies of glucose uptake in muscle and liver cell lines verified that the zinc-free insulin was biologically active. We conclude that zinc atoms, not the insulin molecule itself, provide the switch-off signal from the beta-cell to the alpha-cell to initiate glucagon secretion during hypoglycemia.

Topics: Animals; Blood Glucose; C-Peptide; Glucagon; Glucagon-Secreting Cells; Hyperglycemia; Hypoglycemia; Insulin; Male; Rats; Rats, Wistar; Streptozocin; Zinc

Our aim was to assess the effect of chronic hyperglycemia on glucose- and insulin-mediated suppression of glucagon secretion by the alpha-cell.. Thirty subjects with normal glucose tolerance, 27 with impaired fasting glucose and/or impaired glucose tolerance, and 32 type 2 diabetic subjects were studied with oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp. Fasting plasma glucagon concentration and plasma glucagon concentration during the OGTT and insulin clamp were measured.. During the OGTT, the decrement in the plasma glucagon concentration (area under the curve) was correlated inversely with the fasting plasma glucose concentration (r = -0.35; P < 0.001). As the fasting glucose level increased, the suppression of plasma glucagon progressively diminished. In contrast, during the euglycemic insulin clamp, the suppression of plasma glucagon was not correlated with the fasting plasma glucose concentration and was similar in subjects with normal glucose tolerance, subjects with impaired fasting glucose/impaired glucose tolerance, and diabetic subjects: 18, 23, and 18%, respectively.. Insulin-mediated suppression of glucagon secretion is unrelated to the fasting plasma glucose concentration and is not impaired by chronic hyperglycemia. Thus, the defect in plasma glucagon suppression during the OGTT most likely results from impaired glucose-mediated glucagon suppression. The close correlation between fasting plasma glucose concentration and reduced glucagon suppression suggests a glucotoxic effect on alpha-cell function.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Mexican Americans

There is experimental evidence that a source of fatty acids (FAs) that is either exogenous or endogenous is necessary to support normal insulin secretion. Therefore, FAs comodulate the glucose-induced pancreatic insulin secretion. To assess the role of FAs, 16 morbidly obese nondiabetic patients and 6 healthy volunteers were studied. The controls and the obese subjects, before and after diet-induced weight loss, spent 24 h in a calorimetric chamber, where they consumed standardized meals. Hourly blood samples were drawn from a central venous catheter for the measurement of glucose, C-peptide, and nonesterified fatty acid (NEFA) concentrations. Insulin sensitivity was measured (as the M value) by euglycemic hyperinsulinemic clamp. In the present study, we propose a mathematical model in which insulin secretion rate (ISR) is expressed as a function of both plasma glucose and NEFA concentrations. Model parameters, obtained by fitting the individual experimental data of plasma C-peptide concentration, gave an estimated ISR comparable with that obtained by the deconvolution method. To evaluate the performance of the model in an experimental condition in which incretin effect was minimized, previous data on insulin secretion following a butter load and subsequent hyperglycemic clamp were reanalyzed. This model of nutrient-stimulated insulin secretion is the first attempt to represent in a simple way the interaction between glucose and NEFA in the regulation of insulin secretion in the beta-cell and explains, at least in part, the "potentiation factor" used in previous models to account for other control factors different from glucose after either an intravenous infusion of glucose or a mixed meal.

Topics: Blood Glucose; C-Peptide; Circadian Rhythm; Eating; Fatty Acids, Nonesterified; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Models, Biological; Obesity, Morbid; Osmolar Concentration; Weight Loss

To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG).. Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (approximately 80 pmol/l, "preprandial") or within 30 min of eating (approximately 300 pmol/l, "prandial").. Despite higher (P < 0.001) insulin and C-peptide concentrations and visceral fat (P < 0.05), fasting EGP and glucose disposal did not differ between IFG and NFG subjects, implying hepatic and extrahepatic insulin resistance. This was confirmed during preprandial insulin infusion when glucose disposal was lower (P < 0.05) and EGP higher (P < 0.05) in IFG than in NFG subjects. Higher EGP was due to increased (P < 0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during prandial insulin infusion, indicating that hepatic insulin resistance was mild. Glucose disposal remained lower (P < 0.01) in IFG than in NFG subjects.. Hepatic and extrahepatic insulin resistance contribute to fasting hyperglycemia in IFG with the former being due at least in part to impaired insulin-induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near-maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within 30 min of eating, extrahepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia.

Topics: Adipose Tissue; Blood Glucose; Body Mass Index; C-Peptide; Fasting; Female; Glucagon; Gluconeogenesis; Glucose Intolerance; Humans; Hyperglycemia; Insulin Resistance; Liver; Male; Middle Aged; Reference Values

Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia.. We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l.. The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04).. Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome

The aim of the study was to evaluate the relationship between postprandial blood glucose and first-phase insulin response and, furthermore, to assess whether the intravenous glucagon stimulation test can be used as a predictor for increased postprandial glucose in patients with recently diagnosed type 2 diabetes.. Twenty patients with diet-treated type 2 diabetes, diagnosed within the past 5 years, were included. In random order, on three different days, the patients underwent: 1) a standardized meal tolerance test, 2) an intravenous glucose tolerance test, and 3) an intravenous glucagon stimulation test. The postprandial blood glucose response was defined as the incremental area under the blood glucose curve 0-240 min after the meal.. The first-phase insulin response at an intravenous glucose stimulation test was significantly correlated to the postprandial blood glucose increment (R(2)=0.21, p<0.05) and the maximal increment in plasma glucose concentration (R(2)=0.40, p<0.01) during the meal tolerance test. However, the incremental C-peptide value at 6 min in response to intravenous glucagon stimulation did not correlate to the postprandial blood glucose increment (R(2)=0.09, p=0.14).. Impaired first-phase insulin response is a significant predictor of the increase in postprandial blood glucose in patients with type 2 diabetes in near normal metabolic control, whereas beta-cell function, assessed by glucagon stimulation test, is not.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Middle Aged; Postprandial Period; Predictive Value of Tests; Reference Values; Sensitivity and Specificity

The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes.. Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257 children at 1, 6 and 12 months after diagnosis. Genotyping for the Glu23Lys variant was by PCR-restriction fragment length polymorphism.. Kir6.2 and SUR1 co-localise with GLP-1 in L-cells and with GIP in K-cells in human ileum tissue. Children with type 1 diabetes carrying the hyperactive Glu23Lys variant had higher HbA1C at diagnosis (coefficient = 0.61%, P = 0.02) and 1 month after initial insulin therapy (coefficient = 0.30%, P = 0.05), but later disappeared. However, when adjusting HbA1C for the given dose of exogenous insulin, the dose-adjusted HbA1C remained higher throughout the 12 month study period (coefficient = 0.42%, P = 0.03).. Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L- and K-cells. The hyperactive Glu23Lys variant of the K(ATP) channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes.

Topics: Adolescent; ATP-Binding Cassette Transporters; Blotting, Western; C-Peptide; Child; Diabetes Mellitus, Type 1; Eating; Female; Gastric Inhibitory Polypeptide; Genotype; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Ileum; Immunohistochemistry; Insulin; Islets of Langerhans; Male; Polymorphism, Restriction Fragment Length; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

Topics: Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Postprandial Period; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Sulfonylurea Compounds

This study was conducted to explore the association between nonalcoholic fatty liver disease and glucose metabolism as well as insulin resistance using the homeostasis model assessment method (HOMA).. From July 2003 to June 2004, 23 patients with ultrasound-proved fatty liver and either normal (10 patients) or abnormal (13 patients) serum aminotransferase levels were enrolled. Blood tests included a routine biochemistry, a 75-g glucose oral glucose tolerance test (OGTT) with blood sampled at 30-minute intervals during a 120-minute period. Fasting and 120-minute serum leptin, insulin, and C-peptide concentrations were also measured.. Using the Mann-Whitney U test, significant differences were found in gamma glutamyl transpeptidase (28.6+/-7.9 vs. 65.1+/-65.9 U/L, P=0.008), fasting insulin (FI) (13.11+/-7.53 vs. 31.76+/-42.95 muU/mL, P=0.02), fasting C-peptide (3.82+/-3.00 vs. 2.17+/-0.43 ng/mL, P=0.01), fasting leptin (10.34+/-4.05 vs. 24.27+/-24.97 ng/mL, P=0.01), HOMA-IR (3.34+/-1.06 vs. 8.81+/-13.18, P=0.02), and HOMA beta-cell function (120.32+/-52.50 vs. 242.20+/-247.29, P=0.02) between normal and abnormal ALT/AST function groups. From the 75-g OGTT, no significant difference of plasma glucose was noted at 0, 30, 60, and 90 minutes but significant change was noted in 120-minute plasma glucose (99.3+/-21.5 vs. 131.4+/-27.3 mg/dL, P=0.004) of 2 groups.. In conclusion, patients with fatty liver proved by ultrasound sonography might be at high risk of developing type 2 diabetes, especially when they had elevated liver enzymes. OGTT is warranted for the early diagnosis of these high risk patients.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; C-Peptide; Fatty Liver; Female; Food Deprivation; Glucose Tolerance Test; Homeostasis; Humans; Hyperglycemia; Insulin; Leptin; Liver Function Tests; Male; Metabolic Syndrome; Postprandial Period; Ultrasonography

Measurement of glucose in multiple Field Laboratories requires rigorous standardization when patients and caregivers are masked, unless predefined thresholds are met. Local misclassification of participants at the thresholds can introduce recruitment bias and adversely affect the integrity of study findings.. To describe the challenges and the approach to meeting them in measuring glucose, HbA1c, and C-peptide in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO is an observational epidemiologic study of 25 000 pregnant women from 15 centres in 10 countries, designed to clarify unanswered questions on associations of maternal glycemia, less severe than overt diabetes mellitus, with risks of adverse pregnancy outcome.. Glucose tolerance (75 g two-hour OGTT) is assessed locally at 24-32 weeks' gestation, with results masked if fasting and two-hour plasma glucose are

Topics: Blood Glucose; C-Peptide; Clinical Laboratory Information Systems; Female; Global Health; Glycated Hemoglobin; Hemoglobins; Humans; Hyperglycemia; Infant, Newborn; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R(d)) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S(i)) and insulin-stimulated glucose disposal (S(i)*) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R(d) since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG.

Topics: Blood Glucose; C-Peptide; Fasting; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Postprandial Period; Prediabetic State; Reference Values

To observe related factors in the stress hyperglycemia (SHG) of critical illness and to investigate possible pathogenesis of insulin-resistance (IR).. Blood glucose (BG), insulin (INS), C-peptide (C-P), cortisol (Cor), somatostatin (SS), glucagon (Gluc), tumor necrosis factor-alpha (TNF-alpha),soluble tumor necrosis factor receptor I (sTNFRI) and sTNFRII were determined respectively by radioimmunoassay (RIA) or enzyme linked immunoadsorbent assay (ELISA) in 47 SHG patients with critical illness and 15 healthy volunteers serving as normal controls. Their insulin sensitivity index (ISI) was calculated.. (1)Eleven of 47 patients died, while 36 cases survived. Mean acute pathology and chronic health evaluation II (APACHEII) was (13.89+/-6.29) scores within 24 hours after admission to intensive care unit (ICU), mean days of stay in ICU was (5.5+/-6.3) days,and mean duration of mechanical ventilation (MV) was (51.49+/-66.01) hours. (2)The concentrations of INS, ISI, C-P, Cor, Gluc, TNF-alpha, sTNFRI and sTNFRII in 47 SHG patients with critical illness were significantly higher than those in normal controls, except for SS, the differences among groups were significant (P<0.05 or P<0.01). (3)The results of analysis of severity of SHG showed that the more severe SHG was, the higher C-P and INS were, and the less prominent ISI was. (4)Analysis of scores of APACHEII in 47 cases of SHG showed that BG was not increased, but duration of MV, Cor, Gluc, SS, TNF-alpha, sTNFRI and sTNFRII were significantly increased with higher scores of APACHEII. (5)The effect of SHG was significant on MV (F=10.438,P<0.01), but not significant for outcome and days of stay in ICU. (6)The main correlative factors of BG were respectively concentrations of INS (r=0.674, P<0.01), C-P(r=0.552,P<0.01), ISI (r=-0.787, P<0.01), APACHE II(r=0.267,P<0.05) and sTNFRI(r=0.465, P<0.01).. These results show that main reason of SHG in critical illness is IR. There is no strong significant correlation between acute stress hormones and the level of SHG. sTNFRI has an influence on SHG. However, the over release of TNF-alpha and sTNFRII could be the results of seriousness of the critical illness. There is closely correlation between BG and MV, but not with the age, outcome and days of stay in ICU. The strategy of control and therapy of SHG should be alleviation of stress and improve the utilization of BG in the tissue, and increase sensitivity of INS in the tissue.

Topics: Adult; Aged; C-Peptide; Critical Illness; Female; Glucagon; Humans; Hydrocortisone; Hyperglycemia; Insulin; Insulin Resistance; Intensive Care Units; Male; Middle Aged; Stress, Physiological; Tumor Necrosis Factor-alpha; Young Adult

Hyperinsulinemia, hyperglycemia, and elevated insulin-like growth factor (IGF)-1 levels have been implicated in the etiology of colorectal cancer. However, the joint effects of insulin and IGF-I have not been considered, and whether hyperinsulinemia or hyperglycemia is more etiologically relevant is unclear. IGF binding protein-1 (IGFBP-1) has been hypothesized to mediate the effects of insulin, but epidemiologic data on IGFBP-1 are sparse. We conducted a nested case-control study among the 32,826 women of the Nurses' Health Study who provided a blood sample in 1989 to 1990. After excluding diabetics, we confirmed 182 incident colorectal cancer cases over 10 years of follow-up and 350 controls. Cases were matched to two controls on year of birth, date of blood draw, and fasting status. C-peptide levels were weakly associated with risk of colon cancer [top quartile (Q4) versus bottom quartile (Q1): multivariable relative risk (MVRR), 1.76; 95% confidence interval (95% CI), 0.85-3.63]. Fasting IGFBP-1 was inversely associated with risk of colon cancer (MVRR, 0.28; 95% CI, 0.11-0.75). We observed no clear association between glycosylated hemoglobin and risk for colorectal cancer. The IGF-I to IGFBP-3 molar ratio was associated with colon cancer risk (MVRR, 2.82; 95% CI, 1.35-5.88), and women with low levels of both IGF-I/IGFBP-3 and C-peptide (or high IGFBP-1) were at low risk, and elevation of either was sufficient to increase risk. Although altering IGF-I levels may not be practical, the growing burden of obesity and consequently hyperinsulinemia, which seems increasingly important for colon cancer, may be a target for effective prevention.

Topics: Adult; Biomarkers, Tumor; C-Peptide; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Hyperglycemia; Hyperinsulinism; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Middle Aged; Prospective Studies

We set out to assess whether hyperproinsulinaemia is an early finding in latent autoimmune diabetes in adults (LADA).. We measured plasma proinsulin and C-peptide responses during a 2-h oral glucose tolerance test (OGTT) and in the hyperglycaemic clamp in 21 normoglycaemic offspring of LADA patients testing positive for glutamic acid decarboxylase antibodies (GADA) or islet cell antibodies (ICA), and in 17 healthy control subjects without a family history of diabetes.. The study groups had comparable areas under the curves of blood glucose, plasma proinsulin, C-peptide and proinsulin/C-peptide in the OGTT. However, the offspring of LADA patients had higher proinsulin/C-peptide in the hyperglycaemic clamp (P < 0.01 versus the control group). The offspring of GADA-positive LADA patients (n = 9) had higher proinsulin and proinsulin/C-peptide than did the control group in the OGTT (P < 0.05 for both comparisons) and in the hyperglycaemic clamp (P < 0.001 and P < 0.05 respectively). They also had higher proinsulin than the offspring of ICA-positive LADA patients (n = 12) (P < 0.001) in the hyperglycaemic clamp. The offspring of ICA-positive LADA patients did not clearly show hyperproinsulinaemia during the tests, but they had lower maximal glucose-stimulated insulin secretory capacity than the control group (P < 0.05) and the offspring of GADA-positive LADA patients (P < 0.05) in the hyperglycaemic clamp.. These results suggested that insulin secretion in the offspring of GADA-positive LADA patients is characterised by subtle defects in the processing of insulin precursors. Furthermore, various proinsulin responses among the offspring of LADA patients with different autoimmune markers provided further evidence that LADA is a heterogeneous disorder.

Topics: Adult; Autoantibodies; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Early Diagnosis; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glutamate Decarboxylase; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Male; Middle Aged; Proinsulin

We evaluated insulin release and insulin sensitivity in women with basal and/or postprandial hyperglycemia but normal oral glucose tolerance test (OGTT) in previous pregnancy (GHG). These women were individually matched with females without previous hyperglycemia (NGT). Both groups consisted of normal glucose-tolerant women at the time of this study. They underwent OGTT (75 g; n=32 pairs) and hyperglycemic clamp experiments (10 mmoll(-1); n=27 pairs) with plasma glucose, insulin, and C-peptide measurements and calculation of insulinogenic index, first- and second-phase insulin release, and insulin sensitivity index (ISI). The GHG group showed higher glycosylated hemoglobin levels (6.2+/-0.6% versus 5.8+/-0.8%; P<0.05); lower insulinogenic index at 30 min (134.03+/-62.69 pmol mmol(-1) versus 181.59+/-70.26 pmol mmoll(-1); P<0.05) and diminished C-peptide response in relation to glucose (4.05+/-0.36 nmol mmol(-1) versus 4.23+/-0.36 nmol mmol(-1); P<0.05) at OGTT. Both groups did not show difference in insulin secretion and ISI by hyperglycemic clamp technique. We concluded that in up to 12 years from index pregnancy, women with previous GHG, presenting normal glucose tolerance and well-matched with their controls, showed beta-cell dysfunction without change in ISI. As women with previous GHG are at risk of type 2 diabetes, beta-cell dysfunction may be its primary defect.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Food; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Pregnancy; Risk Factors

Many extremely preterm infants develop hyperglycemia in the first week of life during continuous glucose infusion. The objective of this study was to determine whether defective insulin secretion or resistance to insulin was the primary factor involved in transient hyperglycemia of extremely preterm infants.. A prospective comparative study was conducted in appropriate-for-gestational-age preterm infants <30 weeks of gestational age with the aim specifically to evaluate the serum levels of proinsulin, insulin, and C-peptide secreted during transient hyperglycemia by specific immunoassays. Three groups of infants were investigated hyperglycemic (n = 15) and normoglycemic preterm neonates (n = 12) and normal, term neonates (n = 21). In addition, the changes in beta-cell peptide levels were analyzed during and after intravenous insulin infusion in the hyperglycemic group. Data were analyzed using analysis of variance and analysis of variance for repeated measures.. At inclusion, insulin and C-peptide levels did not differ in hyperglycemic subjects and in preterm controls. Proinsulin concentration was significantly higher in the hyperglycemic group (36.5 +/- 3.9 vs 23.2 +/- 0.9 pmol/L). Compared with term neonates, proinsulin and C-peptide levels were higher in normoglycemic preterm infants (23.2 +/- 0.9 vs 18.9 +/- 2.71 pmol/L and 1.67 +/- 0.3 vs 0.62 +/- 0.12 nmol/L, respectively). During and after insulin infusion in hyperglycemic neonates, plasma glucose concentration fell and proinsulin and C-peptide levels were lowered (18.4 +/- 7.6 and 20.7 +/- 4.5 pmol/L, respectively).. These data suggest that 1) preterm neonates are sensitive to changes in plasma glucose concentration, but proinsulin processing to insulin is partially defective in hyperglycemic preterm neonates; 2) hyperglycemic neonates are relatively resistant to insulin because higher insulin levels are needed to achieve euglycemia in this group compared with normoglycemic neonates. These results also show that insulin infusion is beneficial in extremely preterm infants with transient hyperglycemia.

Topics: Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Insulin; Insulin Resistance; Islets of Langerhans; Male; Proinsulin; Prospective Studies

We investigated the possible causes of diabetes in a young child who presented with hyperglycemia associated with severe hypertriglyceridemia (>166 mmol/l), hypercholesterolemia (>38 mmol/l) and fasting chilomicrons.. The patient did not have any of the HLA and autoantibody markers typically associated with type 1 diabetes. A glucose clamp failed to demonstrate insulin resistance (peripheral glucose utilization rate (M)=4.3 mg/kg per min) and there was no family history of type 2 diabetes or maturity onset diabetes in youth. Both fasting and stimulated C-peptide levels, including those in response to i.v. glucagon, were below the limit of detection. This is consistent with loss of beta-cell function. The family history did not reveal the existence of relatives with lipid abnormalities, coronary heart disease, and pancreatitis. We did not find any abnormality of plasma apoCII, lipoproteinlipase and hepatic lipase activities. The patients had a epsilon3/epsilon3 apoE genotype and she rapidly cleared an oral fat load after normalization of plasma lipids.. The mild hyperglycemia seems an unlikely explanation for both the severe hypertriglyceridemia and chylomicronemia. A more plausible explanation is transient lipoproteinlipase deficiency. This rare condition, occasionally associated with a high-fat diet, could have caused the rapid and dramatic hypertriglyceridemia observed in this patient, which in turn might have led to the beta-cell destruction by direct lipid toxicity.

Topics: Autoantibodies; Autoimmunity; C-Peptide; Child; Chylomicrons; Diabetes Mellitus, Type 1; Fasting; Female; Glucagon; Glucose Clamp Technique; Humans; Hypercholesterolemia; Hyperglycemia; Hypertriglyceridemia; Islets of Langerhans; Lipoprotein Lipase

Dysfunction of the autonomic nervous system is a recognized complication of diabetes, ranging in severity from relatively minor sweating and pupillomotor abnormality to debilitating interference with cardiovascular, genitourinary, and alimentary dysfunction. Neuroaxonal dystrophy (NAD), a distinctive distal axonopathy involving terminal axons and synapses, represents the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in man and several insulinopenic experimental rodent models. Although the pathogenesis of diabetic sympathetic NAD is unknown, recent studies have suggested that loss of the neurotrophic effects of insulin and/or insulin-like growth factor-I (IGF-I) on sympathetic neurons rather than hyperglycemia per se, may be critical to its development. Therefore, in our current investigation we have compared the sympathetic neuropathology developing after 8 months of diabetes in the streptozotocin (STZ)-induced diabetic rat and BB/ Wor rat, both models of hypoinsulinemic type 1 diabetes, with the BBZDR/Wor rat, a hyperglycemic and hyperinsulinemic type 2 diabetes model. Both STZ- and BB/Wor-diabetic rats reproducibly developed NAD in nerve terminals in the prevertebral superior mesenteric sympathetic ganglia (SMG) and ileal mesenteric nerves. The BBZDR/Wor-diabetic rat, in comparison, failed to develop superior mesenteric ganglionic NAD in excess of that of age-matched controls. Similarly, NAD which developed in axons of ileal mesenteric nerves of BBZDR/Wor rats was substantially less frequent than in BB/Wor- and STZ-rats. These data, considered in the light of the results of previous experiments, argue that hyperglycemia alone is not sufficient to produce sympathetic ganglionic NAD, but rather that it may be the diabetes-induced superimposed loss of trophic support, likely of IGF-I, insulin, or C-peptide, that ultimately causes NAD.

Topics: Animals; Autonomic Nervous System Diseases; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Ganglia, Sympathetic; Hyperglycemia; Ileum; Insulin; Insulin-Like Growth Factor I; Male; Microscopy, Electron; Neuroaxonal Dystrophies; Rats; Rats, Mutant Strains; Sympathetic Fibers, Postganglionic

Efforts toward routine islet cell transplantation as a means for reversing type 1 diabetes have been hampered by islet availability as well as allograft rejection. In vitro transdifferentiation of mouse bone marrow (BM)-derived stem (mBMDS) cells into insulin-producing cells could provide an abundant source of autologous cells for this procedure. For this study, we isolated and characterized single cell-derived stem cell lines obtained from mouse BM. In vitro differentiation of these mBMDS cells resulted in populations meeting a number of criteria set forth to define functional insulin-producing cells. Specifically, the mBMDS cells expressed multiple genes related to pancreatic beta-cell development and function (insulin I and II, Glut2, glucose kinase, islet amyloid polypeptide, nestin, pancreatic duodenal homeobox-1 [PDX-1], and Pax6). Insulin and C-peptide production was identified by immunocytochemistry and confirmed by electron microscopy. In vitro studies involving glucose stimulation identified glucose-stimulated insulin release. Finally, these mBMDS cells transplanted into streptozotocin-induced diabetic mice imparted reversal of hyperglycemia and improved metabolic profiles in response to intraperitoneal glucose tolerance testing. These results indicate that mouse BM harbors cells capable of in vitro transdifferentiating into functional insulin-producing cells and support efforts to derive such cells in humans as a means to alleviate limitations surrounding islet cell transplantation.

Topics: Animals; Bone Marrow Cells; Bone Marrow Transplantation; C-Peptide; Cell Differentiation; Cell Line; Cytoplasmic Granules; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Gene Expression; Glucose; Hyperglycemia; Insulin; Mice; Mice, Inbred BALB C; Stem Cells

Experimentally induced prolonged hyperglycemia increases insulin release in humans, and in animals has been demonstrated to increase vagal efferent activity. The objective of the present experiment was to determine whether in humans, the compensatory increase in insulin release in response to short-term mild hyperglycemia is mediated by an induction of vagal efferent activity. Lean male subjects (n = 11; body mass index, 23.6 +/- 0.8 kg/m(2)) underwent a frequently sampled iv glucose tolerance test (FSIGT) to determine B cell function and insulin sensitivity. Subjects were then tested under four conditions over 4 months. Subjects were infused for 48 h with either glucose (15% dextrose at 200 mg/m(2).min) or saline (50 ml/h). Three hours after termination of the infusion, an FSIGT was administered in the presence of either saline or atropine (0.4 mg/m(2) bolus: 0.4 mg/m(2).h). Glucose (117 +/- 14 vs. 98 +/- 5 mg/dl) and insulin (49.5 +/- 10 vs. 23 +/- 5 muU/ml) levels were significantly elevated during the 48-h glucose infusion compared with those during saline treatment. Forty-eight-hour glucose infusions increased insulin and C-peptide levels during the FSIGT. When the FSIGT was conducted in the presence of atropine after glucose infusion, C-peptide levels were significantly attenuated during the period of endogenous insulin secretion (0-20 min; 31.8 +/- 13 vs. 39.2 +/- 11.9, atropine vs. no atropine) and exogenous insulin administration [20-40 min; 18.8 +/- 10.8 vs. 31.6 +/- 12.9., atropine vs. no atropine; F(3,9) = 4.99; P < 0.026]. A significant negative correlation was found between the repression of C-peptide by muscarinic blockade and the magnitude of the C-peptide response to the glucose infusion (r = 0.60; P < 0.045). Insulin AUC was not significantly altered by the presence of muscarinic blockade. In summary, we found that prolonged mild hyperglycemia results in a compensatory increase in C-peptide secretion, which is partially mediated by an induction in vagal efferent activity.

Topics: Adult; Area Under Curve; Atropine; Blood Glucose; C-Peptide; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Vagus Nerve

Taurine has several biological processes such as hypoglycemic action, antioxidation, detoxification, etc. To assess the effect of taurine administration on the guinea pigs with hyperglycemia, blood glucose, C-peptide levels together with morphologic alterations in the pancreatic ultrastructure were investigated in terms of hypoglycemic action and malondialdehyde and total sulfhydryl group levels with regard to oxidation-antioxidation relation. Animals were divided into four groups of six. Glucose supplementation group was administrated a single dose of glucose (400 mg/kg, i.p.) injection. Glucose and taurine supplementation group was administrated glucose treatment (a single dose, 400 mg/kg, i.p.) following taurine (a single dose, 200 mg/kg, i.p.). Taurine and glucose supplementation group was administered taurine treatment (a single dose, 200 mg/kg, i.p.) following glucose treatment (a single dose, 400 mg/kg, i.p.). Control animals received no treatment. Blood samples were collected at the end of the experiments for the determination of glucose, C-peptide (indicator of insulin secretion), lipid peroxidation (thiobarbituric acid reactive substances), and total sulfhydryl groups levels. Pancreatic tissue samples were then collected and processed for transmission electron microscopy. The findings showed that glucose supplementation following taurine administration significantly decreased blood glucose level by increasing C-peptide level and the pancreatic secretion stimulated morphologically and insignificantly changed thiobarbituric acid reactive substances and total sulfhydryl group levels. These observations suggest that taurine administration may be useful in hyperglycemia because of its hypoglycemic and protective effects.

Topics: Animals; Blood Glucose; C-Peptide; Glucose; Guinea Pigs; Hyperglycemia; Lipid Peroxidation; Male; Pancreas; Sulfhydryl Compounds; Taurine; Thiobarbituric Acid Reactive Substances

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Proteins; Energy Intake; Exercise; Fasting; Fatty Acids; Female; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertriglyceridemia; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Proinsulin; Pyrazines

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at approximately 8.3 mmol/l and insulin was increased to approximately 300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 +/- 2.6 vs. 65.0 +/- 7.9 micro mol. kg(-1). min(-1)). Whole-body glucose disappearance (37.0 +/- 2.2 vs. 70.9 +/- 8.7 micro mol. kg(-1). min(-1); P < 0.001) and leg glucose uptake (24.3 +/- 4.2 vs. 59.6 +/- 10.0 micro mol. kg fat-free mass of the leg(-1). min(-1); P < 0.02) were also lower, whereas splanchnic glucose production (8.2 +/- 0.8 vs. 4.3 +/- 0.7 micro mol. kg(-1). min(-1); P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting whole- body glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production.

Topics: Adult; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose; Glycerol; Human Growth Hormone; Humans; Hyperglycemia; Hyperinsulinism; Leg; Muscle, Skeletal; Viscera

Insulin-independent effects of a physiological increase in free fatty acid (FFA) levels on fasting glucose production, gluconeogenesis, and glycogenolysis were assessed by administering [6,6-(2)H(2)]-glucose and deuteriated water ((2)H(2)O) in 12 type 1 diabetic patients, during 6-h infusions of either saline or a lipid emulsion. Insulin was either fully replaced (euglycemic group, n = 6), or underreplaced (hyperglycemic group, n = 6). During saline infusions, plasma FFA levels remained unchanged. Glucose concentrations decreased from 6.7 +/- 0.4 to 5.3 +/- 0.4 mmol/l and 11.9 +/- 1.0 to 10.5 +/- 1.0 mmol/l in the euglycemic and hyperglycemic group, respectively. Accordingly, glucose production declined from 84 +/- 5 to 63 +/- 5 mg x m(-2) x min(-1) and from 84 +/- 5 to 68 +/- 4 mg x m(-2) x min(-1), due to declining rates of glycogenolysis but unaltered rates of gluconeogenesis. During lipid infusions, plasma FFA levels increased twofold. In the euglycemic group, plasma glucose increased from 6.8 +/- 0.3 to 7.8 +/- 0.8 mmol/l. Glucose production declined less in the lipid study than in the saline study due to a stimulation of gluconeogenesis by 6 +/- 1 mg x m(-2) x min(-1) and a decline in glycogenolysis that was 6 +/- 2 mg x m(-2) x min(-1) less in the lipid study than in the saline study. In contrast, in the hyperglycemic group, there were no significant effects of elevated FFA on glucose production, gluconeogenesis, or glycogenolysis. In conclusion, a physiological elevation of plasma FFA levels stimulates glycogenolysis as well as gluconeogenesis and causes mild fasting hyperglycemia. These effects of FFA appear attenuated in the presence of hyperglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Deuterium Oxide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Gluconeogenesis; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Insulin; Kinetics; Male; Reference Values

The purpose of the present study was to assess the effects of exogenously increasing the circulating levels of glucagon on the metabolic responses to exercise in rats. A total of six groups of rats were infused (iv) either with glucagon (20 or 50 ng x kg(-1) x min(-1)) or saline (0.9% NaCl), either in the resting state or during a bout of running exercise (45 min, 26 m x min(-1), 0% grade). Blood samples were taken at the end of the 45-min experiment. Animals infused with glucagon at 50 ng x kg(-1) x min(-1) showed significantly (P<0.01) higher mean plasma glucagon concentrations than animals infused with saline or glucagon at 20 ng x kg(-1) x min(-1). In addition, exercise resulted in significantly (P<0.05) higher mean plasma glucagon concentrations, compared to rest, in all groups. In spite of these differences in glucagon concentrations, there were no significant (P>0.05) effects of exercise and glucagon infusion on mean hepatic glycogen, plasma glucose, insulin, C-peptide, beta-hydroxybutyrate, or catecholamine concentrations. Although exercise resulted in a significant (P<0.01) increase in plasma glycerol and free fatty acid concentrations and a significant (P<0.05) decrease in glycogen in the soleus muscle, these responses were not affected by the glucagon infusion. These results suggest that the liver is non-responsive to physiological hyperglucagonemia in a short-term (45 min) exercise situation.

Topics: 3-Hydroxybutyric Acid; Animals; Ankle; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glycerol; Glycogen; Hyperglycemia; Infusions, Intravenous; Insulin; Liver Glycogen; Male; Muscle, Skeletal; Norepinephrine; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reference Values

To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon ( approximately 130 ng/l) and insulin ( approximately 65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at approximately 5.3 mM (euglycemia), approximately 7.0 mM (sustained hyperglycemia; n = 10), or varied to create a "postprandial" profile (profile; n = 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 +/- 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 +/- 1.21 micromol x kg-1 x min-1. On the profile study day, glucose increased to a peak of 11.2 +/- 0.5 mmol/l, and EGP decreased to a nadir of 6.79 +/- 2.54 micromol x kg-1 x min-1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 +/- 2.45 vs. 12.11 +/- 3.21 micromol x kg-1 x min-1). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (-1,952 +/- 204 vs. -1,922 +/- 246 mmol. kg-1. 6 h-1). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucagon; Glucose; Glucose Clamp Technique; Growth Hormone; Hormone Antagonists; Humans; Hyperglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Somatostatin

The fasting proinsulin-to-insulin ratio is a currently used marker of beta-cell dysfunction. This ratio is calculated at the basal condition, but its behavior in dynamic conditions, i.e., during glucose stimulation, could be more informative. Given the different kinetics of the peptides, a mathematical model was necessary to analyze the oral glucose tolerance test (OGTT) data of insulin, C-peptide, and proinsulin in 55 healthy (NGT), 30 impaired glucose-tolerant (IGT), and 31 type 2 diabetic (T2DM) subjects. The model provided for secretion and disappearance of the peptides and an index of beta-cell function under dynamic conditions. Total proinsulin secretion during the OGTT was not different (P > 0.053) among NGT (0.17 +/- 0.01 mmol/l in 3 h), IGT (0.22 +/- 0.02), and T2DM (0.21 +/- 0.02) subjects. The proinsulin-to-insulin molar ratio measured from basal samples was higher (P < 0.0001) in T2DM (0.39 +/- 0.05) than in NGT (0.14 +/- 0.01) and IGT (0.13 +/- 0.02) subjects, and similar results (P < 0.003) were found by the dynamic index (0.27 +/- 0.04, 0.14 +/- 0.01, 0.15 +/- 0.01 in T2DM, NGT, IGT subjects, respectively). The basal ratio significantly correlated with the dynamic index, and the regression line slope was lower than 1 (0.43 +/- 0.08, 0.61 +/- 0.10, and 0.56 +/- 0.03 in NGT, IGT, and T2DM subjects, respectively, P < 0.0001). Impaired beta-cell function in T2DM could then be indicated by proinsulin-to-insulin indexes at both basal and dynamic phases.

Topics: Adult; Algorithms; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Kinetics; Metabolic Diseases; Models, Biological; Models, Statistical; Pancreatic Function Tests; Pregnancy; Pregnancy in Diabetics; Proinsulin; Regional Blood Flow

Despite improvements in insulin preparation and delivery, physiological normoglycemia is not easily achieved in diabetics. Therefore, there has been considerable interest in developing gene therapy approaches to supply insulin. We studied a nonviral muscle-based method of gene therapy and demonstrated that it could prevent hyperglycemia in murine streptozotocin (STZ)-induced diabetes.. A plasmid encoding mouse furin-cleavable preproinsulin II cDNA (FI), or its B10-analogue (B10FI), and a plasmid encoding furin were coinjected into muscle of CD-1 mice, who were treated a day later with STZ to induce diabetes. Electroporation was applied to increase gene transfer. Blood glucose was measured in fed and fasting mice, and fasting plasma insulin was measured by radioimmunoassay. The form of insulin produced and the presence of C-peptide were analyzed by gel filtration chromatography.. A B10FI plasmid codelivered with a furin plasmid reduced fed and fasting blood glucose levels in STZ-treated diabetic mice. The (pro)insulin levels in plasma were increased by up to 70-fold versus blank plasmid-treated diabetic mice. The administration of FI with furin was less effective. (Pro)insulin levels were greatly increased by using two plasmids carrying different promoter elements (CMV and SV40). Insulin was identified in muscle cells by immunohistochemistry. In plasma, 40-70% of the (pro)insulin was processed to the mature form and free C-peptide was identified. Insulin gene-treated mice had improved growth rates and appeared healthier. A single injection of B10FI with SV40Furin DNA increased plasma (pro)insulin for at least 8 weeks and reduced fed blood glucose levels for 5 weeks and fasting levels for 8 weeks.. This is the first report that electroporation-enhanced intramuscular gene therapy with B10FI can prevent hyperglycemia in murine STZ-induced diabetes. Gene therapy using various routes and methods of furin-cleavable insulin gene delivery has been previously explored but, in muscle, results comparable to ours have not been reported.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Chromatography, Gel; Diabetes Mellitus, Experimental; DNA, Complementary; Electroporation; Furin; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hyperglycemia; Immunohistochemistry; Injections, Intramuscular; Insulin; Mice; Mutation; Pancreas; Plasmids; Proinsulin; Protein Precursors; Radioimmunoassay; Streptozocin; Time Factors

Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.

Topics: Animals; Blood Glucose; C-Peptide; Cell Differentiation; Diabetes Mellitus, Type 1; DNA-Binding Proteins; Female; Gene Expression; Hepatocytes; Homeodomain Proteins; Humans; Hyperglycemia; Insulin; Mice; Mice, Inbred NOD; Mice, SCID; Stem Cell Transplantation; Stem Cells; Telomerase; Trans-Activators; Transduction, Genetic; Transplantation, Heterologous

Diabetes mellitus is a very well recognized risk factor for coronary artery disease in non-transplant patients. With the introduction of new immunosuppressive agents in solid organ recipients, there is an interest in medical complications of immunosuppressive therapy. An influence of long-term cyclosporine-A (CyA) therapy on glucose metabolism was analyzed in a group of 122 heart transplant recipients who developed hyperglycemia after heart transplantation. Based on WHO criteria for diagnosis of diabetes two groups were identified: group 1 (102 pts) included pts with impaired glycemic control and group 2 (20 pts) with clinical diabetes. Fasting insulin, proinsulin, C-peptide, HbA1c and cyclosporine-A trough levels were determined 12-18 months post surgery in clinically stable period without transplant rejection. The immunosuppressive treatment in both groups was the same and consisted of cyclosporine A, azathioprine and prednisone. We observed a statistically significant negative correlation between CyA concentration and insulin in both groups, a statistically significant negative correlation between CyA concentration and proinsulin, C-peptide blood level in group 1 and statistically significant positive correlation between CyA and glucose blood level in both groups.

Topics: Blood Glucose; C-Peptide; Creatinine; Cyclosporine; Drug Administration Schedule; Female; Glycated Hemoglobin; Heart Transplantation; Humans; Hyperglycemia; Immunosuppressive Agents; Insulin; Insulin Antagonists; Insulin Secretion; Male; Middle Aged; Postoperative Period; Proinsulin

The purpose of the present study was to compare relationships between the clinical presentation of type 1 diabetes in children and residual beta-cell secretion and long-term metabolic control.. This retrospective study was conducted in 66 diabetic children with age at diagnosis ranging from 0.7 to 14.8 yr. The patients showed contrasting characteristics at diagnosis: either diabetic ketoacidosis (DKA) (group 1, n = 29) or absence of metabolic derangement (group 2, n = 37) associated with marked (group 2A, n = 12) or mild hyperglycemia (group 2B, n = 25). A regular follow-up was available for at least 10 yr (10-32 yr) in all cases and for 20 yr in 23 cases. C-peptide levels were measured from diagnosis and thereafter at intervals for the first years of disease until becoming permanently undetectable.. C-peptide levels at diagnosis were undetectable in about 20% of the cases both with and without DKA. C-peptide levels at diagnosis, the duration of measurable C-peptide levels and the maximum value found during follow-up were not significantly different in the three groups and were not correlated with glycated hemoglobin (GHb) calculated throughout the whole period. No differences were found between the groups of patients concerning GHb values and insulin dose at 10, 15 and 20 yr of disease. The patients of group 2A, characterized by an extremely high glycemic level without ketoacidosis, had a significantly higher prevalence of HLA DR3/4 heterozygosity.. The severity of clinical presentation at diagnosis does not significantly influence residual beta-cell function, and long-term metabolic control.

Topics: Adolescent; Adult; Blood; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Glycated Hemoglobin; Heterozygote; HLA-DR3 Antigen; HLA-DR4 Antigen; Humans; Hydrogen-Ion Concentration; Hyperglycemia; Islets of Langerhans; Retrospective Studies

The purpose of this study was to identify independent determinants of mild gestational hyperglycemia (MGH) and gestational diabetes mellitus (GDM) and to assess the correlation between fasting glucose and C-peptide levels among control, MGH, and GDM women.. A total of 1,022 consecutive women were evaluated with a 1-h 50-g glucose challenge test (GCT) at between 16 and 33 weeks of gestation. Women with a capillary whole-blood glucose > or =7.8 mmol/l in the GCT underwent a 3-h 100-g oral glucose tolerance test (OGTT). On the basis of a positive GCT, the women with a positive OGTT were classified as GDM, whereas the women with a negative OGTT were classified as MGH. The following data were collected for all women: age, prepregnancy BMI, ethnicity, clinical and obstetric history, pregnancy outcome, and C-peptide level.. A total of 813 women (79.6%) were normal, 138 (13.5%) had MGH, and 71 (6.9%) had GDM. There was a stepwise significant increase in mean fasting glucose (3.6 +/- 0.4, 3.9 +/- 0.4, and 4.7 +/- 0.7 mmol/l, respectively) and C-peptide level (0.60 [0.1-2.4], 0.86 [0.3-2.0], and 1.00 [0.5-1.6] nmol/l, respectively) among the three diagnostic groups. Maternal age, non-Caucasian ethnicity, and prepregnancy BMI were associated with GDM, whereas only maternal age and prepregnancy BMI were associated with MGH. A positive correlation between levels of fasting glucose and C-peptide was found in control women (r = 0.39 [95% CI 0.31-0.46]). A similar result was seen in MGH women (r = 0.38 [95% CI 0.23-0.52]), whereas the correlation between fasting glucose and C-peptide was nearly lost in GDM women (r = 0.14 [CI -0.09 to 0.36]). The fasting C-peptide-to-glucose ratio was reduced by 60% in GDM patients versus control subjects and MGH patients (0.41 +/- 0.25 vs. 0.70 +/- 0.20 and 0.73 +/- 0.23, P < 0.001).. Of the well-known independent determinants of GDM, only maternal age and prepregnancy BMI were associated with MGH. It appears that additional factors promoting loss of beta-cell function distinguish MGH from GDM. One of these factors appears to be ethnicity.

Topics: Adult; Apgar Score; Blood Glucose; Body Mass Index; C-Peptide; Diabetes, Gestational; Ethnicity; Family; Fasting; Female; Gestational Age; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Infant, Newborn; Maternal Age; Netherlands; Parity; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Pregnancy, High-Risk; Reference Values; White People

To investigate the relationships between serum concentrations of soluble adhesion molecules and hyperglycemia, insulin resistance, or other conventional risk factors in type 2 diabetes, we measured soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), insulin sensitivity, and conventional risk factors in 150 Japanese type 2 diabetic patients without apparent diabetic macroangiopathy. High serum concentrations of sVCAM-1 and sE-selectin were observed in patients with type 2 diabetes. Serum concentrations of soluble adhesion molecules were not significantly influenced by sex, hypertension, dyslipidemia, or microangiopathy. Spearman correlation showed that sVCAM-1 concentrations correlated significantly with fasting plasma glucose (FPG), fasting C-peptide, and insulin sensitivity [K index of the insulin tolerance test (K(ITT))] (rho=0.19,0.23, and -0.23, respectively). Soluble E-selectin concentrations correlated significantly with body mass index (BMI), FPG, fasting C-peptide, insulin sensitivity, and triglyceride (rho=0.33,0.42,0.26,-0.48, and 0.29, respectively). Multiple regression analysis showed that FPG, fasting C-peptide, and total cholesterol were independent factors that correlated with sVCAM-1 levels. BMI, FPG, and insulin sensitivity were independent factors that correlated with sE-selectin levels. Serum concentrations of sE-selectin significantly increased associated with clustering of conventional risk factors those obesity, hypertension, dyslipidemia, and current smoking (P<0.01). Thus, sVCAM-1 and sE-selectin levels are related to both hyperglycemia and insulin resistance. Soluble E-selectin levels may be related to obesity, hyperglycemia, and insulin resistance and may reflect the presence of a multiple risk factor clustering syndrome.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Cell Adhesion Molecules; Cholesterol; Diabetes Mellitus, Type 2; E-Selectin; Fasting; Female; Humans; Hyperglycemia; Insulin Resistance; Intercellular Adhesion Molecule-1; Male; Middle Aged; Risk Factors; Solubility; Triglycerides; Vascular Cell Adhesion Molecule-1

First-degree relatives of Type II (non-insulin-dependent) diabetic patients in cross-sectional studies have increased insulin resistance, associated cardiovascular risk factors and abnormalities of fibrinolysis and coagulation. To minimise between-family genetic and environmental confounders, we investigated within-family relationships between early hyperglycaemia and risk factors.. Thirteen age and gender matched sibling pairs of Type II (non-insulin-dependent) diabetic patients, one hyperglycaemic, one normoglycaemic (fasting plasma glucose at screening 6.0-7.7 mmol.l(-1) and < 6.0 mmol.l(-1), respectively) were assessed for plasminogen activator inhibitor antigen (PAI-1), tissue plasminogen activator antigen (t-PA), fibrinogen, Factor VII and Factor VIII/von Willebrand factor antigen. Fasting lipid profiles, blood pressure and HOMA insulin sensitivity (%S) were also measured in siblings and in matched subjects without family history of diabetes.. Hyperglycaemic and normoglycaemic siblings (7 female, 6 male) were aged, mean (SD) 56.8 (8.7) and 55.8 (8.4) years. Hyperglycaemic siblings had increased PAI-1 antigen, geometric mean (i.q.r.): 26.3 (15.1-45.6) vs 11.1 (2.1-23.3) ng/ml, p=0.0002, similar t-PA antigen, mean (SD) 9.5 (4.3) vs 7.4 (2.5) ng/ml, p=0.2 and fibrinogen 2.2 (0.3) vs 2.3 (0.6) g/l, p=0.5, and reduced %S 66.3 (30.5) vs 82.9 (25), p=0.04. PAI-1 correlated negatively with %S ( r=-0.55, p=0.005). No significant differences were found in blood pressure or fasting lipids.. A minor increase in plasma glucose in non-diabetic sibling pairs of Type II (non-insulin-dependent) diabetic patients was associated with reduced insulin sensitivity, increased central adiposity and a doubling of PAI-1 antigen concentration, suggesting impaired fibrinolysis. It is possible that this could contribute to increased cardiovascular risk in these subjects.

Topics: Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Insulin; Insulin Resistance; Islets of Langerhans; Male; Middle Aged; Obesity; Plasminogen Activator Inhibitor 1; Proinsulin; Reference Values; Siblings; Smoking

To prospectively determine the frequency of remission and possible mechanism of beta cell recovery in non-Whites with Type 2 diabetes mellitus in the setting of intensive glycaemic regulation using pharmacological agents.. Twenty-six consecutive, newly diagnosed African-American, Type 2 diabetic patients presenting primarily for severe hyperglycaemia (31.0+/-12.8 mmol/l) were followed for at least 1 year. Initial hospitalization included treatment with insulin, fluids and electrolytes. Outpatient intensive glycaemic regulation included insulin or glibenclamide, diabetes education and diet that altered nutrient content. Plasma glucose and C-peptide responses to an oral glucose tolerance test and HbA1c were measured at < 14, 15-56 and 57-112 days after presentation. Remission was defined as a HbA1c < or = 6.3% and fasting plasma glucose < 6.9 mmol/l, 3 months after discontinuing all pharmacological agents.. Eleven of 26 patients (42.3%) developed remission after a mean of 83 days of pharmacological treatment and remained in remission during follow-up for 248-479 days; one relapsed after 294 days. Fifteen patients who did not develop a remission and were followed for 168-468 days, required continuing pharmacological therapy to be well-controlled. (mean HbA1c = 7.1%). There was no significant difference in age, sex, plasma glucose at presentation, initial glycaemic regulation, final body mass index, magnitude of weight change or pharmacological agents used for treatment between the two groups. Plasma C-peptide response to oral glucose was initially (< 14 days) suppressed in all subjects and subsequently increased. The increase was significantly greater in those who underwent a remission than those who did not. Neither significant weight loss nor severe hypoglycaemia was observed in either group during intensive treatment.. Forty-two per cent of newly diagnosed, unselected African-Americans with Type 2 diabetes, treated intensively using pharmacological agents, education and diet developed near-normoglycaemic remission. Remission was associated with a greater recovery of glucose-stimulated insulin secretion suggesting that therapies directed at promoting beta cell recovery and preservation are potentially useful approaches to the treatment of Type 2 diabetes mellitus.

Topics: Aged; Biomarkers; Black or African American; Black People; Blood Glucose; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Follow-Up Studies; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; New York City; Patient Education as Topic; Prospective Studies; Time Factors

Abnormalities in mitochondrial DNA(mtDNA) have been implicated in the pathogenesis of diabetes mellitus. We recently reported that decreased mtDNA content precedes the development of diabetes mellitus and is associated with parameters of insulin resistance. In this study, we examined whether there is any relation between mtDNA content and insulin secretion. We compared the mtDNA content of peripheral blood leukocytes with the parameters of insulin secretion measured by hyperglycemic clamp in a group of healthy young men. There were statistically significant correlations between mtDNA content in peripheral blood and fasting plasma insulin (r=-0.43, P<0.05) and C-peptide levels (r=-0.44, P<0.05). MtDNA content also correlated negatively with acute insulin response(r=-0.48, P<0.05), late insulin response (r=-0.50, P<0.05) during hyperglycemic clamp and insulin secretion after glucagon stimulation (r=-0.60, P<0.01). mtDNA content in peripheral blood correlated negatively with homeostasis model (HOMA) insulin resistance (r=-0.45, P<0.05) although it did not correlate with the insulin insensitivity index (M/I) during hyperglycemic clamp. In summary, the mtDNA content of peripheral blood correlated negatively with indices of insulin resistance and insulin secretion in healthy young men. The compensatory response of pancreas beta cells to insulin resistance might contribute in part to increased insulin secretion in these subjects.

Topics: Adult; Anthropometry; C-Peptide; DNA, Mitochondrial; Glucagon; Glucose Clamp Technique; Homeostasis; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Leukocytes; Male; Reference Values

Chronically elevated non-esterified fatty acids (NEFAs) can exert negative effects on beta-cell function both in vitro and in vivo. Negative effects of fatty acids have been difficult to evaluate in overt diabetes because of the attendant hyperglycemia that gives rise to the confounding influence of 'glucotoxicity'. In this work, we tested for the effects of NEFAs in diabetes by (i) taking into account potential effects of prevailing levels of hyperglycemia, and (ii) focusing on lingering (and therefore possibly more serious) effects. A diabetic transplantation model was used in which two islet grafts with 200 and 20 rat islets respectively were transplanted under the kidney capsule of syngeneic recipients previously made diabetic by streptozotocin injection. Rats were then fed either a high-fat or a low-fat diet for 7 weeks, followed by 1 week of normal laboratory chow. During dietary intervention, food was consumed ad libitum in one protocol, but was restricted in the low-fat group in a second protocol (in order to match blood-glucose levels). A high-fat diet did not affect body weight. At the end of the protocols, graft-bearing kidneys were isolated and perfused. Insulin responses to 27.8 mM glucose in perfusion were uniformly absent, in keeping with previously documented effects of chronic hyperglycemia. In contrast, 10 mM arginine induced a marked increase in insulin secretion after a low-fat diet, an effect that was significantly reduced after a high-fat diet (109 +/- 39 vs 13 +/- 15 fmol/min (P < 0.05) and 95 +/- 18 vs 32 +/- 5 fmol/min (P < 0.05) in the 2 protocols respectively). Regardless of protocol, no effect of diet could be detected on graft contents of insulin or preproinsulin mRNA. Thus, under conditions in which influences of chronic hyperglycemia could be accounted for, a previous high-fat diet with elevated NEFAs inhibited arginine-induced insulin secretion; however, the results indicate that insulin biosynthesis and/or beta-cell mass were not affected.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Diet; Dietary Fats; Fatty Acids, Nonesterified; Female; Hyperglycemia; In Vitro Techniques; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Male; Proinsulin; Protein Precursors; Rats; Rats, Inbred WF; RNA, Messenger

The hippocampus of rats with uncontrolled insulin-dependent diabetes undergoes retraction and simplification of apical dendrites of the CA3 pyramidal neurons and synaptic rearrangements within mossy fiber terminals that could alter hippocampal connectivity and function. The intraperitoneal implantation of hydrophilic agarose macrobeads containing porcine islets for 17 days in rats with streptozotocin-induced diabetes results in normalization of body weight gain, significant control of hyperglycemia and prevention of hippocampal dendritic remodeling, and therefore, provides an effective therapeutic option.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Capsules; Dendrites; Diabetes Mellitus, Experimental; Glucagon; Graft Survival; Hippocampus; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Male; Nerve Degeneration; Peritoneum; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Swine; Treatment Outcome

The type B insulin-resistance syndrome is characterized by the presence of anti-insulin receptor antibodies that cause severe insulin resistance. Treatments including steroids, cyclophosphamide, plasmapheresis, or insulin-like growth factor-1 (IGF-1) are chosen according to severity of insulin resistance. We describe a patient with type B insulin resistance syndrome who was treated successfully with human recombinant (hr) IGF-1, although this treatment provoked a severe allergic reaction. An elderly man with impaired glucose tolerance and unpredictable hypoglycemic episodes which were gradually worsening increased in hemoglobin (Hb)A1c concentration from 6.5 to 13.4%. His fasting and postprandial hyperglycemia were associated with severe hyperinsulinemia. The patient was diagnosed with type B insulin-resistance syndrome by the presence of anti-insulin receptor antibodies. Double-filtration plasmapheresis, plasma exchange, and immunosuppressive therapy with cyclophosphamide and cyclosporin all failed to suppress anti-insulin receptor antibodies more than transiently. When we attempted the treatment by daily administration of hrIGF-1, fasting and postprandial plasma glucose concentrations became normal and HbA1c levels decreased to 7.1% over 2 months, until on one occasion administration resulted in anaphylaxis. After the patient became stable, desensitization therapy was performed successfully, and hrIGF-1 could be administered again with the plasma glucose returning. We concluded that IGF-1 therapy was an effective treatment choice for type B insulin-resistance syndrome in cases whose plasma exchange and immunosuppressive therapy have failed.

Topics: Aged; Autoantibodies; Blood Glucose; C-Peptide; Cyclophosphamide; Cyclosporine; Desensitization, Immunologic; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Immunosuppressive Agents; Insulin Resistance; Insulin-Like Growth Factor I; Male; Plasma Exchange; Plasmapheresis; Receptor, Insulin; Syncope

In this population-based survey, we investigated the prevalence of varying degrees of glucose tolerance among residents of Kin-Chen, Kinmen, as well as the association of glucose tolerance status with potential risk factors for type 2 diabetes and cardiovascular disease (CVD). We focused particularly on subjects with normal 2-h postload glucose level (<7.8 mmol/l) but persistent fasting hyperglycemia (PFH) (5.6-7.8 mmol/l), to examine whether PFH represents an intermediate state between normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). The target population comprised 6346 residents aged 30 years and older. A total of 4354 subjects could be classified into categories of NGT, PFH, IGT, new diabetes, and known diabetes according to medical history, fasting plasma glucose levels, and the results of a 75-g oral glucose tolerance test (OGTT). The potential cardiovascular risk factors assessed included age, obesity (general and central), systolic blood pressure, and fasting levels of insulin, C-peptide, triglyceride, cholesterol, and high-density lipoprotein cholesterol (HDL-C). The age-standardized prevalences of PFH, IGT, new diabetes, and known diabetes were 2.9%, 3.5%, 4.0%, and 3.0%, respectively. Among nondiabetic subjects, the cardiovascular risk factor profiles worsened with decreasing glucose tolerance, with most values differing significantly among the NGT, PFH, and IGT groups. Subjects with PFH, who would be classified as having NGT according to conventional WHO criteria, had physical and biochemical features between those of the NGT and IGT groups. These findings support our previous observation that PFH may be a transition state between NGT and IGT in the progression toward type 2 diabetes.

Topics: Adult; Analysis of Variance; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Prevalence; Risk Factors; Taiwan

We tested the hypothesis that a lack of suppression of glucagon causes postprandial hyperglycemia in subjects with type 2 diabetes. Nine diabetic subjects ingested 50 g glucose on two occasions. On both occasions, somatostatin was infused at a rate of 4.3 nmol/kg x min, and insulin was infused in a diabetic insulin profile. On one occasion, glucagon was also infused at a rate of 1.25 ng/kg x min to maintain portal glucagon concentrations constant (nonsuppressed study day). On the other occasion, glucagon infusion was delayed by 2 h to create a transient decrease in glucagon (suppressed study day). Glucagon concentrations on the suppressed study day fell to about 70 ng/L during the first 2 h, rising thereafter to approximately 120 ng/L. In contrast, glucagon concentrations on the nonsuppressed study day remained constant at about 120 ng/L throughout. The decrease in glucagon resulted in substantially lower (P < 0.001) glucose concentrations on the suppressed compared with the nonsuppressed study days (9.2+/-0.7 vs. 10.9+/-0.8 mmol/L) and a lower (P < 0.001) rate of release of [14C]glucose from glycogen (labeled by infusing [1-14C]galactose). On the other hand, flux through the hepatic UDP-glucose pool (and, by implication, glycogen synthesis), measured using the acetaminophen glucuronide method, did not differ on the two occasions. We conclude that lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes at least in part by accelerating glycogenolysis. These data suggest that agents that antagonize glucagon action or secretion are likely to be of value in the treatment of patients with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Galactose; Glucagon; Glycogen; Human Growth Hormone; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Postprandial Period

Topics: Adult; Antiviral Agents; C-Peptide; Diabetes Mellitus; Glycated Hemoglobin; HIV Infections; HIV-1; Humans; Hyperglycemia; Insulin; Male; Protease Inhibitors

Type 2 diabetes mellitus has never previously been described in UK children, although an increasing incidence in childhood is recognized in international studies. The prevalence of obesity in UK children is increasing and is a recognized risk factor for the development of diabetes. The aim of this study was to identify and characterize children with Type 2 diabetes in the West Midlands and Leicester.. Children were identified by contacting paediatricians responsible for diabetes in five hospitals. Details were collected on demographics, mode of presentation, investigations and treatment on a standard proforma.. Eight girls were identified with Type 2 diabetes, aged 9-16 years and who were of Pakistani, Indian or Arabic origin. They were all overweight (percentage weight for height 141-209%) and had a family history of diabetes in at least two generations. They presented insidiously with hyperglycaemia and glycosuria without ketosis and five were asymptomatic. Islet cell antibodies measured in seven patients were negative. Four had acanthosis nigricans which is a cutaneous marker of insulin resistance and the other four had high plasma levels of insulin and/or C peptide. These patients are distinct from those with maturity-onset diabetes of the young (MODY). All were initially managed with dietary measures, seven have been treated with oral anti-diabetic agents of whom two have subsequently required insulin.. These are the first UK case reports of Type 2 diabetes in children. Paediatricians need to be aware of the risk of Type 2 diabetes developing in childhood in high-risk ethnic groups, particularly in association with obesity and a positive family history.

Topics: Acanthosis Nigricans; Adolescent; Body Mass Index; C-Peptide; Child; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Glycosuria; Humans; Hyperglycemia; Hypoglycemic Agents; India; Insulin; Insulin Resistance; Obesity; Pakistan; Saudi Arabia; United Kingdom

It is established that disproportionately elevated plasma proinsulin levels occur in patients with Type 2 diabetes. In the present study, multivariate analysis was performed to determine what factors contributed to the disproportionately elevated plasma proinsulin levels in Japanese patients with Type 2 diabetes (n=276). Results from univariate analysis showed that both fasting proinsulin/C-peptide ratio and proinsulin/IRI ratio were approximately 2-fold higher in patients with Type 2 diabetes than those in healthy nondiabetic subjects (n=45). In patients with Type 2 diabetes, both proinsulin/C-peptide ratio and proinsulin/IRI ratio were significantly positively correlated with fasting plasma glucose level (FPG) and HbA1c. Neither proinsulin/C-peptide ratio nor proinsulin/IRI ratio was significantly correlated with BMI. Sulfonylurea-treated subjects had a significant elevation in both proinsulin/C-peptide ratio and proinsulin/IRI ratio compared with diet-treated subjects, whereas nonsulfonylurea hypoglycemic agent-treated subjects did not. Multivariate analysis confirmed that sulfonylurea treatment and FPG were significant determinants of both fasting proinsulin/C-peptide ratio (P=0.006 and P=0.030, respectively) and proinsulin/IRI ratio (P=0.003 and P=0.016, respectively) in patients with Type 2 diabetes. These results imply that disproportionate hyperproinsulinemia may reflect an excessive overwork of beta cells under chronic sulfonylurea treatment as well as hyperglycemia.

Topics: Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Middle Aged; Multivariate Analysis; Proinsulin; Sulfonylurea Compounds

Data on the hypokinesia-induced transformation of the glycemic profile and ultrasonic changes in the pancreas structure are presented. The AOH study gave further evidence of transforming glycemic curves. Moreover, increased sizes of tail and head of the pancreas and a decrease in its echogeneity were observed in all test-subjects. Structural changes in the pancreas were confirmed by biochemical investigations which revealed increased levels of blood enzymes and activation of insulin secretion. Increases in the liver size, thickness of the wall of the stomach, diameter of the splenic vein were indicative of progressing venous plethora in the portal vein system. It was shown that venous plethora are the main cause for changes in the upper GI, and in the pancreas state in particular, which can be qualified as dysfunctional. These structural changes in the pancreas could suppress its functional activity manifested by increases in blood enzymes and hormones and transformation of the glycemic profile during the glucose load.

Topics: Adult; Aerospace Medicine; Amylases; C-Peptide; Humans; Hyperglycemia; Hypokinesia; Hypotension, Orthostatic; Insulin; Male; Pancreas; Portal Vein; Space Flight; Ultrasonography

The objective of this study was to evaluate whether first-degree relatives (FDRs) of patients with type 2 diabetes had abnormal circadian insulin secretion and, if so, whether this abnormality affected their glucose metabolism. Six African-American FDRs with normal glucose tolerance and 12 matched normal control subjects (who had no family history of diabetes) were exposed to 48 h of hyperglycemic clamping (approximately 12 mmol/l). Insulin secretion rates (ISRs) were determined by deconvolution of plasma C-peptide levels using individual C-peptide kinetic parameters. Detrending and smoothing of data (z-scores) and computation of autocorrelation functions were used to identify ISR cycles. During the initial hours after start of glucose infusions, ISRs were approximately 60% higher in FDRs than in control subjects (585 vs. 366 nmol/16 h, P < 0.05), while rates of glucose uptake were the same (5.6 mmol x kg(-1) x h(-1)), indicating that the FDRs were insulin resistant. Control subjects had well-defined circadian (24 h) cycles of ISR and plasma insulin that rose in the early morning, peaked in the afternoon, and declined during the night. In contrast, FDRs had several shorter ISR cycles of smaller amplitude that lacked true periodicity. This suggested that the lack of a normal circadian ISR increase had made it impossible for the FDRs to maintain their compensatory insulin hypersecretion beyond 18 h of hyperglycemia. As a result, ISR decreased to the level found in control subjects, and glucose uptake fell below the level of control subjects (61 vs. 117 micromol x kg(-1) x min(-1), P < 0.05). In summary, we found that FDRs with normal glucose tolerance had defects in insulin action and secretion. The newly recognized insulin secretory defect consisted of disruption of the normal circadian ISR cycle, which resulted in reduced insulin secretion (and glucose uptake) during the ascending part of the 24 h ISR cycle.

Topics: Adult; Black People; Blood Glucose; Body Mass Index; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Family; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Philadelphia; Proinsulin; Reference Values

The present experiments sought to determine whether glucagon concentrations mimicking those observed in people with diabetes mellitus alter postprandial carbohydrate metabolism in nondiabetic humans. We measured the gastric emptying of solids and liquids, the systemic rate of appearance of ingested glucose, and endogenous glucose production either when postprandial suppression of glucagon was prevented by infusing glucagon at a rate of 0.65 ng/kg/min, when postprandial glucagon concentrations were elevated by infusing glucagon at a rate of 3.0 ng/kg/min, or when postprandial suppression of glucagon was permitted by infusion of saline. Despite marked differences in glucagon concentrations, postprandial glucose and insulin concentrations did not differ on any occasion. Although gastric emptying of liquids and solids was comparable on all three occasions, the high-dose, but not the low-dose, glucagon infusion caused a slight delay in the systemic appearance of ingested glucose and a significant decrease (P < .01) in postprandial D-xylose concentrations, suggesting a delay in carbohydrate absorption. However, this was offset by an increase (P < .05) in endogenous glucose production, resulting in no difference in postprandial glucose appearance. We conclude that in the absence of insulin deficiency, neither a lack of suppression of glucagon nor an elevation of glucagon to levels encountered in uncontrolled diabetes mellitus cause postprandial hyperglycemia in nondiabetic humans.

Topics: Blood Glucose; C-Peptide; Carbohydrate Metabolism; Female; Food; Gastric Emptying; Gastrointestinal Hormones; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Postprandial Period; Xylose

We tested whether acute alpha 2-blockade affects insulin secretion, glucose and fat metabolism, thermogenesis, and hemodynamics in humans. During a 5-h epinephrine infusion (50 ng.min-1.kg-1) in five volunteers, deriglidole, a selective alpha 2-receptor inhibitor, led to a more sustained rise in plasma insulin and C-peptide levels (+59 +/- 14 vs. +28 +/- 6, and +273 +/- 18 vs. +53 +/- 14 pM, P < 0.01 vs. placebo) despite a smaller rise in plasma glucose (+0.90 +/- 0.4 vs. +1.5 +/- 0.3 mM, P < 0.01). Another 10 subjects were studied in the postabsorptive state and during a 4-h hyperglycemic (+4 mM) clamp, coupled with the ingestion of 75 g of glucose at 2 h. In the postabsorptive state, hepatic glucose production, resting energy expenditure, and plasma insulin, free fatty acid (FFA), and potassium concentrations were not affected by acute alpha 2-blockade. Hyperglycemia elicited a biphasic rise in plasma insulin (to a peak of 140 +/- 24 pM), C-peptide levels (1,520 +/- 344 pM), and insulin secretion (to 410 +/- 22 pmol/min); superimposed glucose ingestion elicited a further twofold rise in insulin and C-peptide levels, and insulin secretion. However, alpha 2-blockade failed to change these secretory responses. Fasting blood beta-hydroxybutyrate and glycerol and plasma FFA and potassium concentrations all declined with hyperglycemia; time course and extent of these changes were not affected by alpha 2-blockade. Resting energy expenditure (+25 vs. +16%, P < 0.01) and external cardiac work (+28% vs. +19%, P < 0.01) showed larger increments after alpha 2-blockade. We conclude that acute alpha 2-blockade in humans 1) prevents epinephrine-induced inhibition of insulin secretion, 2) does not potentiate basal or intravenous- or oral glucose-induced insulin release, 3) enhances thermogenesis, and 4) increases cardiac work.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Analysis of Variance; Blood Glucose; C-Peptide; Calorimetry, Indirect; Epinephrine; Glucose Clamp Technique; Humans; Hyperglycemia; Imidazoles; Indoles; Insulin; Insulin Secretion; Kinetics; Male; Oxygen Consumption

Insulin secretion is increased in cirrhotic patients without diabetes but decreased in cirrhotic patients with diabetes. Increased glucagon secretion is found in both groups. Our aim was to determine: 1) whether alterations in insulin secretion are due to changes in maximal secretory capacity or altered islet B-cell sensitivity to glucose, and 2) whether regulation of glucagon secretion by glucose is disturbed.. Insulin, C-peptide and glucagon levels were measured basally and during 12, 19 and 28 mmol/l glucose clamps, and in response to 5 g intravenous arginine basally and after 35 min at a glucose of 12, 19 and 28 mmol/l in 6 non-diabetic alcoholic cirrhotic patients, six diabetic alcoholic cirrhotic patients and six normal controls.. Fasting insulin, and C-peptide levels were higher in cirrhotic patients than controls but not different between diabetic and non-diabetic patients. C-peptide levels at t=35 min of the clamp increased more with glucose concentration in non-diabetic cirrhotic patients than controls; there was little increase in diabetic cirrhotic patients. At a blood glucose of approximately 5 mmol/l the 2-5 min C-peptide response to arginine (CP[ARG]) was similar in all groups, but enhancement of this response by glucose was greater in non-diabetic cirrhotic patients and impaired in diabetic cirrhotic patients. Maximal insulin secretion (CP(ARG) at 28 mmol/l glucose) was 49% higher in the non-diabetic cirrhotic patients than controls (p<0.05); in diabetic cirrhotic patients it was 47% lower (p<0.05). The glucose level required for half-maximal potentiation of (CPARG) was not different in the three groups. Cirrhotic patients had higher fasting glucagon levels, and a greater 2-5-min glucagon response to arginine, which was enhanced by concomitant diabetes (p<0.001 vs controls). Suppression of plasma glucagon by hyperglycaemia was markedly impaired in diabetic cirrhotic patients (glucagon levels at 35 min of 28 mmol/l glucose clamp: diabetics, 139 x/divided by 1.25 ng/l, non-diabetic cirrhotic patients, 24 x/divided by 1.20, controls, 21 x/divided by 1.15, p<0.001). Suppression of arginine-stimulated glucagon secretion by glucose was also impaired in diabetic cirrhotic patients, and to a lesser extent in non-diabetic cirrhotic patients.. Insulin secretory abnormalities in diabetic and non-diabetic cirrhotic patients are due to changes in maximal secretory capacity rather than altered B-cell sensitivity to glucose. The exaggerated glucagon response to arginine in alcoholic cirrhotic patients is not abolished by hyperglycaemia/hyperinsulinaemia. In diabetic alcoholic cirrhotic patients, the inhibitory effect of glucose on basal glucagon secretion is also markedly impaired.

Topics: Adult; Aged; Arginine; Basal Metabolism; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Complications; Diabetes Mellitus; Dose-Response Relationship, Drug; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Liver Cirrhosis, Alcoholic; Middle Aged; Secretory Rate

Glucagon-like peptide 1 (GLP-1) is known to stimulate insulin secretion and biosynthesis, but has also been shown to decrease insulin requirements in type 1 diabetic subjects suggesting insulin-independent effects. To assess whether GLP-1 exerts also direct effects on whole-body glucose metabolism, 6,6-D2-glucose kinetics were measured in 8 healthy volunteers receiving once GLP-1, once saline during hyperglycemic glucose clamping, while somatostatin with replacement amounts of insulin, glucagon and growth hormone was infused. Even though endogenous insulin secretion could not be blocked completely (increased plasma concentrations of C-peptide and proinsulin), somatostatin infusion resulted in stable insulin and glucagon plasma levels in both protocols (GLP-1 vs. placebo: NS). After 3 h of GLP-1 infusion, peripheral glucose disappearance significantly increased compared to placebo (p < 0.03) despite of somatostatin-induced suppression of insulin and glucagon secretion. Thus, GLP-1 infusion seems to have direct stimulatory effects on peripheral glucose metabolism in man.

Topics: Adult; Blood Glucose; C-Peptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Kinetics; Male; Peptide Fragments; Proinsulin; Somatostatin

Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (approximately 9 mmol l(-1)) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (approximately 4000 micromol l(-1)) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20-44% (p < 0.05) and C-peptide levels by 17-25% (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45% in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion.

Topics: Adult; Arginine; C-Peptide; Diabetes Mellitus, Type 2; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Heparin; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Triglycerides

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to cha

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucose Clamp Technique; Glycogen; Glycolysis; Human Growth Hormone; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Middle Aged; Somatostatin; Sulfonylurea Compounds

Eccentric exercise (ECC) causes muscle damage, insulin resistance, and increased pancreatic beta-cell secretion in young individuals. However, the effects of age on the pancreatic beta-cell response to glucose after ECC are unknown. Hyperglycemic clamps (180 min, 10.0 mM) were performed on eight young (age 22 +/- 1 yr) and eight older (age 66 +/- 2 yr) healthy sedentary males without exercise (CONT) and 48 h after ECC. ECC increased (P < 0.02) muscle soreness ratings and plasma creatine kinase concentrations in both groups. Insulin and C-peptide secretions were similar between young and older subjects during CONT clamps. ECC increased (P < 0.05) first-phase (0-10 min) C-peptide area under the curve in young (4.2 +/- 0.4 vs. 3.7 +/- 0.6 nM . min; ECC vs. CONT, respectively) but not in older subjects (3.2 +/- 0.7 vs. 3.5 +/- 0.7 nM . min; ECC vs. CONT), with significant group differences (P < 0.02). Indeed, ECC repressed (P < 0.05) first-phase peak C-peptide concentrations in older subjects (0. 93 +/- 0.16 vs. 1.12 +/- 0.11 nM; ECC vs. CONT). Moreover, first-phase C-peptide-to-insulin molar ratios suggest age-related differences (P < 0.05) in insulin/C-peptide clearance after ECC. Furthermore, the observed C-peptide response after ECC was related to abdominal adiposity [r = -0.62, P < 0.02, and r = -0.66, P < 0. 006, for first and second (10-180 min) phases, respectively]. In conclusion, older individuals did not exhibit the compensatory increase in beta-cell secretion observed among young individuals after ECC. Thus, with increasing age, the pancreatic beta-cell may be less responsive to the physiological stress associated with ECC.

Topics: Activity Cycles; Adult; Aged; Aging; Blood Glucose; Body Constitution; Body Mass Index; Body Weight; C-Peptide; Creatine Kinase; Exercise; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Muscle Fatigue; Physical Exertion; Regression Analysis

The glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.

Topics: Adult; Alanine; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exercise; Female; Glucose; Glucose-6-Phosphate; Homeostasis; Humans; Hyperglycemia; Insulin; Lactic Acid; Male; Obesity; Oxidation-Reduction; Oxygen Consumption; Tritium

To examine the significance of alterations in insulin sensitivity index (S(t)), glucose effectiveness (Sg), and beta-cell function in the pathogenesis of type II diabetes in African-Americans with varying degrees of glucose intolerance.. A total of 154 African-Americans residing in Franklin County, Ohio, were studied. There were 101 subjects with normal glucose tolerance (NGT), 36 with impaired glucose tolerance (IGT), and 17 with type II diabetes. An oral glucose tolerance test (OGTT) was performed on each subject. S(t) and Sg were measured by insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT).. The mean fasting and postprandial serum glucose levels were significantly greater in the diabetic groups when compared with the IGT and NGT groups. In contrast, while fasting serum insulin and C-peptide levels tended to be greater in the type II diabetic and IGT groups, the postprandial responses were blunted at 30 min in the IGT and type II diabetic groups when compared with the NGT group. The mean acute first-phase insulin release after intravenous glucose was blunted also in the IGT and type II diabetic groups when compared with the NGT group. The S(t) was significantly lower in the IGT (1.51 +/- 0.19) and type II diabetic (0.61 +/- 0.15) groups when compared with the NGT group (2.94 +/- 0.20 x 10(-4).min-1.microU-1.ml-1). The Sg was not significantly different in the NGT (2.90 +/- 0.20), IGT (2.47 +/- 0.19), and the type II diabetic (2.35 +/- 0.15 x 10(-2)/min) groups. The glucose effectiveness at theoretical zero insulin concentration (GEZI) followed similar patterns as the Sg. Furthermore, the basal insulin effect (BIE) was significantly lower in the IGT and type II diabetic groups compared with the NGT group. In addition, the glucose decay constant (Kg) was significantly lower (P < 0.001) in the IGT (1.21 +/- 0.13) and the type II diabetic (1.07 +/- 0.12) groups when compared with the NGT group (2.03 +/- 0.10% per minute).. Our present study demonstrates that African-American patients with IGT and mild type II diabetes have significant reduction in beta-cell function, insulin sensitivity, and BEI but have normal and intact Sg and GEZI when compared with NGT subjects. We conclude the following: 1) a reduction in Sg does not appear to play a significant role in the pathogenetic mechanism of IGT and type II diabetes in African-American patients, and 2) the intact Sg in the IGT and type II diabetic groups could serve as a compensatory mechanism for hyperglycemia in African-Americans.

Topics: Adult; Black People; Blood Glucose; Body Constitution; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Postprandial Period; Sensitivity and Specificity; Time Factors

A case with diabetes mellitus associated with growth hormone (GH)-producing pituitary adenoma is described. A 56-year-old woman who had been treated for diabetes mellitus for 3 years, was admitted for the treatment of hyperglycemia. She showed a few acromegalic features and her plasma GH level was 146 +/- 16 ng/ml. After improvement of plasma glucose level by insulin injection, octreotide therapy (100 micrograms/8 hours) was started. Seven days after the initiation of octreotide therapy, the fasting plasma glucose level was almost normalized without insulin injection. After the octreotide treatment, urinary C-peptide excretion was significantly decreased and the plasma GH level became within normal range. In this case, octreotide appears to have improved the insulin sensitivity by reducing the plasma GH level.

Topics: Acromegaly; Adenoma; Antineoplastic Agents, Hormonal; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose Intolerance; Human Growth Hormone; Humans; Hyperglycemia; Insulin Resistance; Middle Aged; Octreotide; Pituitary Neoplasms

Substrate competition is an important mechanism of insulin resistance, although its role in the post-absorptive hyperglycemia of NIDDM is not clear: lipid infusion does not raise plasma glucose levels in normal subjects, and total lipid oxidation, the elevation of which is a hallmark of disrupted carbohydrate metabolism, is normal in non-insulin-dependent diabetes mellitus (NIDDM). To examine further these two arguments against the involvement of lipid-carbohydrate interactions in the hyperglycemia of NIDDM, we compared the effect of a 3-hour lipid infusion ('Ivélip') on post-absorptive blood glucose levels, plasma lipids and respiratory exchanges in 15 patients with NIDDM, with that of an infusion of saline in 15 other patients with similar metabolic profiles. The lipid infusion significantly slowed the natural post-absorptive decline in blood glucose levels (saline -0.47 +/- 0.14 and Ivélip -0.10 +/- 0.12 mmol.l-1.h-1, p < 0.05), with marked interindividual differences. Substrate oxidation rates were unchanged during saline infusion, and were immediately (within 30 min) and reciprocally modified by the lipid infusion (lipid oxidation enhanced: 0.90 +/- 0.14 to 1.06 +/- 0.13 mg.kg-1.min-1 at time 30 min, p < 0.05; glucose oxidation inhibited: 1.27 +/- 0.19 to 0.87 +/- 0.18, p < 0.05), but this was not correlated with the alteration in blood glucose levels. In contrast, the increase in plasma lipids was continuous, and positively correlated with the change in blood glucose levels (r = 0.58, p < 0.05 for change of plasma free fatty acids; r = 0.55, p < 0.05 for change of plasma triglycerides, TGs). In line with the Randle mechanism, the lipid infusion affected oxidation rates, but another mechanism, depending on intravascular lipolysis of the infused TGs, was thought to occur in certain individuals whose blood glucose levels rose during the infusion.

Topics: Blood Glucose; C-Peptide; Calorimetry, Indirect; Carbohydrate Metabolism; Carbohydrates; Diabetes Mellitus, Type 2; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Humans; Hyperglycemia; Insulin; Lipid Metabolism; Lipids; Male; Middle Aged; Oxidation-Reduction; Triglycerides

Pheochromocytoma usually is associated with a combination of various manifestations caused by overproduction of catecholamines. We encountered a case of an occult, catecholamine-secreting pheochromocytoma. A 70-year-old man was admitted to the hospital because of anorexia. He had been treated for diabetes mellitus for 4 years; during this period he did not have any other symptoms related to pheochromocytoma. At admission, serum epinephrine, norepinephrine, and glucose levels and urinary excretion of total metanephrine were elevated. A tumor was detected in the left adrenal region and diagnosed as pheochromocytoma. After tumor resection, the increased levels of catecholamines and glucose and the decreased urinary C-peptide were normalized. This suggests that the pheochromocytoma caused hyperglycemia without other manifestations for a long time.

Topics: Aged; Blood Glucose; C-Peptide; Catecholamines; Diabetes Mellitus; Diagnostic Errors; Humans; Hyperglycemia; Insulin; Male; Pheochromocytoma; Tomography, X-Ray Computed

Following a hyperosmolar diabetic coma in a cirrhotic patient with hepatocellular carcinoma undergoing transcatheter arterial chemo-embolization, we assessed the prevalence, severity, causes and prognostic impact of impaired glucose metabolism following transcatheter arterial chemo-embolization.. Plasma glucose, pancreatic and thyroid hormones, cortisol, growth hormone, ACTH and TSH concentrations were determined before and after transcatheter arterial chemo-embolization in 98 patients (70 with a normal fasting glucose, 7 with mild fasting hyperglycaemia and 21 diabetics) undergoing 226 transcatheter arterial chemo-embolization procedures. Child status, body temperature, serum ALT and amylase levels, tumour size, gelfoam embolization and disease aetiology were recorded. Liver function was assessed before and after transcatheter arterial chemo-embolization by measuring monoethylglycinexylidide formation after i.v. lidocaine.. A significant rise in glucose levels (p < 0.0001) was observed in 30/98 patients. Hyperglycaemia was more frequent in diabetics (67%) and patients with mild fasting hyperglycaemia (71%). Glucose concentrations doubled in 12 patients; 4 required long-term insulin. Fever, a previously altered carbohydrate metabolism and raised ALT levels were prognostic factors for hyperglycaemia (p < 0.01). Plasma C-peptide, glucose/insulin and glucose/C-peptide ratios, were increased after transcatheter arterial chemo-embolization (p < 0.05). Transcatheter arterial chemo-embolization was followed by a reduction in the monoethylglycinexylidide formation capacity (p < 0.05), particularly in hyperglycaemia patients (p < 0.02).. Transcatheter arterial chemo-embolization is frequently followed by a derangement in glucose metabolism which is potentially severe, associated with preceding glucose imbalance, fever and a transient deterioration in liver function.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fasting; Female; Hormones; Humans; Hyperglycemia; Insulin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

Increased concentrations of proinsulin immunoreactive material (PIM) absolutely or relative to insulin is a characteristic finding in patients with non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to test if 8 h or mild hyperglycemia (7-9 mmol/l) in healthy subjects could induce a preferential secretion of PIM from B cells. Serum concentrations of insulin, C-peptide and PIM were measured every 10 min during the 8 h of continuous glucose infusion in nine normal-weight healthy subjects without diabetes among their first-degree relatives. After a gradual rise in B-cell peptides, a steady state was reached. From 4 to 8 h no further difference in insulin, C-peptide or PIM concentration was found. Fasting PIM/C-peptide and PIM/insulin ratios of 0.5% and 2.3% increased during the glucose clamp to levels of 1.4% and 7.6%, respectively. Neither testing the regression slope nor comparing individual time points showed any significant difference for the PIM/C-peptide ratio from 2 to 8 h and for the PIM/insulin ratio from 3 to 8 h. These results do not support the hypothesis that an increased glucose drive per se results in an altered B-cell function with increasing PIM/C-peptide ratio. At least 8 h of mild hyperglycemia in healthy subjects does not progressively alter B-cell function.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; C-Peptide; Female; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Proinsulin

Insulin secretion was studied in healthy volunteers at three different levels of glycemia. Plasma glucose was clamped at approximately 5, approximately 8.8 and approximately 12.6 mM for 68 h. Measured were serum insulin concentration and insulin secretion rates (ISR), the latter by deconvolution of plasma C-peptide concentration. Rhythmic patterns of ISR were identified (with a refined first-order Fourier transform) at all three glucose concentrations tested but were most clearly seen at 12.6 mM. ISR and serum insulin concentration changed in a circadian (approximately 24 h) rhythm, increasing from a nadir between midnight and 6 A.M. and reaching a peak between noon and 6 P.M. At 12.6 mM hyperglycemia, the amplitude of the insulin concentration cycles was greater than that of the ISR cycles (+/- 13.0 vs. +/- 8.7%) due to a decrease in insulin clearance (from 1.55 to 0.5 l/min, P < 0.01). Plasma melatonin levels (a marker of light-dark rhythmicity) changed in the opposite direction, i.e., they peaked when ISR bottomed and bottomed when ISR peaked. We concluded that normal human subjects have a circadian rhythm of insulin secretion, which becomes more apparent with rising ISR, and that circadian changes in ISR, rising during the day and falling during the night, may be one explanation for the well-established observation that glucose tolerance and insulin responses to glucose and meals are higher in the morning than at night.

Topics: Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Female; Glucose Clamp Technique; Humans; Hydrocortisone; Hyperglycemia; Insulin; Insulin Secretion; Male; Melatonin; Sleep

Women with the diagnosis of gestational diabetes mellitus (GDM) are at a greater risk for developing diabetes in later life. This raises the question in which time span, to what extent and on which pathophysiological basis disorders of carbohydrate metabolism are to be expected post partum. Therefore 28 former gestational diabetes patients (GDM) were compared to 35 control patients, who had shown no irregularities in the oral glucose tolerance test during pregnancy. The follow-up study took place 5 years after the screening during pregnancy. The Wilcoxon Test for random samples revealed significantly higher blood sugar levels in the GDM group compared to the control group at 0.1 h and 2 h (median: 0 h 96 mg % vs 91 mg %; 1 h 155 mg % vs 126 mg %; 2 h 117 mg % vs 105 mg %; p < 0,05). Whereas no differences were apparent for fasting insulin, the values of the GDM group showed a markedly higher insulin level (Wilcoxon Test: p < 0.05) after 1 h (median: 74 microU/ml vs 56 microU/ml), 2 h (median: 60 microU/ml vs 38 microU/ml) and 3 h (median: 50 microU/ml vs 33 microU/ml). The serum level of C-peptide responded accordingly 2 h (median: 6.7 ng/ml vs 5.4 ng/ml; p = 0.04) and 3 h (median: 5.9 ng/ml vs 4.9 ng/ml; p = 0.04) after an oral glucose load.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin Resistance; Pregnancy; Pregnancy in Diabetics; Reference Values

We have evaluated the feasibility of monitoring the 24-hour urinary excretion rate of C-peptide (U-CPR) as a measure of integrated beta-cell function in patients with non-insulin-dependent diabetes mellitus (NIDDM). In 37 normoalbuminuric patients, U-CPR of 117.9 +/- 9.1 micrograms/d (mean +/- SEM) during the poorly controlled glycemic phase (fasting plasma glucose [FPG], 171 +/- 7 mg/dL; hemoglobin A1C [HbA1c], 8.8% +/- 0.4%) was significantly higher than the value of 83.3 +/- 13.7 micrograms/d (P < .001) during the well-controlled phase (FPG, 135 +/- 6 mg/dL; HbA1c, 7.0% +/- 0.2%), although the plasma insulin response to meals was lower during the former phase (53.3 +/- 6.3 microU/mL) versus the latter phase (65.7 +/- 6.6, P < .005). Endogenous creatinine clearance (Ccr) was significantly elevated during the poorly controlled phase (105.4 +/- 7.3 v 88.7 +/- 4.7 mL/min, P < .005). In 26 microalbuminuric patients, the plasma insulin response was greater during good glycemic control, but U-CPR did not differ between the two phases. Ccr was comparable at two phases in this group (92.7 +/- 7.4 v 91.1 +/- 5.9 mL/min, NS). U-CPR correlated positively with Ccr in both groups (r = .593, P < .001 in normoalbuminuria; r = .585, P < .001 in microalbuminuria). In addition, when biosynthetic human C-peptide was infused intravenously at an identical rate in two healthy subjects, resulting steady-state plasma levels of CPR were lower, and fractional U-CPR was higher during the moderately hyperglycemic phase versus the euglycemic phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Metabolic Clearance Rate; Middle Aged

Our preliminary data indicate that 15% of African-American patients presenting with diabetic ketoacidosis (DKA) are obese. To determine underlying mechanisms, we analyzed the clinical characteristics and indexes of insulin secretion and insulin sensitivity in 35 obese patients with DKA, 22 obese patients with hyperglycemia, 10 lean patients with DKA, and 10 obese nondiabetic subjects. Studies were performed 1 day after resolution of DKA and after 12 weeks of follow-up. At presentation, both obese DKA and obese hyperglycemic patients had no detectable insulin response to intravenous glucose, but they did respond to glucagon administration. The acute insulin response (AIR) to glucagon in obese DKA patients (0.9 +/- 0.1 ng/ml, P < 0.01), but significantly greater than in lean patients with DKA (0.1 +/- 0.1 ng/ml, P < 0.01). After 12 weeks of follow-up, the AIR to glucose improved in both groups of obese diabetic patients but remained significantly lower than in nondiabetic control subjects (both P < 0.01). In contrast, the AIR to glucagon was not significantly different from that in obese control subjects. Insulin sensitivity was decreased in both groups of obese diabetic patients at presentation and improved after follow-up to levels similar to those in obese nondiabetic control subjects. Reactivity with islet cell antibodies was not detected in any of the patients. During follow-up, 25 of 35 obese DKA and 16 of 22 hyperglycemic patients were able to discontinue insulin therapy, with continued good metabolic control. Our results indicate that in African-Americans, obese patients with DKA represent a subset of type II diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Black People; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetic Ketoacidosis; Female; Georgia; Glucagon; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Reference Values; Thinness

To determine whether fatty liver impairs insulin clearance and contributes to insulin resistance in obese and lean healthy non-diabetic men and women.. Cross-sectional, descriptive.. Medical outpatient clinic; university hospital.. Twenty-seven (14 men) non-diabetic obese (Body fat % = 31.5 +/- 9.3; mean +/- s.d.) and 19 (13 men) non-diabetic non-obese (body fat % = 19.0 +/- 6.8; P < 0.01 vs obese) healthy subjects aged 31-64 without liver disease.. Liver density relative to the spleen on CT scan (LFS), glucose infusion rate (GIR) and metabolic insulin clearance rate (MIC) during euglycemic hyperinsulinemic clamp; anthropometric (waist-hip ratio: WHR) and CT-determined (visceral fat area: VFA) measures of fat distribution.. Fatty liver was inversely related to MIC (r = -0.39; P < 0.01) with a positive correlation with fasting p-insulin (r = 0.39; P < 0.01). There were no statistically significant correlations between BMI, body fat % or WHR and MIC. GIR was inversely related to body fat % (r = -0.49; P < 0.01), VFA (r = -0.56; P < 0.01) and WHR (r = -0.36; P < 0.01) in all subjects, with an inverse relationship to fatty liver in men (r = -0.43; P < 0.05).. Increased steatosis of the liver is associated with reduced insulin clearance, contributing to insulin resistance in non-diabetic Japanese men and women.

Topics: Adipose Tissue; Adult; Anthropometry; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Cross-Sectional Studies; Fatty Acids, Nonesterified; Fatty Liver; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Resistance; Japan; Male; Metabolic Clearance Rate; Middle Aged; Obesity; Tomography, X-Ray Computed; Triglycerides

In eight glucokinase (GCK)-deficient subjects, we have investigated insulin secretion rates (ISRs) in response to intravenous arginine. Impairment in the enzymatic activity of mutant GCK leads to a reduced glycolytic flux in beta-cells. This defect translates in vivo as a right shift in the glucose/SR dose-response curve. Insulin secretion in response to other secretagogues has not been reported.. The arginine test was performed immediately after a 2-h hyperglycemic (10 mM) clamp. ISR was computed by deconvolution of peripheral C-peptide levels. Linear regression analyses were performed to assess correlations between the beta-cell secretory responses to the arginine test, an intravenous glucose tolerance test (IVGTT), and a hyperglycemic clamp (areas under the C-peptide curves), and between these parameters and the glucose tolerance status (area under the glucose curve during an oral glucose tolerance test).. Two minutes after the injection of arginine, the increment in ISR was 30.17 +/- 10.01 pmol insulin.kg-1.min-1 in patients and 36.25 +/- 15.46 pmol insulin.kg-1.min-1 in control subjects (P = 0.38). Throughout the experiment, increments in ISR were comparable in both groups. The amount of insulin secreted in response to arginine (0-5 min) was similar in patients and control subjects: 81 +/- 28 vs. 119 +/- 55 pmol/kg (P = 0.16), respectively. The arginine test C-peptide response was not correlated with the IVGTT or hyperglycemic clamp responses. The arginine test and hyperglycemic clamp responses were not correlated to the glucose tolerance status. The best predictor of the glucose tolerance was the C-peptide response to the IVGTT (r2 = 0.78; P = 0.002).. beta-cell secretory increment in response to arginine was found to be in the normal range in GCK-deficient subjects. The arginine test does not seem to reflect either the beta-cell secretory defect or the glucose tolerance status of these subjects. IVGTT seems to be the best predictor of the latter parameter in this population.

Topics: Adolescent; Adult; Arginine; C-Peptide; Dose-Response Relationship, Drug; Female; Glucokinase; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Islets of Langerhans; Male; Middle Aged; Radioimmunoassay; Regression Analysis

Glucose intolerance and diabetes mellitus are both prevalent in cirrhosis, yet the pathogenesis of impaired glucose metabolism remains unknown. Therefore insulin secretion (hyperglycemic clamp, +125 mg/dl), insulin sensitivity (euglycemic hyperinsulinemic insulin clamp, +10 microU/ml and +50 microU/ml), whole-body glucose oxidation (indirect calorimetry) and glucose turnover ([6,6-2H2]glucose isotope dilution) were evaluated in a homogenous group of cirrhotic patients with glucose intolerance (n = 7) or frank diabetes mellitus (n = 6). The results were compared with those obtained in control subjects (n = 8). In glucose-intolerant patients, whole-body glucose uptake (mainly reflecting glucose utilization by muscle) was significantly impaired in patients during both insulin infusions as a result of decreased stimulation of the two major intracellular pathways of glucose disposal--nonoxidative glucose disposal (i.e., glycogen synthesis) and glucose oxidation. Hepatic glucose production was normal in the basal state and was normally suppressed during stepwise insulin infusion (by 65% and 85%, respectively, p = NS vs. controls). Hyperglycemia-induced increases of plasma C-peptide concentrations were comparable to those in controls (p = NS). In diabetic patients, insulin-mediated glucose uptake was significantly reduced, mainly because of impaired non-oxidative glucose disposal. Glucose oxidation appeared to be reduced, too. Hepatic glucose production was significantly increased in the basal state (3.03 +/- 0.24 vs. 2.34 +/- 0.10 mg/kg min, p < 0.02) and during insulin infusion (+50 microU/ml: 0.67 +/- 0.17 vs. 0.13 +/- 0.08 mg/kg min, p < 0.05) compared with that in controls. Both the first and second phases of beta-cell secretion were significantly reduced in response to steady-state hyperglycemia (both p < 0.01 vs. control values). In conclusion, glucose intolerance in cirrhosis results from two abnormalities that occur simultaneously: (a) insulin resistance of muscle and (b) an inadequate response (even when comparable to that of controls) of the beta-cells to appropriately secrete insulin to overcome the defect in insulin action. Diabetes mellitus in insulin-resistant cirrhotic patients develops as the result of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycemia and a diabetic glucose tolerance profile.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Insulin; Lactates; Lactic Acid; Liver Cirrhosis; Male; Middle Aged; Reference Values

Pancreatic beta-cell function was studied in six subjects with mutations in the enzyme glucokinase (GCK) who were found to have elevated fasting and postprandial glucose levels in comparison to six normoglycemic controls. Insulin secretion rates (ISRs) were estimated by deconvolution of peripheral C-peptide values using a two-compartment model and individual C-peptide kinetics obtained after bolus intravenous injections of biosynthetic human C-peptide. First-phase insulin secretory responses to intravenous glucose and insulin secretion rates over a 24-h period on a weight maintenance diet were not different in subjects with GCK mutations and controls. However, the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations and average ISRs over a glucose range between 5 and 9 mM were 61% lower than those in controls. In the controls, the beta cell was most sensitive to an increase in glucose at concentrations between 5.5 and 6.0 mM, whereas in the patients with GCK mutations the point of maximal responsiveness was increased to between 6.5 and 7.5 mM. Even mutations that resulted in mild impairment of in vitro enzyme activity were associated with a > 50% reduction in ISR. The responsiveness of the beta cell to glucose was increased by 45% in the subjects with mutations after a 42-h intravenous glucose infusion at a rate of 4-6 mg/kg per min. During oscillatory glucose infusion with a period of 144 min, profiles from the subjects with mutations revealed reduced spectral power at 144 min for glucose and ISR compared with controls, indicating decreased ability to entrain the beta cell with exogenous glucose. In conclusion, subjects with mutations in GCK demonstrate decreased responsiveness of the beta cell to glucose manifest by a shift in the glucose ISR dose-response curve to the right and reduced ability to entrain the ultradian oscillations of insulin secretion with exogenous glucose. These results support a key role for the enzyme GCK in determining the in vivo glucose/ISR dose-response relationships and define the alterations in beta-cell responsiveness that occur in subjects with GCK mutations.

Topics: Adolescent; Adult; C-Peptide; Female; Glucokinase; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Mutation

Octreotide is a recently available, FDA-approved, long-acting analog of somatostatin. The efficacy and tolerability of octreotide were evaluated in a series of protocols in healthy volunteers to assess its suitability for use in clinical investigations involving short-term inhibition of endogenous hormone secretion. Prolonged (270 minutes) hyperglycemic clamps were used to assess octreotide-mediated suppression of glucose-stimulated endogenous insulin secretion. Compared with a saline-control infusion, octreotide (30 ng/kg/min) suppressed stimulated insulin (P < .0001) and C-peptide (P < .0001) concentrations to basal levels. During insulin-induced hypoglycemia (plasma glucose < 40 mg/dL), octreotide (30 ng/kg/min) effectively suppressed the secretion of glucagon (P < .05) and growth hormone (P < .0005). In islet cell clamp studies, octreotide (30 ng/kg/min) suppressed C-peptide (P < .001), glucagon (P < .01), and growth hormone concentrations to below basal (fasting) levels in all subjects. Subsequent infusion of exogenous insulin, glucagon, and growth hormone resulted in predictable and stable concentrations of each hormone during octreotide-mediated suppression of their endogenous secretion. Consistent with the long half-life of octreotide (approximately 90 minutes), the concentrations of all three hormones remained suppressed below basal levels throughout a 60-minute observation period following the termination of octreotide infusion. In separate high-dose octreotide infusion studies, octreotide (60 ng/kg/min) did not produce any apparent additional metabolic effects, but was associated with an unacceptable degree of gastrointestinal side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Female; Glucagon; Growth Hormone; Humans; Hyperglycemia; Hypoglycemia; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Octreotide; Radioimmunoassay; Time Factors

To examine whether hyperglycemia is an independent regulator of adipose tissue lipolysis, we measured palmitate flux ([3H]palmitate) on two occasions in eight volunteers with insulin-dependent diabetes. On one. occasion, euglycemia was maintained for 4 h continuously; on a different occasion, hyperglycemia (plasma glucose, 12 mmol/l) was induced after 2 h of euglycemia. Palmitate flux decreased from 1.39 +/- 0.22 to 1.25 +/- 0.18 mumol.kg-1 x min-1 during sustained euglycemia and from 1.43 +/- 0.24 to 1.13 +/- 0.19 mumol.kg-1 x min-1 during the transition from the euglycemic to the hyperglycemic study intervals. There were no significant differences between the changes in palmitate flux from the first to the second study interval on the control (euglycemia-euglycemia) and experimental (euglycemia-hyperglycemia) study days and no difference between palmitate flux on different study days. Thus, in the face of euinsulinemia, euglucagonemia, and the absence of somatostatin, no effect of hyperglycemia on free fatty acid metabolism could be detected in humans.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Glucose Clamp Technique; Growth Hormone; Humans; Hyperglycemia; Insulin; Lipolysis; Male; Palmitic Acid; Palmitic Acids; Radioimmunoassay; Time Factors

Insulin resistance is present in patients suffering from lipoatrophic syndromes long before the onset of diabetes mellitus. Thus, the decreased peripheral glucose disposal may not be the only mechanism of hyperglycaemia. The kinetic parameters of glucose homeostasis were evaluated in six young females aged 15, 16, 18, 19 and 24 years with generalized lipoatrophy; one patient was studied both at 12 and 15 years. Insulin resistance was evaluated in vivo by the hyperinsulinaemic euglycaemic clamp (3-4 insulin infusion rates from 1 to 100 mU/kg.min). All patients showed a rightward shift of the dose-response curve, indicating decreased insulin sensitivity. In two patients, maximal glucose disposal was moderately decreased, while in five patients it was dramatically reduced (3.6-6.9 mg/kg.min). Fasting plasma glucose was variable (4.3-18.3 mmol/l) and did not correlate with peripheral glucose disposal rates. Hepatic glucose production, measured by infusion of [6,6-2H] glucose, varied from 1.7 to 8.3 mg/kg.min and was significantly correlated with fasting plasma glucose. The overproduction of glucose despite basal hyperinsulinism suggested hepatic insulin resistance, which was confirmed by the abnormal response to constant unlabelled glucose infusion (2 mg/kg.min) in five patients. In conclusion, impaired glucose tolerance seems to develop in generalized lipoatrophy with aggravated peripheral insulin resistance. The present data show that fasting hyperglycaemia is mainly the consequence of increased hepatic glucose production.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Child; Cholesterol; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipodystrophy; Syndrome; Triglycerides

The effects of an exhaustive bout of eccentric exercise on insulin secretion and action were determined using the hyperglycemic clamp technique. Clamps were performed on eight healthy men after 7 days of inactivity and approximately 36 h after a bout of eccentric exercise. Eccentric exercise consisted of 10 sets of 10 repetitions of combined knee extensions and flexions for each leg at a mean torque 84 +/- 5% of peak concentric torque. During the hyperglycemic clamp procedure, plasma glucose concentration was acutely raised to 10 mmol/l and was maintained near this level for 120 min. Arterialized blood samples were obtained from a heated hand vein to determine plasma glucose and insulin concentrations. Eccentric exercise appeared to produce marked muscle damage, as indicated by a 50-fold increase in plasma creatine phosphokinase (100 +/- 17 vs. 5,209 +/- 3,811 U/l, P < 0.001) and subjective reports of muscle soreness. Peak insulin response during the early phase (0-10 min) of the hyperglycemic clamp was higher after eccentric exercise (183 +/- 38 microU/ml) than after the control clamp (100 +/- 23 microU/ml, P < 0.005). Late-phase (10- to 120-min) insulin response was not altered after eccentric exercise. Peak plasma C-peptide concentrations were higher during the early phase (5.0 +/- 0.7 vs. 4.3 +/- 0.8 ng/ml, P < 0.05) and the late phase (7.5 +/- 0.9 vs. 5.4 +/- 0.6 ng/ml, P < 0.05). Prior eccentric exercise had no significant effect on whole body glucose disposal or glucose disposal rate adjusted for prevailing plasma insulin concentration. These data provide evidence that a single bout of eccentric exercise causes an increase in pancreatic beta-cell insulin secretion in response to hyperglycemia.

Topics: Adult; Blood Glucose; Body Composition; C-Peptide; Creatine Kinase; Diet; Exercise; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Muscles; Oxygen Consumption; Running

To determine whether hyperglycemia in brain-dead donors is a sign of endocrine pancreas insufficiency, we studied pancreatic function in 25 consecutive brain dead patients. Blood samples were drawn at 2-hr intervals from donor referral until organ procurement to analyze glucose, insulin, and C-peptide levels. After donor retrieval, two specimens were taken from the pancreas for a subsequent immunohistochemical examination. At referral mean glycemia was 13.60 +/- 1.49 mmol/L, and there was a large range of plasma glucose levels (4.6-31.6). Of 25 patients, 16 had glycemia above 10 mmol/L. At organ procurement a mean of 20 hr later, mean glycemia as 8.61 +/- 0.58 mmol/L (P < 0.005 with paired t test), and only 5 patients had glycemia above 10 mmol/L. Hyperglycemia was associated with elevated insulin and C-peptide levels during donor management. An elevated C-peptide/glucose molar ratio might be considered a sign of peripheral insulin resistance. Hyperglycemia above 25 mmol/L could not be related to the amount of glucose administered during donor maintenance. Severe hyperglycemia had a natural tendency to be partly corrected. Histologic and immunohistochemical examinations were available in 17 cases and can be considered normal. It is concluded that endocrine pancreatic function can be considered effective after brain death. The mechanism of the relative insulin resistance of these patients requires further study. Blood glucose levels, in the range observed in this study, are not a good donor criterion of endocrine pancreatic function before pancreas transplantation.

Topics: Adolescent; Adult; Blood Glucose; Brain Death; C-Peptide; Child; Dopamine; Female; Hormones; Humans; Hyperglycemia; Immunohistochemistry; Islets of Langerhans; Male; Prospective Studies; Time Factors; Tissue Donors

Conventional immunoassays to quantify insulin concentration do not differentiate between insulin and proinsulin. Thus, previous conclusions as to the relationship between the development of hyperglycemia in patients with noninsulin-dependent diabetes mellitus (NIDDM) and pancreatic insulin secretory function may have been confounded by not being able to determine the contribution made by plasma proinsulin to the putative measurements of plasma insulin concentration in these patients. The current study was initiated to address this issue by making specific measurements of plasma insulin, proinsulin, and C-peptide concentrations in 42 individuals: 14 with normal glucose tolerance, 12 with impaired glucose tolerance (IGT), and 16 with NIDDM. The study population was further subdivided into a nonobese (body mass index, < 30 kg/m2) and an obese (body mass index, > 30 kg/m2) group. Mixed meals were given at 0800, 1200, and 1800 h, and blood was removed at 0800 h (before the meal) and at hourly intervals from then until 1600 h. Plasma glucose concentrations throughout the sampling period were slightly, but significantly (P < 0.01), greater in patients with IGT than in normal individuals. Patients with NIDDM had markedly elevated glycemic excursions, greater than either of the other two groups (P < 0.002). Both plasma immunoreactive insulin and C-peptide concentrations from 0800-1600 h were higher (P < 0.002-0.001) in patients with either IGT or NIDDM than in the group with normal glucose tolerance. Although day-long plasma immunoreactive insulin and C-peptide concentrations were higher, on the average, in patients with IGT compared to those with NIDDM, the difference was not statistically significant. Plasma proinsulin concentrations were highest in patients with NIDDM (P < 0.002), lower in those with normal glucose tolerance (P < 0.002), and intermediate in patients with IGT. When the calculated "true" insulin concentration was determined by taking the proinsulin content into consideration, patients with IGT had the highest day-long levels, with the lowest values found in the control population (P < 0.002). Although absolute values varied as a function of obesity, the generalizations outlined above were found in both weight groups. These results show that ambient plasma proinsulin concentrations increase as glucose tolerance declines. However, true plasma insulin concentrations in response to mixed meals remain highest in patients with IGT, lowest in normal ind

Topics: Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Obesity; Proinsulin; Reference Values

The effect of human recombinant insulin-like growth factor I (rhIGF-1) on glucose stimulated insulin secretion was studied in 14 healthy human volunteers. Each subject received a primed-continuous infusion of rhIGF-1 (20 micrograms kg prime, 0.4 micrograms kg-1 min-1) or saline while plasma glucose was raised +2.8 mmol/l (+50 mg/dl) (n = 6) or +7.0 mmol/l (+125 mg/dl) (n = 8) above baseline for 2 h using the hyperglycemic clamp technique. Total IGF-1 levels during the IGF-1 studies increased from 196 +/- 37 to 449 +/- 71 ng/ml. At the +2.8 mmol/l (+50 mg/dl) stimulus, first and second phase C-peptide levels were suppressed during IGF-1 infusion vs control (885 +/- 157 vs 544 +/- 99 pmol/l, p < 0.05 and 1379 +/- 246 vs 832 +/- 130 pmol/l, p < 0.05, respectively), whereas insulin levels were suppressed during the second phase only (215 +/- 43 vs 151 +/- 28 pmol/l, p < 0.05). Despite this, the rate of glucose metabolism was two-fold higher in the IGF-1 infused group (8.0 +/- 0.5 vs 3.5 +/- 0.1 mg kg-1 min-1, p < 0.01). At the higher glucose stimulus +7.0 mmol/l (+125 mg/dl) only second phase C-peptide levels were significantly reduced (1922 +/- 251 vs 1466 +/- 74 pmol/l, p < 0.05). Again, rates of glucose metabolism were higher during IGF-1 infusion (11.8 +/- 1.2 vs 8.9 +/- 0.8 mg kg-1 min-1, p < 0.01). These data suggest that rhIGF-1 inhibits glucose-stimulated insulin secretion in humans, but that this inhibitory effect is partially overcome by increasing the hyperglycemic stimulus. Moreover, despite the decrease in insulin secretion, glucose disposal is accelerated by rhIGF-1.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Female; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Antagonists; Insulin Secretion; Insulin-Like Growth Factor I; Male; Recombinant Proteins; Reference Values

The association of blood pressure with clinical and biochemical measures was studied in 185 newly diagnosed Type 2 diabetic patients, 74 impaired-glucose-tolerant (IGT) and 128 non-diabetic control subjects. Hyperglycaemic subjects were older than control subjects (controls 40 (24-59) years, IGT 48 (29-64) years, diabetic 43 (29-60) years, median (5th-95th centile) both p < 0.05). They were also more obese (body mass index (BMI) controls 23.5 kg m-2 (17.2-29.9), IGT 26.0 kg m-2 (19.8-33.9), diabetic 24.2 kg m-2 (19.3-32.2)) and with a greater waist-hip ratio (controls 0.83 (0.70-0.98), IGT 0.88 (0.75-0.98), diabetic 0.89 (0.75-1.00)). Blood pressure was significantly higher in both IGT (systolic 127 mmHg (108-162), diastolic 84 mmHg (66-99)) and diabetic patients (systolic 130 mmHg (104-160), diastolic 84 mmHg (66-102)) compared to non-diabetic controls (systolic 120 mmHg (100-151), diastolic 80 mmHg (60-94)). Univariate analysis showed that in diabetic patients systolic blood pressure was related to age (r = 0.17, p < 0.05), BMI (r = 0.23, p < 0.01) and plasma immunoreactive insulin (fasting and post glucose, r = approximately 0.25, p < 0.01) but not to C-peptide concentrations; diastolic blood pressure to BMI (r = 0.35, p < 0.001), waist-hip ratio (r = 0.23, p < 0.01) and plasma immunoreactive insulin (fasting r = 0.30, p < 0.001, post glucose r = approximately 0.20, p < 0.05) but not to C-peptide concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diastole; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Obesity; Systole

Hypertensive obese subjects with glucose intolerance have hyperinsulinaemia, insulin resistance and intracellular cation imbalance resulting in increased sodium content. The aim of our study was to assess in these patients plasma levels of endogenous digoxin-like factor (EDLF), an inhibitor of the sodium-pump mechanism. We studied 14 hypertensive and 12 normotensive subjects with obesity and glucose intolerance for fasting blood glucose, and plasma insulin, C-peptide and EDLF levels: the two groups were matched for age and BMI and were studied after a 2-week wash-out period from hypotensive drugs. Compared with normotensives, hypertensive subjects had higher plasma insulin levels, a greater immunoreactive insulin/C-peptide ratio, a lower glucose/insulin ratio and higher plasma EDLF levels. Our results confirm that among obese people with glucose intolerance, hypertensives are more hyperinsulinaemic and insulin-resistant than normotensives and indicate that the intracellular cation imbalance in these patients may be attributable, at least in part, to EDLF.

Topics: Blood Glucose; Blood Proteins; C-Peptide; Cardenolides; Digoxin; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase

In order to better understand the mechanisms responsible for the diminished glucose tolerance that occurs in the elderly, the present study aimed at investigating the effect of mild hyperglycaemia on glucose production and uptake in a group of aged subjects. For comparison, a group of young subjects was simultaneously investigated.. Seven aged (71.8 +/- 2.3 yrs) and seven young (25.5 +/- 1.7 yrs) healthy non-obese subjects underwent two hyperglycaemic glucose-clamps having as targets plasma glucose levels 7.5 and 10.0 mmol/L. Contemporary infusion of D-[3-3H]-glucose allowed determination of glucose turnover parameters in basal conditions and during the clamps. Endogenous pancreatic secretion was inhibited by somatostatin (8.3 micrograms/min) while glucagon (67 ng/min) and insulin (0.15 mU/kg/min) were replaced by exogenous infusions.. In basal conditions, glucose uptake (12.9 +/- 0.5 vs 14.4 +/- 0.4 mumol/kg/min; p < 0.05) and glucose metabolic clearance rate (2.58 +/- 0.15 vs 3.35 +/- 0.10 ml/kg/min; p < 0.01) were lower in elderly vs young subjects. In the hyperglycaemic glucose-clamps, we observed, in the elderly subjects, the persistence of a greater glucose production during mild (7.5 mmol/L) (11.6 +/- 0.4 vs 9.7 +/- 0.2 mumol/kg/min; p < 0.005) but not moderate (10 mmol/L) (3.5 +/- 0.1 vs 3.4 +/- 0.1 mumol/kg/min; NS) hyperglycaemia. In contrast, glucose-induced glucose uptake and glucose metabolic clearance rate were similarly affected by glucose infusions in both groups of subjects. Moreover, in elderly but not in young subjects, basal glucose disappearance rate was significantly negatively correlated with fasting plasma glucose levels (r = -0.84; p < 0.01).. In the basal state, glucose uptake and glucose metabolic clearance rate are slightly impaired in elderly, compared to young subjects. Furthermore, in the elderly, endogenous glucose production is less suppressed by mild hyperglycaemia i.e. 7.5 mmol/L, than it is in young people. Such impairment in the inhibition of endogenous glucose production is not seen when blood glucose attains 10 mmol/L. We suggest that impairment in glucose tolerance in the elderly results from both reduced glucose uptake (in basal conditions) and excessive glucose production (at mild hyperglycaemic levels).

Topics: Adult; Age Factors; Aged; Blood Glucose; C-Peptide; Glucagon; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Metabolic Clearance Rate; Severity of Illness Index; Time Factors

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Homeostasis; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Kidney; Mice; Mice, Nude; Tacrolimus; Transplantation, Heterologous; Transplantation, Heterotopic

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol; Fatty Liver; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Middle Aged; Triglycerides; Ultrasonography

NIDDM patients with overt fasting hyperglycemia are characterized by multiple defects involving both insulin secretion and insulin action. At this point of the natural history of NIDDM, however, it is difficult to establish which defects are primary and which are acquired secondary to insulinopenia and chronic hyperglycemia. To address this question, we have studied the glucose-tolerant offspring (probands) of two Mexican-American NIDDM parents. Such individuals are at high risk for developing NIDDM later in life. The probands are characterized by hyperinsulinemia in the fasting state and in response to both oral and intravenous glucose. Insulin-mediated glucose disposal (insulin clamp technique), measured at two physiological levels of hyperinsulinemia (approximately 240 and 450 pM [approximately 40 and 75 microU/ml]), was reduced by 43 and 33%, respectively. During both the low- and high-dose insulin clamp steps, impaired nonoxidative glucose disposal, which primarily represents glycogen synthesis, was the major defect responsible for the insulin resistance. During the lower dose insulin clamp step only, a small decrease in glucose oxidation was observed. No defect in suppression of HGP by insulin was demonstrable. The ability of insulin to inhibit lipid oxidation (measured by indirect calorimetry) and plasma FFA concentration was impaired at both levels of hyperinsulinemia. These results indicate that the glucose-tolerant offspring of two NIDDM parents are characterized by hyperinsulinemia and manifest all of the metabolic abnormalities that characterize the fully established diabetic state, including insulin resistance, a major impairment in nonoxidative glucose disposal, a quantitatively less important defect in glucose oxidation, and a diminished insulin-mediated suppression of lipid oxidation and plasma FFA concentration.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Lipid Metabolism; Male; Mexico; Reference Values; Texas

To study effects of high carbohydrate intake on hyperglycemia, islet functions, and plasma lipoproteins in patients with NIDDM.. An attempt was made to induce hyperglycemia in 10 men with NIDDM by feeding them an isocaloric high-carbohydrate diet (65% of energy as simple carbohydrates [31% as glucose] and 20% as fat) for 28 days in a metabolic ward. Response to the high-carbohydrate diet was compared with that of feeding a diet rich in monounsaturated fat (45% of energy as fat [31% as monounsaturated fat] and 38% as carbohydrates) for 28 days in a cross-over manner. Islet functions were assessed by evaluating plasma glucose, insulin, C-peptide and glucagon responses to standard meal tolerance tests on days 0, 14, 21, and 28 of each dietary period. Fasting plasma lipoproteins were determined during the last week of each dietary period.. The high-carbohydrate diet caused significant but modest accentuation of hyperglycemia, particularly in patients with moderately severe diabetes mellitus, whereas no change was observed with the high-monounsaturated fatty-acid diet. Accentuation of hyperglycemia was accompanied by an increase in plasma glucagon levels, but no significant change in insulin and C-peptide responses. In 1 patient, feeding the high-carbohydrate diet for 68 days produced marked hyperglycemia and caused definite suppression of insulin and C-peptide responses along with an increase in glucagon levels. Compared with the high-monounsaturated fat diet, the high-carbohydrate diet also raised plasma triglyceride and VLDL cholesterol concentrations.. High-carbohydrate diets may cause accentuation of hyperglycemia and a rise in plasma glucagon levels in NIDDM patients. High-carbohydrate diets also adversely affect lipoproteins and therefore may not be desirable in all NIDDM patients.

Topics: Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Fatty Acids, Monounsaturated; Glucagon; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Lipoproteins; Male; Middle Aged; Triglycerides

Dietary constituents other than glucose can influence insulin secretion in non-insulin-dependent diabetes mellitus and administration of a standard mixed meal has been proposed as a more physiological test in regard to human diet for evaluating the patient both at the time of diagnosis and during follow-up. This study was carried out to compare the effects of a standard meal and the oral glucose tolerance test on glucose, insulin and C-peptide plasma levels in four groups of subjects: healthy controls, subjects with impaired glucose tolerance, patients with mild non-insulin-dependent diabetes, and non-insulin-dependent diabetic patients with secondary failure to oral agents. Plasma glucose values were significantly higher after the oral glucose tolerance test than after the mixed meal in all four groups of subjects. Plasma insulin and C-peptide values were similar during the two tests in all groups of subjects except in non-insulin-dependent diabetics with secondary failure (flattened curves). Insulin and C-peptide responses per unit rise in blood glucose were significantly higher after the oral glucose tolerance test than after the mixed meal both in mild non-insulin-dependent diabetics (P less than 0.05 and P less than 0.05) and in non-insulin-dependent diabetics in secondary failure (P less than 0.01 and P less than 0.05). There was significant correlation between oral glucose tolerance test and mixed meal glucose incremental areas (r = 0.511, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Reference Values; Time Factors

Insulin resistance and a defective insulin activation of the enzyme glycogen synthase in skeletal muscle during euglycaemia may have important pathophysiological implications in Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia may serve to compensate for these defects in Type 2 diabetes by increasing glucose disposal through a mass action effect. In the present study, rates of whole-body glucose oxidation and glucose storage were measured during fasting hyperglycaemia and isoglycaemic insulin infusion (40 mU.m-2.min-1, 3 h) in 12 patients with Type 2 diabetes. Eleven control subjects were studied during euglycaemia. Biopsies were taken from the vastus lateralis muscle. Fasting and insulin-stimulated glucose oxidation, glucose storage and muscle glycogen synthase activation were all fully compensated (normalized) during hyperglycaemia in the diabetic patients. The insulin-stimulated increase in muscle glycogen content was the same in the diabetic patients and in the control subjects. Besides hyperglycaemia, the diabetic patients had elevated muscle free glucose and glucose 6-phosphate concentrations. A positive correlation was demonstrated between intracellular free glucose concentration and muscle glycogen synthase fractional velocity insulin activation (0.1 mmol/l glucose 6-phosphate: r = 0.65, p less than 0.02 and 0.0 mmol/l glucose 6-phosphate: r = 0.91, p less than 0.0001). In conclusion, this study indicates an important role for hyperglycaemia and elevated muscle free glucose and glucose 6-phosphate concentrations in compensating (normalizing) intracellular glucose metabolism and skeletal muscle glycogen synthase activation in Type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Calorimetry; Diabetes Mellitus, Type 2; Enzyme Activation; Fasting; Female; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Muscles; Reference Values

It is well known that intensive insulin treatment of non-insulin-dependent diabetics (NIDDM) suppresses endogenous insulin secretion and thereafter improves it. To determine whether 'peripheral normo-insulinemia' or 'normoglycemia' established by the treatment is responsible for this suppression, the following five experiments were conducted on 15 well-controlled non-obese NIDDM patients. Experiment 1: a 100 g oral glucose load (OGL) was performed and blood glucose was monitored by an artificial endocrine pancreas (AP). Experiment 2: a 100 g OGL was done and blood glucose was normalized by AP-controlled insulin infusion. Experiments 3 and 4: a 100 g OGL was conducted while 'hyperglycemia' seen in experiment 1 was mimicked by AP-controlled glucose infusion with pre-programmed insulin infusion at the same rates as those in experiment 2 ('normoinsulinemia') or at rates 1.5 times higher than those in experiment 2 ('relative hyperinsulinemia'), respectively. Experiment 5: a 40 g OGL was conducted while AP-controlled insulin and glucose infusions were administered to make the plasma insulin level lower than in experiment 2 ('hypoinsulinemia') and to mimic the normoglycemic profile observed in experiment 2, respectively. In experiments 3 and 4, neither 'normoinsulinemia' nor 'relative hyperinsulinemia' suppressed the increase in plasma C-peptide after a 100 g OGL. In experiment 5, where the plasma insulin level showed a significantly (P less than 0.05) lower level than in experiment 2 and glycemia was normalized, C-peptide did not show a significant rise after OGL. These results indicate that 'normoglycemia' rather than 'normoinsulinemia' attained during exogenous insulin therapy, is responsible for suppressing endogenous insulin secretion against orally administered glucose.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Infusion Systems; Insulin Secretion; Male; Middle Aged

The purpose of this study was to gain insight into the mechanisms responsible for encainide-induced diabetes. Specifically, we sought to determine if absolute insulinopenia was present or whether encainide-induced diabetes was metabolically more like type II than type I diabetes.. Islet function was assessed in a 65 year old white male with encainide-induced diabetes. After 6 months of encainide treatment and 2 months duration of diabetes, C-peptide, glucagon, and glucose levels were measured at baseline and at 30 minute intervals for 120 minutes following an oral mixed meal. These measurements allowed assessment of islet beta and alpha cell function in comparison to control data from our laboratory.. In this patient with encainide-induced diabetes, basal and peak C-peptide concentrations were similar to controls although peak C-peptide occurred substantially later than in controls. At peak glucose, the patient's C-peptide/glucose ratio was low indicating relative (but not absolute) insulinopenia. At baseline, glucagon was relatively depressed. Following Sustacal, there was an increase in glucagon of 100% over baseline compared to a mean glucagon rise in controls of only 8%. There was no serological evidence for autoimmune diabetes as islet cell autoantibodies were absent.. Similar to other forms of diabetes, encainide-induced diabetes is a bihormonal disorder. The metabolic pattern was more like type II than type I diabetes with C-peptide secretion in the normal range, yet persistent hyperglycemia that suggests relative insulinopenia and concurrent insulin resistance.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet; Encainide; Glucagon; Humans; Hyperglycemia; Insulin Resistance; Islets of Langerhans; Male

To determine whether glucose transport or intracellular glucose metabolism is rate-limiting for in vivo glucose uptake, rates of glucose disposal were measured in a group of normal subjects at varying levels of hyperglycemia designed to attain saturating rates of glucose disposal at low and high physiological insulin concentrations. At insulin levels of approximately 200 pmol/L, glucose disposal rates were 2.9 +/- 0.4, 4.7 +/- 0.5, 6.4 +/- 0.6, and 6.5 +/- 0.8 mg/kg/min at plasma glucose concentrations of 5.55, 11.10, 13.88, and 19.43 mmol/L (or 100, 200, 250, and 350 mg/dL, respectively). At insulin levels of approximately 750 pmol/L, glucose disposal rates were 1.7 to 2.1-fold higher: 6.2 +/- 0.7, 9.2 +/- 1.1, 11.0 +/- 1.1, and 12.3 +/- 1.4 mg/kg/min at glucose levels of 5.55, 11.10, 13.88, and 19.43 mmol/L. Thus, during both the 15- and 40-mU/m2/min insulin infusions, glucose disposal increased in a linear fashion from 5.55 to 13.88 mmol/L (r = .90) and then effectively plateaued at the same plasma glucose level. If the plateau of glucose disposal during the 40-mU/m2/min insulin infusion was due to saturation of the intracellular capacity to metabolize glucose, then when plasma glucose was increased from 13.88 to 19.43 mmol/L at the lower insulin level, the glucose disposal should have continued to increase and not plateau, since the rate of glucose disposal was only approximately 50% of that attained at the higher insulin infusion rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biological Transport; Blood Glucose; C-Peptide; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Male; Middle Aged

Topics: Anthropometry; Blood Glucose; Body Height; Body Mass Index; C-Peptide; Cholesterol; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Middle Aged; Reference Values; Triglycerides

The long-acting effect of a 10-min pulse infusion of the beta 2-adrenergic agonist fenoterol on oral glucose tolerance tests in controls and in normotensive patients with type 2 diabetes mellitus on diet was compared. During an oral glucose load starting 2 h after fenoterol control persons showed hyperglycemia (area: 25,950 +/- 467 vs. 22,650 +/- 410, P less than 0.01), hyperinsulinemia (area: 13,980 +/- 1050 vs. 8160 +/- 405, P less than 0.02) and a pronounced fall of serum potassium (area: 775 +/- 26 vs. 748 +/- 25, P less than 0.02). The patient group showed no late response to fenoterol: plasma glucose (area: 51,000 +/- 382 vs. 51,300 +/- 413, n.s.), serum insulin (area: 7215 +/- 233 vs. 8280 +/- 410, n.s.), serum potassium (area: 748 +/- 26 vs. 750 +/- 24, n.s.). The data show that there is a defect of the beta 2-adrenergic long-acting effect on glucose metabolism and on insulin release in type 2 diabetes mellitus.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Fenoterol; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Potassium; Receptors, Adrenergic, beta; Time Factors

The variation of urinary C-peptide clearance in relation to hyperglycemia and renal damage was evaluated in 57 patients with non-insulin-dependent diabetes mellitus (NIDDM) with and without overt proteinuria, 14 nondiabetic patients with renal disease (RD) and 18 healthy control subjects. Urinary C-peptide clearance expressed as the ratio of urinary C-peptide to creatinine clearance (CCP/CCR) in the fasting state did not differ in control subjects and RD patients, and was higher equally in NIDDM patients with and without proteinuria. In NIDDM patients without overt proteinuria, urinary levels of C-peptide, beta 2-microglobulin (B2M), N-acetyl-beta-D-glucosaminidase (NAG) and albumin as well as CCP/CCR ratio all decreased significantly with short-term glycemic control (P less than 0.05). Despite a wide range of CCP/CCR ratio (0.07-0.73), a weak but significant correlation (r = 0.56, P less than 0.005) was found between fasting serum and urinary C-peptide levels in NIDDM patients. These results suggest that urinary C-peptide may easily be affected by hyperglycemia per se rather than renal damage, while urinary B2M, NAG and albumin may be affected by both hyperglycemia and renal damage. When the urinary C-peptide level is interpreted, the influence of hyperglycemia on it must be taken into consideration.

Topics: Acetylglucosaminidase; beta 2-Microglobulin; Biomarkers; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hyperglycemia; Kidney Diseases; Male; Middle Aged; Proteinuria; Reference Values

Release of immature secretory granules rich in incompletely processed proinsulin has been proposed to explain the relative hyperproinsulinemia in type 2 diabetic and insulinoma patients because of a constant secretory drive resulting from hyperglycemia and autonomous secretion, respectively. To test this hypothesis, insulin secretion was stimulated by a combination of hyperglycemia (11 mmol/L clamp), intravenous (i.v.) tolbutamide (1 g), and i.v. glucagon (initial bolus 10 micrograms/kg body weight, maintenance infusion 2 micrograms/kg body weight per hour) for 3 h. Circulating IR-insulin and IR-C-peptide concentrations increased 89-fold and 14-fold over basal values, respectively, but IR-proinsulin concentrations increased only ninefold over basal values. Estimation of the amount of insulin secreted (based on deconvolution analysis of plasma C-peptide values) showed that approximately 76 +/- 21 U were secreted during the stimulation period. This amount is a significant proportion of pancreatic insulin content in normal humans. In molar terms, IR-proinsulin (integrated incremental response multiplied by metabolic clearance rate of proinsulin) relative to IR-C-peptide (= insulin) secretion (deconvolution analysis) was estimated to be equal or even lower than the known proportion in islets (0.22 +/- 0.05%). Thus, using a near-maximal stimulation of insulin secretion maintained long enough to cause release of amounts of insulin approaching the estimated pancreatic content, no preferential release of proinsulin was observed in normal humans. Therefore, the hyperproinsulinemia of type 2 diabetes and in insulinoma patients may be caused by additional defects in the proinsulin to insulin conversion process.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Proinsulin; Tolbutamide

In NIDDM patients the deficient initial rise in insulin is a consistent finding. This early phase of insulin secretion influences the degree of hyperglycaemia following a meal. In this study insulin was infused intravenously into newly diagnosed NIDDM patients in an attempt to mimic the non-diabetic insulin response to a mixed meal and to determine the effect of early insulin availability on post-prandial glucose, C-peptide and insulin concentrations in NIDDM patients. The study involved standardized meal tolerance tests (MTT) with and without insulin on 2 separate days, 1 week apart. Insulin was given by intravenous infusion (2.5 U Actrapid over 30 min) immediately following the start of a 500 kcal MTT. The subjects were divided into non-obese and obese sub-groups with 8 subjects in each group (BMI 24.0 vs 32.0 kg/m2, HbA1, 12.7 vs 9.8%, age 44.4 vs 43.0 yrs, respectively). Following intravenous insulin in non-obese diabetics a peak plasma insulin concentration of 0.393 pmol/ml was observed at 15 min compared to 0.148 pmol/ml at 90 min without exogenous insulin. The post-prandial glucose excursion between 60 and 120 min was significantly lowered with insulin (p less than 0.01). Similarly in the obese patients a higher and earlier insulin peak was achieved with intravenous insulin, with a lower level during the second half of the 4 h post-prandial period, the difference reaching significance at 150 min (p less than 0.05). No differences were observed in the C-peptide concentrations between the 2 study days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Female; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Infusion Systems; Male

The responses of circulating intermediary metabolites to a low-dose sequential insulin infusion (basal, 0.005, 0.01, and 0.05 U kg-1 h-1) were assessed in eight non-obese men with Impaired Glucose Tolerance (IGT), and in eight healthy control subjects with normal glucose tolerance matched for age, gender, and body mass index. Fasting hyperinsulinaemia was observed in the subjects with IGT (7.4 +/- 1.0 vs 2.9 +/- 0.3 mU I-1, p less than 0.001). While there was no significant difference (p greater than 0.1) in fasting venous glucose levels between the groups, fasting concentrations of lactate (p less than 0.02), alanine (p less than 0.01), and glycerol (p less than 0.05) were significantly elevated in the subjects with IGT. During the incremental insulin infusion, overall concentrations of glucose (p less than 0.05), lactate (p less than 0.05), alanine (p less than 0.05), glycerol (p less than 0.05), immunoreactive insulin (p less than 0.001), and C-peptide (p less than 0.01) were significantly higher in the subjects with IGT. Linear dose-response relationships (p less than 0.005) for circulating immunoreactive insulin (log) vs metabolite concentrations were demonstrated by analysis of variance for glucose, non-esterified fatty acids (NEFA), glycerol, and total ketone bodies. For glucose, glycerol, and NEFA, group dose-response regression lines for the subjects with IGT were displaced significantly to the right (p less than 0.001 for each) of those for the normal control subjects, implying insulin insensitivity. In addition to the recognized defect in glucose homeostasis, these results indicate impaired regulation of multiple aspects of intermediary metabolism including lipolysis in IGT.

Topics: Alanine; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Glucose Tolerance Test; Glycerol; Humans; Hyperglycemia; Insulin; Ketone Bodies; Kinetics; Lactates; Male; Middle Aged; Pyruvates; Reference Values

Phenytoin is known to induce hyperglycaemia. The mechanism has generally been considered primarily an inhibition of insulin release. We have recently treated a patient who became hyperglycaemic on phenytoin and whose markedly increased insulin requirements suggested an insulin resistant state. Reduction of the phenytoin dose resulted in amelioration of the hyperglycaemia. In vitro studies of phenytoin in a primary culture system of adipocytes that allowed assessment of both insulin receptor binding and post-binding function showed a 57% reduction in maximum [14C]3-0-methylglucose transport in the presence of phenytoin while having no effect on maximum insulin binding. These results suggest that phenytoin administration can result in insulin insensitivity by inducing a post-binding defect in insulin action.

Topics: Aged; Aged, 80 and over; C-Peptide; Coronary Artery Bypass; Coronary Disease; Epilepsies, Partial; Humans; Hyperglycemia; Insulin; Male; Phenytoin

Pancreatic endocrine function was studied in 50 patients with cystic fibrosis (CF) and 15 healthy controls by measuring glucose, insulin, C-peptide, glucagon and gastro-inhibitory polypeptide responses to an oral glucose tolerance test (OGTT). Biochemical and clinical parameters were also measured, including glycosylated hemoglobin A1, serum immunoreactive trypsin, fasting urinalysis, pulmonary function, percentage body fat and 3-day dietary records. According to National Diabetes Data Group (NDDG) criteria, 6 CF patients had impaired glucose tolerance (ICF), with elevated serum glucose concentrations and reduced and delayed insulin secretion compared with control (CON) subjects, although none were overtly diabetic. Although the remaining 44 CF patients (NCF) did not meet NDDG criteria for impaired glucose tolerance, mean area under the concentration curve (AUC) for glucose was greater than control values and AUC for insulin diminished. HbA1 levels in the 2 CF groups were greater than that of controls subjects, but there was little difference between ICF and NCF groups. C-peptide levels paralleled those of insulin for the 3 groups throughout OGTT. There was little difference in GIP secretion between groups, and the enteroinsular axis was intact in the control and NCF groups and slightly increased in the ICF group. Basal glucagon concentrations and AUC for glucagon during OGTT were similar for the 3 groups, but glucose-induced glucagon suppressibility i.e., basal to nadir change in each subject, was reduced in the ICF group. Serum IRT concentration was significantly lower in the ICF and NCF groups compared to control subjects, and was lowest in the ICF group. A strong correlation was observed in the ICF group between FEF25-75 and AUC for insulin, as well as HbA1 level and AUC for glucose. The prevalence of impaired glucose tolerance in 50 CF patients was 12%. Despite extensive comparisons of biochemical and clinical parameters with endocrine function in this population, we were unable to define reliable criteria for predicting glucose intolerance.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cystic Fibrosis; Eating; Female; Forced Expiratory Flow Rates; Gastric Inhibitory Polypeptide; Glucagon; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Reference Values; Time Factors

Sixteen non-obese non insulin dependent diabetic patients had a 75 g oral glucose tolerance test with simultaneous measurement of intermediary metabolites and of overall energy expenditure by indirect calorimetry during the test. The same patients had a 3H3 glucose infusion and hyperinsulinaemic glucose clamp procedure with glucose held at 10.0 mmol/l and insulin infused at 40 mU/m2/min. The changes in glucose and fat metabolism, in total energy balance and the fall in RQ during the glucose tolerance test did not correlate with the measures of hepatic glucose output or peripheral insulin resistance in these patients. Although the concept of insulin resistance is useful in considering the non insulin dependent diabetic state, the data derived from the body responses to a single glucose load are more relevant to the day to day fluctuation of the internal environment.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Energy Metabolism; Fasting; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glyburide; Humans; Hyperglycemia; Insulin; Ketone Bodies; Liver; Male; Middle Aged

At physiological glucose concentrations, isolated pancreatic islets release a minor portion of their newly synthesized insulin and precursors in a phase of secretion which is largely complete by 4 h of chase. Discharge during this period can be amplified by secretagogues, yet is not abolished by conditions which fully suppress regulated release from dense core secretory granules. The ability to stimulate the secretion and the biochemical profile of released proinsulin-related peptides indicate that secretion during this period originates from immature granules. The stoichiometry of release of labeled C-peptide:insulin during this phase is 1:1 at high glucose concentrations. However, at physiologic or low concentrations, C-peptide is released in molar excess of insulin as if the exocytotic vesicles carrying this secretion were budding from a post-Golgi compartment in which the lumen was composed of condensing insulin and soluble C-peptide. These findings can be explained by a model for regulated secretory protein traffic in which direct exocytosis of young granules is stimulated by higher glucose concentrations and vesicle budding from immature granules occurs at lower concentrations. Thus, insulin targeting from immature granules exhibits both regulated and constitutive-like characteristics.

Topics: Animals; C-Peptide; Cytoplasmic Granules; Glucose; Hyperglycemia; Hypoglycemia; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Precipitin Tests; Rats; Rats, Inbred Strains

Renal disease is a frequent and serious complication of type I glycogen storage disease. A type I glycogen storage disease patient with focal segmental glomerulosclerosis and progressive renal insufficiency underwent a renal allograft transplantation. Despite the same cornstarch therapy, the post-transplantation course was complicated by worsening of the metabolic control manifested by exacerbated lactic acidaemia and hyperlipidaemia. This lactic acidaemia was remarkable for its association with hyperglycaemia. Hyperglycaemia accompanied by lactic acidaemia is strikingly unusual in type I glycogen storage disease, since this is a disease characterized by hypoglycaemia and an inverse relationship between blood glucose concentration and lactate levels. Both fasting insulin and C-peptide levels in the patient were greater than similar age-matched type I glycogen storage disease controls, indicating hyperinsulinaemia. The most likely mechanism responsible for the combined hyperglycaemia and lactic acidaemia was insulin resistance due to glucocorticoid treatment, instituted for immunosuppression. The hyperglycaemia associated with the lactic acidaemia was transient and resolved with steroid tapering. The exacerbated hyperlipidaemia, however, persisted after renal transplantation. Type I glycogen storage disease patients may be prone to glucocorticoid-induced insulin resistance, since the cellular metabolism in these patients may already be compromised with ineffective insulin action and/or reduced insulin output.

Topics: Acidosis, Lactic; Adolescent; Blood Glucose; C-Peptide; Creatinine; Female; Glucocorticoids; Glycogen Storage Disease Type I; Humans; Hyperglycemia; Insulin; Kidney Transplantation

In vitro and in vivo studies have suggested that metabolic deterioration can be induced by hyperglycaemia per se. The effect of 53 h of 2.2 mg glucose.kg ideal body weight-1.min-1 was examined in four normal male subjects. This produced overnight hyperglycaemia of 6.0 mmol/l on the two nights of the study compared with 4.7 mmol/l on the control night (p less than 0.05). In response there was a sustained, two-fold increase in basal plasma insulin (p less than 0.005) and C-peptide (p less than 0.05) levels. After two days of hyperglycaemia an increased Beta-cell response was demonstrated in response to an additional glucose infusion stimulus (estimated Beta-cell function median of 84% on the control day to 100% after two days glucose infusion). Plasma insulin and C-peptide responses to a 10.0 mmol/l hyperglycaemic clamp increased over the two days of the study (insulin from median 48 mU/l to 73 mU/l and C-peptide from median 2.0 pmol/ml to 2.6 pmol/l). Glucose tolerance to the additional glucose infusion stimulus improved, suggesting that the increased insulin response during hyperglycaemia was enhancing peripheral glucose uptake. The calculated peripheral insulin sensitivity was unchanged during the hyperglycaemic clamp. Thus, in response to the two days of basal hyperglycaemia, both the basal and stimulated Beta-cell responses were enhanced and there was no evidence for 'glucose toxicity' to the Beta-cells.

Topics: Adult; Blood Glucose; C-Peptide; Eating; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Liver; Male; Reference Values; Time Factors

The syndrome of type A insulin resistance is encountered in young women and is characterized by glucose intolerance or frank diabetes mellitus, endogenous hyperinsulinism, insensitivity to insulin administration, acanthosis nigricans and virilization. The insulin resistance is due to reduced cellular insulin binding because of a lack of or defective binding sites and/or because the interaction with the tyrosine kinase of the beta-subunit is hindered. This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin-like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 micrograms/kg body weight to three women with type A insulin resistance. An immediate but slow fall of blood glucose was observed. The glucose disappearance rate was 28.0 mumol/min, i.e. considerably lower than that seen in healthy subjects. The markedly elevated insulin and C-peptide levels fell in a parallel manner to blood glucose but not to normal levels. The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. We suggest that the potential or recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Female; Growth Hormone; Humans; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kinetics; Recombinant Proteins; Syndrome

We investigated the effect of chronic hyperglycemia on glucose transporters in erythrocytes of subjects with and without diabetes mellitus. We found a 22% increase in D-glucose-displaceable cytochalasin-B binding in erythrocyte membranes of diabetic subjects over those of controls (311 +/- 13 vs. 254 +/- 8 pmol/mg protein; P less than 0.001). This increased binding was due to a higher density of binding sites without a significant change in binding affinity. Cytochalasin-B binding to erythrocyte membrane correlated positively with both erythrocyte glycohemoglobin and serum glucose levels, but not with plasma C-peptide levels. The data are compatible with up-regulation of glucose transporters in the erythrocytes of subjects with chronic hyperglycemia. We suspect that this is brought about by increased synthesis and membrane incorporation of the glucose transporter during erythropoiesis.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Cytochalasin B; Diabetes Mellitus; Erythrocyte Membrane; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Middle Aged; Monosaccharide Transport Proteins; Reference Values

The effects of a single bout of exercise to exhaustion on pancreatic insulin secretion were determined in seven untrained men by use of a 3-h hyperglycemic clamp with plasma glucose maintained at 180 mg/100 ml. Clamps were performed either 12 h after an intermittent treadmill run at approximately 77% maximum O2 consumption or without prior exercise. Arterialized blood samples for glucose, insulin, and C-peptide determination were obtained from a heated hand vein. The peak insulin response during the early phase (0-10 min) of the postexercise clamp was higher (81 +/- 8 vs. 59 +/- 9 microU/ml; P less than 0.05) than in the nonexercise clamp. Incremental areas under the insulin (376 +/- 33 vs. 245 +/- 51 microU.ml-1.min) and C-peptide (17 +/- 2 vs. 12 +/- 1 ng.ml-1.min) curves were also greater (P less than 0.05) during the early phase of the postexercise clamp. No differences were observed in either insulin concentrations or whole body glucose disposal during the late phase (15-180 min). Area under the C-peptide curve was greater during the late phase of the postexercise clamp (650 +/- 53 vs. 536 +/- 76 ng.ml-1.min, P less than 0.05). The exercise bout induced muscle soreness and caused an elevation in plasma creatine kinase activity (142 +/- 32 vs. 305 +/- 31 IU/l; P less than 0.05) before the postexercise clamp. We conclude that in untrained men a bout of running to exhaustion increased pancreatic beta-cell insulin secretion during the early phase of the hyperglycemic clamp. Increased insulin secretion during the late phase of the clamp appeared to be compensated by increased insulin clearance.

Topics: Adult; Blood Glucose; C-Peptide; Exercise; Fatigue; Humans; Hyperglycemia; Insulin; Male; Time Factors

To characterize pancreatic endocrine secretion and to examine interrelationships among alterations in alpha, beta, and pancreatic polypeptide cell function in patients with cystic fibrosis (CF), we studied 19 patients with exocrine insufficiency (EXO), including 9 receiving insulin therapy (EXO-IT); 10 patients with no exocrine insufficiency (NEXO); and 10 normal control subjects. First-phase C-peptide response to intravenously administered glucose was significantly impaired in CF patients with exocrine insufficiency (EXO-IT = 0.02 +/- 0.01; EXO = 0.11 +/- 0.02; NEXO = 0.25 +/- 0.05; control subjects = 0.30 +/- 0.04 nmol/L). Lowering fasting glucose levels with exogenous insulin administration in EXO-IT did not improve beta cell responsivity to glucose. The C-peptide response to arginine was less impaired (EXO-IT = 0.12 +/- 0.02; EXO = 0.15 +/- 0.02; NEXO = 0.23 +/- 0.06; control subjects = 0.28 +/- 0.04 nmol/L). Alpha cell function, measured as peak glucagon secretion in response to hypoglycemia, was diminished in EXO but not NEXO (EXO-IT = 21 +/- 10; EXO = 62 +/- 19; NEXO = 123 +/- 29; control subjects = 109 +/- 12 ng/L). Despite diminished glucagon response, EXO patients recovered normally from hypoglycemia. Peak pancreatic polypeptide response to hypoglycemia distinguished CF patients with exocrine insufficiency from those without exocrine insufficiency (EXO-IT = 3 +/- 2; EXO = 3 +/- 1; NEXO = 226 +/- 68; control subjects = 273 +/- 100 pmol/L). Thus CF patients with exocrine disease have less alpha, beta, and pancreatic polypeptide cell function than CF patients without exocrine disease. These data suggest either that exocrine disease causes endocrine dysfunction in CF or that a common pathogenic process simultaneously and independently impairs exocrine and endocrine function.

Topics: Adult; Arginine; C-Peptide; Cystic Fibrosis; Fasting; Glucagon; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Insulin; Pancreas; Pancreatic Polypeptide; Time Factors

The dose-response relationships between prestimulatory blood glucose concentration and the plasma C-peptide responses to stimulation with 1 mg of glucagon iv or a standard mixed meal were studied in 8 C-peptide positive patients with insulin-dependent diabetes mellitus. Hyperglycemia was maintained for 90 min before stimulation using a hyperglycemic clamp technique. Each test was performed at the steady state blood glucose levels approximately 5, approximately 12, and approximately 20 mmol/l. The glucose potentiation of the incremental plasma C-peptide area under the curve at the two levels of hyperglycemia in percent of the area at normoglycemia (median and range) was 343% (53-1053) (p less than 0.05) and 341% (267-1027) (p less than 0.05) after glucagon and 140% (76-227) (NS) and 251% (95-1700) (p less than 0.05) after the meal. The corresponding relative glucose potentiation of plasma C-peptide 6 min after stimulation with glucagon was 124% (100-427) (p less than 0.02) and 144% (100-209) (p less than 0.05). There was no significant difference in the degree of glucose potentiation at approximately 12 or approximately 20 mmol/l. Furthermore, there was no significant difference in the degree of glucose potentiation of the different estimated values of B-cell function. In conclusion, the plasma C-peptide responses to iv glucagon or to a standard test meal were markedly potentiated by acute hyperglycemia in insulin-dependent diabetes mellitus. No further potentiation was, however, obtained when the prestimulatory blood glucose concentration was raised above 12 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Food; Glucagon; Humans; Hyperglycemia; Injections, Intravenous; Islets of Langerhans; Male

Controversy exists regarding whether plasma glucose concentrations are independently involved in the regulation of adipose tissue lipolysis. In the present study, six subjects with insulin-dependent diabetes and six nondiabetic volunteers were studied during infusion of somatostatin, growth hormone, and insulin at rates designed to maintain basal rates of lipolysis, which was traced using a constant infusion of [1-14C]palmitate. A euglycemic (approximately 5 mmol/l) clamp was performed for 3 h, followed by 3 h of hyperglycemia (approximately 9 and approximately 11 mmol/l in nondiabetic and diabetic subjects, respectively). Ten nondiabetic subjects were studied during 6 h of euglycemia to exclude time-dependent changes in lipolysis. The results showed that palmitate concentrations did not change between euglycemia and hyperglycemia in either group [118 +/- 10 vs. 132 +/- 14 mumol/l and 145 +/- 21 vs. 134 +/- 15 mumol/l in nondiabetic and diabetic subjects, respectively; both P = not significant (NS)]. Similarly, palmitate rate of appearance (Ra) did not change during hyperglycemia (1.0 +/- 0.1 and 1.7 +/- 0.4 mumol.kg-1.min-1 in nondiabetic and diabetic subjects, respectively) compared with euglycemia (1.0 +/- 0.1 and 1.6 +/- 0.4 mumol.kg-1.min-1 in nondiabetic and diabetic subjects, respectively; P = NS). Palmitate concentrations and Ra did not change during 6 h of euglycemia in nondiabetic volunteers. Thus hyperglycemia per se has no effect on free fatty acid turnover. Changes in lipolysis that occur coincident with hyperglycemia are probably due to changes in other circulating substrates or hormones known to affect lipolysis.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Female; Glucagon; Glycated Hemoglobin; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Insulin; Lipolysis; Male; Palmitic Acid; Palmitic Acids; Reference Values; Somatostatin

To assess the effect of metyrapone on the early morning plasma glucose (PG) rise, seven NIDDM patients were studied from 2400 to 0900 h on two separate occasions one week apart. During the control study nights, patients received conventional therapy only (diet plus sulphonylurea) whereas on treatment nights, patients received in addition 30 mg/kg metyrapone orally at 2400 h. The plasma glucose (PG) levels from 0530 to 0900 h were significantly higher during the control night than the corresponding values following metyrapone. The control mean PG concentrations increased continuously from a nadir 8.4 +/- 1.1 mmol/l at 0400 h to a maximum of 9.4 +/- 1.1 mmol/l at 0800 h (p less than 0.01). In contrast following metyrapone administration a continuous decline in the PG concentration was noted from 2400 to 0800 h. The plasma glucose levels fell from 9.0 +/- 1.2 at 0400 h to 7.7 +/- 1.0 mmol/l at 0800 h (p less than 0.05). The mean overnight cortisol levels were 167.2 +/- 13.2 and 55.9 +/- 6.4 nmol/l (p less than 0.001) during the control and treatment studies, respectively. The cortisol levels were significantly higher during the control study at all time points from 0400 to 0900 h. No significant changes in insulin, C-peptide, glucagon, GH or catecholamine levels were observed between the two study periods. We conclude that the physiologic early morning rise in plasma cortisol possibly contributes to the pathogenesis of the dawn phenomenon in NIDDM patients.

Topics: Aged; Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Epinephrine; Female; Glucagon; Glycated Hemoglobin; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Insulin; Male; Metyrapone; Norepinephrine

Glucose intolerant relatives of Type 2 diabetic subjects have impaired insulin secretory responses to glucose but their proinsulin secretion has not been assessed. Plasma intact proinsulin was measured in 101 normoglycaemic and glucose intolerant first-degree relatives of Type 2 diabetic subjects both fasting and one hour after an infusion of glucose of 5 mg glucose.kg ideal weight.min-1. Geometric mean (+/- SD) plasma proinsulin increased from 2.4 (+2.5-1.2) and increased to 4.5 (+4.2-2.1) pmol/l at 1 hour (p less than 0.001). Linear regression revealed no relationship of fasting or achieved proinsulin with sex or obesity and a non-significant trend towards increasing fasting and achieved proinsulin with age and fasting plasma glucose. Proinsulin was assessed as a ratio to the simultaneous plasma C-peptide to estimate the relative amounts of insulin and proinsulin secreted by the beta-cells. Analysis of partial correlation coefficients, controlling for age and obesity, showed that the Achieved Proinsulin/Achieved C-peptide ratio was related to both fasting (r = 0.27, p = 0.004) and achieved plasma glucose (r = 0.25, p = 0.008). Glucose intolerant relatives (n = 37) had a small but significant increase in relative proinsulin secretion compared with normoglycaemic relatives (n = 64) (Achieved Proinsulin/Achieved C-peptide 0.07 +/- 0.05 vs 0.04 +/- 0.02 p less than 0.01). This is in accord with abnormal beta cell function being an early feature of Type 2 diabetes but does not distinguish between a primary beta-cell abnormality and a secondary effect of mild hyperglycaemia.

Topics: Adult; Age Factors; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Family; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Prediabetic State; Proinsulin

The occurrence of hyperglycaemia following a morning hypoglycaemic episode was studied in nine patients with Type 1 diabetes. Each patient was studied twice, once following induced hypoglycaemia and once in a control study when hypoglycaemia was prevented by glucose infusion. After the initial hypoglycaemic/control period the patients were maintained on their regular insulin regimens and were given standard meals. Hypoglycaemia induced postprandial hyperglycaemia (3.1 +/- 0.8 mmol l-1 above control) which lasted for about 8 h. Maximal growth hormone levels were seen 40 min after glucose nadir (control 7.8 +/- 3.2, hypoglycaemia 74.0 +/- 12.3 mU l-1) and the magnitude of the hyperglycaemia was related to the growth hormone levels following the hypoglycaemia (r = 0.80, p less than 0.01).

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Eating; Epinephrine; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Hypoglycemia; Insulin; Male

Impairment in pancreatic production of insulin, a cardinal feature of noninsulin dependent diabetes mellitus (NIDDM), was quantified and the kinetics of insulin secretion characterized in six obese individuals with NIDDM before and after weight loss (18.0 +/- 3.0 kg, mean +/- SEM) using a validated mathematical model that employs C-peptide as a marker of the in vivo rate of insulin secretion. The metabolic clearance of C-peptide, assessed by decay analysis after bolus injection of biosynthetic human C-peptide, was not changed by weight loss (0.143 +/- 0.009 L/min.m2 vs. 0.137 +/- 0.010 L/min.m2). Kinetic parameters from each individual's decay curve before and after weight loss were used to derive accurate rates of secretion during the basal (postabsorptive) state, an oral glucose tolerance test and two hyperglycemic clamps. Basal rates of insulin secretion declined 20 +/- 5 pmol/min.m2 (96 +/- 15 to 76 +/- 15 pmol/min.m2, P less than 0.05) concomitant with decreases of 6.9 +/- 0.9 mmol/L in fasting serum glucose (13.7 +/- 1.0 to 6.8 +/- 0.7 mmol/L, P less than 0.05), 60 +/- 14 pmol/L in serum insulin (134 +/- 30 to 74 +/- 15 pmol/L, P less than 0.05), and 0.15 +/- 0.03 pmol/ml in plasma C-peptide (0.67 +/- 0.11 to 0.52 +/- 0.08 pmol/ml, P less than 0.05) concentrations. As expected, weight loss resulted in improved glucose tolerance as measured by the glycemic profiles during the oral glucose tolerance test (P less than 0.05 analysis of variance). The insulin secretory response before weight loss showed a markedly reduced ability to respond appropriately to an increase in the ambient serum glucose. After weight loss, the pancreatic response was more dynamic (P less than 0.05, analysis of variance) and parralleled the moment-to-moment changes in glycemia. Insulin production above basal doubled (11.2 +/- 3.2 to 24.5 +/- 5.8 nmol/6h.m2, P less than 0.05) and peak rates of insulin secretion above basal tripled (55 +/- 16 to 157 +/- 32 pmol/min/m2, P less than 0.05). To assess the beta-cell response to glucose per se and the changes associated with weight reduction, two hyperglycemic clamps were performed at steady state glucose levels in the range characteristic of individuals with severe NIDDM. At a fixed glycemia of 20 mmol/L, average rates of insulin secretion increased almost 2-fold with treatment (161 +/- 41 to 277 +/- 60 pmol/min.m2, P less than 0.05). At an increment of 6 mmol/L glucose above prevailing fasting glucose levels, the average rate of insu

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Models, Theoretical; Obesity; Weight Loss

To study the consequences of hyperglycemia on glucose and nitrogen metabolism in cirrhosis, an hyperglycemic clamp was performed in 5 cirrhotic patients and 5 normal controls during two subsequent periods of 90 min, at 7.78 and then at 13.89 mmol/l. In the first period, glucose infusion and metabolic clearance rates were decreased in cirrhotics vs controls (p less than 0.05). In the second period, this difference between the two groups disappeared because of a more important enhancement in cirrhotics. Baseline plasma C peptide levels and those during hyperglycemia were the same during hyperglycemia in both groups, but plasma insulin level rose more in cirrhotics (p less than 0.05). Baseline insulin secretion following IV glucagon was reduced in cirrhotics vs controls (p less than 0.05), but became normal in the hyperglycemic state. Plasma glucagon levels were enhanced at all times in cirrhotics vs controls (p less than 0.01), but dropped more in cirrhotics vs controls (p less than 0.05). Insulin responsiveness, defined as the "glucose consumption: plasma insulin concentration" ratio was reduced in cirrhotics at 7.78 mmol/l (p less than 0.01), but was the same in both groups at 13.80 mmol/l because of a more important enhancement in cirrhotics, reflecting an improvement of insulin action probably at the post-receptor level and of non-insulin-mediated glucose transport. Hyperglycemia induced a drop in plasma concentration and muscular release of all aminoacids, excepted alanine, between the basal state and the end of the study. Aminoacid concentration rose only in cirrhotics, without any change in muscular output. In the same time, blood ammonia level rose only in cirrhotics, without reduction of muscular uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Amino Acids; Ammonia; C-Peptide; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Insulin Infusion Systems; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Nitrogen

The present study aimed at investigating the hyperglycaemic, lipolytic and ketogenic effects of small doses of glucagon delivered continuously or in a pulsatile manner. The study was performed in eight healthy young volunteers (24.2 +/- 1.2 years) and in eight healthy aged subjects (69.4 +/- 2.0 years). In all the subjects, endogenous pancreatic hormone secretion was inhibited by somatostatin and only glucagon was replaced. Consequently, the effects of pulsatile and continuous glucagon delivery were studied in conditions of progressive somatostatin-induced insulin deficiency. In both the young and the aged subjects, pulsatile glucagon delivery resulted in increases in plasma glucose, non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels greater than those observed when the same amount of glucagon was delivered in a continuous manner. The net increases in plasma glucose, glycerol and non-esterified fatty acid levels were similar between the young and the aged subjects when glucagon was infused continuously; in contrast, the rise in plasma beta-hydroxybutyrate in the aged was only about half that observed in the young subjects. Surprisingly, when glucagon was infused in a pulsatile manner, the rises in plasma glycerol, non-esterified fatty acid and beta-hydroxybutyrate levels were all significantly smaller in the aged subjects, while no significant differences were observed in the blood glucose responses. We conclude that, in the presence of somatostatin-induced insulin deficiency, pulsatile glucagon exerts greater effects on blood glucose, plasma non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels than its continuous delivery. In the elderly, the lipolytic and ketogenic, but not the hyperglycaemic, responses to pulsatile glucagon are significantly reduced.

Topics: 3-Hydroxybutyric Acid; Adult; Age Factors; Aged; Aging; Blood Glucose; C-Peptide; Drug Administration Schedule; Fatty Acids, Nonesterified; Glucagon; Glycerol; Humans; Hydroxybutyrates; Hyperglycemia; Infusions, Intravenous; Insulin; Ketone Bodies; Kinetics; Lipolysis; Reference Values

Secondary failure to oral hypoglycemic agents occurs in some 5% of type II diabetic patients per year, such that treatment with insulin becomes warranted. In most of the cases only hyperglycemia is apparent, while signs of severe metabolic derangement such as thirst, polyuria and weight loss are lacking. However, the hyperglycemic state adversely affects endogenous insulin secretion and favors the development of microvascular complications and neuropathy. In addition, dyslipidemia is often present, and the patient's well-being may be impaired. To differentiate between real secondary drug failure and transient metabolic impairment due to insufficient compliance with the diet prescriptions, plasma C-peptide should be measured. Insulin therapy should be initiated with a dose of 6-8 IU of an intermediate-action preparation and subsequently adjusted based on blood glucose measurements. Frequently it will be necessary to employ twice daily a mixture of (rapid- and intermediate-action) insulin in order to achieve adequate control of postprandial hyperglycemia. In some cases insulin therapy can be discontinued since the endogenous insulin secretion may improve during insulin treatment. We do not recommend to use as initial therapy of patients with secondary failure to oral hypoglycemic agents a combination of sulfonylureas and insulin since the 'insulin-saving' effect is small and not cost-effective.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Sulfonylurea Compounds

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glyburide; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Middle Aged

Disorders of glucose metabolism were investigated in 177 patients undergoing cardiac surgery. In group I patients, the cardiopulmonary bypass (CPB) priming fluid contained glucose. Patients in group II received neither glucose nor insulin during the operation. Group III received insulin-glucose therapy (IGT) during the operation (insulin, 1 U/kg/h, glucose, 0.5 g/kg/h). At the onset of CPB in group I, hyperglycemia was produced by the glucose load and by a relative reduction in insulin secretion. In group II, the start of the operation was accompanied by a rise in the titer of insulin antibodies. IGT resulted in normalization of the blood glucose level after CPB and stability of the insulin antibody titer during the investigation. The indices of myocardial contractility in group III were better than those of the "glucose-free" group II before and after CPB. In group II, indices of beta-cell function were moderately depressed 16 to 18 hours after the operation. Insulin and c-peptide level measurements demonstrated insulin production in group III on the first postoperative day. The results demonstrate that IGT has some potential benefit for glucose metabolism and myocardial function during cardiac surgery.

Topics: Adolescent; Adult; Aorta; Blood Glucose; C-Peptide; Cardiac Output; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Female; Glucose; Humans; Hyperglycemia; Hypothermia, Induced; Insulin; Insulin Antibodies; Male; Middle Aged; Monitoring, Intraoperative; Regional Blood Flow; Stroke Volume

We compared estimates of in vivo insulin action derived from insulin tolerance tests (ITT) and euglycemic and hyperglycemic glucose clamp studies in 17 normal subjects and 19 patients with various diseases characterized by insulin resistance. Fifteen subjects underwent an ITT and a euglycemic clamp study, 17 subjects underwent an ITT and a hyperglycemic clamp study, and 4 subjects underwent all 3 tests. The ITT consisted of a bolus iv injection of regular insulin (0.1 U/kg BW). The plasma glucose disappearance rate during the 3- to 15-min period following the insulin injection was taken as a measure of insulin action. In both euglycemic and hyperglycemic clamp studies, which were carried out with standard techniques, the ratio between the amount of glucose infused to maintain glycemia at the desired level and the mean plasma insulin concentration from 60-120 min (M) (euglycemic clamp studies) or 20-120 min (I) (hyperglycemic clamp studies) was used as a measure of insulin action. A close correlation was found between plasma glucose disappearance rate and the M/I ratio during either the euglycemic (r = 0.811; P less than 0.001) or the hyperglycemic (r = 0.826; P less than 0.001) clamp studies. These results suggest that the 15-min ITT is suitable as a simple and rapid estimation of in vivo insulin action when glucose clamp studies are not feasible, as in large series of subjects or serial studies.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Glucagon; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Infusion Systems; Insulin Resistance; Male; Norepinephrine; Obesity

Homoharringtonine (HHT) has been reported to induce hyperglycemia. This report describes a study conducted to characterize the effect of HHT on insulin production and action. Our data indicate that HHT-induced hyperglycemia results from the development of insulin resistance. A review of the literature suggests that patients receiving HHT continuous infusions of 5 mg/m2/d or greater and patients greater than 10 years of age may be at increased risk for the development of HHT-induced hyperglycemia. We recommend that patients with these risk factors, as well as diabetic patients and patients concurrently receiving asparaginase and/or prednisone, have their blood glucoses routinely monitored for hyperglycemia.

Topics: Acute Disease; Alkaloids; Antineoplastic Agents, Phytogenic; Blood Glucose; C-Peptide; Drug Evaluation; Harringtonines; Homoharringtonine; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Resistance; Leukemia; Risk Factors; Time Factors

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Infusion Systems; Insulin Secretion; Male; Middle Aged

Antiinsulin receptor antibodies were detected in the serum of a patient with insulin-resistant diabetes. Fasting hypoglycemia and postprandial hyperglycemia recurred every day. The plasma insulin level was 553 +/- 359 pmol/L [77 +/- 50 microU/mL (mean +/- SD)] in the fasting state and rose above 7500 pmol/L postprandially. The glycemic clamp at 2.8 mmol/L (50 mg/dL) without insulin infusion revealed that the half-life of plasma endogenous insulin was 173 min, indicating severely impaired plasma insulin clearance. During the clamp the glucose infusion rate was almost constant (0.9-1.2 mg/kg.min) despite an exponential decline in the plasma insulin level from 460 pmol/L (65 microU/mL) to 129 pmol/L (18 microU/mL). Intravenous insulin administration did not appreciably accelerate the basal constant decrease in the plasma glucose level during the postabsorptive period. These results indicate the coexistence of marked insulin resistance and constant ability to decrease plasma glucose level. In in vitro experiments, antireceptor immunoglobulin G from this patient increased the fructose 2,6-bisphosphate concentration in the presence of glucagon (less than 0.1 nmol/L) in primary cultured rat hepatocytes. The antireceptor immunoglobulin G stimulated autophosphorylation of rat liver insulin receptor. We conclude that antiinsulin receptor antibodies could impair plasma insulin clearance, resulting in persistent hyperinsulinemia, and that continuous receptor stimulation by the antibodies was responsible for the development of hypoglycemia.

Topics: Animals; Antibodies, Anti-Idiotypic; Blood Glucose; C-Peptide; Cells, Cultured; Eating; Fasting; Fructosediphosphates; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Immunoglobulin G; Insulin; Liver; Male; Middle Aged; Phosphorylation; Rats; Rats, Inbred Strains; Receptor, Insulin

To examine the importance of first-phase insulin secretion on total body glucose homeostasis, six normal subjects (age, 24 +/- 1 yr; ideal body wt, 100 +/- 1%) received three hyperglycemic (+75 mg/100 ml) clamp studies in combination with [3-3H]glucose: study I, 150 min hyperglycemic clamp; study II, hyperglycemic clamp plus somatostatin (6 micrograms/min) plus basal glucagon replacement (0.4 ng.kg-1.min-1) plus an insulin infusion designed to mimic only the second phase of insulin secretion; and study III, hyperglycemic clamp plus somatostatin plus basal glucagon plus an insulin infusion designed to mimic both the first and second phase of insulin secretion. Basal plasma C-peptide concentrations averaged 0.21 +/- 0.01 pmol/ml in the three study protocols. In study I the plasma C-peptide response demonstrated an early burst within the first 10 min followed by a gradually increasing phase of C-peptide secretion that lasted until the end of the study. In studies II and III plasma C-peptide declined within the first 10 min after somatostatin was started and averaged 0.06 +/- 0.01 and 0.05 +/- 0.01 pmol/min, respectively. Basal hepatic glucose production (2.3 +/- 0.2 mg.kg-1.min-1) was suppressed by 90% at 20 min and remained suppressed thereafter in studies I and III. In contrast, in study II hepatic glucose production was inhibited by only 50% (1.1 +/- 0.2 mg.kg-1.min-1) at 60 min (P less than 0.01 vs. studies I and III) and remained incompletely suppressed even after 150 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucagon; Gluconeogenesis; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Kinetics; Liver; Male; Reference Values

To test secretory capacity of the beta-cell to a glucose stimulus in uremic patients on chronic dialysis, three hyperglycemic clamps (plasma glucose increments: 1, 4.5 and 11 mmol/l) were performed in 8 uremic and 8 healthy subjects. Early-phase insulin and C-peptide responses (delta I and delta C) during the initial 6 min were consistently exaggerated at all three steps in uremic patients compared with controls (delta I. 16 +/- 4 vs 4 +/- 2, 41 +/- 11 vs 15 +/- 4 and 60 +/- 12 vs 24 +/- 5 mU/l; delta C. 0.39 +/- 0.13 vs 0.07 +/- 0.02, 0.40 +/- 0.13 vs 0.16 +/- 0.02 and 0.73 +/- 0.15 vs 0.29 +/- 0.04 nmol/l, p less than 0.05 in all cases). Similarly, late-phase insulin secretion defined as the insulin increment between 90 and 120 min after initiation of the glucose challenge was enhanced in uremic patients at the two highest glycemic steps (44 +/- 10 vs 16 +/- 2 and 123 +/- 29 vs 44 +/- 5 mU/l, both p less than 0.01). The raised late-phase insulin response allowed comparable glucose disposal in the two groups (uremic patients: 9.2 +/- 1.0 and 15.5 +/- 1.6 mg.kg-1.min-1.. 9.0 +/- 1.3 and 19.9 +/- 2.4 mg.kg-1.min-1). The slopes of potentiation, i.e. the slopes of the regression lines expressing the relationship between changes in insulin increments and changes in glucose, were markedly steeper in uremic patients (0.45 +/- 0.09 and 0.66 +/- 0.20, early and late-phase respectively) than in controls (0.20 +/- 0.06 and 0.25 +/- 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Renal Dialysis; Uremia

To test the hypothesis that glucose only affects the responsiveness (maximum velocity) of the beta-cell to arginine without changing the sensitivity (ED50) of the beta-cell to arginine, we investigated the influence of hyperglycemia on the responsiveness and sensitivity of arginine-induced insulin secretion in eight healthy male volunteers. Plasma C-peptide and insulin levels achieved during infusions of five doses of arginine (30 min) with and without a 60-min hyperglycemic clamp (17 mmol/L) were analyzed using a modified Michaelis-Menten equation. At euglycemia, the ED50 (half-maximally stimulating serum arginine concentration) was significantly less for first phase than for second phase plasma C-peptide secretion (0.7 +/- 0.1 vs. 2.7 +/- 0.4 mmol/L; P less than 0.002). Hyperglycemia significantly increased arginine-induced insulin secretion at all arginine infusion rates (P less than 0.01) without significantly altering the ED50 for either phase. We conclude 1) that the regulation of arginine-induced insulin secretion differs between both phases of insulin secretion, and 2) that a 1-h infusion with glucose significantly potentiates arginine-induced insulin secretion without influencing the difference in regulation of both phases of arginine-induced insulin secretion, supporting the validity of the use of arginine as a secretagogue in studies involving hyperglycemia.

Topics: Adult; Arginine; Blood Glucose; Blood Specimen Collection; C-Peptide; Dose-Response Relationship, Drug; Glucose Clamp Technique; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mathematics

Pancreatic islet cell function and tissue metabolism were studied during and after cardiopulmonary bypass in 38 patients undergoing an open heart operation. Twenty patients were operated on with pulsatile cardiopulmonary bypass (group I) and 18, with nonpulsatile cardiopulmonary bypass (group II). Hyperglycemia was observed during and early after operation in both groups. In group I during cardiopulmonary bypass, the immunoreactive insulin and c-peptide levels and the insulin to glucagon molar ratio increased significantly compared with the preoperative values, but in group II, these variables did not alter significantly. An hour postoperatively, the immunoreactive insulin (71 +/- 34 muIU/mL) and c-peptide (8.3 +/- 3.0 ng/mL) levels and the insulin to glucagon molar ratio (11.0 +/- 5.2) in group I were significantly higher than those in group II (immunoreactive insulin, 29 +/- 20 muIU/mL; c-peptide, 4.8 +/- 1.8 ng/mL; insulin to glucagon molar ratio, 3.4 +/- 2.6). The blood lactate level in group I (41 +/- 22 mg/dL) was significantly lower than that in group II (78 +/- 30 mg/dL) an hour postoperatively. In conclusion, pulsatile cardiopulmonary bypass is quite effective in preserving pancreatic beta cell function and tissue metabolism during and early after open heart procedures.

Topics: Blood Glucose; C-Peptide; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Female; Glucagon; Humans; Hyperglycemia; Insulin; Intraoperative Care; Islets of Langerhans; Lactates; Lactic Acid; Male; Middle Aged; Pulsatile Flow

The dose-response relationships between acutely established hyperglycaemia and the plasma C-peptide and insulin responses to i.v. stimulation with 1 mg of glucagon and a standard mixed meal were investigated in 10 patients with well-controlled Type 2 (non-insulin dependent) diabetes mellitus. Hyperglycaemia was maintained for 90 min before stimulation using a hyperglycaemic clamp technique. Each test was performed on different steady state blood glucose levels of approximately 6 mmol/l, approximately 12 mmol/l, and approximately 20 mmol/l, respectively. The plasma C-peptide and insulin responses after glucagon and the meal were potentiated markedly at each level of prestimulatory hyperglycaemia. After glucagon injection, the relative glucose potentiation of the insulin response was significantly higher than the relative glucose potentiation of the C-peptide response at each level of hyperglycaemia (p less than 0.01). This difference may be explained by a higher fractional hepatic removal of insulin at normoglycaemia, since the molar ratio between the incremental C-peptide and insulin responses after glucagon stimulation was higher at prestimulatory normoglycaemia (4.85 (3.65-12.05] than at the prestimulatory blood glucose concentrations approximately 12 mmol/l (2.41 (2.05-4.09] (p less than 0.01) and approximately 20 mmol/l (2.24 (1.37-3.62] (p less than 0.01). In conclusion, the islet B-cell responses to glucagon and a standard mixed meal are potentiated to a high degree by acutely established prestimulatory hyperglycaemia in patients with well-controlled Type 2 diabetes. Acute prestimulatory hyperglycaemia is also associated with a markedly reduced incremental C-peptide/insulin ratio after glucagon stimulation in such patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Fasting; Female; Glucagon; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Time Factors

To determine whether the deranged glucose metabolism in uremia, in addition to insulin resistance can be attributed also to reduced glucose-induced glucose uptake, a two-step sequential hyperglycemic clamp (plasma glucose: 120 and 300 mg/dl) was performed in 6 non-dialyzed uremic and 8 healthy subjects. A constant infusion of somatostatin (300 micrograms/h) and soluble insulin (0.2 mU/kg/min) resulted in peripheral serum insulin slightly higher than basal in both uremics (16 +/- 3 and 22 +/- 3 microU/ml; step 1 and 2, respectively) and controls (20 +/- 2 and 22 +/- 1 microU/ml). The glucose-induced glucose uptake (3-3H-glucose) assessed as the difference between step 2 and 1 glucose disposal at the final 30 min of each step was markedly reduced in uremics (3.2 +/- 0.5 mg/kg/min) compared to healthy subjects (5.7 +/- 0.8 mg/kg/min; p less than 0.03). However, the percentage increment in glucose uptake from step 1 to step 2 hyperglycemia was comparable in the two groups (134 +/- 27 and 148 +/- 17%). Modest hyperglycemia (120 mg/dl) and slightly raised insulinemia resulted in comparable suppression of the endogenous (hepatic) glucose production (EGP) in healthy (1.6 +/- 0.2 mg/kg/min) and uremic subjects (1.5 +/- 0.3 mg/kg/min). In controls, pronounced hyperglycemia (300 mg/dl) further reduced EGP (0.6 +/- 0.3 mg/kg/min; p less than 0.01) while EGP in uremics on the contrary tended to rise (2.0 +/- 0.4 mg/kg/min; p = 0.09), thus indicating an abnormal reaction of the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose; Humans; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Middle Aged; Renal Dialysis; Somatostatin; Uremia

The efficacy of dietary regulation was examined in 38 consecutive primary health care patients with hyperglycaemia detected on screening. Ten weeks of dietary regulation reduced overall mean fasting blood glucose from 8.2 to 6.5 mmol l-1. Fasting blood glucose fell more (from 12.3 to 7.6 mmol l-1 and from 8.4 to 6.6 mmol l-1) in the two quartiles initially above the median (7.15 mmol l-1), than in the lower quartiles (6.7 to 6.1 mmol l-1 and 5.7 to 5.8 mmol l-1), even though weight reduction was similar. The reduction in blood glucose correlated (r = 0.87) with the degree of fasting hyperglycaemia before treatment. Sixteen patients (42%) reached or maintained fasting blood glucose less than or equal to 6.0 mmol l-1, and they had a milder degree of glucose intolerance, a higher insulin response to a meal and a greater reduction in weight than the 22 patients (58%) who did not reach less than or equal to 6.0 mmol l-1. Nine patients (24%) maintained fasting blood glucose less than or equal to 6.0 mmol l-1 for greater than 5 years, and showed a considerable improvement of insulin action. Dietary regulation improved glucose control mainly by reducing fasting hyperglycaemia; neither the delay in early insulin release nor the associated elevation and prolongation of the post-prandial glucose excursions were reduced.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Eating; Fasting; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Male; Mass Screening; Middle Aged; Primary Health Care; Sweden

An early defect in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and the preceding phase of impaired glucose tolerance (IGT) is a reduction in early insulin release and hence a prolonged elevation of postprandial blood glucose. We therefore assessed whether a rapidly acting sulphonylurea (glipizide 5 mg 0.5 h before a test meal) could correct these disturbances in 38 IGT/NIDDM subjects, whose early insulin release and postprandial blood glucose elevations remained unimproved after 10 weeks of dietary regulation. We also assessed whether the efficacy of glipizide was dependent upon the ambient blood glucose concentration, and if early systemic availability of the drug was important for the blood glucose lowering effect. A single dose of glipizide normalized early insulin release and hence reduced the postprandial blood glucose increase that was not lowered by dietary regulation. The efficacy of glipizide was dependent upon the early systemic availability of the drug, but early systemic availability and efficacy were independent of the extent of blood glucose elevation, at least within a range of 6-12 mmol.l-1 of fasting blood glucose.

Topics: Aged; Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Sulfonylurea Compounds

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

Topics: Blood Glucose; C-Peptide; Humans; Hyperglycemia; Insulin; Insulin Secretion; Liver; Metabolic Clearance Rate; Obesity

To investigate whether exertion changes beta-cell reactivity to glucose stimulation and to characterize the beta-cell response to glucose in humans, we performed four sequential 90-min hyperglycemic clamps (7, 11, 20, and 35 mM). Concentrations of hormones and metabolites involved in glucoregulation were measured. Metabolic rate and substrate utilization were studied by indirect calorimetry. Studies were performed without prior exercise, as well as 2 and 48 h after 60 min of bicycle exercise at 150 W. We found 1) a progressive increase in insulin concentrations reaching 1,092 +/- 135 microU/ml with increasing glucose levels, 2) linear relationships between glucose concentrations and concentrations of C-peptide (r = 0.931 +/- 0.008) and proinsulin (r = 0.952 +/- 0.009),3) increased glucose oxidation with increasing glucose uptake, 4) increased plasma norepinephrine, O2 uptake, and beta-hydroxybutyrate at greater than or equal to 20 mM glucose, and 5) no change in beta-cell response or glucose-induced thermogenesis after one bout of exercise despite no compensating changes in plasma concentrations of hormones or metabolites. We conclude that the beta-cell has a very large secretory potential. Secretion of the beta-cell increases linearly with prolonged, graded hyperglycemia. The processing of proinsulin is unchanged during prolonged beta-cell stimulation. In addition, hyperglycemia and sympathetic nervous activity induced by hyperinsulinemia enhance metabolic rate and ketone body production. Finally, a single bout of exercise does not influence either the beta-cell response to intravenous glucose or glucose-induced thermogenesis.

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Blood Glucose; Blood Pressure; C-Peptide; Calorimetry; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glucose; Glycerol; Growth Substances; Heart Rate; Humans; Hydrocortisone; Hydroxybutyrates; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Lactates; Male; Norepinephrine; Physical Exertion; Proinsulin

Elevated rates of basal hepatic glucose output (bHGO) are significantly correlated with the fasting serum glucose (FSG) level in subjects with non-insulin-dependent diabetes mellitus (NIDDM). This observation suggests that bHGO is a major determinant of the severity of the diabetic state in these subjects. In addition, basal glucagon levels (bGL) are higher in these diabetics than in control subjects, despite the concurrent basal hyperglycemia and hyperinsulinemia, two factors known to suppress glucagon secretion. Although bGL is responsible for sustaining two-thirds of bHGO in normal humans, its role in sustaining elevated rates of bHGO in NIDDM has not been previously defined. To this end, we have studied 13 normal and 10 NIDDM subjects; mean FSG levels were 90 +/- 2 and 262 +/- 21 mg/dl, respectively (P less than .001). The mean fasting serum insulin and glucagon levels were higher in the diabetics than in the controls: 17 +/- 2 vs. 9 +/- 1 microU/ml (P less than .01) and 208 +/- 37 vs. 104 +/- 15 pg/ml (P less than .01), respectively. On separate days, HGO was assessed isotopically (with 3-[3H]glucose) in the basal state and during infusion of somatostatin (SRIF) (600 micrograms/h) alone and in conjunction with replacement infusions of glucose and insulin. The results demonstrate that bHGO is higher in diabetics than in controls (145 +/- 12 vs. 89 +/- 3 mg X m-2 X min-1, P less than .01); during infusion of SRIF alone, HGO was suppressed by 25% (P less than .05) and 34% (P less than .05) of the basal value in controls and diabetics, respectively; when the studies were repeated with glucose levels held constant at or near the FSG level by the glucose-clamp technique, the pattern and degree of HGO suppression was similar to that obtained by infusion of SRIF alone; during isolated glucagon deficiency (SRIF + insulin, 5 mU X m-2 min-1, with serum glucose maintained at basal level), HGO was suppressed by 71 +/- 8% of the basal value in controls (P less than .001) and by 58 +/- 7% in diabetics (P less than .001); and when isolated glucagon deficiency with similar hyperglycemia was created in control subjects, HGO was suppressed by 87% of the basal value.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Liver; Middle Aged; Somatostatin

To determine whether hyperglycaemia alters the accuracy with which [2(3)H] and [3(3)H]glucose reflect glucose turnover measured with [6(14)C]glucose in patients with Type 1 (insulin-dependent) diabetes mellitus, glucose utilisation rates were measured during a simultaneous infusion of [2(3)H], [3(3)H] and [6(14)C]glucose after maintenance of normoglycaemia overnight and when glucose concentrations were clamped at 5.3, 7.5 and 9.7 mmol/l while insulin and glucagon concentrations were held constant. Glucose utilisation rates determined with all three isotopes were comparable in the diabetic patients at all glucose concentrations studied. On the other hand, glucose utilisation rates in nondiabetic subjects determined with [6(14)C]glucose were greater (p less than 0.01) than those determined with [3(3)H]glucose and lower (p less than 0.04) than those determined with [2(3)H]glucose during the 5.3, 7.5 and 9.7 mmol/l clamps. Nevertheless, glucose utilisation rates in the diabetic patients were lower (p less than 0.05) than those in the nondiabetic subjects for each glucose isotope. We conclude that hyperglycaemia does not alter the pattern of metabolism of [2(3)H] or [3(3)H]glucose in patients with Type 1 (insulin-dependent) diabetes mellitus.

Topics: Adult; Blood Glucose; C-Peptide; Carbon Radioisotopes; Diabetes Mellitus, Type 1; Female; Glucagon; Glucose; Growth Hormone; Humans; Hyperglycemia; Insulin; Kinetics; Male; Radioisotope Dilution Technique; Reference Values; Somatostatin; Tritium

We have investigated insulin responsiveness in relation to insulin sensitivity during sequential hyperglycemic clamping in low insulin responders (LIR), high insulin responders (HIR) and in women with a history of gestational diabetes (GD). Designation of HIR and LIR was done on the basis of mathematical modeling of the insulin response to a glucose infusion test. Insulin sensitivity was determined by a somatostatin-insulin-glucose infusion test (SIGIT) according to which LIR were subdivided into groups with higher or lesser sensitivity. Hyperglycemic clamping (60 min, 11 mmol/L of glucose) induced diphasic insulin and C-peptide responses in all groups. Insulin and C-peptide responses were significantly higher in HIR than in other groups. The ratio of first phase to total insulin response was higher in HIR v GD but did not differ between other groups. A second identical clamp was performed after a 60-minute rest period. Except in HIR, insulin levels attained were then moderately but significantly higher than during the first clamp. Conversely, the glucose utilization (mg/kg/min) to insulin (mU/L) = M/L ratio was markedly increased in LIR with high insulin sensitivity but not in other groups. We conclude that (1) large and consistent differences exist in glucose-induced insulin secretion from the pancreas between nondiabetic subjects; (2) time dynamics of insulin secretion and priming effects of glucose are similar in LIR with lesser and higher sensitivity; and (3) in the latter group a glucose stress affects insulin sensitivity more markedly than insulin responsiveness.

Topics: Blood Glucose; C-Peptide; Female; Glucose; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Pregnancy; Pregnancy in Diabetics; Somatostatin

Glyburide (GB) and glipizide (GZ) differ in their pharmacokinetics, but it is not known whether they also differ in mode of action. To examine this question, 10 young healthy subjects and 6 non-insulin-dependent diabetic (NIDDM) patients participated in each of three studies: 1) infusion of saline for 120 min followed by a 100-min hyperglycemic (125 mg/dl) clamp; 2) 120-min primed continuous infusion of GZ followed by a 100-min hyperglycemic clamp; and 3) 120-min primed continuous infusion of GB followed by a 100-min hyperglycemic clamp. The GB and GZ infusions were continued throughout the hyperglycemic clamp. Similar plasma concentrations of GB and GZ were obtained in both groups. All studies were performed with [3-3H]glucose to allow quantification of hepatic glucose production. When administered under basal conditions of glycemia, the acute phase (0-10 min) of plasma insulin and C-peptide increase in both control and NIDDM subjects was twice as great with GZ compared with GB (P less than .01). During the hyperglycemic-clamp studies performed in normal subjects, both GB and GZ increased the first- (1.6-fold) and second- (2.2-fold) phase plasma insulin responses more than hyperglycemia alone. During the hyperglycemic clamp in NIDDM subjects, the first-phase plasma insulin response was absent, and the second-phase insulin response was markedly impaired. Neither GB nor GZ improved first-phase insulin secretion in the NIDDM patients. In both NIDDM and control subjects, the effects of hyperglycemia and sulfonylurea drugs (both GB and GZ) on the first- and second-phase plasma insulin responses were simply additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glipizide; Glucagon; Glucose; Glyburide; Humans; Hyperglycemia; Insulin; Insulin Secretion; Kinetics; Liver; Sulfonylurea Compounds

Studies were made on the effect of the enteroinsular axis on amino acid-induced insulin and glucagon secretion during hyperglycaemia in man. The responses of plasma immunoreactive insulin, C-peptide, and immunoreactive glucagon to arginine infusion were investigated in nine healthy subjects after induction of hyperglycaemia by an oral glucose load and by intravenous glucose infusion to produce similar glucose concentrations in the arterialised blood. The plasma immunoreactive insulin and C-peptide levels increased to higher levels after an oral glucose load than after an intravenous infusion of glucose. The incremental areas under the immunoreactive insulin and C-peptide curves during arginine infusion were significantly greater (p less than 0.01) after oral than after intravenous glucose administration. The plasma immunoreactive glucagon level was suppressed equally after oral and intravenous glucose loads. However, during subsequent arginine infusion, the plasma immunoreactive glucagon level rose more in the presence of hyperglycaemia induced by oral than intravenous glucose. The incremental area under the plasma immunoreactive glucagon curve during arginine infusion was 1.6-fold greater after glucose ingestion than after intravenous glucose infusion. These results suggest that the enteroinsular axis has a stimulatory effect on the responses of pancreatic A and B cells to arginine after oral glucose administration.

Topics: Administration, Oral; Adult; Arginine; Blood Glucose; C-Peptide; Female; Glucagon; Glucose; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged

We assessed the effects of insulin and normalization of blood glucose on plasma levels of somatostatin-like immunoreactivity (SLI) in patients with noninsulin-dependent diabetes mellitus (NIDDM). In one series of experiments, normalization of blood glucose was achieved by Biostator-controlled feedback infusion of insulin. This procedure reduced plasma SLI levels by 34% [from 17.1 +/- 2.1 (+/- SEM) to 11.3 +/- 1.9 pg/ml; P less than 0.05], concomitant with a significant reduction in plasma glucagon and C-peptide and an evanescent decrease in plasma gastric inhibitory peptide (GIP) levels. An ensuing mixed meal elicited a rise in SLI that reached the same levels during infusion of insulin as during uncontrolled hyperglycemia; the incremental increase was, however, 45% higher (P less than 0.005) during insulin infusion. Furthermore feedback insulin infusion enhanced GIP and decreased C-peptide responses, but did not affect the glucagon response to the meal. To further evaluate the influence of insulin of SLI levels, we compared the effects of normo- and hyperglycemia during constant hyperinsulinemia by varying the rate of glucose infusion (glucose clamping). Basal SLI levels decreased significantly only during the normoglycemic clamp. The SLI response to a meal was more pronounced during the normoglycemic than the hyperglycemic clamp. The patterns of glucagon and GIP were similar during the two clamp conditions, while both basal and stimulated C-peptide levels were lower during the normoglycemic clamp. To investigate the temporal relationship between changes in blood glucose and SLI levels, patients were studied during a prolonged (270-min) period of normoglycemic clamp and fasting. After attaining normoglycemia, SLI levels continued to decline for 150 min, whereas glucagon and GIP levels did not change. We conclude that in patients with NIDDM, insulin significantly lowers basal SLI levels if normoglycemia is concomitantly attained; this action of insulin was partially dissociated from its hypoglycemic action; hyperglycemia per se inhibits a meal-induced SLI response, and insulin effects on SLI are not secondary to changes in glucagon or GIP levels.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Eating; Fasting; Feedback; Female; Gastric Inhibitory Polypeptide; Glucagon; Humans; Hyperglycemia; Insulin; Insulin Infusion Systems; Male; Middle Aged; Somatostatin

The effect of hyperglycemia per se on glucose uptake by muscle tissue was quantitated in six controls and six type II diabetics by the forearm technique, under conditions of insulin deficiency induced by somatostatin (SRIF) infusion (0.7 mg/h). Blood glucose concentration was clamped at its basal value during the first 60 min of SRIF infusion and then raised to approximately 200 mg/dl by a variable glucose infusion. Plasma insulin levels remained at or below 5 microU/ml during SRIF infusion, including the hyperglycemic period. No appreciable difference between controls and diabetics was present in the basal state as to forearm glucose metabolism. After 60 min of SRIF infusion and euglycemia, forearm glucose uptake fell consistently from 2.1 +/- 0.7 mg X liter-1 X min-1 to 1.0 +/- 0.6 (P less than 0.05) and from 1.7 +/- .2 to 0.4 +/- 0.3 (P less than 0.02) in the control and diabetic groups, respectively. The subsequent induction of hyperglycemia caused a marked increase in both the arterial-deep venous blood glucose difference (P less than 0.02-0.01) and forearm glucose uptake (P less than 0.01-0.005). However, the response in the diabetic group was significantly greater than that observed in controls. The incremental area of forearm glucose uptake was 276 +/- 31 mg X liter-1 X 90 min and 532 +/- 81 in the control and diabetic groups, respectively (P less than 0.02). In the basal state, the forearm released lactate and alanine both in controls and diabetic subjects at comparable rates. No increment was observed after hyperglycemia, despite the elevated rates of glucose uptake. It is concluded that (1) hyperglycemia per se stimulates forearm glucose disposal to a greater extent in type II diabetics than in normal subjects; and (2) the resulting increment of glucose disposal does not accelerate the forearm release of three carbon compounds. The data support the hypothesis that hyperglycemia per se may play a compensatory role for the defective glucose disposal in type II diabetes.

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; C-Peptide; Diabetes Mellitus, Type 2; Female; Hemoglobin A; Humans; Hydroxybutyrates; Hyperglycemia; Insulin; Lactates; Lactic Acid; Male; Middle Aged; Somatostatin

Peripheral venous plasma insulin and C-peptide concentrations were measured in 10 healthy volunteers, given either 100 g glucose orally or sufficient intravenous (i.v.) glucose to produce similar glucose concentrations when measured in arterialized blood. The incremental areas under both the insulin and C-peptide curves were significantly increased after oral as compared with i.v. glucose administration by 229% and 138%, respectively. Arteriovenous plasma glucose differences were higher after oral glucose administration and were positively correlated with plasma insulin concentrations. Plasma gastric inhibitory polypeptide (GIP) and insulin concentrations were measured in seven healthy volunteers given oral glucose loads ranging from 25 to 200 g. Both the magnitude and duration of the GIP and insulin responses after oral glucose ingestion were dose dependent. These results suggest that the main cause of the increase in peripheral insulin levels after large oral carbohydrate loads is augmented insulin secretion rather than reduced hepatic extraction, indicating the possibility that an enteroinsular factor does exist, in accordance with the "incretin" concept. They also emphasize the need to document both arterial and venous glucose concentrations for the correct interpretation of experiments investigating glucose homeostasis.

Topics: Administration, Oral; Adult; Animals; Blood Glucose; C-Peptide; Dogs; Dose-Response Relationship, Drug; Female; Gastric Inhibitory Polypeptide; Glucose; Humans; Hyperglycemia; Infusions, Parenteral; Insulin; Insulin Secretion; Islets of Langerhans; Male

The present study was undertaken with the aims of studying the pharmacological effects and the pharmacokinetics of porcine GIP in pigs in vivo. Infusion of GIP and glucose resulted in a significant increase in the insulin release compared to the insulin release after glucose infusion in the control group. A significant increase in glucose clearance was also seen during GIP infusions. A two compartment open model with first order kinetics was used for the description of the pharmacokinetics of the infused GIP. The plasma half-life for GIP was found to be between 34-35 minutes.

Topics: Animals; Blood Glucose; C-Peptide; Gastric Inhibitory Polypeptide; Glucose; Hyperglycemia; Insulin; Insulin Secretion; Kinetics; Swine

Patients with noninsulin-dependent diabetes mellitus (NIDDM) have both preprandial and postprandial hyperglycemia. To determine the mechanism responsible for the postprandial hyperglycemia, insulin secretion, insulin action, and the pattern of carbohydrate metabolism after glucose ingestion were assessed in patients with NIDDM and in matched nondiabetic subjects using the dual isotope and forearm catheterization techniques. Prior to meal ingestion, hepatic glucose release was increased (P less than 0.001) in the diabetic patients measured using [2-3H] or [3-3H] glucose. After meal ingestion, patients with NIDDM had excessive rates of systemic glucose entry (1,316 +/- 56 vs. 1,018 +/- 65 mg/kg X 7 h, P less than 0.01), primarily owing to a failure to suppress adequately endogenous glucose release (680 +/- 50 vs. 470 +/- 32 mg/kg X 7 h, P less than 0.01) from its high preprandial level. Despite impaired suppression of endogenous glucose production during a hyperinsulinemic glucose clamp (P less than 0.001) and decreased postprandial C-peptide response (P less than 0.05) in NIDDM, percent suppression of hepatic glucose release after oral glucose was comparable in the diabetic and nondiabetic subjects (45 +/- 3 vs. 39 +/- 2%). Although new glucose formation from meal-derived three-carbon precursors (53 +/- 3 vs. 40 +/- 7 mg/kg X 7 h, P less than 0.05) was greater in the diabetic patients, it accounted for only a minor part of this excessive postprandial hepatic glucose release. Postprandial hyperglycemia was exacerbated by the lack of an appropriate increase in glucose uptake whether measured isotopically or by forearm glucose uptake. Thus as has been proposed for fasting hyperglycemia, excessive hepatic glucose release and impaired glucose uptake are involved in the pathogenesis of postprandial hyperglycemia in patients with NIDDM.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Eating; Female; Glucagon; Gluconeogenesis; Glucose; Humans; Hyperglycemia; Insulin; Liver; Male; Middle Aged; Tritium

Studies with tritiated isotopes of glucose have demonstrated that hyperglycemia per se stimulates glucose utilization and suppresses glucose production in humans. These conclusions rely on the assumption that tritiated glucose provides an accurate measure of glucose turnover. However, if in the presence of hyperglycemia the isotope either loses its label during "futile" cycling or retains its label during cycling through glycogen, then this assumption is not valid. To examine this question, glucose utilization and glucose production rates were measured in nine normal subjects with a simultaneous infusion of [23H]glucose, an isotope that may undergo futile cycling but does not cycle through glycogen; [614C]glucose, an isotope that may cycle through glycogen but does not futile cycle; and [33H]glucose, an isotope that can both undergo futile cycling and cycle through glycogen. In the postabsorptive state at plasma glucose concentration of 95 mg X dl-1, glucose turnover determined with [614C]glucose (2.3 +/- 0.1 mg X kg-1 X min-1) was greater than that determined with [33H]glucose (2.1 +/- 0.1 mg X kg-1 X min-1, P = 0.002) and slightly less than that determined with [23H]glucose (2.7 +/- 0.2 mg X kg-1 X min-1, P = 0.08). Plasma glucose was then raised from 95 to 135 to 175 mg X dl-1 while insulin secretion was inhibited, and circulating insulin, glucagon, and growth hormone concentrations were maintained constant by infusion of these hormones and somatostatin. Glucose production and utilization rates determined with [614C]glucose continued to be less than those determined with [23H]glucose and greater than those seen with [33H]glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Carbon Radioisotopes; Female; Glucagon; Glucose; Glucose-6-Phosphate; Glucosephosphates; Growth Hormone; Humans; Hyperglycemia; Insulin; Liver Glycogen; Male; Middle Aged; Tritium

Stepwise glucose clamps were used to study beta-cell insulin response to glucose in normal and noninsulin-dependent diabetic subjects and to study changes in response after hyperglycemia. In normal subjects, insulin increment, delta I, correlated with glucose increment above basal, delta G, during the first 6 min of hyperglycemia, r = 0.748, P less than 0.0001. After 1 h of hyperglycemia, mean delta I/ delta G was reduced from 50 to 23 (mean difference 23 +/- 5) pmol/mmol, P = 0.0002; but delta I/% change in glucose (delta G') was unaltered (2.3 vs. 1.7, mean difference 0.4 +/- 0.3 pmol/%). Second-phase response correlated with mean glucose elevation (r = 0.835, P less than 0.0001), and no plateau was reached after 3 h at 3 mmol/l above basal glucose (rate of change of insulin concentration = 0.5; range, 0.3-0.8 pmol . l-1 . min-1). In diabetic subjects, delta I/ delta G was 20% of normal, while delta I/ delta G' was 63% of normal and second-phase response 30% of normal. We conclude that hyperglycemia per se reduces delta I/ delta G and must be considered when assessing insulin responses. Noninsulin-dependent diabetic subjects have defective first- and second-phase responses.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Proinsulin

To determine the effects of prolonged hyperglycaemia on pancreatic islet A- and B-cell function, plasma glucose was clamped for 12 h at approximately 11 and 5 mmol/l in control experiments by infusing glucose and somatostatin along with replacement amounts of insulin, glucagon, and growth hormone in seven normal volunteers. Following restitution of euglycaemia for 1 h after prolonged hyperglycaemia, termination of the somatostatin-replacement hormone infusions resulted in a sustained decrease in plasma glucose to 3 mmol/l (p less than 0.01). Despite this, plasma glucagon did not increase above values observed in control experiments in which plasma glucose did not decrease; moreover, there was a persistent increase in insulin secretion nearly threefold above that observed in control experiments (p less than 0.01). Plasma growth hormone, cortisol and adrenaline responses were appropriate. This failure of a decrement in plasma glucose to suppress insulin secretion and to stimulate glucagon secretion was not observed when comparable hypoglycaemia was induced by exogenous insulin after a prolonged euglycaemic clamp. Our results indicate that hyperglycaemia can induce altered sensitivity of pancreatic A and B cells to glucose and suggest that abnormal A- and B-cell responses to glucose in diabetes mellitus may not represent a wholly intrinsic defect.

Topics: Adult; Blood Glucose; C-Peptide; Drug Resistance; Epinephrine; Female; Glucagon; Glucose; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Insulin; Islets of Langerhans; Male; Somatostatin; Time Factors

The effect of acetyl-salicylic acid (ASA, 3 g per day for 3 days) on glucose utilization and insulin secretion was studied in healthy volunteers and Type 2 diabetic patients using the hyperglycaemic and euglycaemic insulin clamp technique. When in healthy subjects arterial plasma glucose was acutely raised and maintained at +7 mmol/l above fasting level, the plasma insulin response was enhanced by ASA (70 +/- 7 vs. 52 +/- 7 mU/l), whereas the plasma C-peptide response was identical. Despite higher insulin concentrations, glucose utilization was not significantly altered (control, 61 +/- 7; ASA, 65 +/- 6 mumol X kg-1 X min-1) indicating impairment of tissue sensitivity to insulin by ASA. Inhibition of prostaglandin synthesis was not likely to be involved in the effect of ASA, since insulin response and glucose utilization were unchanged following treatment with indomethacin. In the euglycaemic insulin (1 mU X kg-1 X min-1) clamp studies, glucose utilization was unaltered by ASA despite higher insulin concentrations achieved during constant insulin infusion (103 +/- 4 vs. 89 +/- 4 mU/l). In Type 2 diabetic patients, fasting hyperglycaemia (10.6 +/- 1.1 mmol/l) and hepatic glucose production (15 +/- 2 mumol X kg-1 X min-1) fell upon ASA treatment (8.6 +/- 0.7 mmol/l; 13 +/- 1 mumol X kg-1 X min-1). During the hyperglycaemic clamp study, the plasma response of insulin, but not of C-peptide, was enhanced by ASA, whereas tissue sensitivity to insulin was reduced by 30 percent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aspirin; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Indomethacin; Injections, Intravenous; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Reference Values

The effect of sulphonylurea therapy for 3 weeks on glucose-stimulated insulin secretion and insulin resistance was studied in Type 2 diabetic patients. The fasting plasma insulin and C-peptide concentrations on diet alone were compared with each subject's fasting concentrations on sulphonylurea treatment at a lower fasting plasma glucose and at the original diet-alone glycaemic level obtained by the hyperglycaemic clamp technique. At this isoglycaemic level (mean 11 mmol/l), plasma insulin levels increased from 6.9 mU/l on diet alone to 12.1 mU/l on sulphonylurea treatment (p less than 0.01). The subjects were also studied by the hyperglycaemic clamp technique at mean glycaemic levels of 13 mmol/l before and after sulphonylurea treatment; the incremental insulin response was similarly enhanced from 7.6 +/- 3.5 to 13.7 +/- 6.9 mU/l (p less than 0.02) respectively. Sulphonylureas appear to reduce glycaemia by enhancing B-cell function two-fold. In the patients studied this was from approximately 21% to 37% of a normal response. Insulin resistance assessed by the same hyperglycaemic clamps as endogenous plasma insulin concentrations divided by glucose infusion rates was unchanged by sulphonylurea therapy (mean 4.37 compared to 4.40 mU X 1(-1) X mg-1 X kg X min on diet alone).

Topics: Aged; Blood Glucose; C-Peptide; Chlorpropamide; Diabetes Mellitus, Type 2; Glucose; Glyburide; Humans; Hyperglycemia; Insulin; Insulin Resistance; Islets of Langerhans; Middle Aged; Sulfonylurea Compounds

Diabetic hyperosmolar coma is a syndrome of marked hyperglycemia and minimal ketoacidosis. In general, the serum glucose concentrations are not predictive of the serum ketoacid concentrations in acutely decompensated diabetes. The endocrine factors that modulate glucose concentrations may be different from those that modulate ketoacid concentrations in patients with acutely decompensated diabetes. To test this hypothesis, regression analysis was used to determine the endocrine and metabolic characteristics that correlated with serum concentrations of glucose and ketoacids in 26 diabetic patients with spontaneous, acute hyperglycemia. All patients had a serum glucose level greater than 390 mg/dl, and ketoacid levels were from 0.17 to 25.5 mM. Multiple regression analysis showed that increased serum glucose concentrations correlated with increased plasma glucagon levels (p = 0.0007, r2 = 0.45), but with no other factors. Increased total ketoacid levels (acetoacetate plus 3-hydroxybutyrate) correlated with increased free fatty acid levels (p = 0.0001), decreased C-peptide levels (p = 0.002), and increased body mass index (p = 0.002) (r2 = 0.72). Body mass index only correlated with ketoacid levels, when it was analyzed with C-peptide and free fatty acid levels. A model is proposed that predicts the serum glucose and ketoacid concentrations in patients with acutely decompensated diabetes. Glucagon modulates the serum glucose concentration in these patients with an absolute or relative insulin deficiency. Total serum ketoacid levels are determined by the serum free fatty acid concentration, residual pancreatic insulin secretion (as reflected by C-peptide), and the patient's body habitus. This model allows for the marked hyperglycemia and minimal ketosis of diabetic nonketotic hyperosmolar coma, as well as the glucose and ketoacid concentrations in other presentations of acutely decompensated diabetes.

Topics: Acute Disease; Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetic Coma; Diabetic Ketoacidosis; Fatty Acids, Nonesterified; Female; Glucagon; Growth Hormone; Humans; Hyperglycemia; Hyperglycemic Hyperosmolar Nonketotic Coma; Keto Acids; Male; Middle Aged; Models, Biological; Regression Analysis

Topics: Adrenal Cortex Hormones; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Insulin; Insulin Antibodies; Islets of Langerhans; Male; Middle Aged; Pancreas Transplantation; Phenytoin

Topics: Abdomen, Acute; Acute Disease; Adult; Aged; C-Peptide; Female; Glucagon; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Pancreatitis; Peptides

Early phase hyperglycemia, associated with increased rates of insulin and C-peptide secretion after oral administration of 100 g glucose, was observed among patients with pulmonary tuberculosis who were taking rifampicin. This early phase hyperglycemia appeared shortly after rifampicin was started and it disappeared completely a few days after rifampicin was discontinued. No difference in oral glucose tolerance was noted between healthy normal subjects and patients with pulmonary tuberculosis who were not taking any medications. Antituberculous drugs other than rifampicin did not induce early phase hyperglycemia. Because intravenous glucose tolerance was normal in patients treated with rifampicin, it is suggested that rifampicin produces an early phase hyperglycemia possibly by augmenting intestinal absorption of glucose.

Topics: Administration, Oral; Adolescent; Aged; Antitubercular Agents; Blood Glucose; C-Peptide; Food; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Hyperthyroidism; Insulin Antibodies; Islets of Langerhans; Male; Peptides; Radioimmunoassay; Time Factors

Insulin resistance was studied in seven non-obese male subjects with impaired glucose tolerance and four healthy, age and body-weight matched male control subjects by means of a continuous intravenous infusion of somatostatin, glucose and insulin over 150 min. Glucose tolerance was evaluated by means of a 2-h glucose infusion test. Endogenous insulin (C-peptide), growth hormone, and glucagon secretion were suppressed by somatostatin in both groups. Steady-state plasma insulin and glucose levels were achieved between 90-135 min. Since similar steady-state levels of exogenous insulin were achieved, the resulting steady-state plasma glucose level provided a direct estimate of the ability of insulin to dispose of the infused glucose. The glucose levels were higher in subjects with impaired glucose tolerance with values of 14.6 +/- 1.8 mmol/l compared with 5.1 +/- 1.2 mmol/l in control subjects (p less than 0.01), thus indicating insulin resistance. There was a direct correlation between the steady-state plasma glucose level and glucose tolerance suggesting that the degree of glucose intolerance is proportional to the degree of insulin resistance. These results revealed that decreased insulin sensitivity is found in non-obese subjects with impaired glucose tolerance.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Glucagon; Glucose Tolerance Test; Glycerol; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Male; Reference Values; Somatostatin

Plasma levels of IRI, C-peptide and glucagon were determinated in 19 patients with liver cirrhosis and 9 control subjects after an oral glucose load (OGTT). 9 of the cirrhotics showed chemical diabetes, the remaining 7 cases showed ascites and a normal OGTT. Both groups of cirrhotics showed high IRI and C-peptide values in basal conditions, peaks of these parameters, higher than those observed in the control subjects, were found during the OGTT. The C-peptide/IRI ratio, which was lower than normal both during fasting and after glucose load, presented the lowest value in patients with ascites. In the conditions adopted for this study, glucagon showed higher plasma levels in all the cirrhotics studied than those found in the controls, but the highest levels were found in patients with ascites and with a normal OGTT. It can be concluded that the high levels of insulin found in liver cirrhosis are due to a B-pancreatic hypersecretion (high C-peptide levels) but are also maintained by a decreased hepatic degradation of the hormone (C-peptide/IRI ratio below normal). Hyperglucagonemia is not the chief factor in determining the insulin-resistance observed in liver cirrhosis.

Topics: Adult; Aged; Ascites; C-Peptide; Female; Glucagon; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Liver Cirrhosis; Male; Middle Aged; Peptides

Topics: Adolescent; Adult; Aged; Aldosterone; Blood Glucose; C-Peptide; Dehydration; Diabetic Ketoacidosis; Epinephrine; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Insulin; Male; Middle Aged; Norepinephrine; Pancreatic Polypeptide; Parathyroid Hormone; Prolactin

Using a Biostator glucose-controlled insulin infusion system to monitor blood glucose during surgery, we have shown that both nondiabetic and diabetic patients have a tendency towards hyperglycemia during surgery. This appears to be due to suppression of endogenous insulin secretion as measured by serum C-peptide levels. Some diabetic patients maintained relatively normal glucose values during surgery when infused with saline alone and not given glucose or insulin, but 2 of 5 were not well controlled by this means. Hyperglycemia in both diabetic and non-diabetic patients was related to the rate of infusion of exogenous glucose. The biostator glucose-controlled insulin infusion system could be used in feedback mode as an apparently safe and effective means of controlling blood glucose during surgery on diabetic patients.

Topics: Artificial Organs; Blood Glucose; C-Peptide; Diabetes Mellitus; Humans; Hydrocortisone; Hyperglycemia; Infusions, Parenteral; Insulin; Islets of Langerhans; Surgical Procedures, Operative

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Glucagon; Glucose; Growth Hormone; Humans; Hyperglycemia; Insulin; Male

"Essential labile diabetes" is an insulin-dependent diabetes, in the course of which irregular and unpredictable hyperglycemias, frequently with ketosis, and sometimes serious hypoglycemias alternate. In spite of careful treatment with insulin, diet and suitable hygienic measures, this form of diabetes cannot be influenced. Fortunately, it seldom occurs, not more frequently than in 1 to 2% of diabetics. Various attempts have been made to explain the pathogenesis of this form of the disease. The most probable explanation is that there is an almost complete exhaustion of insulin secretion. This hypothesis is based on the extremely low level of the C peptide below 0.60 ng/ml, whereas in non-labile insulin-dependent diabetics the C peptide amounts to more than 2.2 ng/ml

Topics: Activities of Daily Living; Adult; Arginine; C-Peptide; Diabetes Mellitus; Diabetic Ketoacidosis; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Male; Middle Aged