c-peptide and Hyperinsulinism

Topics: Adiposity; Blood Glucose; C-Peptide; Diet; Female; Humans; Hyperinsulinism; Infant; Infant, Newborn; Insulin; Obesity; Pregnancy

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Autoimmune Diseases; C-Peptide; Dexamethasone; Diazoxide; Diet, Diabetic; Female; Glucose; Glucose Intolerance; Humans; Hyperinsulinism; Hypoglycemia; Immunosuppressive Agents; Insulin; Liver Neoplasms; Polyethylene Glycols; Proinsulin; Sigmoid Neoplasms

Insulin resistance is common among obese adolescents; however, the extent of this problem is not clear. We conducted a systematic review of PubMed-Medline, CINAHL, The Web of Science, EMBASE and Scopus for observational studies evaluating components defining insulin resistance (insulin, C-peptide and homeostatic model assessment-insulin resistance [HOMA-IR]) in obese adolescents (12-18 years) versus non-obese adolescents. Our systematic review and meta-analysis followed the PRISMA guidelines. Data were combined using a random-effects model and summary statistics were calculated using the mean differences (MDs). 31 studies were included (n = 8655). In 26 studies, fasting insulin levels were higher in obese adolescents when compared to non-obese adolescents (MD = 64.11 pmol/L, 95%CI 49.48-78.75, p < 0.00001). In three studies, fasting C-peptide levels were higher in obese adolescents when compared to non-obese adolescents (MD = 0.29 nmol/L, 95%CI 0.22-0.36, p < 0.00001). In 24 studies, HOMA-IR values were higher in obese adolescents when compared to non-obese adolescents (MD = 2.22, 95%CI 1.78-2.67, p < 0.00001). Heterogeneity of effects among studies was moderate to high. Subgroup analyses showed similar results to the main analyses. Circulating insulin and C-peptide levels and HOMA-IR values were significantly higher in obese adolescents compared to those non-obese.

Topics: Adolescent; Adolescent Nutritional Physiological Phenomena; Biomarkers; C-Peptide; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Metabolic Syndrome; Observational Studies as Topic; Pediatric Obesity; Reproducibility of Results

Insulin stimulates cell proliferation and inhibits apoptosis. While epidemiologic studies have investigated associations between markers of insulin resistance/hyperinsulinemia (i.e., circulating insulin, homeostasis model assessment-insulin resistance (HOMA-IR), C-peptide) and risk of colorectal adenoma (CRA), the effect size has not yet been quantified.. We aimed to summarize the association between hyperinsulinemia/insulin resistance and risk of CRA, including whether the association is independent of adiposity.. Pubmed and Embase were searched through April, 2015 to identify observational studies investigating the associations between insulin, C-peptide and HOMA-IR and CRA risk. Using the highest versus lowest category meta-analysis and dose-response meta-analysis based on a random-effects model, we estimated summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI).. A total of 27 studies (insulin: 16 studies including 14,007 cases; C-peptide: 11 studies including 8639 cases; HOMA-IR: 8 studies including 11,619 cases) were included in this meta-analysis. The summary ORs of CRA comparing the highest with the lowest quantile were 1.33 for insulin (95% CI=1.12-1.58, I(2)=73.9%, Pheterogeneity<0.001), 1.44 for C-peptide (95% CI=1.13-1.83, I(2)=63.5%, Pheterogeneity=0.003), and 1.33 for HOMA-IR (95% CI=1.10-1.60, I(2)=69.1%, Pheterogeneity=0.004). Upon stratification by ethnicity, higher levels of insulin and C-peptide were significantly associated with increased risk of CRA in non-Asian ethnicity (summary OR for insulin=1.67 [95% CI=1.28-2.17], I(2)=34.9%, Pheterogeneity=0.16; summary OR for C-peptide=1.59 [95% CI=1.22-2.08], I(2)=21.5%, Pheterogeneity=0.27) but not in Asians (summary OR for insulin=1.10 [95% CI=0.92-1.33], I(2)=76.6%, Pheterogeneity=0.001; summary OR for C-peptide=1.27 [95% CI=0.84-1.91], I(2)=72.6, Pheterogeneity=0.01). We observed evidence for the existence of publication bias for insulin (P=0.01 by Egger test) and HOMA-IR (P=0.05 by Egger test). The results were confirmed in linear dose-response meta-analysis. These significant positive associations generally persisted even after adjustment for adiposity, although the effect size was substantially attenuated.. Independent of adiposity, higher levels of insulin, C-peptide, and HOMA-IR were significantly associated with increased risk of CRA. The weaker associations and high heterogeneity in Asian studies warrant further research. These results indicate that insulin resistance and hyperinsulinemia may contribute in part to the association between obesity and CRA risk.

Topics: Adenoma; Adiposity; Blood Glucose; C-Peptide; Colorectal Neoplasms; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Obesity; Risk Factors

Fibroblast growth factor receptor 3 (FGFR3) gene mutations in the germline are well-known causes of skeletal syndromes. Somatic FGFR3 mutations have been found in malignant neoplasms and more recently in several cutaneous elements. We present a 14-year-old girl with mild hypochondroplasia who developed acanthosis nigricans. The report of a K650Q mutation in the FGFR3 gene in a similar case prompted us to conduct a point mutation analysis. The K650Q mutation was confirmed, but in contrast to the previous case, we additionally report findings of hyperinsulinemia. In the recent literature, an increasing number of different cutaneous elements have been found to harbor mutations of FGFR3, suggesting that FGFR3 plays a role in the pathogenesis of these elements. We review the present literature, describing studies in which FGFR3 mutations have been investigated in skin lesions: primarily seborrheic keratoses and epidermal nevi, but also other benign skin tumors and a single case of a squamous cell carcinoma. In addition, an overview of the FGFR3 point mutations in relation to each cutaneous element is given. Based on the current knowledge, it seems likely that these cutaneous lesions have a common genetic background. Our case shows that FGFR3 mutation analysis should be considered in case of the coexistence of acanthosis nigricans and a skeletal dysplasia. Testing for hyperinsulinemia is essential, also if a gene mutation is confirmed.

Topics: Acanthosis Nigricans; Adolescent; Blood Glucose; C-Peptide; Dwarfism; Female; Gonadotropin-Releasing Hormone; Human Growth Hormone; Humans; Hyperinsulinism; Keratosis, Seborrheic; Metformin; Point Mutation; Receptor, Fibroblast Growth Factor, Type 3

A substantial body of evidence links sex hormones, diet, excess body weight and physical activity to the risk of developing cancer at several sites common in affluent countries. The hypothesis that high circulating levels of insulin could be the underlying factor increasing cancer risk has been proposed. Epidemiological studies on markers of hyper-insulinaemia and cancer are reviewed and summarized.. Studies of cancers of the colon and rectum, pancreas, breast, and endometrium examining the association with blood levels of C-peptide, insulin, glucose, glycated haemoglobin (HbA1c) were searched in PubMed. Multivariate, adjusted relative risks (RR) and their 95% confidence intervals were abstracted and summarized by meta-analyses.. Most of the studies identified were cohorts that relied on measurements obtained at baseline or assessed in blood stored at low temperature several years before the onset of cancer. The meta-analyses showed excess risks of colorectal and pancreatic cancers associated with higher levels of circulating C-peptide/insulin and with markers of glycaemia. Significant heterogeneity was found among four epidemiological studies of endometrial cancer and C-peptide giving a summary RR compatible with no association. Overall breast cancer risk was significantly higher in the upper categories of C-peptide/insulin, however, the excess derived entirely from retrospective studies.. Current evidence suggests that subjects who develop colorectal and pancreatic cancers have increased pre-diagnostic blood levels of insulin and glucose.

Topics: Biomarkers; Blood Glucose; C-Peptide; Humans; Hyperinsulinism; Insulin; Neoplasms

Topics: Atherosclerosis; C-Peptide; Cardiovascular Diseases; Cell Proliferation; Diabetic Angiopathies; Humans; Hyperinsulinism; Insulin Resistance; Mitogens; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle

The diagnosis of a hypoglycemic disorder requires a high level of suspicion, careful assessment of the patient for the presence of mediating drugs or a predisposing illness, and, where indicated, methodical evaluation on the basis of well-defined diagnostic criteria. The diagnostic burden is heaviest for healthy-appearing persons with episodes of confirmed neuroglycopenia. Our criteria for insulin mediation of hypoglycemia are: plasma insulin >or=18 pmol (ICMA [immunochemiluminometric assay]), C-peptide >or=200pmol/L (ICMA), proinsulin >or=5pmol/L (ICMA), betaOH butyrate,

Topics: Adult; Blood Glucose; C-Peptide; Child; Fasting; Humans; Hyperinsulinism; Hypoglycemia; Proinsulin

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diagnosis, Differential; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Reagent Kits, Diagnostic; Reference Values; Sensitivity and Specificity

Topics: Algorithms; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

Insulin is both produced and degraded within the pancreatic Beta cell. Production involves the synthesis of the initial insulin precursor preproinsulin, which is converted to proinsulin shortly after (or during) translocation into the lumen of the rough endoplasmic reticulum. Proinsulin is then transported to the trans-cisternae of the Golgi complex where it is directed towards nascent secretory granules. Conversion of proinsulin to insulin and C-peptide arises within secretory granules, and is dependent upon their acidification. Granule contents are discharged by exocytosis in response to an appropriate stimulus. This represents the regulated secretory pathway to which more than 99% of proinsulin is directed in Beta cells of a healthy individual. An alternative route also exists in the Beta cell, the constitutive secretory pathway. It involves the rapid transfer of products from the Golgi complex to the plasma membrane for immediate release, with, it is supposed, little occasion for prohormone conversion. Even if delivered appropriately to secretory granules, not all insulin is released; some is degraded by fusion of granules with lysosomes (crinophagy). Each event in the molecular lifestyles of insulin and its precursors in the Beta cell will be seen to be governed by their own discrete functional domains. The identification and characterisation of these protein domains will help elucidate the steps responsible for delivery of proinsulin to secretory granules and conversion to insulin. Understanding the molecular mechanism of these steps may, in turn, help to explain defective insulin production in certain disease states including diabetes mellitus.

Topics: Animals; C-Peptide; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Proinsulin; Protein Precursors

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

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

About 8%-15% of the patients with organic hyperinsulinism have an islet cell carcinoma (13% in our series). In addition to a history of complaints of relatively recent onset, the patients present clinically the typical intermittent neurologic-psychiatric symptoms concurrently associated with hypoglycemia. The diagnosis is established biochemically on the basis of hypoglycemia, with inadequate incrementation of the insulin concentration subsequent to suppression and provocation tests. Elevated serum proinsulin and, in most patients, an increased insulin secretion rate are usually found after administration of agents such as glucose or leucine. Localization of the tumors is achieved by selective coeliacography as well as abdominal computerized axial tomography. The islet cell carcinoma is found most frequently in the tail of the pancreas, less frequently in the body and head of the pancreas. Metastatic spread is seen early into adjacent lymph nodes and especially in the liver. The treatment of choice is surgical resection of the tumor. Even in cases with advanced metastatic involvement, surgical intervention appears indicated. Medical treatment includes the administration of diazoxide, long-acting glucagon as well as the cytostatic agent streptozotocin. The average survival time is 30-40 months after diagnosis (in our series 79 months). Thus, the prognosis of patients with islet cell carcinoma appears relatively favorable, especially when compared with adenocarcinoma of the pancreas.

Topics: Adenoma; Adenoma, Islet Cell; C-Peptide; Diagnosis, Differential; Diazoxide; Female; Glucagon; Humans; Hyperinsulinism; Liver Neoplasms; Lymphatic Metastasis; Male; Pancreatic Neoplasms; Prognosis; Proinsulin; Streptozocin

The recent work on proinsulin and C-peptide has been reviewed with major emphasis on the most significant findings since 1972. Proinsulin has now been established as the biosynthetic precursor of insulin in all species examined, including man, with a preproinsulin as a possible precursor of the prohormone. The conversion of proinsulin which appears to occur exclusively in the pancreas leads to equimolar production of insulin and C-peptide. Although proinsulin has a direct biologic effect which is one-tenth as much as that of insulin, C-peptide has no biologic activity on homologous or heterologous tissue and no ability to modify the action of insulin and/or proinsulin. Previous work on proinsulin immunoassay suggested that this prohormone, but not C-peptide, cross-reacts with insulin antiserum. On the other hand, in the C-peptide immunoassay, proinsulin but not insulin cross-reacts with the antiserum. Up to this time, therefore, it has not been possible to immunoassay human proinsulin or C-peptide specifically. The very recent work from the laboratory of Heding, however, has brought about major advances in this area in which human C-peptide and proinsulin can be separated in the plasma by the use of Sepharose particles. With this recent major advancement, it is now possible to measure human C-peptide specifically. This measurement has been shown to be a useful tool for the assessment of beta-cell function in diabetic patients treated with insulin and in insulinoma patients in whom endogenous C-peptide secretion is not suppressed with exogenous insulin-induced hypoglycemia. With the use of a specific enzyme which degrades insulin but not proinsulin, postprandial plasma proinsulin values have been measured in a large number of subjects under a variety of physiologic and pathologic conditions. These results, which are comparable to those obtained by the more laborious column chromatography, could be summarized as follows: (1) proinsulin values in lean, young normal subjects do not vary greatly in response to insulin secretagogues; (2) proinsulin secretion in response to glucose results in a greater percentage of proinsulin in the older age group than in the younger group; (3) in lean adult and juvenile diabetic patients, the percentage of proinsulin is not excessive, whereas obese diabetics and pregnant diabetics appear to secrete relatively greater proinsulin than their diabetic controls; and (4) whereas most hyperinsulinemic states (Cusing's syndrome, adul

Topics: Amino Acid Sequence; Animals; Antibodies; C-Peptide; Cattle; Cross Reactions; Diabetes Mellitus; Dogs; Endoplasmic Reticulum; Female; Guinea Pigs; Haplorhini; Horses; Humans; Hyperinsulinism; Insulin; Male; Mice; Molecular Conformation; Pancreas; Pancreatic Neoplasms; Peptides; Proinsulin; Rats; Structure-Activity Relationship; Swine; Terminology as Topic

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

Topics: Adolescent; Adult; Antipsychotic Agents; C-Peptide; Diet; Double-Blind Method; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Hyperinsulinism; Insulin Secretion; Liver; Male; Muscarinic Antagonists; Olanzapine; Weight Gain; Young Adult

Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 international units [IU] (10 and 20 IU every 15 min) of the insulin analog aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via intravenous infusion of ins-asp at a dose of 0.12 IU/kg/24 h (n = 10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia.

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Male; Young Adult

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

The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program.. Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m(2), underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry.. Weight loss averaged -8.3 ± 0.6% of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9%, P = 0.04) and exogenous insulin clearance (by 12 ± 5%, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by -12 ± 5%, whole-body norepinephrine spillover rate by -14 ± 8%, and MSNA by -9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = -0.63, P = 0.01) which explained 40% of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64% of the variance.. Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850.

Topics: Aged; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Caloric Restriction; Female; Fingers; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Kinetics; Liver; Male; Manometry; Middle Aged; Muscle, Skeletal; Norepinephrine; Obesity; Plethysmography; Sympathetic Nervous System; Treatment Outcome; Vascular Resistance; Victoria; Weight Loss

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

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

To compare the ability of customized versus normalized population fetal growth norms in identifying neonates at risk for adverse perinatal outcomes (APOs) associated with fetal overgrowth and gestational diabetes (GDM).. Secondary analysis of a multicenter treatment trial of mild GDM. The primary outcome was a composite of neonatal outcomes associated with fetal overgrowth and GDM. Birth weight percentiles were calculated using ethnicity- and gender-specific population and customized norms (Gardosi).. Two hundred three (9.8%) and 288 (13.8%) neonates were large for gestational age by population (LGApop) and customized (LGAcust) norms, respectively. Both LGApop and LGAcust were associated with the primary outcome and neonatal hyperinsulinemia, but neither was associated with hypoglycemia or hyperbilirubinemia. The ability of customized and population birth weight percentiles for predicting APOs were poor (area under the receiver operating characteristic curve < 0.6 for six of eight APOs).. Neither customized nor normalized population norms better identify neonates at risk of APOs related to fetal overgrowth and GDM.

Topics: Adult; Area Under Curve; Birth Weight; Blood Glucose; C-Peptide; Confidence Intervals; Diabetes, Gestational; Female; Fetal Macrosomia; Gestational Age; Humans; Hyperbilirubinemia, Neonatal; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Odds Ratio; Pregnancy; Pregnancy Outcome; Reference Values; ROC Curve; Young Adult

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

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

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

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

It is clinically relevant and of physiological interest to investigate whether GH-induced insulin resistance depends on the timing of GH exposure relative to when insulin sensitivity is assessed.. GH-induced insulin resistance is rapidly reversible.. Eight male GH-deficient patients underwent a 6-h euglycemic-hyperinsulinemic glucose clamp thrice in a randomized crossover design receiving either no GH (study 0), a 7-h GH infusion (0.2-0.3 mg in total) that terminated 5 h before the clamp (study 1), or a similar GH infusion timed to continue during the first hour of the clamp (study 2). A muscle biopsy was obtained 30 min into the clamp. The patients were compared with eight healthy untreated control subjects (study c).. The glucose infusion rate, indirect calorimetry, and free fatty acid metabolism were assessed. In muscle biopsies, protein phosphorylation of signal transducer and activator of transcription 5, Akt, and Akt substrate 160 (phospho-Akt substrate signal) and gene expression of IGF-I and SOCS1-3 were assessed.. Insulin sensitivity differed significantly between the GH-deficiency studies (P = 0.005) with distinct insulin resistance in study 2 and increased insulin sensitivity in study 0 [area under the glucose infusion rate curve (mg/kg · min): 1663 ± 151 (study 0) vs. 1482 ± 166 (study 1) vs. 1123 ± 136 (study 2) vs. 1492 ± 229 (control group)]. Free fatty acid levels and lipid oxidation were elevated in response to GH exposure but became suppressed during the clamp. IGF-I and SOCS3 gene expression was increased in study 2.. Very-low-dose GH exposure evokes acute insulin resistance that subsides after 5 h. This time-dependent reversibility should be considered when assessing the impact of GH on glucose homeostasis.

Topics: Acute Disease; Adult; Aged; Biopsy; Blood Glucose; C-Peptide; Calorimetry, Indirect; Cross-Over Studies; Fatty Acids, Nonesterified; Gene Expression; Glucose Clamp Technique; Glucose Intolerance; Human Growth Hormone; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Male; Middle Aged; Muscle, Skeletal; Signal Transduction; Suppressor of Cytokine Signaling Proteins

Evidence suggests that somatostatin not only inhibits the secretion of GH but also suppresses GH action in peripheral tissues.. We tested the hypothesis that somatostatin suppresses GH activity in human skeletal muscle in vivo.. Eight healthy young men (25.3 ± 2.8 yr) were studied on a single occasion after an overnight fast for 4 h [including a basal period (0-2 h) and a hyperinsulinemic euglycemic clamp (2-4 h)] during an iv GH infusion (50 ng/kg⁻¹ · min⁻¹). Each subject received an intraarterial somatostatin infusion (150 μg/h⁻¹) into one femoral artery and an intraarterial saline infusion into the contra lateral artery. The simultaneous blood samples were drawn from both femoral veins. Muscle biopsies were obtained from one leg at t = 0 and from both legs during the basal period and during the clamp.. Muscle glucose uptake, signaling proteins for GH (phosphorylated signal transducer and activator of transcription-5) and insulin (phosphorylation of AS160), and expression of GH-regulated genes (IGF-I and suppressor of cytokine signaling 1-3) were measured.. Somatostatin significantly increased glucose uptake measured by arteriovenous glucose difference during the basal period (P = 0.03) but not during the clamp. There was a tendency for the phosphorylation of AS160 to be higher in the somatostatin-infused leg compared with the saline leg (P = 0.055). The expression of suppressor of cytokine signaling-1 mRNA was significantly elevated in the clamp-biopsy from the saline-infused leg (P = 0.024).. We concluded the following: 1) in the presence of systemic GH exposure, somatostatin increases basal glucose uptake and reduces the expression of GH-regulated genes directly in skeletal muscle; 2) this supports the concept that somatostatin suppresses GH activity in peripheral tissues, and 3) this may add to the therapeutic effects of somataostatin analogs.

Topics: Adult; Biopsy; Blood Glucose; C-Peptide; Gene Expression; Glucagon; Glucose Clamp Technique; GTPase-Activating Proteins; Human Growth Hormone; Humans; Hyperinsulinism; Infusions, Intra-Arterial; Insulin Resistance; Insulin-Like Growth Factor I; Leg; Lipids; Male; Muscle, Skeletal; Somatostatin; STAT5 Transcription Factor; Suppressor of Cytokine Signaling Proteins; Young Adult

Intensive insulin therapy for diabetic patients has been demonstrated as an appropriate treatment. Regular fast-acting insulin can hardly mimic the efficiency of endogenous meal-activated insulin secretion. Glulisine is a new rapid-acting insulin analog for mealtime insulin supplementation. We compared the pharmacokinetics and pharmacodynamics end points between the two rapid-acting insulin analogs Glulisine and Lispro. Twenty healthy adult males age ranging from 22 to 32 years were included in a randomized, open-label, cross contrast research. Two long duration hyperinsulinemic euglycemic clamp tests, one with Glulisine and the other with Lispro, were conducted on two separate days for all the participants. The two rapid-acting insulin analogs were administrated randomly to each participant. Glucose infusion rate (GIR) began to increase 20 min after injection in both Glulisine and Lispro groups. GIR increased sharply during the first 150 min and reached a peak at 6.23 ± 1.35 mg/(kg min) in the Glulisine group and 6.02 ± 1.27 mg/(kg min) in the Lispro group. It returned to the initial level at hour 5. The Area Under Curve (AUC(0-clamp end)) in Glulisine and Lispro groups were 1455.04 ± 381.88 mg/kg and 1356.25 ± 287.30 mg/kg (P > 0.05), respectively. However, AUC(0-1h) between the two groups showed significant difference, with Glulisine showed greater AUC(0-1h) in the first hour after injection. Other parameters showed no significant difference between the two groups. Insulin analogs Glulisine and Lispro were proved to have equivalent pharmacokinetic and pharmacodynamic parameters when administered to healthy Chinese adults, but with Glulisine showing greater AUC(0-1h) after injection.

Topics: Adult; Asian People; C-Peptide; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Lispro; Male; Reference Values; Therapeutic Equivalency; Young Adult

Prolonged elevation of plasma nonesterified fatty acids (NEFA) induces insulin resistance and impairs pancreatic β-cell adaptation to insulin resistance. Studies in rodents suggest that inflammation may play a role in this "lipotoxicity." We studied the effects of sodium salicylate, an anti-inflammatory agent, on lipid-induced alterations in β-cell function and insulin sensitivity in six overweight and obese nondiabetic men. Each subject underwent four separate studies, 4-6 wk apart, in random order: 1) SAL, 1-wk placebo followed by intravenous (iv) infusion of saline for 48 h; 2) IH, 1-wk placebo followed by iv infusion of intralipid plus heparin for 48 h to raise plasma NEFA approximately twofold; 3) IH + SS, 1-wk sodium salicylate (4.5 g/day) followed by 48-h IH infusion; and 4) SS, 1-wk oral sodium salicylate followed by 48-h saline infusion. After 48-h saline or lipid infusion, insulin secretion and sensitivity were assessed by hyperglycemic clamp and euglycemic hyperinsulinemic clamp, respectively, in sequential order. Insulin sensitivity was reduced by lipid infusion (IH = 67% of SAL) and was not improved by salicylate (IH + SS = 56% of SAL). Lipid infusion also reduced the disposition index (P < 0.05), which was not prevented by sodium salicylate. Salicylate reduced insulin clearance. These data suggest that oral sodium salicylate at this dose impairs insulin clearance but does not ameliorate lipid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Area Under Curve; C-Peptide; Emulsions; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Heparin; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Overweight; Phospholipids; Sodium Salicylate; Soybean Oil; Triglycerides

Obesity is positively associated with hyperinsulinaemia, and it has been suggested that hyperinsulinaemia may contribute to maintain the obese state in insulin-resistant obese individuals. The aim of the present study was to investigate the effect of inhibition of insulin secretion by diazoxide on weight loss in obese, normoglycaemic (fasting plasma glucose of > or =6.1 mmol/l), hyperinsulinaemic (fasting plasma insulin of > or =100 pmol/l) adults during a 2.5 MJ/day energy-deficient diet.. In an 8-week, double-blind, placebo-controlled parallel design, 35 overweight and obese subjects (age: 23-54 years, body mass index: 27-66 kg/m(2)) were randomized either to 2 mg/kg/day (maximum 200 mg/day) of oral diazoxide or to placebo. Body composition and resting energy expenditure (REE) were measured before and after the intervention. Blood samples, and appetite sensations by visual analogue scales, were collected during fasting, during an oral glucose tolerance test (OGTT) and 4 h postprandially after a test meal. Subsequently, an ad libitum meal was given.. Thirty-one subjects completed the protocol. Eight weeks of diazoxide decreased incremental area under the response curve (iAUC) for insulin (iAUC(insulin)) and for C-peptide (iAUC(C-peptide)) and increased iAUC for glucose (iAUC(glucose)) during the OGTT and the test meal compared with the use of placebo (p < 0.003). No differences in changes between the groups in body weight, body fat, REE or appetite were observed during the 8-week trial.. These findings do not suggest that hyperinsulinaemia per se contributes to maintenance of the obese state, and insulin secretion inhibition seems not a promising drug target.

Topics: Adult; Blood Glucose; C-Peptide; Counseling; Diazoxide; Diet, Reducing; Double-Blind Method; Energy Intake; Female; Humans; Hyperinsulinism; Insulin; Insulin Antagonists; Insulin Secretion; Male; Obesity; Patient Dropouts; Placebos; Vasodilator Agents; Weight Loss

We evaluated the respective value of insulin, C-peptide and proinsulin levels in 33 patients with endogenous hyperinsulinism and in 67 controls to determine the best parameters and thresholds to make or to rule out the diagnosis of endogenous hyperinsulinism.. When blood glucose levels were below 2.5 mmol/l, insulin was <21 pmol/l in 8-35% of the patients and in all controls; C-peptide was >0.2 nmol/l in all insulinomas but not in the nesidioblastosis or in the controls; proinsulin was >5 pmol/l in all patients but not in the controls. When fasting blood glucose levels reached 2.5-3.3 mmol/l, proinsulin was <22 pmol/l in all the controls and >22 pmol/l in 74% of the patients. Proinsulin after an overnight fast was below 22 pmol/l in all non-obese controls and above 22 pmol/l in 73% of non-obese patients.. Proinsulin levels above 5 pmol/l with blood glucose levels below 2.5 mmol/l during a 72 h fast test represent the best criterion for the diagnosis of endogenous hyperinsulinism, reaching 100% diagnostic specificity and sensitivity. Concomitant C-peptide levels above 0.2 nmol/l also make the diagnosis of all our insulinoma patients, not the diagnosis of nesidioblastosis, while insulin levels have much less diagnostic accuracy. Whether proinsulin levels above 22 pmol/l could also make the diagnosis of endogenous hyperinsulinism in part of the patients at the time of fasting blood glucose levels between 2.5 and 3.3 mmol/l or after an overnight fast in non-obese subjects needs further study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Circadian Rhythm; Diagnostic Techniques, Endocrine; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Proinsulin; Sensitivity and Specificity; Time Factors

Concentrations of the orexigenic peptide ghrelin is affected by a number of hormones, which also affect circulating levels of free fatty acids (FFAs). The present study was therefore designed to determine the direct effect of FFAs on circulating ghrelin.. Eight lean, healthy men were examined for 8 h on four occasions using variable infusion rates (0, 3, 6 and 12 microl/kg per min) of intralipid to create different plasma FFA concentrations. Constant levels of insulin and GH were obtained by administration of acipimox (250 mg) and somatostatin (300 microg/h). At the end of each study day a hyperinsulinaemic-euglycaemic clamp was performed.. Four distinct levels of FFAs were obtained at the end of the lipid infusion period (FFA(LIPID): 0.03 +/- 0.00 vs: 0.49 +/- 0.04, 0.92 +/- 0.08 and 2.09 +/- 0.38 mmol/l; ANOVA P < 0.0001) and during hyperinsulinaemia (FFA(LIPID+INSULIN): 0.02 +/- 0.00 vs: 0.34 +/- 0.03, 0.68 +/- 0.09 and 1.78 +/- 0.32 mmol/l; ANOVA P < 0.0001). Whereas, somatostatin infusion alone reduced ghrelin concentration by approximately 67%, concomitant administration of increasing amounts of intralipid reduced circulating ghrelin by a further 14, 19 and 19% respectively (change in ghrelin: 0.52 +/- 0.05 vs: 0.62 +/- 0.06, 0.72 +/- 0.09 and 0.71 +/- 0.05 microg/l; ANOVA P = 0.04). No further reduction in ghrelin concentration was observed during hyperinsulinaemia.. FFA exposure between 0 and 1 mmol/l significantly suppresses ghrelin levels independent of ambient GH and insulin levels.

Topics: Adult; Anticoagulants; Blood Glucose; C-Peptide; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Ghrelin; Glucose Clamp Technique; Heparin; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypolipidemic Agents; Insulin; Male; Peptide Hormones; Pyrazines; Somatostatin

To determine the effect of naltrexone (an opiate receptor blocker) on insulin metabolism in postmenopausal women with different insulinemic patterns.. Randomized placebo-controlled study.. Academic research environment.. Forty-one healthy normoinsulinemic or hyperinsulinemic postmenopausal women.. Oral glucose tolerance test (OGTT) before and after 5 weeks of the opioid antagonist (naltrexone, 50 mg/d orally) or the placebo administration; euglycemic-hyperinsulinemic glucose clamp.. Glucose, insulin, and C-peptide plasma levels assessed in fasting condition and during the OGTT. Insulin sensitivity was calculated as total body glucose utilization.. Naltrexone reduced fasting and stimulated insulin response to the glucose load while inducing a significant improvement of the hepatic extraction, only in the hyperinsulinemic patients. No differences were found in the C-peptide pancreatic secretion and in the peripheral insulin sensitivity. No net change in the glycoinsulinemic metabolism was observed in normoinsulinemic patients or in placebo-controlled normoinsulinemic and hyperinsulinemic subjects.. Similar to that reported in premenopausal women, endogenous opioid peptides are involved in the modulation of glycoinsulinemic metabolism in postmenopause. Through a prevalent action on liver insulin metabolism, without any clear improvement of insulin resistance and pancreatic beta-cell function, the chronic administration of naltrexone appears to reduce the hyperinsulinemia in those women with an exaggerated insulin response to the OGTT.

Topics: Blood Glucose; C-Peptide; Fasting; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Middle Aged; Naltrexone; Narcotic Antagonists; Pilot Projects; Postmenopause; Treatment Outcome

Hyperproinsulinaemia reflects both beta cell dysfunction and insulin resistance in cross-sectional studies, but it is not known whether changes in proinsulin concentrations are related to insulin resistance over time. As trans10cis12 (t10c12)-conjugated linoleic acid (CLA) supplementation induces insulin resistance in obese men, we used this fatty acid to investigate the effects on plasma proinsulin, insulin, C-peptide and adiponectin concentrations, including their associations with change in insulin sensitivity.. We randomised (double-blind) 57 non-diabetic abdominally obese men to receive either 3.4 g t10c12CLA, CLA-isomer mixture or control oil for 12 weeks. Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), intact proinsulin, insulin, the proinsulin : insulin ratio, C-peptide, glucose and adiponectin were assessed before and after supplementation.. Supplementation with t10c12CLA increased proinsulin (p<0.01), the proinsulin : insulin ratio (p<0.05) and C-peptide concentrations (p<0.001) in comparison with control subjects. Adiponectin, however, did not change significantly. The change in proinsulin, but not the proinsulin : insulin ratio, was related to impaired insulin sensitivity (r= -0.58, p<0.0001), independently of changes in insulin, C-peptide, glucose, adiponectin and BMI. Conversely, the correlation between insulin sensitivity and specific insulin (r=-0.46, p<0.001) did not remain significant after adjustment for proinsulin. Induced hyperproinsulinaemia was also correlated to adiponectin concentrations ( r= -0.34, p<0.01).. In obese men, t10c12CLA induces hyperproinsulinaemia that is related to impaired insulin sensitivity, independently of changes in insulin concentrations. These results are of clinical interest, as hyperproinsulinaemia predicts diabetes and cardiovascular disease. The use of weight-loss supplements containing this fatty acid is worrying.

Topics: Abdomen; Adiponectin; Adipose Tissue; Analysis of Variance; Blood Glucose; C-Peptide; Dietary Supplements; Double-Blind Method; Drug Administration Schedule; Humans; Hyperinsulinism; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Linoleic Acids, Conjugated; Male; Obesity; Time Factors

To examine the insulinomimetic insulin-independent effects of glucagon-like peptide (GLP)-1 on glucose uptake in type 1 diabetic patients.. We used the hyperinsulinemic-euglycemic clamp (480 pmol. m(-2) x min(-1)) in paired randomized studies of six women and five men with type 1 diabetes. In the course of one of the paired studies, the subjects also received GLP-1 at a dose of 1.5 pmol. kg(-1) x min(-1). The patients were 41 +/- 3 years old with a BMI of 25 +/- 1 kg/m(2). The mean duration of diabetes was 23 +/- 3 years.. Plasma glucose was allowed to fall from a fasting level of approximately 11 mmol/l to 5.3 mmol/l in each study and thereafter was held stable at that level. Plasma insulin levels during both studies were approximately 900 pmol/l. Plasma C-peptide levels did not change during the studies. In the GLP-1 study, plasma total GLP-1 levels were elevated from the fasting level of 31 +/- 3 to 150 +/- 17 pmol/l. Plasma glucagon levels fell from the fasting levels of approximately 14 pmol/l to 9 pmol/l during both paired studies. Hepatic glucose production was suppressed during the glucose clamps in all studies. Glucose uptake was not different between the two studies ( approximately 40 micromol. kg(-1) x min(-1)).. GLP-1 does not augment insulin-mediated glucose uptake in lean type 1 diabetic patients.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Liver; Male; Neurotransmitter Agents; Peptide Fragments; Peptides

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural and adrenomedullary response and the resulting neurogenic [autonomic] symptom responses) and thus causes a vicious cycle of recurrent hypoglycemia. To assess the suggestion that it is the cortisol response to antecedent hypoglycemia that mediates HAAF, we tested the hypothesis that plasma cortisol elevations during euglycemia that are comparable to those that occur during hypoglycemia reduce sympathoadrenal and neurogenic symptom responses to subsequent hypoglycemia. To do this, 12 healthy subjects were studied with hyperinsulinemic-stepped hypoglycemic clamps the day after saline or cortisol (1.3 +/- 0.2 micro g. kg(-1) x min(-1)) infusions from 0930 to 1200 and from 1330 to 1600. Compared with saline, antecedent cortisol elevations did not reduce the sympathoadrenal (e.g., final plasma epinephrine levels of 674 +/- 84 vs. 606 +/- 80 pg/ml and final plasma norepinephrine levels of 332 +/- 26 vs. 304 +/- 26 pg/ml) or neurogenic symptom (e.g., final scores of 9.3 +/- 1.1 vs. 13.2 +/- 1.3) responses to subsequent hypoglycemia. Thus, these data do not support the suggestion that cortisol mediates HAAF.

Topics: Adult; Anti-Inflammatory Agents; Autonomic Nervous System Diseases; C-Peptide; Diabetic Neuropathies; Epinephrine; Female; Glucose Clamp Technique; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Male; Norepinephrine; Sodium Chloride

Insulin is normally secreted in man in regular pulses every 5 to 15 minutes. Disordered pulsation has been demonstrated in several insulin-resistant states and it is unclear whether this represents a primary beta-cell defect contributing to impairment of peripheral insulin action or rather is a consequence of insulin resistance. Basal or near basal insulin administration by pulsatile infusion augments hypoglycemic effect and improves insulin-mediated glucose uptake compared with insulin by continuous infusion. To date no study has examined whether normal basal insulin pulsatility is required to preserve subsequent insulin sensitivity during hyperinsulinemia. We studied the effect of overnight pulsatile versus continuous basal insulin on a subsequent hyperinsulinemic euglycemic clamp. Nineteen normal volunteers (male:female ratio, 17:2; mean age +/- SEM, 26.1 +/- 2.3 years) were studied on 2 occasions each. Endogenous insulin secretion was inhibited by octreotide (0.43 microg kg(-1). h(-1)) and replaced overnight at 5.4 mU kg(-1). h(-1) either by continuous infusion or in 2-minute pulses every 13 minutes (n = 10) or every 7 minutes (n = 9). Glucagon was replaced at physiological concentration by continuous infusion (30 ng. kg(-1). h(-1)). Venous plasma glucose overnight was not significantly different between the pulsatile and continuous protocols. After discontinuing the overnight insulin infusion, insulin action was assessed during a hyperinsulinemic euglycemic clamp (1 mU kg(-1). h(-1)). Glucose infusion rates at steady-state during the hyperinsulinemic clamp were similar between continuous and both frequencies of pulsatile infusion (continuous 44.6 +/- 4.3 micromol. kg(-1). min(-1) v 13-minute pulsatile 41.7 +/- 5.9 micromol. kg(-1). min(-1), P =.27; continuous 34.6 +/- 2.5 micromol. kg(-1) min(-1) v 7-minute pulsatile 41.4 +/- 3.2 micromol. kg(-1). min(-1), P =.08). We conclude that overnight pulsatile compared with continuous insulin administration has no different effect on subsequent peripheral insulin-mediated glucose uptake. A priming effect cannot therefore explain the previously demonstrated association between endogenous insulin pulse frequency and peripheral insulin action.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Fatty Acids; Female; Gastrointestinal Agents; Glucagon; Glycerol; Human Growth Hormone; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Male; Octreotide

The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients.. We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin.. Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l.. Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Immunoradiometric Assay; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin

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

To evaluate the influence of the opioid system on glyco-regulation in postmenopausal women before and after hormone replacement therapy (HRT).. Prospective nonrandomized clinical study.. Academic research environment.. Twenty-one healthy normo- or hyperinsulinemic postmenopausal women.. Oral glucose tolerance test (OGTT) (saline study), OGTT with IV injection of naloxone (naloxone study), and hyperinsulinemic euglycemic clamp performed before treatment, after 12 weeks of estrogen replacement therapy (ERT), and after 12 additional weeks of estro-progestin combined therapy (i.e., HRT).. Glucose, insulin, and c-peptide plasma levels assessed in fasting condition and during the two OGTTs (area under the curve [AUC]). Evaluation of fractional hepatic insulin extraction (FHIE) and peripheral sensitivity to insulin.. At baseline, there is a greater increase of the FHIE and a more significant reduction of the insulin AUC in the hyperinsulinemic patients during the naloxone study compared with the saline study. In these women, ERT enhanced the c-peptide AUC and improved the FHIE; naloxone infusion mainly increased these two parameters. HRT did not induce any further change.. Endogenous opioid peptides are involved in the modulation of carbohydrate metabolism in menopause in hyperinsulinemic patients more than in other patients. The favorable changes of the glyco-insulinemic metabolism induced by HRT may be partially due to the induction of the opioidergic activity.

Topics: Area Under Curve; C-Peptide; Drug Synergism; Estrogen Replacement Therapy; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Antagonists; Insulin Secretion; Middle Aged; Naloxone; Narcotic Antagonists; Postmenopause; Prospective Studies; Sodium Chloride

Hypoglycemia-associated autonomic failure (HAAF)-reduced autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia caused by recent antecedent hypoglycemia-plays a key role in the pathogenesis of defective glucose counterregulation and hypoglycemia unawareness and thus iatrogenic hypoglycemia in type 1 diabetes. On the basis of the findings that cortisol infusion mimics and deficient or inhibited cortisol secretion minimizes this phenomenon, it has been suggested that the cortisol response to antecedent hypoglycemia mediates HAAF. We tested the hypothesis that any stimulus that releases cortisol, such as exercise, reduces autonomic and symptomatic responses to subsequent hypoglycemia. Thirteen healthy young adults (four women) were studied on three occasions in random sequence: 1) cycle exercise ( approximately 70% peak oxygen consumption) from 0830 to 0930 h and from 1200 to 1300 h on day 1 and hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic (85, 75, 65, 55, and 45 mg/dl) clamps on day 2, 2) rest on day 1 and identical hypoglycemic clamps on day 2, and 3) hyperinsulinemic-euglycemic clamps. Exercise raised plasma cortisol concentrations to 16.9 +/- 1.9 (0930 h) and 16.6 +/- 1.6 microg/dl (1300 h) on day 1. Compared with rest on day 1, exercise on day 1 was associated with reduced epinephrine (P = 0.0113) responses-but not norepinephrine (P = 0.6270), neurogenic symptom (P = 0.6470), pancreatic polypeptide (P = 0.0629), or glucagon (P = 0.0436, but higher) responses-to hypoglycemia on day 2. However, the effect was small. (The final day 2 hypoglycemia epinephrine values were 765 +/- 106 pg/ml after rest on day 1 and 550 +/- 94 pg/ml after exercise on day 1 compared with 30 +/- 6 pg/ml during euglycemia.) These data are consistent with the hypothesis that the cortisol response to hypoglycemia mediates in part the reduced epinephrine response to subsequent hypoglycemia, one key component of HAAF in type 1 diabetes. However, the small effect suggests that an additional factor or factors may well be involved. These data do not support the hypothesis that the cortisol response to hypoglycemia mediates the reduced neurogenic symptom response to subsequent hypoglycemia, another key component of HAAF in type 1 diabetes.

Topics: Adult; Autonomic Nervous System; Blood Glucose; C-Peptide; Epinephrine; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Male; Norepinephrine; Physical Exertion; Rest

Elevation of plasma concentrations of nonesterified fatty acids (NEFA) has been reported to result in protein sparing and in impaired insulin-mediated glucose metabolism. To assess the influence of the chain length of fatty acids on these effects, medium-chain (MC) and long-chain (LC) fatty acid-containing lipid emulsions (2 mg/kg/min each) combined with heparin were administered during 390 minutes to 25 healthy overnight-fasted male subjects. Whole body leucine flux (a parameter of whole body protein breakdown) decreased during MC triglycerides (MCT) by 20% (P <.005). Irreversible leucine catabolism (oxidation of [1-(13)C]-leucine) decreased during LC triglycerides (LCT) by 40% (P <.01) but not during MCT when compared to controls receiving glycerol infusions. MCT administration resulted in a marked (52 %, P <.001) decrease of alpha-ketoisocaproate (alpha-KIC) concentration, suggesting diminished leucine transamination and decreased leucine nonoxidative disappearance (P <.015). Hyperinsulinemia (30 to 40 microU/mL, euglycemic clamping) resulted in decreased leucine flux and oxidation during both lipid infusions, particularly during MCT. The increase in glucose disappearance during hyperinsulinemia in subjects receiving MCT or LCT was less than in controls, and endogenous glucose production measured by 6,6-D(2)-glucose infusions was less suppressed (P <.01). Thus, elevation of plasma LC fatty acids (but not of MC fatty acids) results in decreased leucine oxidation (protein catabolism). This protein-sparing effect of LCT appears to be dissociated from fatty acid effects on glucose metabolism; both MCT and LCT diminished insulin's ability to increase glucose disappearance and to decrease hepatic glucose production.

Topics: Adult; C-Peptide; Carbon Isotopes; Fatty Acids; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Keto Acids; Lactic Acid; Leucine; Liver; Male; Oxidation-Reduction; Proteins; Reference Values; Triglycerides

The purpose of this investigation was to examine the effect of caffeine (an adenosine receptor antagonist) on whole-body insulin-mediated glucose disposal in resting humans. We hypothesized that glucose disposal would be lower after the administration of caffeine compared with placebo. Healthy, lean, sedentary (n = 9) men underwent two trial sessions, one after caffeine administration (5 mg/kg body wt) and one after placebo administration (dextrose) in a double-blind randomized design. Glucose disposal was assessed using a hyperinsulinemic-euglycemic clamp. Before the clamp, there were no differences in circulating levels of methylxanthines, catecholamines, or glucose. Euglycemia was maintained throughout the clamp with no difference in plasma glucose concentrations between trials. The insulin concentrations were also similar in the caffeine and placebo trials. After caffeine administration, glucose disposal was 6.38 +/- 0.76 mg/kg body wt compared with 8.42 +/- 0.63 mg/kg body wt after the placebo trial. This represents a significant (P < 0.05) decrease (24%) in glucose disposal after caffeine ingestion. In addition, carbohydrate storage was 35% lower (P < 0.05) in the caffeine trial than in the placebo trial. Furthermore, even when the difference in glucose disposal was normalized between the trials, there was a 23% difference in the amount of carbohydrate stored after caffeine administration compared with placebo administration. Caffeine ingestion also resulted in higher plasma epinephrine levels than placebo ingestion (P < 0.05). These data support our hypothesis that caffeine ingestion decreases glucose disposal and suggests that adenosine plays a role in regulating glucose disposal in resting humans.

Topics: Administration, Oral; Adult; C-Peptide; Caffeine; Calorimetry; Double-Blind Method; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glycerol; Humans; Hyperinsulinism; Insulin; Lactic Acid; Life Style; Male; Physical Exertion; Purinergic P1 Receptor Antagonists

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

Glargine, a product of recombinant technology, has different structural and physicochemical properties compared with native human insulin. We determined whether such differences are associated with alterations in the responses to hypoglycaemia induced by glargine.. Nineteen adults (six healthy and 13 with type 1 diabetes) underwent a 5-h hyperinsulinaemic (2 mU/kg/min(-1)) stepped hypoglycaemic clamps (hourly targets of 4.7, 4.2, 3.6, 3.1 and 2.5 mmol/l, respectively) on two occasions using intravenous infusion of regular human insulin or glargine, in random sequence. Hypoglycaemic symptoms, counter-regulatory hormones and glucose disposal rates were assessed at intervals throughout the clamps. A 1-week 'wash out' period was observed between studies.. The peak total symptoms scores (mean +/- s.e.m.) at nadir blood glucose (2.5 mmol/1) were 18.83 +/- 2.68 (healthy) and 17.46 +/- 3.62 (diabetic) during regular insulin, and 18.50 +/- 3.20 (healthy) and 19.08 +/- 3.83 (diabetic) during glargine infusion. The peak epinephrine levels during hypoglycaemia were 767.8 +/- 140.4 pg/ml (regular insulin) and 608.8 +/- 129.9 pg/ml (glargine) among healthy subjects, and 332.5 +/- 54.8 pg/ml (regular insulin) and 321.8 +/- 67.4 pg/ml (glargine) in diabetic patients. Diabetic patients had blunted glucagon responses during hypoglycaemia with either insulin. Both insulins also elicited similar rates of glucose disposal.. We conclude that insulin glargine and regular human insulin elicit comparable symptomatic and counter-regulatory hormonal responses during hypoglycaemia in healthy or diabetic subjects, and induce similar rates of glucose disposal. Since glargine is designed for subcutaneous (s.c.) use, it is possible (though unlikely) that our findings obtained using an intravenous protocol could differ from responses to hypoglycaemia induced by the s.c. route.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Norepinephrine; Recombinant Proteins; Reference Values

Insulin sensitivity can be quantitatively measured by the hyperinsulinaemic euglycaemic glucose clamp technique. Infusion of insulin during the clamp procedure leads to a decline of kalaemia unless potassium is supplied. We investigated whether supplementation of potassium during euglycaemic glucose clamps influences insulin sensitivity. In a randomised study the insulin sensitivity index (S(I)) was determined with two-step hyperinsulinaemic (insulin infusion rates 0.25 (step 1) and 1.0 mU kg(-1) min(-1) (step 2)) euglycaemic (5.0 mmol L(-1)) glucose clamps in 20 healthy male volunteers on two different study days. On one day blood potassium was kept constant by means of a variable i.v. potassium chloride infusion ("eukalaemic potassium clamp"), whereas on the other day the decline in blood potassium was monitored only. Without potassium supply kalaemia decreased from basal levels of 4.35 +/- 0.18 mval L(-1) to 4.25 +/- 0.17 (step 1) and further to 3.88 +/-0.14 mval L(-1) (step 2 (mean +/- SD)). Without and with potassium supply the insulin sensitivity index measured was comparable (S1 10.6 +/- 3.6 vs. 9.5 +/- 3.5 ml min(-1) m2 per microU ml(-1), n.s.; glucose infusion rates 3.6+/-1.6/12.6 +/- 2.6 (step 1/step 2) vs. 3.7 +/- 1.5/12.2 +/- 2.7 mg kg(-1) min(-1), n.s.). In conclusion, this study shows that potassium supply during hyperinsulinaemic euglycaemic glucose clamps in healthy subjects does not influence the insulin sensitivity index.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Glucose Clamp Technique; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Male; Metabolic Clearance Rate; Potassium; Reference Values; Renin

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the beta-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 microg/kg, s.c., every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 +/- 11.1 vs. 6.3 +/- 2.2 microIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 +/- 0.7 vs. 1.2 +/- 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.

Topics: Adult; ATP-Binding Cassette Transporters; Blood Glucose; C-Peptide; Child; Child, Preschool; Fasting; Female; Humans; Hyperinsulinism; Infant; Insulin; Insulin Secretion; Insulin-Like Growth Factor I; Islets of Langerhans; Male; Mutation; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Recombinant Proteins; Sulfonylurea Receptors

To investigate insulin metabolism and its modifications induced by the administration of flutamide, a specific antiandrogen compound, in women with idiopathic hirsutism (IH) and in nonobese women with polycystic ovary syndrome (PCOS).. Prospective, randomized trial.. Endocrinological Centre of the Department of Obstetrics and Gynecology, University of Caligari, Caligari, Italy.. Thirty-two women with normal body mass index participated in the study: 11 with clinical and hormonal features of PCOS and 21 age- and weight-matched normally cycling women with IH (n = 11) and without IH (n = 10, controls).. Each subject with PCOS or IH was assigned randomly to receive either flutamide tablets (250 mg twice a day) or placebo for > or =5 months. Twelve subjects (6 with PCOS, 6 with IH) received flutamide and 10 (5 with PCOS, 5 with IH) received placebo. All subjects ingested 75 g of glucose and then underwent an oral glucose tolerance test (OGTT), 3-7 days after spontaneous or medroxyprogesterone acetate (5 mg daily for 5 days)-induced menses. In women with PCOS or IH, the OGTT was repeated at the fourth month of treatment.. Fasting and OGTT-stimulated levels of glucose, insulin, and C peptide.. Both fasting and OGTT-stimulated levels of insulin and C peptide were significantly higher in women with PCOS and in those with IH than in controls. Placebo did not modify parameters of glucose metabolism. Flutamide was capable of significantly blunting fasting and OGTT-stimulated secretion of insulin only in women with IH.. Hyperinsulinemia exists in women with IH as well as in nonobese women with PCOS. Treatment with flutamide can completely reverse hyperinsulinemia only in women with IH, which suggests that the efficacy of the drug is dependent on peripheral androgen hyperactivity.

Topics: Adult; Androgen Antagonists; Blood Glucose; C-Peptide; Female; Flutamide; Follicle Stimulating Hormone; Glucose Tolerance Test; Hirsutism; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Luteinizing Hormone; Polycystic Ovary Syndrome; Prospective Studies

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

Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis.. A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels.. There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group.. These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Topics: Aged; Antioxidants; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycosuria; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis, Alcoholic; Male; Malondialdehyde; Middle Aged; Silymarin; Time Factors

We investigated how fasting or postprandial insulin levels were altered by treatment with acarbose or sulfonylureas. Plasma glucose and serum insulin, C-peptide, and proinsulin levels were measured before as well as 1 and 2 h after breakfast in 23 patients with non-insulin-dependent diabetes mellitus and 17 patients with impaired glucose tolerance. In the diabetic patients, 12 weeks of acarbose therapy decreased the postprandial levels of glucose (1 h: -60.0%; 2 h: -67.6%), insulin (1 h: -67.5%; 2 h: -72.2%) and proinsulin (1 h: -55.2%; 2 h: -46.7%), and proinsulin (1 h: -20.9%; 2 h: -57.5%). In contrast, sulfonylurea treatment increased postprandial insulin and proinsulin levels. Since increased in the serum insulin or proinsulin levels are associated with a higher risk of cardiovascular disease, the present findings suggest that the acarbose-induced reduction of the postprandial serum insulin or proinsulin responses to food intake might be useful for preventing vascular complications in patients with diabetes.

Topics: Acarbose; Aged; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Gliclazide; Glucose Intolerance; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Middle Aged; Postprandial Period; Proinsulin; Time Factors; Tolbutamide; Triglycerides; Trisaccharides

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

Our paper is discussing the presence and intensity of metabolic, humoral and haemodynamic abnormalities in mild middle-aged essential hypertensives (EH) and in hereditary predisposed still normotensive offspring from hypertensive families and their possible association with candidate genes changes. Four groups of subjects were compared (middle-aged normotensive controls (n = 21), corresponding patients with EH (n = 21), normotensive offspring from hypertensive (SH) (n = 56) and normotensive families (SN) (n = 56). Our results demonstrate that middle-aged patients with EH in our country have the same indices of hyperinsulinemia, impared glucose tolerance and insulin-sensitivity as previously described for other populations. They are accompanied by higher plasma concentrations of vasopressor substance like catecholamines, endothelin and lower levels of vasodepressor substances as ANP and kallikrein. The finding of similar, but quantitatively less expressed metabolic and humoral changes in SH but not in SN support the evidence for hereditary background of these abnormalities. The humoral and metabolic abnormalities may participate in BP elevation and in morphological and functional changes of left ventricle seen in SH (higher LV mass index, impaired diastolic filling). We did not prove an association between BP and polymorphism of ACE and angiotensinogen genes, however, our findings of association of DD genotype for ACE and M235 for angiotensinogen with higher insulinemia, plasma catecholamines and plasma renin activity evoke the hypothesis, whether the bearers of these genotypes, exposed for long-time to the higher concentrations of vascoactive substances, are not the subset of hereditary threatened subjects in whom clinically evident EH will manifest during their life.

Topics: Adult; Angiotensinogen; C-Peptide; Disease Susceptibility; Echocardiography; Epinephrine; Genotype; Humans; Hyperinsulinism; Hypertension; Kallikreins; Male; Norepinephrine; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To investigate the effect of insulin on cholesterol synthesis in vivo we measured plasma mevalonic acid (MVA) concentrations using gas chromatography-mass spectrometry in six non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM) [four men, two women; age 57.5 +/- 2.2 years (mean +/- SEM); glycated haemoglobin (HbA1) 8.5 +/- 0.5%; total cholesterol (TC) 5.7 +/- 0.5 mmol L-1, triglyceride (TG) 3.8 +/- 0.9 mmol L-1] and six non-diabetic, sex- and age-matched control subjects (age 55.7 +/- 2.8 years; HbA1 6.5 +/- 0.1%; TC 5.4 +/- 0.3 mmol L-1, TG 1.2 +/- 0.1 mmol L-1). Subjects were studied twice: during 13-h hyperinsulinaemic (1 mu kg-1 min-1), euglycaemic (5 mmol L-1) clamp and during a saline infusion. Baseline MVA concentration was significantly higher in diabetic patients than in control subjects (9.8 +/- 0.7 ng mL-1 vs. 5.6 +/- 0.9 ng mL-1, P = 0.004). At the end of each study, MVA concentration, expressed as a percentage of baseline, was significantly lower during the hyperinsulinaemic, euglycaemic clamp than during the saline study in both the diabetic (54.4 +/- 5.3% vs. 69.6 +/- 6.3%, P = 0.036) and control subjects (30.5 +/- 3.4% vs. 61.7 +/- 6.0%, P = 0.01). However, the decrease in MVA during the hyperinsulinaemic clamp study was more marked in the control subjects than in the diabetic subjects (P = 0.03). A significant positive correlation was found between percentage decrease of MVA and non-esterified fatty acids following the insulin clamp in NIDDM (r = 0.83, P = 0.04). We conclude that acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with NIDDM than in non-diabetic subjects and that this phenomenon, together with increased basal cholesterol synthesis in NIDDM, may in part be due to insulin resistance.

Topics: Analysis of Variance; Apolipoproteins E; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, HDL; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Gas Chromatography-Mass Spectrometry; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Male; Mevalonic Acid; Middle Aged; Phenotype; Random Allocation; Reference Values; Triglycerides

To establish the possible role of hyperinsulinemia in the elevation of plasma beta-endorphin (beta-EP) levels observed in obese patients after an oral glucose load.. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp.. Two groups of six (age: 22-39 y, BMI: 30-48 kg/m2) and eight obese men (age: 18-37 y, BMI: 35-45 kg/m2), respectively, and five normal weight healthy men (age: 22-30 y, BMI 22-23 kg/m2).. Glucose, insulin and beta-EP levels at baseline and every 30 min until 180 min during the OGTT; glucose, insulin, C-peptide and beta-EP concentrations at baseline and in steady state condition (i.e. during the last 30 min of insulin infusion) in the euglycemic-hyperinsulinemic clamp studies.. In the six obese patients undergoing the OGTT a significant elevation of beta-EP plasma levels was observed between 60 and 90 min after glucose ingestion. In the clamp studies no significant differences in beta-EP plasma levels, blood glucose and serum insulin were observed between obese and normal weight subjects both at baseline and at steady state. A markedly diminished insulin sensitivity along with a lower inhibition of C-peptide during insulin infusion was observed in obese patients compared to control subjects.. A rise in serum insulin levels unaccompanied by a concomitant increase in blood glucose concentration is unable to elicit a beta-EP response in obese patients.

Topics: Adolescent; Adult; beta-Endorphin; Blood Glucose; C-Peptide; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Obesity

The aim of this study was the evaluation of the relationships among hyperinsulinemia, a family history of hypertension, and essential hypertension. Insulin and C-peptide responses to an oral glucose load were studied in 175 lean normotensives (N) and untreated hypertensives (H) with (F+) and without (F-) a family history of hypertension: 30 NF-, 30 NF+, 45 HF-, and 70 HF+. The groups were comparable for age, sex, body mass index, and blood pressure. The following parameters were evaluated: plasma glucose (G), serum insulin (I), and C-peptide (Cp) before and 30, 60, 90, and 120 min after the glucose load, fasting glucose/insulin ratio (ISI), fasting insulin/C-peptide ratio (I/Cp), and 24-h ambulatory blood pressure monitoring. Plasma glucose was measured, fasting and during the test, and it and I/Cp were similar in the four groups. Serum insulin and Cp, both fasting and stimulated, were significantly higher and ISI lower in normotensives and hypertensives with hypertensive parents. Grouping the subjects first on the basis of blood pressure and then on the basis of family history, no differences were found between normotensives and hypertensives, whereas I and Cp, fasting and stimulated, were significantly higher and ISI lower in subjects with positive as compared to negative family history. The closest correlations between insulin and ambulatory blood pressure were found in normotensive with hypertensive parents; in hypertensives with hypertensive parents we only found a direct correlation between fasting Cp and nocturnal blood pressure fall; in hypertensives with normotensive parents insulin inversely correlated with nocturnal blood pressure fall. Insulin resistance seems to have a familial basis, independently of the presence of hypertension. Instead of showing a causal relationship between insulin resistance and hypertension, our results indicate that the two are partly independent components of a common familial pattern.

Topics: Adult; Area Under Curve; Blood Pressure; Blood Pressure Monitoring, Ambulatory; C-Peptide; Female; Glucose Tolerance Test; Heart Rate; Humans; Hyperinsulinism; Hypertension; Insulin; Male; Middle Aged

The aims of the present study were to investigate the effects of changes in sodium intake in patients with untreated mild essential hypertension on the hormonal (plasma renin activity and aldosterone) and renal tubular responses to short-term hyperinsulinemia as achieved by an oral glucose tolerance test (OGTT). Fourteen patients with essential hypertension (mean age, 46 years; average blood pressure (BP), 151/96 mm Hg) were studied. After a 1 week run-in period on their usual diet they entered a randomized double-blind crossover study of a week of low (10 mmol/day) vs a week of high (350 mmol/day) sodium intake. On the last day of each diet they underwent a standard 2-h OGTT. Blood and urines were taken hourly and segmental tubular sodium handling was assessed by the endogenous lithium clearance. The results demonstrate that the plasma insulin and glucose response to a short-term oral glucose load were not influenced significantly by the changes in dietary sodium intake. However, the glucose load was associated with marked renal sodium retention in the absence of any change in systemic BP. The reduction in renal sodium excretion was independent of circulating aldosterone but appeared to be due to an increase in renal distal tubular re-absorption.

Topics: Adolescent; Adult; Aldosterone; C-Peptide; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypertension; Insulin; Kidney; Male; Middle Aged; Renin; Sodium

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

It has been suggested that deviations from arterial euglycaemia during hyperinsulinaemic clamp experiments that use venous plasma glucose measurements may alter the results of such tests (glucose infusion rate, C-peptide suppression, etc.) and that 'arterialized' venous blood ('heated-hand' technique) may be suitable to circumvent these problems. Therefore, nine normal male fasting volunteers (age 25 +/- 4 years, body mass index 23.5 +/- 2.3 kg m-2) were examined three times using an insulin infusion of 1 mU kg min-1 over 120 min. Glucose was infused to maintain a concentration of 4.7 mmol I-1 (85 mg dl-1) in venous (V), 'arterialized' venous ('heated-hand' technique; HH), or capillary (C) plasma. The 'heated-hand' technique caused a rise in (rectal) body temperature of 0.3 +/- 0.1 degree C (P < 0.0001). Whereas the glucose aim was reached to a similar degree in all experiments (P = 0.36), capillary glucose concentrations differed slightly, but significantly (higher in experiments with venous and 'arterialized' venous blood specimens; P = 0.034). There were no significant differences regarding steady-state insulin concentrations (P = 0.77), glucose infusion rates (V, 7.1 +/- 0.5; HH, 7.2 +/- 0.6; C, 6.4 +/- 0.5 mg kg-1 min-1; P = 0.98), C-peptide suppression (P = 0.78), reduction in glucagon (P = 0.27) and free fatty acids (P = 0.16), and all parameters of indirect calorimetry (non-protein RQ: P = 0.67; glucose and lipid oxidation: P = 0.72 and 0.46 respectively; and energy expenditure: P = 0.42). Therefore, hyperinsulinaemic clamp experiments performed using venous, 'arterialized' venous, or capillary euglycaemia appear to be almost equally useful for the determination of insulin sensitivity and C-peptide or glucagon suppression. The elevation in body temperature that accompanies use of the 'heated-hand' technique does not noticeably influence measured metabolic parameters.

Topics: Adult; Arteries; Blood Gas Analysis; Blood Glucose; Blood Specimen Collection; Body Temperature; C-Peptide; Calorimetry, Indirect; Capillaries; Double-Blind Method; Humans; Hyperinsulinism; Insulin; Male; Oxygen; Veins

Insulin sensitivity was measured by insulin tolerance test using KITT as an index of insulin mediated glucose metabolism in 9 non-obese healthy offspring of conjugal diabetic parents (OCDP) and 9 non-obese NIDDM patients. The mean KITT value in the offspring of conjugal diabetic parents was 3.85 +/- 1.64 min-1 x 100 which was lower (P < 0.05) than the value of 5.49 +/- 1.9 min-1 x 100 in the control subjects. While, the mean KITT value in NIDDM patients was 1.85 +/- 0.9 min-1 x 100 which was significantly lower (P < 0.001) than that in the control subjects. Estimation of plasma immunoreactive insulin (IRI) and C-peptide in these subjects and in subjects with impaired glucose tolerance (IGT) showed significantly higher levels of insulin than that in the control subjects but there was no corresponding increase in the C-peptide levels. The mean area under the insulin curve (IRI) was 242 +/- 69 microU/ml in the control subjects versus 527 +/- 206 microU/ml in IGT (P < 0.001), 648 +/- 215 microU/ml in NIDDM (P < 0.001) and 466 +/- 130 microU/ml in OCDP (P < 0.001). These results suggest that 1) healthy offspring of two type II diabetic parents have decreased insulin sensitivity and insulin resistance is present in all the NIDDM patients, 2) peripheral hyperinsulinism is a common feature in healthy offspring of conjugal diabetic parents, and in subjects with IGT and mild NIDDM and this hyperinsulinism is not due to increased B-Cell secretion but due to some metabolic alterations of insulin occurring at the extra pancreatic levels.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male

The aim of this study was to examine the effect of acute alcohol intake on circulating concentrations of insulin, C-peptide, insulin-like growth factor (IGF) binding protein-1 (IGFBP-1), and plasma glucose levels. We measured these parameters for 12 hours after administration of 0, 0.5, or 1.0 g ethanol/kg body weight to nine healthy volunteers between 7:00 and 7:45 PM according to a randomized, double-blind, crossover design. Following a snack at 9:00 PM, plasma insulin (P < .05) and C-peptide (P < .01) concentrations were significantly increased at 10:00 PM in the 1.0-g group as compared with the control group. C-peptide to insulin molar ratios were significantly higher (P < .05) in both ethanol groups at 10:00 PM and 2:00 AM than in the control group. No differences were observed in plasma glucose levels between the three groups. Plasma IGFBP-1 levels showed a dose-dependent increase in the ethanol groups, and remained increased from 10:00 PM for 3 hours (P < .05 or less) at the lower dose and for 6 hours (P < .05 or less) at the higher dose. These observations indicate that ethanol-induced postprandial hyperinsulinemia is due to increased insulin secretion and that alcohol may increase hepatic insulin extraction. The lack of any effect on plasma glucose levels suggests that alcohol intake must be associated with decreased insulin sensitivity. Alcohol intake results in a paradoxical increase in peripheral concentrations of IGFBP-1 despite simultaneous hyperinsulinemia. This implies that ethanol has a direct stimulatory effect on hepatic IGFBP-1 synthesis.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Eating; Ethanol; Female; Humans; Hyperinsulinism; Insulin; Insulin-Like Growth Factor Binding Protein 1; Male

Women with a history of gestational diabetes mellitus (GDM) tend to be insulin-resistant and hyperinsulinemic and are predisposed to the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM). In the evolution of glucose intolerance, the first clinically detectable abnormality has not been defined and the relative importance of contributions of abnormal insulin secretion and insulin resistance is controversial. The present study was performed to evaluate the insulin secretory responses to oral and intravenous glucose and to mixed meals in women with a history of GDM, and to determine if the hyperinsulinemia present in these subjects is appropriate for the degree of insulin resistance. To address these questions, we studied the insulin secretory responses to oral glucose over a 3-hour period and to three mixed meals over a 24-hour period, and quantified the acute insulin response to glucose (AIRglucose) and insulin sensitivity (SI) during frequently sampled intravenous glucose tolerance tests (FSIVGTTs). Studies were performed in seven subjects with a history of GDM and in seven matched controls. Insulin secretion rates (ISRs) were derived by deconvolution of peripheral C-peptide values using a two-compartment model and standard C-peptide kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Causality; Diabetes Mellitus, Type 2; Diabetes, Gestational; Eating; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Injections, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Pregnancy; Proinsulin; Time Factors

In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 +/- 0.4% [mean +/- SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 +/- 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 +/- 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-(13)C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg.kg-1. h-1). VLDL apoB isotopic enrichment was determined with gas chromatography-mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 +/- 3.6 vs. 24.5 +/- 7.1 mg.kg-1.day-1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.

Topics: Apolipoprotein B-100; Apolipoproteins B; Apolipoproteins E; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Kinetics; Lipoproteins, VLDL; Liver; Male; Middle Aged; Phenotype; Time Factors

Hyperinsulinaemia and abnormalities in hepatic insulin extraction commonly coexist in ethnic groups with severe insulin resistance. Therefore, we compared the effects of ethnicity on glucose/insulin/C-peptide dynamics, hepatic insulin extraction, and insulin sensitivity in healthy black (n = 32) and white (n = 30) Americans. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified, frequently sampled, intravenous glucose tolerance (FSIVGT) tests were performed in each subject. Insulin sensitivity index (S1)) was calculated using the MINIMOD method described by Bergman et al. Basal and post-stimulation hepatic insulin extraction were calculated by the molar ratios of C-peptide and insulin concentrations during the basal steady state and areas under the post-stimulation hormone curves, respectively. Apart from a slightly greater mean serum glucose peak response after oral glucose in the whites, mean glucose levels were identical in the blacks and whites during both stimulations. In contrast, serum insulin levels at basal and during both stimulations were significantly greater (2-3 fold) in the blacks than whites. However, the corresponding C-peptide responses were identical in both groups. The basal and postprandial hepatic insulin extraction were 33% and 45% lower in the blacks when compared to whites, respectively. The mean S1 was significantly (p < 0.02) lower in the blacks (4.93 +/- 0.46) than the whites (7.17 +/- 0.88 x 10(-4).min-1 (mU l-1)-1). We conclude that ethnicity may be a major determinant of the mechanism of peripheral hyperinsulinaemia and insulin insensitivity in black and white Americans.

Topics: Administration, Oral; Adult; Black People; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; United States; White People

To evaluate whether beta-cell hyperfunction characterizes glucose intolerant states per se independent of fasting glycemia, we conducted a case-control study among 430 subjects who were classified, by NDGG criteria, as having normal glucose tolerance (n = 230, 130M/130F), nondiagnostic tolerance (NDT, n = 100, 50M/50F) and impaired glucose tolerance (IGT, n = 100, 50M/50F). Thirty-four subjects (17M/17F) with normal glucose tolerance were matched by age, sex, body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose and HbA1c with 30 NDT (15M/15F) and 30 IGT (15M/15F) subjects. The continuous and significant increase in insulin and C-peptide levels across categories of glucose tolerance (from normal to NDT to IGT) was no longer evident in the case-control study: at a fasting plasma glucose ranging from 5.2-5.5 mmol/L (HbA1c was 5%) the concentration of fasting C-peptide was 0.793 +/- 225 nmol/L (mean +/- SD) in subjects with normal glucose tolerance, 0.805 +/- 200 nmol/L in NDT and 0.807 +/- 231 nmol/L in IGT subjects (p = NS). Similarly, plasma concentrations of triglycerides and blood pressure values were similar when subjects of different categories were compared at the same level of glycemia. Sixteen normal subjects were rendered mildly hyperglycemic by a 24-h glucose infusion to match the fasting glucose level of NDT (1 mg/kg/min) and IGT (2 mg/kg/min) subjects. At the same fasting glucose level, normal subjects presented elevations of fasting C-peptide significantly (p < 0.01) higher than subjects belonging to the NDT and IGT categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Body Constitution; Body Mass Index; C-Peptide; Case-Control Studies; Female; Glucose Intolerance; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Triglycerides

To test the hypothesis that differing physiological insulin levels can modify the counter-regulatory response to prolonged hypoglycemia, experiments were carried out in 10 healthy male subjects. Insulin was infused subcutaneously for 8 h in two separate randomized protocols, so that steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucose-clamp technique. Plasma glucose fell slowly and similarly in both groups, reaching an identical steady-state (final 120 min of each study) level of 3.4 +/- 0.1 mM. Steady-state plasma epinephrine (2.5 +/- 0.4 vs. 1.5 +/- 0.2 nM) and norepinephrine (1.5 +/- 0.2 vs. 1.1 +/- 0.1 nM) were significantly (P < 0.05) greater during high- compared with low-dose insulin infusions. Plasma glucagon was reduced during high compared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Growth hormone, cortisol, and pancreatic polypeptide increased significantly but were not different during the two insulin infusions. Hepatic glucose production (HGP) was equal during the steady-state period (8.4 +/- 1.0 mumol.kg-1.min-1) of each infusion. Blood lactate levels (1,255 +/- 73 vs. 788 +/- 69 mumol/l, P < 0.02) were increased in high compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mumol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mumol/l) were reduced (P < 0.002) during the high-compared with low-dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Cardiovascular System; Glucose; Glucose Clamp Technique; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Kinetics; Liver; Male

A total of 507, newly diagnosed, white Caucasian Type 2 diabetic patients entered into UK Prospective Diabetes Study, mean age 52 +/- 9 (SD) years have been compared with 195 age-matched normal subjects (fasting plasma glucose < 6 mmol l-1) who had no known first degree relatives with diabetes. Diabetic patients were more obese BMI(kg m-2) 30.1 +/- 6.2 vs 26.2 +/- 4.0, respectively, with female (F) diabetic patients more so than male (M). Fasting plasma glucose (mmol l-1) was 12.2 +/- 3.8 vs 5.0 +/- 0.6 in diabetic and normal subjects, and, haemoglobin A1c(%) 9.3 +/- 2.3 vs 5.4 +/- 0.4. Hyperinsulinaemia (mU l-1) was prevalent in both male and female diabetic patients, after adjustment for BMI (geometric mean 1SD interval, M 12.1 (11.8 to 12.4) vs 8.3(7.8 to 8.9) and F 13.3 (12.9 to 13.7) vs 7.4 (7.1 to 7.7). Plasma triglyceride (mmol l-1) was higher in diabetic patients, 1.8 (1.1 to 2.9) vs 1.1 (0.6 to 1.8). Total cholesterol (mmol-1) was slightly elevated in diabetic patients, with females in both populations higher than males, M 5.5 +/- 1.2 vs 5.2 +/- 0.9 and F 5.8 +/- 1.1 vs 5.5 +/- 1.1. HDL cholesterol (mmol l-1) was slightly lower in male and markedly lower in female diabetic patients than in normal subjects, M 1.00 +/- 0.26 vs 1.11 +/- 0.22 and F 1.12 +/- 0.27 vs 1.42 +/- 0.33. Urine albumin was raised in diabetic patients (mg l-1) 16.3 (5.2 to 50.9) vs 7.2 (3.2 to 16.5), as was urine N-acetylglucosaminidase (U l-1 6.4 (3.5 to 11.7) vs 2.9 (1.9 to 4.5) and plasma N-acetylglucosaminidase (U l-1) 11.5 +/- 3.2 vs 10.2 +/- 2.3. Normal subjects aged above 65 years, had slightly higher haemoglobin A1c, insulin, C-peptide, plasma and LDL cholesterol, triglyceride, plasma and urine N-acetylglucosaminidase and lower HDL cholesterol than younger subjects. The 2.5 and 97.5 percentiles for biochemical variables are presented for both populations aged 25-65 years.

Topics: Acetylglucosaminidase; Adult; Age Factors; Aged; Albuminuria; Biomarkers; Blood Glucose; C-Peptide; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Female; Fructosamine; Glycated Hemoglobin; Growth Hormone; Hexosamines; Humans; Hyperinsulinism; Insulin; Laboratories; Male; Middle Aged; Prevalence; Prospective Studies; Quality Control; Reference Values; Risk Factors; Sex Characteristics; Triglycerides; United Kingdom

Insulin resistance and hyperinsulinaemia are, in some prospective studies, linked to an increased cardiovascular risk, at least in men. We tested the hypothesis that hyperinsulinaemia may be reduced by non-pharmacological methods independently of other cardiovascular risk factors.. In a non-pharmacological intervention study for 1 year three groups of subjects (hypertensives as well as normotensives) were selected after stratification for insulin level at baseline. Half of the hyperinsulinaemic subjects were randomly assigned to active intervention with physical exercise and dietary regulation (HI-A group), the other half were followed passively during the study period (HI-P group). Normo-insulinaemics and hypo(low)-insulinaemics also underwent active intervention (NI-A and LI-A groups, respectively).. Primary health care in Sweden.. During the 1-year follow-up subjects in the HI-A group reduced their weight, waist:hip ratio and systolic and diastolic blood pressure, as well as their low:high-density lipoprotein (LDL:HDL)-cholesterol ratio. Glucose levels before and during an oral glucose tolerance test did not change. However, plasma insulin and plasma-C-peptide decreased both in the fasting state and after 1 and 2 h of oral glucose tolerance testing. This decrease was independent of the previously mentioned reduction in weight, waist:hip ratio, blood pressure and LDL:HDL-cholesterol ratio. No reduction in insulin levels was seen in the HI-P, NI-A or LI-A groups, but in the HI-P group there was a slight decrease in fasting plasma-C-peptide levels. In the HI-A group dietary improvements were observed during the study period, with a reduction in energy intake, fat consumption and cholesterol intake. Fibre intake was increased. No major changes were seen in the HI-P group.. We conclude that in hypertensive and normotensive subjects with hyperinsulinaemia insulin levels can be reduced by active non-pharmacological treatment for 1 year without altering glucose tolerance. This shows that insulin resistance may be lowered by non-pharmacological treatment, which may be of considerable importance, and not only for hypertensives.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cholesterol, HDL; Female; Follow-Up Studies; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Life Style; Male; Middle Aged; Multivariate Analysis; Smoking Prevention; Surveys and Questionnaires; Sweden; Weight Loss

To determine whether hyperinsulinaemia of human obesity is dependent on the activity of the parasympathetic nervous system, and whether activation of the parasympathetic nervous system plays a role in glucose-induced thermogenesis, the metabolic effect of a continuous intravenous glucose infusion [44.4 mumol kg-1 body weight (bw) min-1] with or without atropine infusion was assessed in 11 obese patients and 10 lean controls. Compared with lean controls, obese patients had increased basal and glucose-stimulated plasma insulin and C-peptide concentrations and increased plasma glucose concentrations during glucose infusion. Glucose oxidation during i.v. glucose was lower in obese patients than in lean controls. Glucose-induced thermogenesis was similar in obese patients and in lean controls. Atropine infusion did not affect basal plasma glucose, insulin or free fatty acid concentrations nor glucose-stimulated plasma glucose, insulin, C-peptide, glucagon or free fatty acid concentrations in both groups of subjects. Glucose and lipid oxidation rates and glucose-induced thermogenesis were also unaffected by atropine administration. It is concluded that (1) glucose-stimulated hyperinsulinaemia in human obesity is not dependent on a hyperactivity of the parasympathetic nervous system, which indicates that human obesity is different from most animal models of obesity; (2) glucose-induced thermogenesis is similar in obese and lean subjects when a similar load of glucose is administered; (3) inhibition of the parasympathetic nervous system does not affect the thermic effect of i.v. glucose.

Topics: Adult; Atropine; Blood Glucose; Body Temperature Regulation; C-Peptide; Female; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Male; Obesity; Parasympathetic Nervous System

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

Seven normal volunteers were studied on two different occasions during which 4-h pulsatile (PULS: 0.8 mU X kg-1 X min-1, 7.5 min of 15) and continuous (CONT: 0.4 mU X kg-1 X min-1) intravenous (i.v.) infusions of human insulin (Actrapid HM, Novo) were randomly compared. A euglycemic glucose clamp was performed and a 3-3H-glucose infusion was used for determination of endogenous glucose production (EGP) and metabolic clearance rate (MCR) of glucose. Plasma glucose was similar in both conditions; plasma insulin was stable at about 29 mU/L (CONT) and fluctuated between 10 and 45 mU/L (mean: 28, PULS). Exogenous glucose infused was 1.137 +/- 0.058 and 1.088 +/- 0.099 g X kg-1 X 4 h-1 in CONT and PULS, respectively (NS). EGP was totally suppressed in both conditions. Glucose MCR increased similarly to a maximum of 6.71 +/- 0.19 (CONT) and 6.79 +/- 0.59 (PULS) ml X kg-1 X min-1 during the fourth hour. C-peptide plasma levels remained stable, whereas plasma glucagon, free fatty acids, and 3-hydroxybutyrate were similarly suppressed in both tests. Thus, under these conditions, pulsatile and continuous insulin infusions have similar metabolic effects. These data contrast with those of Matthews et al. (1983) who reported that, at lower plasma concentrations (5-19 mU/L), pulsatile insulin had greater hypoglycemic effect than did continuous delivery. It is concluded that pulsatile insulin shows no greater activity under normoglycemic, moderately hyperinsulinemic conditions in man.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Glucagon; Humans; Hydroxybutyrates; Hyperinsulinism; Insulin; Male; Metabolic Clearance Rate

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose-insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.

Topics: Animals; C-Peptide; Diet, High-Fat; Gastrectomy; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin, Regular, Human; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Weight Loss

Diagnosis of endogenous hyperinsulinism relies on the occurrence of a hypoglycemia, concomitant with inadequate high insulin and C-peptide levels. However, diagnostic cutoffs are not consensual among the different learned societies. The objective of this work was to propose optimized cutoffs for these three parameters for the diagnosis of endogenous hyperinsulinism.. All the patients having performed a fasting trial in Cochin Hospital Endocrinology Department between February 2012 and August 2022 were included. The results of glycemia, insulin and C-peptide levels during fasting trial were collected and analyzed.. One hundred and fifty-nine patients were included: 26 with endogenous hyperinsulinism and 133 without endogenous hyperinsulinism. ROC analysis of glycemia nadir during fasting trial identified the value of 2.3 mmol/L as the optimal cutoff, ensuring a sensitivity of 100% associated with a specificity of 81%. ROC analysis of insulin and C-peptide levels concomitant with hypoglycemia <2.3 mmol/L showed very good diagnostic performances of both parameters with respective cutoffs of 3.1 mUI/L (=21.5 pmol/L; sensitivity = 96%; specificity = 92%) and 0.30 nmol/L (sensitivity = 96%; specificity = 100%). Insulin to glycemia ratio as well as C-peptide to glycemia ratio (in pmol/mmol) at the time of glycemia nadir did not show better diagnostic performances than C-peptide alone.. A C-peptide level 0.3 nmol/L concomitant with a hypoglycemia <2.3 mmol/L appears as the best criterion to make the diagnosis of endogenous hyperinsulinism. Insulin level can be underestimated on hemolyzed blood samples, frequently observed in fasting trial, and thus shows lower diagnostic performances.

Topics: Blood Glucose; C-Peptide; Fasting; Humans; Hyperinsulinism; Hypoglycemia; Insulin

Gestational diabetes mellitus and antenatal depression are common comorbidities. However, the combined effects of antenatal depression and diabetes mellitus during pregnancy on fetal β-cell function are unknown.. This study aimed to test whether the association of maternal gestational diabetes mellitus and glucose metabolism with cord blood C-peptide levels varies with antenatal depression.. Data on mother-child pairs (N=5734) from the Maternal and Infant Health Cohort Study in Hefei were analyzed. Gestational diabetes mellitus was diagnosed using the 75-g oral glucose tolerance test at 24 to 28 weeks of gestation. Antenatal depression was measured using the Edinburgh Postnatal Depression Scale during midpregnancy and late pregnancy. Cord blood samples were collected at delivery and tested for C-peptide levels.. A total of 1054 mothers (18.38%) were diagnosed with gestational diabetes mellitus. Gestational diabetes mellitus was associated with a 5.57 (95% confidence interval, 3.65-7.50) percentile higher cord blood C-peptide level. This association varied with depression severity: the differences in cord blood C-peptide percentile for gestational diabetes mellitus vs no gestational diabetes mellitus were 5.12 (95% confidence interval, 2.81-9.75) for nonantenatal depression, 7.36 (95% confidence interval, 2.85-13.38) for moderate antenatal depression, and 10.06 (95% confidence interval, 4.69-14.8) for severe antenatal depression in midpregnancy. Similar associations stratified by antenatal depression in late pregnancy were observed. Antenatal depression was significantly positively correlated with fetal hyperinsulinism in participants with gestational diabetes mellitus but not in participants without gestational diabetes mellitus.. Antenatal depression, which is related to maternal hyperglycemia, can aggravate the risk of fetal hyperinsulinism in early life.

Topics: C-Peptide; Cohort Studies; Depression; Diabetes, Gestational; Female; Humans; Hyperinsulinism; Pregnancy

Topics: C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hyperinsulinism; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, Third; Regeneration

Topics: C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hyperinsulinism; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, Third; Regeneration

Type A Insulin resistance syndrome (TAIRS) is an autosomal dominant or recessive genetic disorder caused by insulin dysfunction resulting from insulin receptor (INSR) gene mutation. The main features of TAIRS include hyperinsulinemia, abnormal glucose metabolism, and changes in acanthosis nigricans. We identified, in China, a TAIRS family with a novel heterozygous missense gene mutation type. One patient from the Chinese Han family exhibited signs and symptoms of TAIRS and was presented for evaluation. Whole-exome sequencing revealed a heterozygous mutation. Both the patient proband and his father were identified with insulin receptor exon 19c.3472C>T(p.Arg1158Trp), which resulted in a missense mutation that led to replace by a base in the amino acid codon. We found that the patient proband and his father exhibited high insulin and C-peptide release after glucose stimulation by insulin and C-peptide release tests. At the same time, we also ruled out the possibility of islet βcell tumor through relevant examinations. These findings indicate that the INSR gene mutation may cause pancreatic β cell functional impairment and contribute to the development of diabetes.

Topics: C-Peptide; Diabetes Mellitus; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Mutation, Missense; Receptor, Insulin

A structured approach in the diagnostic process of hypoglycemia is important to find the right diagnosis. The first step is to recognize the symptoms of hypoglycemia, confirming the hypoglycemia during symptoms and dissolvement of complaints once the glucose level is restored to normal. This confirms the Whipple triad. The second step is to exclude common causes. The third, and most important, step is a diagnostic fasting test. Measurement of insulin and C-peptide during hypoglycemia will guide to exogenic or endogenic causes of hyperinsulinism. Targeted additional investigation is then required. Often the underlying cause is treatable. This justifies the need to measure a well-timed serum glucose when hypoglycemia is suspected to make a quick diagnosis.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Glucose; Humans; Hyperinsulinism; Hypoglycemia; Insulin

Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hours. At the same time, an IV infusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hours, but the glucose was allowed to fall to approximately 50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL but remained unchanged from the basal period in CPEP condition. During hypoglycemia, glucagon secretion in CPEP was 2 times higher than SAL, and this increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Dogs; Female; Glucagon; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Male

Determination of C-peptide is important in the investigation of unexplained hyperinsulinemic hypoglycemia because a high C-peptide concentration usually indicates endogenous insulin hypersecretion. Insulin autoimmune syndrome (IAS) denotes hyperinsulinemic hypoglycemia due to insulin-binding antibodies that prolong insulin half-life. C-peptide clearance is considered to be unaffected, and although a marked C-peptide immunoreactivity in hypoglycemic samples has been reported, it has been suspected to be artifactual. High-resolution mass spectrometry enables examination of the basis of C-peptide-immunoreactivity in IAS.. Precipitation of plasma with polyethylene glycol was followed by C-peptide immunoassay. Plasma peptides extracted by solvent precipitation were characterized by nano-LC-MS/MS and analyzed using an untargeted data-dependent method. Peptides related to proinsulin, in amino acid sequence, were identified using proprietary bioinformatics software and confirmed by repeat LC-MS/MS analysis. Gel filtration chromatography coupled to LC-MS/MS was used to identify proinsulin-related peptides present in IAS immunocomplexes. Results were compared with those from C-peptide immunoassay.. Polyethylene glycol precipitation of IAS plasma, but not control plasma, depleted C-peptide immunoreactivity consistent with immunoglobulin-bound C-peptide immunoreactivity. LC-MS/MS detected proinsulin and des 31,32 proinsulin at higher abundance in IAS plasma compared with control plasma. Analysis by gel filtration chromatography coupled to LC-MS/MS demonstrated proinsulin and des 31,32 proinsulin, but no C-peptide, in plasma immunocomplexes.. Antibody binding can enrich proinsulin and des 31,32 proinsulin in IAS immunocomplexes. Proinsulin cross-reactivity in some C-peptide immunoassays can lead to artifactually increased C-peptide results.

Topics: Autoimmune Diseases; C-Peptide; Chromatography, Liquid; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Molecular Weight; Peptides; Polyethylene Glycols; Proinsulin; Tandem Mass Spectrometry

The aim of the study was to characterize factors that may serve as clinical tools to identify neonates with transient neonatal hyperinsulinism hypoglycemia (HH) who may benefit from diazoxide treatment. This retrospective study included 141 neonates with transient HH (93 males) of whom 34 (24%) were treated with diazoxide. Diazoxide treatment was started at median age of 13 days (range 5-35) and discontinued at median age of 42 days (range 14-224). The maximal dose was 7.1 ± 2.3 mg/kg/day. Diazoxide-treated neonates required a higher glucose infusion rate (GIR) compared with non-treated neonates (16.6 ± 3.4 vs. 10.4 ± 4.0 mg/kg/min, respectively, P < .01), had a longer duration of intravenous fluids (15.9 ± 9.3 vs. 7.8 ± 6.5 days, P < .01), a longer hospitalization (32.8 ± 22.7 vs. 20.4 ± 13.4 days, P < .01), a longer duration of carbohydrate supplementation (38.9 ± 40.4 vs. 17.8 ± 21.4 days, P < .01), and higher mean C-peptide levels on "critical sample" (1.4 ± 0.9 vs. 0.8 ± 0.5 ng/ml, P < .01). Their insulin levels also tended to be higher (3.5 ± 2.9 vs. 2.2 ± 3.8 μU/ml, P = .07). A stepwise logistic regression model revealed that significant predictors of prolonged HH were maximal GIRs (odds ratio (OR) 1.56, 95%; confidence interval (CI) 1.3-1.88, P < .001) and C-peptide levels (OR 3.57, 95%; CI 1.3-12.1, P = .005).Conclusion: Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.What is Known:• Neonates with transient hyperinsulinism usually do not require treatment beyond glucose supplementation due to its self-limited clinical course, but some may benefit from diazoxide treatment.What is New:• Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.• The incidence of prolonged neonatal HH is higher than the currently accepted figures.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Diazoxide; Female; Gestational Age; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Pregnancy; Retrospective Studies

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

Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage. Lowering blood sugar by the sodium-glucose co-transporter 2 inhibitor empagliflozin provides cardiac protection. We established a new rat model that develops both inducible diabetes and genetic hypertension and investigated the effect of empagliflozin treatment to test the hypothesis if empagliflozin will be protective in a heart failure model which is not based on a primary vascular event. The transgenic Tet29 rat model for inducible diabetes was crossed with the mRen27 hypertensive rat to create a novel model for heart failure with two stressors. The diabetic, hypertensive heart failure rat (mRen27/tetO-shIR) were treated with empagliflozin (10 mg/kg/d) or vehicle for 4 weeks. Cardiovascular alterations were monitored by advanced speckle tracking echocardiography, gene expression analysis and immunohistological staining. The novel model with increased blood pressure und higher blood sugar levels had a reduced survival compared to controls. The rats develop heart failure with reduced ejection fraction. Empagliflozin lowered blood sugar levels compared to vehicle treated animals (182.3 ± 10.4 mg/dl vs. 359.4 ± 35.8 mg/dl) but not blood pressure (135.7 ± 10.3 mmHg vs. 128.2 ± 3.8 mmHg). The cardiac function was improved in all three global strains (global longitudinal strain - 8.5 ± 0.5% vs. - 5.5 ± 0.6%, global radial strain 20.4 ± 2.7% vs. 8.8 ± 1.1%, global circumferential strain - 11.0 ± 0.7% vs. - 7.6 ± 0.8%) and by increased ejection fraction (42.8 ± 4.0% vs. 28.2 ± 3.0%). In addition, infiltration of macrophages was decreased by treatment (22.4 ± 1.7 vs. 32.3 ± 2.3 per field of view), despite mortality was not improved. Empagliflozin showed beneficial effects on cardiovascular dysfunction. In this novel rat model of combined hypertension and diabetes, the improvement in systolic and diastolic function was not secondary to a reduction in left ventricular mass or through modulation of the afterload, since blood pressure was not changed. The mRen27/tetO-shIR strain should provide utility in separating blood sugar from blood pressure-related treatment effects.

Topics: Animals; Benzhydryl Compounds; C-Peptide; Cardiotonic Agents; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucosides; Heart Failure; Humans; Hyperinsulinism; Hypertension; Male; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Sodium-Glucose Transporter 2 Inhibitors

To examine whether proinflammatory and hyperinsulinemic diets are associated with increased risk of type 2 diabetes.. We prospectively followed 74,767 women from the Nurses' Health Study (1984-2016), 90,786 women from the Nurses' Health Study II (1989-2017), and 39,442 men from the Health Professionals Follow-up Study (1986-2016). Using repeated measures of food-frequency questionnaires, we calculated empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which are food-based indices that characterize dietary inflammatory or insulinemic potential based on circulating biomarkers of inflammation or C-peptide. Diagnoses of type 2 diabetes were confirmed by validated supplementary questionnaires.. We documented 19,666 incident type 2 diabetes cases over 4.9 million person-years of follow-up. In the pooled multivariable-adjusted analyses, individuals in the highest EDIP or EDIH quintile had 3.11 times (95% CI 2.96-3.27) and 3.40 times (95% CI 3.23-3.58) higher type 2 diabetes risk, respectively, compared with those in the lowest quintile. Additional adjustment for BMI attenuated the associations (hazard ratio 1.95 [95% CI 1.85-2.05] for EDIP and hazard ratio 1.87 [95% CI 1.78-1.98] for EDIH), suggesting adiposity partly mediates the observed associations. Moreover, individuals in both highest EDIP and EDIH quintiles had 2.34 times higher type 2 diabetes risk (95% CI 2.17-2.52), compared with those in both lowest quintiles, after adjustment for BMI.. Higher dietary inflammatory and insulinemic potential were associated with increased type 2 diabetes incidence. Findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking dietary patterns and type 2 diabetes development.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Diet; Female; Follow-Up Studies; Food; Humans; Hyperinsulinism; Incidence; Inflammation; Male; Middle Aged; Nurses; Obesity; Proportional Hazards Models; Prospective Studies; Risk; Self Report; United States

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

We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads.. Targeted and non-targeted metabolomics assays were performed on fasting and 1 h serum samples from a total of 1600 mothers in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, underwent an OGTT at ~28 weeks gestation and whose newborns had anthropometric measurements at birth.. In this observational study, meta-analyses demonstrated significant associations of maternal fasting and 1 h metabolites with birthweight, cord C-peptide and/or sum of skinfolds across ancestry groups. In particular, maternal fasting triacylglycerols were associated with newborn sum of skinfolds. At 1 h, several amino acids, fatty acids and lipid metabolites were associated with one or more newborn outcomes. Network analyses revealed clusters of fasting acylcarnitines, amino acids, lipids and fatty acid metabolites associated with cord C-peptide and sum of skinfolds, with the addition of branched-chain and aromatic amino acids at 1 h.. The maternal metabolome during pregnancy is associated with newborn outcomes. Maternal levels of amino acids, acylcarnitines, lipids and fatty acids and their metabolites during pregnancy relate to fetal growth, adiposity and cord C-peptide, independent of maternal BMI and blood glucose levels.

Topics: Adult; Birth Weight; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Infant, Newborn; Male; Metabolome; Metabolomics; Pregnancy; Pregnancy Outcome; Triglycerides

To determine the association of insulin sensitivity and metabolic status with declining cognition in HIV-infected individuals.. We conducted targeted clinical and metabolic measures in longitudinal plasma samples obtained from HIV-infected patients enrolled in the Central Nervous System HIV Anti-Retroviral Therapy Effects Research Study (CHARTER). Findings were validated with plasma samples from the Multicenter AIDS Cohort Study (MACS). Patients were grouped according to longitudinally and serially assessed cognitive performance as having stably normal or declining cognition.. Patients with declining cognition exhibited baseline hyperinsulinemia and elevated plasma c-peptide levels with normal c-peptide/insulin ratios, suggesting that insulin production was increased, but insulin clearance was normal. The association of hyperinsulinemia with worsening cognition was further supported by low high-density lipoprotein (HDL), high low-density lipoprotein/HDL ratio, and elevated cholesterol/HDL ratio compared to patients with stably normal cognition.. These findings suggest that hyperinsulinemia and impaired insulin sensitivity are associated with cognitive decline in antiretroviral therapy-treated HIV-infected patients.

Topics: Adult; Anti-HIV Agents; C-Peptide; Case-Control Studies; Cognition; Cognitive Dysfunction; Cohort Studies; Female; HIV Infections; Humans; Hyperinsulinism; Insulin Resistance; Lipoproteins; Male; Middle Aged

Insulinoma is the commonest functioning pancreatic neuroendocrine tumor causing hyperinsulinemic hypoglycemia.. This study is aimed to evaluate the clinical features, preoperative laboratory and imaging diagnosis and pathologic findings of insulinoma.. Data of the patients from 2001 to 2016 diagnosed as insulinoma in Tongji Hospital, China were retrospectively extracted and analyzed.. A total of 40 patients were diagnosed as insulinoma with a male/female ratio of 0.68:1. The median onset age was 46.5 years. Nearly all the included patients presented neurological symptoms and 60% presented autonomic symptoms. More than 95% of the patients met the functional European Neuroendocrine Tumor Society criteria including glucose, insulin and C-peptide levels. The preoperative detection rates of ultrasonography, enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography were 60.50%, 84.95%, 80% and 83.3% respectively. The joint imaging examinations can markedly increase the detection rate. The mean tumor size was 1.89 ± 0.72 cm. Ki-67 index by histopathological diagnosis were all less than 20%. The positive rates of insulin, synaptophysin and chromogranin A were close to 100%.. Laboratory tests of glucose, insulin and C-peptide are reliable for preoperative diagnosis. Combination of the imaging examinations can improve the diagnosis.

Topics: Adult; Aged; Blood Glucose; C-Peptide; China; Endosonography; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Magnetic Resonance Imaging; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Ultrasonography; Young Adult

The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30·1 (sem 1·0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0·3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0·8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41-80) and 73 d (IQR 48-128), respectively, P=0·246), or in body composition (P≥0·437). For postprandial measures, neither diet significantly altered glycaemia (P=0·266), whereas insulinaemia was reduced comparatively (P=0·903). The reduction in C-peptide tended (P=0·057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol×360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol×360 min/l). The relative reduction in TAG responses was greater (P=0·045) following IER (106 (sem30) to 68 (sem 15) mmol×360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol×360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.

Topics: Adult; Blood Glucose; Body Composition; Body Weight; C-Peptide; Caloric Restriction; Diet, Reducing; Energy Intake; Fasting; Female; Humans; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Obesity; Overweight; Postprandial Period; Weight Loss

To evaluate the association between cord blood amino acid and acylcarnitine profiles and measures of adiposity and hyperinsulinemia in healthy newborns.. A cross-sectional study of 118 full-term infants born to mothers without gestational diabetes was performed. Cord blood leptin, C-peptide, acylcarnitine, and amino acid levels were measured. Body composition was measured by air displacement plethysmography. Multivariate linear regression and principal component analysis were used to analyze associations of cord blood metabolites with newborn anthropometrics, leptin, and C-peptide.. Acylcarnitines AC C2, AC C4-DC/Ci4-DC, and AC C8:1-OH/C6:1-DC were positively associated with leptin, and AC C14, AC C14:2, AC C16, AC C18, and AC C18:2 were negatively associated with C-peptide (P ≤ .0016). Principal component analysis revealed a positive association between factor 1(AC C2, AC C3, AC C5, AC C4/Ci4, AC C4-OH, AC C4-DC/Ci4-DC, glutamate/glutamine, and glycine) and adiposity measures.. The positive association of AC C2 and AC C4-DC/Ci4-DC levels with leptin may reflect excess fat stores, higher fatty acid oxidation rate, and mitochondrial dysfunction leading to accumulation of acylcarnitine intermediates. Principal component analysis revealed a positive association between branched chain amino acid and ketone body metabolites and adiposity, confirming prior findings in adults. Cord blood acylcarnitine profiles may identify at-risk children before obesity or insulin resistance develops.

Topics: Adiposity; Adult; Amino Acids; C-Peptide; Carnitine; Cross-Sectional Studies; Female; Fetal Blood; Humans; Hyperinsulinism; Infant, Newborn; Leptin; Male; Multivariate Analysis; Principal Component Analysis

Fetal hyperinsulinemia in gestational diabetes mellitus (GDM) not only is important during intrauterine life, a time when it can result in macrosomia, but also at delivery, since it can result in neonatal hypoglycemia and hyperbilirubinemia. The question is, how long before delivery does maternal glycemic control contribute to newborn insulinemia in GDM?. In 72 women with GDM, we calculated Spearman's rank (r. At an early visit (32.95 ± 1.8 weeks), r. To further reduce the risk of hypoglycemia and hyperbilirubinemia in infants born to women with GDM, besides applying a strict in-patient glucose control protocol at delivery, it is necessary to improve even more the quality of maternal glucose control during the last 2 weeks prior to delivery.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes, Gestational; Female; Fetal Blood; Fetal Diseases; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Longitudinal Studies; Pregnancy; Prospective Studies

The aim of the study was to address the origin and natural history of malignant insulinoma.. Retrospective review of medical records of patients diagnosed with insulinoma at Cedars-Sinai Medical Center between 2000 and 2015 was conducted. Hormonal expression in tumor specimens was examined by immunostaining.. All the 9 patients with malignant insulinoma (35% of 26 patients with insulinoma) already had liver metastasis at hypoglycemia presentation with bulky cumulative tumor burden. Six patients had de novo diagnosis, 2 had known metastatic nonfunctioning pancreatic neuroendocrine tumor, and 1 had a known pancreatic mass. Tumor grade at presentation was G1 in 4 patients, G2 in 4, and unknown in 1. Four patients died 2 to 32 months after presentation, all with extensive liver tumor involvement. Tumor expression of proinsulin and insulin was heterogeneous and overall infrequent. The proinsulin levels and proinsulin/insulin molar ratio in patients with malignant versus benign insulinoma were 334 versus 44 pmol/L and 2.1 versus 0.9, respectively.. Malignant insulinoma seems to arise from and behave like nonfunctioning pancreatic neuroendocrine tumor oncologically but with metachronous hyperinsulinemic hypoglycemia. High proinsulin levels and proinsulin/insulin molar ratio may suggest malignant insulinoma.

Topics: Adult; Aged; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Proinsulin; Retrospective Studies

Topics: Animals; Blood Glucose; C-Peptide; Glucagon; Glucose; Hyperinsulinism; Injections, Intravenous; Insulin; Insulin Secretion; Kinetics; Mice

Elevated testosterone levels during prenatal life lead to hyperandrogenism and insulin resistance in adult females. This study evaluated whether prenatal testosterone exposure leads to the development of insulin resistance in adult male rats in order to assess the influence of gonadal hormones on glucose homeostasis in these animals. Male offspring of pregnant rats treated with testosterone propionate or its vehicle (control) were examined. A subset of male offspring was orchiectomized at 7 wk of age and reared to adulthood. At 24 wk of age, fat weights, plasma testosterone, glucose homeostasis, pancreas morphology, and gastrocnemius insulin receptor (IR) beta levels were examined. The pups born to testosterone-treated mothers were smaller at birth and remained smaller through adult life, with levels of fat deposition relatively similar to those in controls. Testosterone exposure during prenatal life induced hyperinsulinemia paralleled by an increased HOMA-IR index in a fasting state and glucose intolerance and exaggerated insulin responses following a glucose tolerance test. Prenatal androgen-exposed males had more circulating testosterone during adult life. Gonadectomy prevented hyperandrogenism, reversed hyperinsulinemia, and attenuated glucose-induced insulin responses but did not alter glucose intolerance in these rats. Prenatal androgen-exposed males had decreased pancreatic islet numbers, size, and beta-cell area along with decreased expression of IR in gastrocnemius muscles. Gonadectomy restored pancreatic islet numbers, size, and beta-cell area but did not normalize IRbeta expression. This study shows that prenatal testosterone exposure leads to a defective pancreas and skeletal muscle function in male offspring. Hyperinsulinemia during adult life is gonad-dependent, but glucose intolerance appears to be independent of postnatal testosterone levels.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Female; Glucose Intolerance; Hyperandrogenism; Hyperinsulinism; Insulin-Secreting Cells; Islets of Langerhans; Male; Muscle, Skeletal; Orchiectomy; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Testosterone; Testosterone Propionate

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Pancreatic Neoplasms; Proinsulin; Syndrome

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job.

Topics: Biopsy; Blood Glucose; C-Peptide; Carcinoma, Neuroendocrine; Diazoxide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Liver Neoplasms; Male; Middle Aged; Octreotide; Pancreas; Pancreatectomy; Pancreatic Neoplasms

Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.. The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of. These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Topics: Adiposity; Biomarkers; Body Mass Index; Body Size; C-Peptide; Case-Control Studies; Chi-Square Distribution; Colorectal Neoplasms; Europe; Female; Health Status; Humans; Hyperinsulinism; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Obesity; Obesity, Metabolically Benign; Odds Ratio; Phenotype; Prospective Studies; Protective Factors; Risk Assessment; Risk Factors; Waist Circumference

Managing equine hyperinsulinemia is crucial for preventing laminitis, but our understanding of the mechanisms involved in insulin dysregulation in this species is incomplete. C-peptide is co-secreted with insulin but is resistant to hepatic metabolism and can be used to study insulin dysregulation. This study examined C-peptide secretion in serial blood samples collected after oral and i.v. dextrose (0.75 g/kg) administration to 9 ponies (BCS, 7.1 ± 0.5). The ponies were designated as hyperinsulinemic (HI) or normoinsulinemic (NI) responders before the study, using oral glucose tests and fasted glucose-to-insulin ratios, and responses were compared between the 2 groups. C-peptide concentrations increased ( < 0.01) rapidly from fasted levels after both oral and i.v. dextrose, with similar area under the concentration-time curve (AUC) for both tests and a significant correlation with AUC. The AUC was similar in HI and NI ponies after i.v. dextrose, indicating similar pancreatic capacity for both groups. However, for oral dextrose, the AUC and the AUC were markedly higher ( < 0.05) in the HI ponies, indicating a greater secretion rate of these peptides. Slower insulin clearance might have also contributed to the larger AUC in HI ponies, but this hypothesis requires further investigation with specific measures of hepatic insulin clearance.

Topics: Administration, Intravenous; Administration, Oral; Animals; Blood Glucose; C-Peptide; Female; Glucose; Horses; Hyperinsulinism; Insulin; Male; Pancreas

HNF4A is an established cause of maturity onset diabetes of the young (MODY). Congenital hyperinsulinism can also be associated with mutations in the HNF4A gene. A dual phenotype is observed in HNF4A-MODY with hyperinsulinaemic hypoglycaemia in the neonatal period progressing to diabetes in adulthood. The nature and timing of the transition remain poorly defined. We performed an observational study to establish changes in glycaemia and insulin secretion over a 6-year period. We investigated glycaemic variability and hypoglycaemia in HNF4A-MODY using a continuous glucose monitoring system (CGMS).. An OGTT with measurement of glucose, insulin and C-peptide was performed in HNF4A participants with diabetes mellitus (DM) (n = 14), HNF4A-IGT (n = 7) and age- and BMI-matched MODY negative family members (n = 10). Serial assessment was performed in the HNF4A-IGT cohort. In a subset of HNF4A-MODY mutation carriers (n = 10), CGMS was applied over a 72-h period.. There was no deterioration in glycaemic control in the HNF4A-IGT cohort. The fasting glucose-to-insulin ratio was significantly lower in the HNF4A-IGT cohort when compared to the normal control group (0.13 vs. 0.24, p = 0.03). CGMS profiling demonstrated prolonged periods of hypoglycaemia in the HNF4A-IGT group when compared to the HNF4A-DM group (432 vs. 138 min p = 0.04).. In a young adult HNF4A-IGT cohort, we demonstrate preserved glucose, insulin and C-peptide secretory responses to oral glucose. Utilising CGMS, prolonged periods of hypoglycaemia are evident despite a median age of 21 years. We propose a prolonged hyperinsulinaemic phase into adulthood is responsible for the notable hypoglycaemic episodes.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucose Tolerance Test; Hepatocyte Nuclear Factor 4; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Mutation

Patients with psoriasis have increased risk of type 2 diabetes. The pathophysiology is largely unknown, but it is hypothesized that systemic inflammation causes insulin resistance. Insulin sensitivity has only been sparsely investigated in patients with psoriasis, and previous studies have used suboptimal methodology. The hyperinsulinemic euglycemic clamp remains the gold standard for quantifying whole-body insulin sensitivity.. We sought to investigate if normal glucose-tolerant patients with psoriasis exhibit impaired insulin sensitivity.. Three-hour hyperinsulinemic euglycemic clamps were performed in 16 patients with moderate to severe, untreated psoriasis and 16 matched control subjects.. The 2 groups were similar with regard to age, gender, body mass index, body composition, physical activity, fasting plasma glucose, and glycosylated hemoglobin. Mean ± SEM psoriasis duration was 23 ± 3 years and Psoriasis Area and Severity Index score was 12.7 ± 1.4. Patients with psoriasis exhibited reduced insulin sensitivity compared with control subjects (median M-value 4.5 [range 1.6-14.0] vs 7.4 [range 2.1-10.8] mg/kg/min, P = .046). There were no differences between groups in plasma glucose, insulin, C-peptide, and glucagon during the clamp.. The classic hyperinsulinemic euglycemic clamp technique does not allow assessment of endogenous glucose production.. Patients with psoriasis were more insulin resistant compared with healthy control subjects. This supports that psoriasis may be a prediabetic condition.

Topics: Adult; Anthropometry; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucagon; Gluconeogenesis; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Male; Middle Aged; Prediabetic State; Psoriasis; Risk

Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72-h fast. However, the prognostic value of parameters in the standardized 72-h fast on histopathological tumour criteria and clinical presentation has not been examined.. In thirty-three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki-67 index. Cut-off values for classical grading (G(clas)) were set at G1(clas) ≤ 2%, G2(clas) 3-20% & G3(clas) >20% and for modified grading (G(mod)) at G1(mod) <5%, G2(mod) 5-20% & G3(mod) >20%.. When G(mod) criteria were applied, the initial blood glucose was lower in GII/III(mod) patients compared to GI(mod) (2.8 ± 0.8 vs 3.8 ± 1.3 mmol/l; P = 0.046). Basal and end of fast levels of insulin (basal insulin 71 ± 61 vs 20 ± 16 mU/l; P < 0.001; end of fast insulin 77 ± 51 vs 21 ± 20 mU/l; P < 0.001) and c-peptide (basal c-peptide 5.4 ± 2.4 vs 2.7 ± 1.6 μg/l; P = 0.004; end of fast c-peptide 5.3 ± 2.4 vs 2.5 ± 1.4 μg/l; P = 0.001) were significantly higher in GII/III(mod) than in GI(mod). No differences between the groups were observed when G(clas) criteria were applied. Additionally, close correlations were observed between insulin concentration, Ki-67 index and tumour size.. This study shows an impact of histopathological tumour characteristics in patients suffering from an insulinoma on clinical presentation during a standardized 72-h fast. Lower initial blood glucose levels and higher concentrations of insulin and c-peptide are associated with worse tumour grading and larger tumour size.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pancreatic Neoplasms; Retrospective Studies; Tumor Burden

Postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis. Diabetes mellitus (DM) has an impact on lipid metabolism, however, little is known about the relationship between the postprandial lipid and glucose metabolism in normoglycemic patients with coronary artery disease (CAD).. To compare the postprandial lipid and glucose metabolism in normoglycemic patients with and without CAD, a total of 36 normoglycemic patients: 19 patients with stable CAD (CAD group, age 60.2±11.3 years) and 17 patients without CAD (Non-CAD group, age 60.4±9.6 years) were loaded with a high-fat and high-glucose test meal, and the changes in serum level of the lipid and glucose parameters were monitored before and 0, 2, 4, and 6h later.. In the Non-CAD group, postprandial serum levels of triglycerides (TG) and remnant-like particle cholesterol increased significantly and reached peak levels at the 4th hour and decreased significantly at the 6th hour of observation, whereas those levels in CAD group kept rising during 6h of observation. Although there was no significant difference in the area under the curves (AUCs) for the postprandial plasma glucose levels between CAD and Non-CAD group, the AUCs for the postprandial plasma insulin and C-peptide levels were significantly higher in the CAD group than in the Non-CAD group. The AUCs for postprandial TG levels showed good correlation with those for postprandial plasma insulin and C-peptide levels (insulin: r=0.455, p<0.005; C-peptide: r=0.462, p<0.05).. These findings suggest that postprandial hyperlipidemia and hyperinsulinemia may have a close relationship in CAD patients without DM and might play an important role in the development of atherosclerosis even before the onset of diabetes.

Topics: Aged; Area Under Curve; Atherosclerosis; Blood Glucose; C-Peptide; Cholesterol; Coronary Artery Disease; Diet, High-Fat; Female; Glucose; Humans; Hyperinsulinism; Hyperlipidemias; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Lipoproteins; Male; Middle Aged; Postprandial Period; Sweetening Agents; Time Factors; Triglycerides

Stress during pregnancy is a known contributing factor for the development of obesity in the offspring. Since maternal obesity is on the rise, we wanted to identify the effects of prenatal stress in the offspring of diet-induced obese (DIO) rats and compare them with the offspring of dietary-resistant (DR) rats. We hypothesized that prenatal stress would make both DIO and DR offspring susceptible to obesity, but the effect would be more pronounced in DIO rats. Pregnant DIO and DR rats were divided into two groups: nonstressed controls (control) and prenatal stress (subjected to restraint stress, three times/day from days 14 to 21 of gestation). After recording birth weight and weaning weight, male offspring were weaned onto a chow diet for 9 wk and shifted to a high-fat (HF) diet for 1 wk. At the end of the 10th wk the animals were euthanized, and visceral adipose mass, blood glucose, serum insulin, and C-peptide levels were measured. Prenatal stress resulted in hyperinsulinemia and higher C-peptide levels without altering caloric intake, body weight gain, or fat mass in the DIO offspring after 1 wk of HF intake, but not in DR offspring. To determine the mechanism underlying the hyperinsulinemia, we measured the levels of CEACAM1 that are responsible for insulin clearance. CEACAM1 levels in the liver were reduced in prenatally stressed DIO offspring after the HF challenge, suggesting that preexisting genetic predisposition in combination with prenatal stress increases the risk for obesity in adulthood, especially when offspring are fed a HF diet.

Topics: Animals; Blood Glucose; C-Peptide; Carcinoembryonic Antigen; Diet, High-Fat; Female; Genetic Predisposition to Disease; Hyperinsulinism; Insulin; Intra-Abdominal Fat; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Restraint, Physical; Stress, Psychological

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

The supervised 72-h fast remains the gold standard test for the diagnosis of endogenous hyperinsulinism and has recently been suggested to be shortened or even avoided.. This study aimed to evaluate whether measurement of blood glucose, insulin and C-peptide levels after a 12 h overnight fast (mini-fasting test), in at least 3 consecutive days, could allow making or ruling out diagnosis of endogenous hyperinsulinism, according to the Endocrine Society's recent guidelines.. We performed 12 h mini-fasting test in at least 3 consecutive days, dosing blood glucose, insulin and C-peptide levels in 26 inpatient patients with pathologically proven endogenous hyperinsulinism.. In our series, 100% of patients showed insulin levels of at least 3 μU/ml and C-peptide levels of at least 0.6 ng/ml concomitant with symptomatic hypoglycemia (≤ 55 mg/dl).. It leads to the conclusion that mini-fasting test might avoid, in most cases, prolonged fasting test for the diagnosis of hypoglycemia due to endogenous hyperinsulinism.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Child, Preschool; Fasting; Female; Follow-Up Studies; Humans; Hyperinsulinism; Infant; Insulin; Insulinoma; Male; Middle Aged; Predictive Value of Tests; Treatment Outcome; Young Adult

Hypoglycemia in apparently healthy adults is a rare finding in clinical practice requiring a thorough investigation of the cause. During the investigation, identification of hypoglycemia associated with inappropriately high levels of insulin and C-peptide should prompt the exclusion of rare causes of hypoglycemia, including pancreatic islet-cells disease and autoimmune hypoglycemia. In this paper, we describe two cases of hypoglycemia associated with endogenous hyperinsulinism, whose causes are uncommon in clinical practice, and review important aspects of the diagnosis and treatment of hyperinsulinemic hypoglycemia.

Topics: C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Multiple Myeloma; Pancreas; Pancreatic Neoplasms; Proinsulin; Ultrasonography

Recent studies have demonstrated an association between increased insulin secretion and cognitive impairment. However, there is no previous study that directly evaluates the association between increased insulin secretion and cortical thickness to our knowledge. Therefore, our aim was to evaluate the effect of hyperinsulinemia, as measured by C-peptide level, on cortical thickness in a large sample of cognitively normal individuals.. Cortical thickness was measured in 1093 patients who visited the Samsung Medical Health Promotion Center and underwent brain magnetic resonance imaging (MRI) and a blood test to measure C-peptide concentration. Automated surface-based analyses of the MRI data were used to measure cortical thickness. C-peptide levels were divided into quartiles for comparison. Patients in the first to third quartiles were used as the reference category.. Patients in the highest quartile group (Q4) of C-peptide levels showed cortical thinning, predominantly in both medial temporal lobes, the right inferior temporal gyrus, both medial prefrontal lobes and the right superior parietal lobule, compared with the lower quartile groups (Q1-Q3) after controlling for age, gender, body mass index, history of hypertension, hyperlipidemia, previous stroke, cardiovascular disease and fasting glucose level.. A higher C-peptide level is associated with regional cortical thinning, even in cognitively normal individuals.

Topics: Aged; C-Peptide; Cerebral Cortex; Female; Humans; Hyperinsulinism; Magnetic Resonance Imaging; Male; Middle Aged

The objective of the present study was to determine whether a plasma β-hydroxybutyrate (BOHB) level >2700 μmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH).. We retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-H fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels 2700 MOL/L (group 1), EHH PATIENTS with BOHB levels 2700 MOL/L (group 2) and 59 controls (median glycaemia: 3.2  mmol/l and median BOHB: 6095 μmol/l).. During a 72-h fasting test, nine patients (group 1) had BOHB levels >2700  μmol/l (median 6140 and range 2957-7824) and 30 patients (group 2) had BOHB levels <2700 μmol/l (median 542 and range 0-2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation.. During a fasting test, a BOHB level >2700 μmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Diagnosis, Differential; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Time Factors; Treatment Outcome

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

The aim of the present study was to determine the effects of a cafeteria diet on the function and apoptosis of the pancreas, and the activity and expression of the insulin-degrading enzyme (IDE). Female Wistar rats were fed either with a cafeteria diet or a control diet for 17 weeks, and blood and tissues were then collected for analysis. The cafeteria diet-treated rats had higher plasma insulin and C-peptide levels (P<0·05), showing increased insulin secretion by the pancreas. Insulin protein and gene expression levels were higher in the pancreas of obese rats, as was its transcriptional controller, pancreatic duodenal homeobox 1 (P<0·05). Feeding a cafeteria diet down-regulated the gene expression of the anti-apoptotic marker B-cell/lymphoma 2 (BCL2), and up-regulated the protein levels of BCL2-associated X protein, a pro-apoptotic marker (P<0·05). The cafeteria diet caused lipid accumulation in the pancreas and modified the expression of key genes that control lipid metabolism. To assay whether insulin clearance was also modified, we checked the activity of the IDE, one of the enzymes responsible for insulin clearance. We found increased liver IDE activity (P<0·05) in the cafeteria diet-fed animals, which could, in part, be due to an up-regulation of its gene expression. Conversely, IDE gene expression was unmodified in the kidney and adipose tissue; although when the adipose tissue weight was considered, the insulin clearance potential was higher in the cafeteria diet-treated rats. In conclusion, treatment with a cafeteria diet for 17 weeks in rats mimicked a pre-diabetic state, with ectopic lipid accumulation in the pancreas, and increased the IDE-mediated insulin clearance capability.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; C-Peptide; Diet, High-Fat; Disease Models, Animal; Female; Gene Expression Regulation; Homeodomain Proteins; Hyperinsulinism; Insulin; Insulin Resistance; Insulysin; Liver; Organ Specificity; Pancreas; Prediabetic State; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; RNA, Messenger; Trans-Activators; Triglycerides

This study analysed the relationship of plasma testosterone with β-cell secretion, insulin sensitivity and other pituitary-target gland hormones in normoglycaemic adult men. The sample frame was the 'Offspring of individuals with diabetes study' database. A total of 358 offspring of individuals with type-2 diabetes (T2DM) and 287 individuals without known family history of T2DM were recruited for the study. Normoglycaemic men aged ≥18 years (maximum 55) were selected for this analysis. All participants underwent 75 g oral glucose tolerance test (OGTT); blood samples were collected at 0, 30, 60 and 120 min for plasma insulin and C-peptide. Total testosterone, cortisol, adrenocorticotropic hormone, thyroid stimulating hormone and thyroxine (T4) were measured in the fasting sample. A total of 164 men (age 28 ± 7.7 years) were included in analysis. Testosterone correlated negatively with BMI, waist to hip ratio (WHR), area under curve (AUC) of C-peptide and insulin (during OGTT) and was positively correlated with insulin sensitivity (r ~ 0.4). Cortisol and T4 positively correlated (weak) with testosterone (r ~ 0.2). In multivariate analysis, AUC C-peptide, BMI, WHR (negatively) and cortisol (positively) were related to testosterone. Concluding, testosterone correlated negatively with BMI and β-cell secretion. There was a positive association of testosterone with insulin sensitivity, cortisol and T4.

Topics: Adult; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hydrocortisone; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Testosterone; Thyrotropin; Thyroxine

Topics: Blood Glucose; C-Peptide; Choristoma; Confusion; Diagnosis, Differential; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatic Diseases; Postprandial Period; Spleen; Syncope

Gut hormones play a role in diabetes remission after a Roux-en-Y gastric bypass (RYGB). Our aim was to investigate differences in gut hormone secretion according to diabetes remission after surgery. Second, we aimed to identify differences in insulin secretion and sensitivity according to diabetes remission after RYGB.. Twenty-two severely obese patients with type 2 diabetes underwent RYGB. A meal tolerance test (MTT) was performed 12 months after RYGB. The secretions of active glucagon-like peptide-1 (active GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY, C-peptide and insulin during the MTT test were calculated using total area under the curve values (AUC). Remission was defined as glycated haemoglobin (A(1C)) of <6.5% and a fasting glucose concentration of <126 mg/dL for 1 year or more without active pharmacological therapy.. Of the 22 patients, 16 (73%) had diabetes remission (remission group). The secretion CURVES of active GLP-1, GIP and peptide YY were not different between the groups. AUC of insulin and C-peptide were also not different. Homeostasis model assessment estimate of insulin resistance was significantly lower (1.26 ± 1.05 versus 2.37 ± 1.08, p = 0.006), and Matsuda index of insulin sensitivity was significantly higher in the remission group (10.5 ± 6.2 versus 5.8 ± 2.1, p = 0.039). The disposition index (functional reserve of beta cells) was significantly higher in the remission group compared with that in the non-remission group (5.34 ± 2.74 versus 1.83 ± 0.70, p < 0.001).. Remission of diabetes after RYGB is not associated with a difference in gut hormone secretion. Patients remaining diabetic had higher insulin resistance and decreased β cell functional reserve.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Prognosis; Prospective Studies; Remission Induction; Young Adult

We present the case of a 55 yr female who had recurrent severe hypoglycemic attacks with neuroglycopenic symptoms and altered sensorium including coma. The hypoglycemic episodes were not related to fasting. The hypoglycemia was hyperinsulinemic but all imaging modalities for insulinoma were negative. Selective arterial calcium stimulation test localized the lesion to splenic artery territory and distal pancreatectomy left to the splenic vein was done. The histopathology was consistent with nesidioblastosis and gradient guided pancreatectomy relieved the hypoglycemic episodes.

Topics: Blood Glucose; C-Peptide; Calcium; Female; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Immunohistochemistry; Injections, Intra-Arterial; Insulin; Insulinoma; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syndrome; Treatment Outcome

Our study was carried out to ascertain the role of valproic acid for inducing metabolic disorders like hyperinsulinemia, insulin resistance and metabolic syndrome. Seventy-nine subjects were enrolled into the study. They were divided in 3 groups: 26 patients with epilepsy on VPA monotherapy and 28 patients with epilepsy on CBZ monotherapy and 25 healthy controls. Blood samples for fasting insulin, glucose, C-peptide, TG and HDL were collected. We compared insulin, C-peptide, C-peptide/insulin ratio, HOMA-IR, BMI, central obesity and metabolic syndrome in patients treated with VPA, patients treated with CBZ and in healthy controls. VPA treatment was associated with insulin resistance (30.8%) in opposite to CBZ treatment (7.1%). Metabolic syndrome existed in 34,6%, 14,3% and 12% among VPA, CBZ and control groups, respectively. There was no difference in C peptide/insulin ratio between study groups. Interestingly lean VPA treated patients showed high frequency of insulin resistance and metabolic syndrome compared to lean CBZ treated patients and controls. Therefore we suppose that obesity should not be an obligatory factor for VPA induced metabolic disturbances. VPA treatment is associated with insulin resistance and metabolic syndrome. This metabolic disorders were not connected with diminished hepatic insulin extraction. Although VPA treated patients showed central obesity predominance, we suggest that VPA can induce such metabolic and endocrine changes without obesity.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Carbamazepine; Cholesterol, HDL; Epilepsy; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Obesity; Triglycerides; Valproic Acid

Childhood diabetes is thought to usually result from autoimmune beta cell destruction (type 1A) with eventual total loss of beta cells. Analysis of C-peptide in children characterised at diabetes onset for autoantibodies shows heterogeneous preservation of insulin secretion in long-standing diabetes. The aim of this study was to characterise the pancreases of childhood-onset diabetes in order to define the pathological basis of this heterogeneity.. We evaluated 20 cadaveric organ donor pancreases of childhood-onset long-term patients for disease heterogeneity and obtained corresponding C-peptide measurements.. Pancreases from the majority of cadaveric donors contained only insulin-deficient islets (14 of 20). The remaining six patients (30%) had numerous insulin-positive cells within at least some islets, with two different histological patterns. Pattern A (which we would associate with type 1A diabetes) had lobular retention of areas with 'abnormal' beta cells producing the apoptosis inhibitor survivin and HLA class I. In pattern B, 100% of all islets contained normal-appearing but quantitatively reduced beta cells without survivin or HLA class I.. Our data demonstrate that C-peptide secretion in long-standing diabetic patients can be explained by two different patterns of beta cell survival,possibly reflecting different subsets of type 1 diabetes.

Topics: Adolescent; Adult; Age of Onset; Autoantibodies; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Histocompatibility Testing; HLA-DR Antigens; Humans; Hyperinsulinism; Insulin-Secreting Cells; Male; Middle Aged; Pancreas; Sex Characteristics; Tissue Donors

An 8-week-old infant presented to the emergency department with lethargy, tachycardia, and a blood glucose concentration of 1.8 mmol/L. After admission, hypoglycemia recurred on 3 additional occasions. Initial urinalysis results were negative for ketones, and the results of additional laboratory tests did not support the diagnosis of cortisol or growth hormone deficiency, oral hypoglycemic ingestion, or an inborn error of metabolism. Difficulty restoring and maintaining glucose concentrations along with a transient response to glucagon during 1 hypoglycemic episode suggested hyperinsulinism. In 1 hypoglycemic episode, elevated insulin and low C-peptide concentrations suggested exogenous insulin administration, but 2 subsequent blood samples obtained during hypoglycemia contained appropriately decreased concentrations of insulin. The insulin immunoassay initially used in this case (Roche ElecSys/cobas [Roche Diagnostics, Indianapolis, IN]) was insensitive to insulin analogs. Two additional immunoassays, 1 with intermediate (Immulite [Siemens, Deerfield, IL]) and 1 with broad (radioimmunoassay [Millipore, Inc, Billerica, MA]) reactivity to insulin analogs were used to characterize insulin in each of the critical blood samples. Samples obtained during hypoglycemia displayed a graded reactivity similar to that observed in type 1 diabetic patients prescribed insulin analogs, whereas a sample obtained from the patient and a control subject during euglycemia showed equal reactivity among the 3 assays. These data suggested administration of insulin analog to the child, and further characterization of insulin by using tandem mass spectrometry confirmed the presence of Humalog. The child was subsequently placed in foster care with no further recurrence of hypoglycemia.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diagnosis, Differential; Emergency Service, Hospital; Female; Glucagon; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Infant; Insulin; Insulin Aspart; Male; Munchausen Syndrome by Proxy; Pregnancy; Pregnancy in Diabetics; Recurrence

Circulating levels of insulin and insulin-like growth factor (IGF) hormones have been associated with colorectal cancer risk, but few studies have examined their associations with colorectal adenoma.. We measured plasma C-peptide, a marker of insulin secretion, and IGF hormones in a case-control study of 554 pathologically confirmed, first-time adenoma cases and 786 controls with normal endoscopy among Caucasians, Japanese, and Native Hawaiians in Hawaii.. High plasma levels of C-peptide were statistically significantly associated with risk of colorectal adenoma [multivariate odds ratio (95% confidence interval) for increasing quartiles: 1.0, 0.91 (0.65-1.27), 1.21 (0.86-1.71), and 1.79 (1.23-2.60); P(trend) = 0.0002]. We also observed a statistically significant inverse association between levels of plasma IGF binding protein-1 (IGFBP-1) and adenoma risk [1.0, 0.97 (0.70-1.34), 0.82 (0.58-1.15), and 0.47 (0.32-0.70); P(trend) <0.0001]. These associations remain significant after adjusting for each other and were not confounded by known risk factors. IGF-I, IGFBP-3, body mass index, and waist or hip circumference were not independently associated with adenoma risk.. These results provide evidence for an association of insulin and IGFBP-1 levels with colorectal adenoma.. This study suggests that hyperinsulinemia and IGF hormones may act as etiologic factors in colorectal carcinogenesis, as early as during adenoma formation.

Topics: Adenoma; Aged; Asian People; Body Mass Index; C-Peptide; Case-Control Studies; Colorectal Neoplasms; Ethnicity; Female; Hawaii; Humans; Hyperinsulinism; Insulin-Like Growth Factor Binding Protein 1; Japan; Male; Middle Aged; Risk Factors; White People

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

Glucose is a more efficient substrate for ATP production than free fatty acid (FFA). Insulin resistance (IR) results in higher FFA concentrations and impaired myocardial glucose use, potentially worsening ischemia. We hypothesized that metabolic manipulation with a hyperinsulinemic euglycemic clamp (HEC) would affect a greater improvement in left ventricular (LV) performance during dobutamine stress echo (DSE) in subjects with IR.. 24 subjects with normal LV function and coronary disease (CAD) awaiting revascularization underwent 2 DSEs. Prior to one DSEs they underwent an HEC, where a primed infusion of insulin (rate 43 mU/m 2/min) was co-administered with 20% dextrose at variable rates to maintain euglycemia. At steady-state the DSE was performed and images of the LV were acquired with tissue Doppler at each stage for offline analysis. Segmental peak systolic velocities (Vs) were recorded, as well as LV ejection fraction (EF). Subjects were then divided into two groups based on their insulin sensitivity during the HEC.. HEC changed the metabolic environment, suppressing FFAs and thereby increasing glucose use. This resulted in improved LV performance at peak stress, measured by EF (IS group mean difference 5.3 (95% CI 2.5-8) %, p = 0.002; IR group mean difference 8.7 (95% CI 5.8-11.6) %, p < 0.0001) and peak V s in ischemic segments (IS group mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR group mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001) , that was greater in the subjects with IR.. Increased myocardial glucose use induced by HEC improves LV function under stress in subjects with CAD and IR. Cardiac metabolic manipulation in subjects with IR is a promising target for future therapy.

Topics: Aged; Blood Glucose; C-Peptide; Coronary Artery Disease; Echocardiography, Doppler, Color; Echocardiography, Stress; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Myocardium; Stroke Volume; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

Diabetes, characterized by perturbations in insulin production and signaling, is inversely associated with prostate cancer risk irrespective of stage. Obesity, a diabetes risk factor, is inversely associated with localized disease but positively associated with advanced disease. To understand the complex association between hyperinsulinemia and prostate cancer, we evaluated the association of plasma C-peptide, an insulin secretion marker, with prostate cancer risk in a case-control study nested in a prospective community cohort. Prostate cancer cases (n = 264) and matched controls (n = 264) were identified in the CLUE II cohort between 1989 (baseline) and 2002. C-peptide concentration was measured in baseline plasma by ELISA. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression, adjusting for being overweight or obese and family history. Median C-peptide concentration was lower in cases (1,180 pmol/L) than in controls (1,365 pmol/L; P = 0.03). Men in the highest (versus lowest) fourth of C-peptide had a lower risk for prostate cancer (OR, 0.65; 95% CI, 0.37-1.14; P-trend = 0.08), primarily localized disease (OR, 0.44; 95% CI, 0.19-1.03; P-trend = 0.04). Associations were similar to overall, when excluding cases diagnosed during the first 5 years of follow-up, men with diabetes, or men who had not had a prostate-specific antigen test. C-peptide concentration was inversely associated with subsequent diagnosis of prostate cancer, primarily localized disease, similar to the association for obesity. However, we cannot rule out detection bias that might result if men with higher C-peptide have lower prostate-specific antigen irrespective of whether prostate cancer is present or not.

Topics: Aged; Aged, 80 and over; Body Mass Index; C-Peptide; Case-Control Studies; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Humans; Hyperinsulinism; Incidence; Male; Middle Aged; Neoplasm Staging; Obesity; Prostatic Neoplasms; Risk Factors

Obesity is associated with insulin resistance and the resulting hyperinsulinemia has been attributed to an increase of insulin secretion and a reduction of insulin clearance. The present study was intended to further characterize the relative contribution of secretion and clearance especially in the postprandial state. In relation to WHO body weight classes 291 subjects were divided in 5 subgroups Basal insulin concentrations rose stepwise and significantly with increasing BMI. This was paralleled by C-peptide concentrations and insulin secretion, while the reduction of insulin clearance was less stringent in relation to BMI. Basal glucose was unchanged in the BMI25 group and 8% higher in the obese groups (BMI 30, 35, 40) compared to normal weight (NW). Although postprandial insulin concentrations were significantly higher in the overweight and obese groups compared to NW the correlation was not as tight as in the basal state. Furthermore, the present data demonstrate for the first time that insulin secretion only increased in the overweight group without further augmentation in the obese groups. Further hyperinsulinemia of the latter was due to weight-dependent reduction of insulin clearance. The postprandial glucose response was 38-82% higher with increasing weight compared to NW. In summary basal hyperinsulinemia is mainly due to weight related increase of insulin secretion with moderate contribution of reduced insulin clearance. Postprandially, hyperinsulinemia of overweight is predominantly due to secretion while further postprandial hyperinsulinemia of obese subjects is mainly due to reduced clearance. Thus, postprandial insulin secretion cannot respond adequately to the challenge of weight-dependent insulin resistance already in non-diabetic obese subjects.

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Male; Obesity

Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hyperinsulinism; Insulin Resistance; Locomotion; Olanzapine; Rats; Rats, Sprague-Dawley

Excess body-mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator, but prospective data are sparse. We assessed the effect of prediagnostic BMI and plasma C-peptide concentration (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis.. This study involved men diagnosed with prostate cancer during the 24 years of follow-up in the Physicians' Health Study. BMI measurements were available at baseline in 1982 and eight years later in 1990 for 2546 men who developed prostate cancer. Baseline C-peptide concentration was available in 827 men. We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death to assess the risk of prostate cancer-specific mortality according to BMI and C-peptide concentration.. Of the 2546 men diagnosed with prostate cancer during the follow-up period, 989 (38.8%) were overweight (BMI 25.0-29.9 kg/m(2)) and 87 (3.4%) were obese (BMI >/=30 kg/m(2)). 281 men (11%) died from prostate cancer during this follow-up period. Compared with men of a healthy weight (BMI <25 kg/m(2)) at baseline, overweight men and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1.47 [95% CI 1.16-1.88] for overweight men and 2.66 [1.62-4.39] for obese men; p(trend)<0.0001). The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991-2007) compared with during the pre-PSA screening era (1982-1990) or when using BMI measurements obtained in 1990 compared with those obtained in 1982. Of the 827 men with data available for baseline C-peptide concentration, 117 (14%) died from prostate cancer. Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality (HR 2.38 [95% CI 1.31-4.30]; p(trend)=0.008). Compared with men with a BMI less than 25 kg/m(2) and low C-peptide concentrations, those with a BMI of 25 kg/m(2) or more and high C-peptide concentrations had a four-times higher risk of mortality (4.12 [1.97-8.61]; p(interaction)=0.001) independent of clinical predictors.. Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of their disease. Patients with both factors have the worst outcome. Further studies are now needed to confirm these findings.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; C-Peptide; Case-Control Studies; Follow-Up Studies; Humans; Hyperinsulinism; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Obesity; Physicians; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; United States

Topics: C-Peptide; Humans; Hyperinsulinism; Life Style; Male; Obesity; Prostatic Neoplasms

Mononuclear cells (MNCs) are the primary cell type involved in the pro-inflammatory state of obesity-linked insulin-resistance, and atherosclerosis. Increased serum levels of MMP-9 are reported in insulin-resistant type 2 diabetic patients. Here we demonstrate insulin facilitating human monocytic THP-1 cell chemotaxis via prolonged Erk1/2-dependent induction of MMP-9. In vivo, significantly increased serum levels of MMP-9 were found in obesity-induced hyperinsulinemic C57BL/J6 mice, which were diminished by treatment with the anti-diabetic PPARgamma-ligand pioglitazone. In line with this, pioglitazone inhibited Erk1/2-phosphorylation and subsequent insulin-dependent MMP-9 synthesis in THP-1 cells. Thus, insulin increases MMP-9 gelatinolytic activity in monocytic cells, which results in accelerated chemotaxis. Hyperinsulinemia is associated with enhanced MMP-9 serum levels, potentially facilitating monocyte migration to and infiltration of adipose tissue and the arterial wall, thereby contributing to the increased cardiovascular risk in obese, hyperinsulinemic patients.

Topics: Animals; C-Peptide; Cell Line; Cell Movement; Chemotaxis, Leukocyte; Diet; Dietary Fats; Endothelium, Vascular; Humans; Hyperinsulinism; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Monocytes; Muscle, Smooth, Vascular; Obesity; Pioglitazone; Thiazolidinediones

Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m(2) BMI within 4(1/2) mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher post-weight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Kinetics; Male; Weight Gain

To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance.. Twenty baboons received a hyperinsulinemic-euglycemic clamp with skeletal muscle and visceral adipose tissue biopsies at baseline and at 30 and 120 min after insulin. Genes and protein expression of key molecules involved in the insulin signaling cascade (insulin receptor, insulin receptor substrate-1, p85, phosphatidylinositol 3-kinase, Akt, and AS160) were sequenced, and insulin-mediated changes were analyzed.. Overall, baboons show a wide range of insulin sensitivity (6.2 +/- 4.8 mg x kg(-1) x min(-1)), and there is a strong inverse correlation between indexes of adiposity and insulin sensitivity (r = -0.946, P < 0.001 for % body fat; r = -0.72, P < 0.001 for waist circumference). The genes and protein sequences analyzed were found to have approximately 98% identity to those of man. Insulin-mediated changes in key signaling molecules were impaired both in muscle and adipose tissue in obese insulin-resistant compared with lean insulin-sensitive baboons.. The obese baboon is a pertinent nonhuman primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance and eventual development of type 2 diabetes.

Topics: Animals; Biopsy; Blood Glucose; C-Peptide; Cloning, Molecular; Disease Models, Animal; Female; Glucose Clamp Technique; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Male; Muscle, Skeletal; Obesity; Papio; Thinness

Much evidence demonstrates that elevated free fatty acids (FFAs) are associated with insulin resistance. However, it is not clear whether different FFAs can cause different degrees of peripheral insulin resistance. This study aimed to investigate the effects of short-term elevation of FFAs on hepatic and peripheral insulin action, and determine whether FFAs with different degrees of saturation have differential effects on hepatic insulin resistance.. Intralipid+heparin (IH, polyunsaturated fatty acids), oleate (OLE), lard oil+heparin (LOH), and saline (SAL) were separately infused intravenously for 7 hours in normal Wistar rats. During the last 2 hours of the fat/saline infusion, a hyperinsulinemic-euglycemic clamping was performed with [6-3H] glucose tracer. Plasma glucose was measured using the glucose oxygenase method. Plasma insulin and C-peptide were determined by radioimmunoassays. Plasma FFAs were measured using a colorimetric method.. Compared with infusion of SAL, plasma FFA levels were significantly elevated by infusions of IH, OLE, and LOH (P<0.001). All three fat infusions caused remarkably higher hepatic glucose production (HGP) than SAL (P<0.001). OLE and LOH infusions induced much higher HGP than IH (P<0.01). Glucose utilization (GU) was decreased with all three fat infusions relative to SAL (P<0.001), but GU did not differ among the three types of fat infusions.. Short-term elevation of FFAs can induce hepatic and peripheral insulin resistance. Polyunsaturated fatty acids induced less hepatic insulin resistance than monounsaturated or saturated fatty acids. However, IH, OLE, and LOH infusions induced similar peripheral insulin resistance.

Topics: Animals; Anticoagulants; Blood Glucose; C-Peptide; Dietary Fats; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Female; Glucose Clamp Technique; Heparin; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Oleic Acid; Rats; Rats, Wistar

To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains.. Hyperinsulinemic-euglycemic (approximately 8.5 mmol/l) and -hypoglycemic (approximately 3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (approximately 15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets.. Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets.. Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments.

Topics: Animals; Animals, Genetically Modified; Animals, Laboratory; Blood Glucose; Body Weight; C-Peptide; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Species Specificity

Diabetes and prediabetic conditions are growing cardiovascular risk factors. Better understanding and earlier recognition and treatment of dysglycemia-related risk are health priorities. We assessed the predictive value of 3 proposed new markers for diabetes and cardiovascular risk. We tested whether the plasma levels of (1) asymmetric dimethylarginine (ADMA), (2) cortisol/cortisone (Cl/Cn) ratio, and (3) C-peptide predicted glycemic status, coronary artery disease, and death or myocardial infarction (MI) in a nested case-control cohort (N = 850) with normal fasting glucose (< 110 mg/dL), impaired fasting glucose (110-125), or diabetic (> or = 126) status.. High-sensitivity C-reactive protein (hsCRP) served as a control risk marker. Follow-up averaged 2.6 +/- 1.4 years. High-pressure liquid chromatography with pre-column derivitization and fluorescence was used to assay ADMA, liquid chromatography/tandem mass spectrometry for Cl and Cn, and chemiluminescent immunoassay for C-peptide.. Asymmetric dimethylarginine levels were positively associated with glycemic category (P < .001). Quartiles 2 to 4 ADMA also conferred increased risk of death/MI independent of hsCRP and other risk factors (adjusted hazard ratio, 2.1; P = .002). Cortisol/Cortisone ratios (P = .013) and C-peptide (P = .047) were associated with glycemic categories but less strongly than ADMA. Quartiles 2 to 4 Cl/Cn were protective against incident death/MI (adjusted hazard ratio, 0.48; P < .001), whereas C-peptide did not predict outcomes.. Among a high coronary risk case-control cohort, ADMA (strongly), Cl/Cn (moderately), and C-peptide (weakly) predicted glycemic categories. Asymmetric dimethylarginine and Cl/Cn also predicted clinical outcome independent of and more strongly than hsCRP. Asymmetric dimethylarginine and Cl/Cn represent promising new candidate markers of dysglycemia and associated cardiovascular risk.

Topics: Arginine; Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Coronary Disease; Cortisone; Diabetes Mellitus; Female; Humans; Hydrocortisone; Hyperinsulinism; Logistic Models; Male; Middle Aged; Myocardial Infarction; Nitric Oxide Synthase; Predictive Value of Tests; Risk Assessment

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model.

Topics: Animals; Blood Glucose; Body Composition; C-Peptide; Circadian Rhythm; Diet; Dogs; Fasting; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glycerol; Hormones; Hyperinsulinism; Insulin; Insulin Resistance; Male; Triglycerides

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C zeta (PKC zeta) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC zeta with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.

Topics: Animal Feed; Animals; Blood Glucose; C-Peptide; Caloric Restriction; Diabetes, Gestational; Dietary Fats; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Glucose Clamp Technique; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipid Metabolism; Liver; Male; Muscle, Skeletal; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

To investigate the contribution of HCV infection to insulin resistance in chronic haemodialysis patients.. The study was performed with 55 patients who were on regular haemodialysis therapy three times per week. Of the 55 patients, 34 (20 females and 14 males with an average age of 40.9 years) were anti-HCV (+) and were defined as the HCV (+) group. The remaining 21 patients (8 females and 11 males with an average age of 50 years) were negative for HCV and other viral markers and were defined as the HCV (-) group. BMI of all patients were below 27. Insulin resistance (IR) was calculated according to the HOMA formula and patients were called HOMA-IR (+) if their HOMA scores were higher than 2.5. All of the HOMA-IR (+) patients in both groups were called the HOMA-IR (+) subgroup. None of the patients had a history of drug use or any diseases that were related to insulin resistance except uremia. In both groups and the healthy control group, insulin and glucose levels were studied at three different venous serum samples taken at 5- minute intervals after 12 hours of fasting. Other individual variables were studied at venous serum samples taken after 12 hours of fasting.. HOMA scores were (3)2.5 in 22 of 34 HCV (+) patients (64.7%) and 7 of 21HCV (-) patients (33.33%) (p=0.024). Insulin levels of HCV (+) group (13.32 +/- 9.44mIU/mL) were significantly higher than HCV (-) (9.07 +/- 7.39mIU/mL) and the control groups (6.40 +/- 4.94mIU/ mL) (p=0.039 and p=0.021 respectively). HCV (+) patients were younger (40.94 +/- 17.06 and 52.62 +/- 20.64 years, respectively) and had longer dialysis duration (7.18 +/- 3.61 and 2.91 +/- 2.69 years, respectively). Significant positive correlations of HOMA score with insulin (r=0.934, p=0.000) and fasting glucose levels (r=0.379, p=0.043) were found in the HOMA- IR (+) subgroup. Also, a significant positive correlation was found between ALT and insulin levels in the HOMA IR (+) subgroup. C-peptide levels of both HCV (+) and (-) groups were significantly higher than the control group (p < 0.001). There were not any significant correlations between HOMA score and some of the other individual variables including levels of triglyceride, ferritin, ALT, iPTH and Mg in any of the groups.. In chronic haemodialysis patients; HCV infection is related to a high prevalence of insulin resistance, higher insulin and glucose levels.

Topics: Adult; C-Peptide; Female; Hepatitis C; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Colon carcinogenesis is a multi-steps process in which many growth factors are involved. In some studies the increased risk of colon cancer development was observed in patients with diabetes mellitus type 2 with accompanying hyperinsulinemia. It is also known that insulin-like growth factor I (IGF-I) plays an important role in proliferation, growth, differentiation and inhibiting apoptosis of both epithelial and carcinoma cells. The aim of the study was to evaluate the serum concentration of insulin, C-peptide and IGF-I in patients with colon adenomas and colorectal cancer.. In 17 patients with colon cancer, 32 patients with colon adenomas and in 12 healthy persons the serum concentration of insulin, C-peptide and IGF-I was determined using ELISA kits.. In patients with colon cancer significantly higher serum IGF-I concentration comparing to the control group was observed (85.66 ng/ml vs. 60.96 ng/ml; p < 0.05). Higher IGF-I concentration was also observed in patients with distal tumors comparing to the proximal localisation (95.40 ng/ml vs. 64,65 ng/ml, p < 0.05) and in more differentiated tumors (84.36 ng/ml vs. 75.24 ng/ml). Similarly, higher C-peptide concentrations were observed in distal tumors (635.64 pmol/ I vs. 578.69 pmol/l) and in well-differentiated carcinoma (671.32 pmol/ I vs. 575.66 pmol/l). In patients with colon adenomatous polyps we also observed higher serum IGF-I concentrations I comparing to the control group (82.1 ng/ml vs. 60.96 ng/ml), in high dysplasia adenomas (84.12 ng/ml vs. 79.67 ng/ml) and in smaller adenomas to 1 cm diameter (97.98 ng/ml vs. 73.28 ng/ml), but the differences were not significant. We also observed higher concentration of C-peptide in patients with low grade dysplasia adenomas (665.24 pmol/l vs. 498.13 pmol/l) and with small polyps (611.51 pmol/l vs. 514.89 pmol/l). There were no differences in serum concentration of IGF-I and C-peptide between patients with tubular and villous adenomas. There was no statistical difference observed in insulin serum concentration in all groups of patients.. IGF-I is probably involved particularly in the early stage of colon carcinogenesis.

Topics: Adenoma; Adenomatous Polyps; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; C-Peptide; Colonic Polyps; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Hyperinsulinism; Insulin; Insulin-Like Growth Factor I; Male; Middle Aged

Low birth weight is associated with insulin resistance and type 2 diabetes in adults. The fetal programming hypothesis has shown that insulin resistance and its associated metabolic disturbances result from a poor gestational environment, for which low birth weight is a surrogate. An at-home questionnaire survey was performed on 660 middle school students (12-15 years) in Seoul, Korea, and 152 cases were randomly selected based on their birth weight. Subjects were divided into three groups according to birth weight. We recorded their birth weight and measured their current anthropometric data, blood pressure, lipid profile, HOMA-IR, and HOMA-beta, and compared these parameters among the groups. The relation of birth weight to physiological characteristics in adolescence was examined. Systolic blood pressure, lipid profiles, and fasting plasma glucose, HOMA-beta were not significantly different among the groups, but diastolic blood pressure was lower in the third tertile. Insulin, C-peptide, and HOMA-IR were higher in the lower birth weight tertile. After adjustment for confounding factors, birth weight was inversely related to diastolic blood pressure, insulin, C-peptide, and HOMA-IR. We conclude that low birth weight may predict the risk of the insulin resistance and its progression over age, and that adequate gestational nutrition is therefore necessary to prevent low birth weight.

Topics: Adolescent; Birth Weight; Blood Pressure; C-Peptide; Child; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Korea; Male

Determinants of insulin secretion and insulin-like growth factors (IGF) have been directly associated with risk for colorectal cancer. However, few studies have evaluated whether these factors are also associated with risk of colorectal adenoma, the main precursor lesion to colorectal cancer.. We identified 380 distal colorectal adenoma cases diagnosed between 1989 and 1998 and 380 controls among nondiabetic women from the cohort of 32,826 women, nested in the Nurses' Health Study, who provided blood samples in 1989 to 1990. Cases and controls were individually matched on year of birth, time period of and indication(s) for endoscopy, and date of blood draw.. High concentrations of C-peptide, an indicator of insulin secretion, were statistically significantly associated with risk of distal colorectal adenoma [multivariable relative risk (MVRR) top versus bottom quartile, 1.63; 95% confidence interval (95% CI), 1.01-2.66; P = 0.01], even after including body mass index and physical activity in the statistical model. Fasting IGF binding protein-1 (IGFBP-1) concentrations did not show any clear association with risk for adenoma (MVRR top versus bottom quartile, 1.08; 95% CI, 0.56-2.07). These associations did not differ significantly by size/stage of adenoma. Glycosylated hemoglobin (HbA1c) was associated with a nonstatistically significant increased risk of colorectal adenoma (MVRR top versus bottom quartile, 1.47; 95% CI, 0.89-2.44).. High HbA1c and low IGFBP-1 were not clearly associated with increased risk of distal colorectal adenoma. However, our current results and previous associations between C-peptide and colorectal cancer suggest that hyperinsulinemia may play a role throughout the development of colorectal neoplasia.

Topics: Adenoma; Adult; C-Peptide; Colorectal Neoplasms; Female; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin-Like Growth Factor Binding Protein 1; Middle Aged; Prospective Studies; Risk

Valproate (VPA) treatment has been reported to be associated with obesity and high fasting serum insulin concentrations in parallel with an unfavorable serum lipid profile and hyperandrogenism and polycystic ovaries in women. The pathogenetic mechanism underlying these changes has remained unknown, although several mechanisms have been implicated.. Fifty-one patients receiving monotherapy (31 male and 20 female patients) were included in this study, with 45 (23 male and 22 female) healthy control subjects. These participants were interviewed, clinically examined, and blood samples for fasting plasma glucose, serum insulin, proinsulin, and C-peptide concentrations were taken after an overnight fast.. The valproate-treated patients had fasting hyperinsulinemia (11.30 +/- 6.23 pM vs. 6.28 +/- 4.66 pM in the control subjects; p < 0.001), although the fasting serum proinsulin and C-peptide concentrations were not significantly higher in the patients than in the control subjects. In addition, proinsulin/insulin (0.30 +/- 0.14) and C-peptide/insulin ratios (35.48 +/- 24.09) were lower (p < 0.001) in the VPA-treated patients when compared with the control subjects (0.53 +/- 0.36 and 94.27 +/- 61.85, respectively), and they also had lower fasting plasma glucose concentrations (4.72 +/- 0.35 mM) than the control subjects (5.12 +/- 0.58 mM; p < 0.01).. This study suggests that valproate does not induce insulin secretion but might interfere with the insulin metabolism in the liver, resulting in higher insulin concentrations in the peripheral circulation. These changes are seen irrespective of concomitant weight gain, suggesting that increased insulin concentrations induce weight gain and not vice versa.

Topics: Adult; Anticonvulsants; Blood Glucose; C-Peptide; Epilepsy; Fasting; Female; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Liver; Male; Obesity; Proinsulin; Secretory Rate; Valproic Acid; Weight Gain

Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease.. Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests.. All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation.. Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

Topics: Adult; Aged; Amyloid; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; C-Peptide; Cell Proliferation; Diazoxide; Fasting; Female; Homeodomain Proteins; Humans; Hyperinsulinism; Hypoglycemia; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Lectins, C-Type; Male; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatitis-Associated Proteins; Postprandial Period; Proinsulin; Receptors, Calcium-Sensing; Syndrome; Trans-Activators

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

Tyrosinaemia type I (TT I) (McKusick 276700) is a heterogeneous disorder with a broad spectrum of clinical phenotypes. Although histological abnormalities of the pancreas are well recognized, there are only incidental reports of pancreatic dysfunction manifested as insulin-dependent diabetes mellitus. We report three subjects with TT I and acute liver dysfunction who had hyperinsulinism in early infancy. Hypoglycaemia persisted despite dietary treatment and one patient had inadequate lipolysis at the time of hypoglycaemia. All three patients were successfully treated with diazoxide (10 mg/kg per day) and chlorthiazide (35 mg/kg per day) and treatment was gradually withdrawn after 9, 13 and 34 months, respectively. The mechanism of pancreatic dysfunction in TT I is unknown but may be related to the toxic metabolites that accumulate in this condition. We conclude that hyperinsulinism is not a rare complication in TT I. In patients with persistent hypoglycaemia, C-peptide should always be measured. Treatment with diazoxide and chlorthiazide is highly effective, appears to be safe, and does not need to be continued lifelong.

Topics: Blood Glucose; C-Peptide; Chlorothiazide; Diazoxide; Diuretics; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Liver Diseases; Pancreatic Diseases; Sodium Chloride Symporter Inhibitors; Tyrosinemias

Ovarian enlargement is a constant feature of syndromes of extreme insulin resistance. The objective of this study is to show the role of insulin on ovarian growth in the presence of low gonadotropin levels.. Seven young patients with syndromes of extreme insulin resistance (five with lipodystrophy, one with Type B syndrome and one with Rabson-Mendenhall syndrome) were studied.. Baseline LH concentrations and luteinizing hormone releasing hormone (LHRH) tests were performed. Total testosterone, insulin and C-peptide values were measured. Pelvic ultrasounds were performed.. Four patients were prepubertal (age range 7-10 years old) and had prepubertal gonadotropin levels, and 2 of the 4 who were tested did not respond to LHRH (NIH 10 and RM-PAL). Three patients were Tanner stage 4 (age range 13-17 years old) and had low gonadotropins that did not respond to LHRH stimulation test. All seven patients had marked hyperinsulinaemia and 6 of 7 had at least one enlarged ovary. Testosterone values were increased in 4 of 7 patients.. This represents the first example of the pathologic role of insulin to stimulate ovarian growth with low circulating gonadotropins. Thus, while ovarian growth and steroidogenesis are normally stimulated by gonadotropins at puberty, hyperinsulinaemia stimulates pathologic growth of the ovary and an androgenic steroid profile that is active at all ages. We suggest that these patients constitute a model to separate the effect of insulin from gonadotropin in stimulating ovarian growth and/or steroidogenesis.

Topics: Adolescent; C-Peptide; Child; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Lipodystrophy; Luteinizing Hormone; Ovary; Puberty; Testosterone; Ultrasonography

Clinical history and inappropriate insulin secretion during hypoglycemic episodes permit the diagnosis of hyperinsulinism. We report 2 cases of factitious hyperinsulinism leading to partial pancreatectomy. Case 1 was an 8-year-old girl who presented with severe hypoglycemia and elevated insulin and C-peptide levels. Catheterization of pancreatic veins was performed to localize the excess insulin secretion. Insulinoma was suspected, and partial pancreatectomy was performed. Ten days after surgery, severe hypoglycemia recurred with severely elevated plasma insulin levels (x100) but very low C-peptide plasma levels, suggesting factitious hyperinsulinemia. Hypoglycemic episodes before surgery were provoked by oral sulfonamides; postoperative episodes were caused by parenteral insulin. Falsified prescriptions for sulfonamides and insulin by the mother, a nurse, were found. Case 2 was a 6-month-old girl who presented with seizures and hypoglycemia but had a symptom-free interval of many months afterward. At 2 years of age, repeated hypoglycemic seizures and elevated insulin plasma levels suggested congenital hyperinsulinism. C-peptide plasma level, measured once, was normal, but blood sampling was performed 15 minutes after a hypoglycemic episode. Partial pancreatectomy was performed. Two weeks after surgery, hypoglycemic seizures recurred, and the patient was admitted for pancreatic vein catheterization. This investigation was performed during hypoglycemia and revealed high insulin levels and undetectable C-peptide levels, suggesting factitious hypoglycemia. Insulin/C-peptide ratio analysis is crucial to assess factitious hypoglycemia, although sulfonamide-induced hypoglycemia is not thereby detected. One percent (2 of 250) of all cases of hyperinsulinemic hypoglycemia in our unit have been identified as Munchausen syndrome by proxy. Atypical disease history should raise the question of factitious hypoglycemia.

Topics: Blood Glucose; C-Peptide; Child; Child, Preschool; Congenital Hyperinsulinism; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Munchausen Syndrome by Proxy; Pancreatectomy

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

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

Topics: Adult; Aged; Biomarkers, Tumor; C-Peptide; Case-Control Studies; Chronic Disease; Cohort Studies; Endometrial Neoplasms; Female; Humans; Hyperinsulinism; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Middle Aged; Prognosis; Prospective Studies; Risk Factors

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. This study tested the hypothesis that C-peptide might participate in atherogenesis in these patients.. We demonstrate significantly higher intimal C-peptide deposition in thoracic aorta specimens from young diabetic subjects compared with matched nondiabetic controls as determined by immunohistochemical staining. C-peptide colocalized with monocytes/macrophages in the arterial intima of artery specimen from diabetic subjects. In vitro, C-peptide stimulated monocyte chemotaxis in a concentration-dependent manner with a maximal 2.3+/-0.4-fold increase at 1 nmol/L C-peptide. Pertussis toxin, wortmannin, and LY294002 inhibited C-peptide-induced monocyte chemotaxis, suggesting the involvement of pertussis toxin-sensitive G-proteins as well as a phosphoinositide 3-kinase (PI3K)-dependent mechanism. In addition, C-peptide treatment activated PI3K in human monocytes, as demonstrated by PI3K activity assays.. C-peptide accumulated in the vessel wall in early atherogenesis in diabetic subjects and may promote monocyte migration into developing lesions. These data support the hypothesis that C-peptide may play an active role in atherogenesis in diabetic patients and suggest a new mechanism for accelerated arterial disease in diabetes.

Topics: Adolescent; Adult; Androstadienes; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; C-Peptide; Cells, Cultured; Chemotaxis; Chromones; Diabetes Mellitus, Type 2; Disease Progression; Enzyme Inhibitors; Female; GTP-Binding Proteins; Humans; Hyperinsulinism; Insulin Resistance; Macrophages; Male; Metabolic Syndrome; Models, Biological; Monocytes; Morpholines; Pertussis Toxin; Phosphatidylinositol 3-Kinases; Wortmannin

Traditional criteria to diagnose hyperinsulinaemic hypoglycaemia are based on insulin measurements by unspecific insulin assays. This study was performed to test whether these traditional criteria can be applied when insulin is measured by specific immunoassays.. 29 consecutive patients undergoing a prolonged fast were included; 11 patients with insulinoma and 18 healthy individuals. We determined plasma glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate concentrations at the termination of the fast. Insulin was measured by an unspecific radioimmunoassay (RIA) and a specific enzyme-linked immunosorbent assay (ELISA).. In 11 insulinoma patients, insulin concentrations at median plasma glucose concentration of 2.1 (range 1.3-2.5) mmol/l were 170 (76-340) pmol/l measured by RIA and 61 (11-156) pmol/l by ELISA. Insulin concentrations measured by RIA confirmed hyperinsulinaemia (i.e., >36 pmol/l, the proposed cut-off value for traditional insulin assays) in all insulinoma patients, whereas insulin concentrations measured by ELISA were <36 pmol/l in four patients. In three insulinoma patients, insulin concentrations measured by ELISA were <18 pmol/l, a proposed cut-off level to diagnose hyperinsulinaemia for specific insulin assays.. When insulin concentrations are measured by specific immunoassays in patients evaluated for fasting hypoglycaemia, traditional reference values cannot be applied.

Topics: 3-Hydroxybutyric Acid; Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Humans; Hyperinsulinism; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay; Reference Values; Sensitivity and Specificity; Time Factors

Transient hyperinsulinism (HI) occurs in infants born to diabetic mothers, in infants experiencing perinatal asphyxia and in infants with intrauterine growth retardation. The precise mechanism of transient HI in these different aetiologies is not fully understood. Lactic acidosis is commonly seen in neonates as a secondary phenomenon due to hypoxia, hypovolaemia, anaemia and infection. The combination of transient HI and lactic acidosis is rare. We present the clinical and biochemical features of five infants presenting with transient HI associated with hyperlactataemia in the absence of markers of perinatal stress. This combination lasted for 3-4 weeks with complete resolution except in one patient in whom the hyperinsulinism lasted until 6 months before resolution. The precise mechanism of this association is not clear but may be related either to immaturity of the pyruvate dehydrogenase complex or to the accumulation of abnormal intramitochondrial intermediary metabolites. Infants presenting with HI should have a free flowing blood sample drawn for the measurement of plasma lactate levels.

Topics: Acidosis; Age of Onset; Blood Glucose; C-Peptide; Chlorothiazide; Diazoxide; Diuretics; Fasting; Fatty Acids, Nonesterified; Female; Fibroblasts; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Ketone Bodies; Lactates; Male; Skin

The role of gut-derived incretin, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide [GIP]), in compensatory beta-cell hypersecretion during insulin-resistant states and in transition to beta-cell failure in type 2 diabetes is unknown.. We carried out oral glucose tolerance testing followed by blood sampling 10 times for 2 h on 68 age- and BMI-matched participants of the Baltimore Longitudinal Study on Aging (BLSA) with normal glucose tolerance (34 subjects), impaired glucose tolerance (IGT) (18 subjects with both impaired fasting and 2-h plasma glucose levels), and type 2 diabetes (16 subjects with both diabetic fasting and 2-h plasma glucose levels). We assayed plasma glucose, insulin, C-peptide, glucagon, and intact and total GIP levels and quantitated glucose and hormone responses to the oral glucose tolerance test. We also compared GIP and insulin release and sensitivity indexes between groups.. After glucose ingestion, subjects with IGT had both hyperinsulinemia and hyperemia, while subjects with type 2 diabetes had both beta- and GIP-cell deficiency. In the former group, there was also a significant positive correlation between the augmented plasma intact and total GIP levels and both fasting and post-oral glucose load plasma insulin levels.. Elevated plasma GIP levels are correlated with hyperinsulinemia in the impaired glucose-tolerant state, whereas type 2 diabetes is associated with a failure to secrete adequate amounts of both GIP and insulin, indicating a common pathway of resistance to and eventually failure of glucose responsiveness in beta- and GIP-cells.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Gastric Inhibitory Polypeptide; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Longitudinal Studies; Male; Middle Aged; Reference Values

Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of hypoglycemia in Western countries. It is characterized by hypoglycemic episodes, elevated insulin levels, and positive insulin antibodies. Our objective is to report a case of IAS identified in South America.. A 56-year-old Caucasian male patient started presenting neuroglycopenic symptoms during hospitalization due to severe trauma. Biochemical evaluation confirmed hypoglycemia and abnormally high levels of insulin. Conventional imaging examinations were negative for pancreatic tumor. Insulin antibodies were above the normal range. Clinical remission of the episodes was not achieved with verapamil and steroids. Thus, a subtotal pancreatectomy was performed due to the lack of response to conservative treatment and because immunosuppressants were contraindicated due to bacteremia. Histopathological examination revealed diffuse hypertrophy of beta cells. The patient continues to have high insulin levels but is almost free of hypoglycemic episodes.

Topics: Autoimmune Diseases; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Male; Middle Aged; Syndrome

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

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immunologic self-tolerance and the subsequent development of autoantibodies. These antibodies are thought to be important in relation to the clinical manifestations of the disease. One example is the development of multiple cytopenias secondary to cytolytic or cytotoxic antibodies directed toward red blood cells, platelets, and white blood cells. Other antibodies may mediate abnormal cellular mechanisms such as those seen with neuropsychiatric manifestations of SLE. We report the occurrence of autoantibodies directed toward insulin receptors and the subsequent development of type B insulin resistance syndrome in a woman with SLE. This syndrome was treated successfully with cyclophosphamide and mycophenolate mofetil.

Topics: Adult; C-Peptide; Cyclophosphamide; Female; Glycated Hemoglobin; Humans; Hyperinsulinism; Immunosuppressive Agents; Insulin; Insulin Resistance; Lupus Erythematosus, Systemic; Mycophenolic Acid; Treatment Outcome

To examine the impact of important weight loss on insulin inhibition of its own secretion during experimentally induced hyperinsulinemia under euglycemic conditions.. Longitudinal, clinical intervention study--bariatric surgery (vertical banded gastroplasty--gastric bypass--Capella technique), re-evaluation after 4 and 14 months.. Nine obese patients class III (BMI=54.6+/-2.6 kg/m2) and nine lean subjects (BMI=22.7+/-0.7 kg/m2).. Euglycemic hyperinsulinemic clamp (insulin infusion: 40 mU/min m2), C-peptide plasma levels, electrical bioimpedance methodology, and oral glucose tolerance test (OGTT).. BMI was reduced in the follow-up: 44.5+/-2.2 and 33.9+/-1.5 kg/m2 at 4 and 14 months. Insulin-induced glucose uptake was markedly reduced in obese patients (19.5+/-1.9 micromol/min kg FFM) and improved with weight loss, but in the third study, it was still lower than that observed in controls (35.9+/-4.0 vs 52.9+/-2.2 micromol/min kg FFM). Insulin-induced inhibition of its own secretion was blunted in obese patients (19.9+/-5.7%, relative to fasting values), and completely reversed to values similar to that of lean ones in the second and third studies (-60.8+/-4.2 and -54.0+/-6.1%, respectively).. Weight loss in severe obesity improved insulin-induced glucose uptake, and completely normalized the insulin inhibition on its own secretion.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Fasting; Female; Gastroplasty; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Longitudinal Studies; Male; Obesity, Morbid; Weight Loss

Insulin resistance is nearly universal in patients with nonalcoholic steatohepatitis (NASH) when tested by glucose tolerance tests or clamp methods. However, the pattern of insulin resistance in these patients after a physiological challenge is unknown. We conducted a study to characterize the metabolic response to a mixed meal in nondiabetic patients with NASH (NDN) and to identify anthropometric determinants of insulin resistance in these patients.. Serum insulin, C-peptide, glucose, and free fatty acid (FFA) levels were measured at 0, 30, 60, 90, and 120 min after a 500-kcal standard meal in 18 NDN and 18 age-, gender-, and body mass index (BMI)-matched controls. Correlations were made between insulin resistance and various anthropometric, calorimetric, and serological variables.. Compared with controls, NDN had significantly higher levels of insulin and C-peptide at baseline and after the mixed meal. However, glucose levels were not different either at baseline or after the meal. NDN had higher fasting levels of FFA than the controls (459 +/- 190 vs 339 +/- 144 micro mol/L, respectively, p = 0.03); however, meal-induced suppression in lipolysis was similar between the two groups (39 +/- 113% vs 46 +/- 60%, p = 0.8). Insulin resistance was significantly correlated with BMI (r = 0.39, p = 0.02) and visceral fat (r = 0.50, p = 0.004). Whereas BMI, percent total body fat, and subcutaneous abdominal fat were similar between the groups, the NASH group had significantly higher percent visceral fat compared with controls (28 +/- 10% vs 22 +/- 14%, p = 0.02).. NDN are significantly hyperinsulinemic, both at fasting and after the mixed meal; however, their glucose homeostasis and suppression in lipolysis after a meal challenge are maintained. Insulin resistance in these patients is likely related to their higher visceral fat mass.

Topics: Adult; Anthropometry; C-Peptide; Chronic Disease; Diabetes Mellitus; Dietary Fats; Fatty Liver; Female; Glucose; Humans; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Lipolysis; Male; Middle Aged

Hyperinsulinemic hypoglycemia associated with trimethoprim-sulfamethoxazole (TMP-SMX) has generally been reported in adults who had renal impairment or in patients with AIDS using high dose TMP-SMX. We present a 5 month-old infant with immunodeficiency due to major histocompatibility complex class II expression defect, developing hypoglycemic convulsion on the third day of high dose TMP-SMX administration. High insulin and C-peptide levels were documented at the time of hypoglycemia. To overcome hypoglycemia while TMP-SMX tapered off, diazoxide was administered which resolved hypoglycemia in 2 months.

Topics: Blood Glucose; C-Peptide; Diazoxide; Drug Administration Schedule; Female; Gene Expression; Genes, MHC Class II; Glucose; Histocompatibility Antigens Class II; Hospitalization; Humans; Hyperinsulinism; Hypoglycemia; Immunologic Deficiency Syndromes; Infant; Infusions, Intravenous; Pneumonia; Seizures; Time Factors; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

To determine whether hyperinsulinemia has a negative effect on uterine blood supply in patients with polycystic ovary syndrome (PCOS).. Sixty-three patients with normal body mass index were included prospectively in the study: 48 had clinical and hormonal features of PCOS and 15 were normo-ovulatory. All patients underwent Doppler flow measurement of the uterine artery, and determination of serum concentrations of luteinizing hormone, follicle stimulating hormone, prolactin, estradiol, androgens, insulin and C-peptide during the early follicular phase of the menstrual cycle. The 48 PCOS-patients were divided into two groups according to the pulsatility index (PI) value of the uterine artery: Group 1, PI < 3; Group 2, PI >or= 3 and the groups were compared.. The mean PI of the uterine artery (3.01 +/- 1.0 vs. 1.93 +/- 0.3, respectively) and fasting levels of insulin (50.9 +/- 9.3 vs. 40.3 +/- 10.9) and C-peptide (366.9 +/- 118.4 vs. 243.6 +/- 120.3) of PCOS-patients were significantly higher than those of the control group. No correlation was found between insulinemia and C-peptide and PI of the uterine artery and no significant difference was found in insulin and C-peptide levels among the two groups of PCOS-affected patients. Only the serum level of dehydroepiandrosterone sulfate was significantly higher in Group 2, and a direct correlation was found between PI values of the uterine artery and DHEAS plasma levels.. Insulin and C-peptide do not seem to interfere with uterine perfusion in PCOS-affected patients.

Topics: C-Peptide; Case-Control Studies; Female; Humans; Hyperinsulinism; Perfusion; Polycystic Ovary Syndrome; Uterus

Mutations in genes encoding the two subunits of the beta-cell ATP-sensitive potassium channel (K(ATP)) channel (SUR1 and Kir6.2) are the major cause of congenital hyperinsulinism (CHI). In this study, the K(ATP) channel genes were screened in a population-based study that included all verified Finnish CHI patients (n = 43) in a 27-yr period. Seven different mutations were identified, which accounted for 60% of all cases. The functional consequences of the major missense mutations were studied in vivo by determining acute (1-3 min) plasma insulin and C-peptide responses to calcium (n = 18), glucose (n = 12), and tolbutamide (n = 11) in those CHI patients who were able to take part in these studies. C-peptide and insulin responses to calcium were significantly higher in the patients with SUR1-E1506K mutation, compared with patients without K(ATP) channel mutations. The patients with SUR1-V187D mutation showed a reduced response to tolbutamide but unexpectedly did not show any response to calcium stimulation. A compound heterozygous patient with Kir6.2-(-54)/K67N mutations responded to calcium but also to tolbutamide. In conclusion, our results show that a positive response in the calcium test is indicative of a K(ATP) channel mutation, but all mutations cannot be identified with this method. The insulin response to tolbutamide in patients with SUR1 mutations is impaired to different extents, depending on the genotype. The combination of calcium and tolbutamide tests is a useful tool for the detection of CHI patients with K(ATP) channel dysfunction. Our results, however, also demonstrate the complexity of these responses and the difficulties in their interpretation.

Topics: Adolescent; Adult; C-Peptide; Calcium; Child; Child, Preschool; Diagnosis, Differential; DNA Mutational Analysis; Female; Glucose Tolerance Test; Glycosyltransferases; Humans; Hyperinsulinism; Insulin; Islets of Langerhans; Male; Membrane Proteins; Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Potassium Channels, Inwardly Rectifying; Repressor Proteins; Saccharomyces cerevisiae Proteins; Sequence Analysis, DNA; Tolbutamide

Human liver cirrhosis is commonly associated with increased fasting and glucose induced insulin concentrations. However, whether the hyperinsulinaemia is a consequence of increased pancreatic insulin secretion, decreased hepatic insulin removal, or impaired feedback regulation of insulin secretion is still doubtful. To investigate these issues, insulin secretion-during 24 hours of standardised living conditions-insulin sensitivity, and hepatic insulin extraction were assessed in cirrhotic patients compared with matched healthy subjects.. Nine Child's disease grade B cirrhotic patients and seven healthy volunteers, participated in the study. The subjects were studied on two separate days, one for the assessment of insulin secretion during a standardised 24 hour life period (calorimetric chamber), and one for the determination of insulin sensitivity.. Insulin secretion rates were reconstructed from plasma C peptide concentrations by deconvolution, and indices of beta cell function were derived using a mathematical model describing the functional dependence of insulin secretion on plasma glucose concentrations. Insulin sensitivity was determined using the euglycaemic hyperinsulinaemic clamp technique.. Cirrhotic patients showed a marked hypersecretory response, both in absolute terms (mean (SEM) 295 (53) versus 138 (11) nmol/m(2), p<0.02), and in relation to glucose (175 (26) versus 57 (5) pmol/min/m(2), p<0.02). In particular, the beta cell dose-response function was shifted upward compared with controls. The sensitivity of insulin secretion to the rate of glucose change was also increased. Insulin sensitivity, markedly reduced in cirrhosis (157 (10) versus 296 (30) ml/min/m(2), p<0.002), was strongly inversely correlated (r=0.89, p<0.002) in these patients with insulin secretion at 5 mM glucose. Insulin clearance and hepatic insulin extraction were not reduced. A frank hypermetabolism with increased lipid oxidation was found in this series.. This study suggests that hyperinsulinaemia, at least in Child's disease grade B cirrhotic patients, is the consequence of increased beta cell sensitivity to glucose, while hepatic insulin extraction does not seem to play a significant part.

Topics: Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Liver Cirrhosis; Male; Middle Aged; Models, Biological; Monitoring, Physiologic; Regression Analysis; Statistics, Nonparametric

Initiation and/or promotion of endometrial carcinoma is considered to be associated with estrogens and androgens (androstendione) excess as well as hyperinsulinemia and resistance to insulin. It is possible that certain polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to carcinoma susceptibility. In the current study, we compared the role of CYP17 biallelic MspA1) polymorphism in 114 endometrial carcinoma patients and 182 healthy women. According to our data, A2/A2 CYP17 genotype traditionally regarded as "unfavorable" was less frequent in cancer patients than in control which confirmed the results of two previous publications. For the first time, carriers of the genotype were shown to have relatively low levels of blood insulin and C-peptide. No significant difference was found between mean concentrations of testosterone, dehydroepiandrosterone sulfate and those of estradiol in the carriers of various CYP17 genotypes with endometrial cancer. Hence, CYP17 polymorphism which is represented by the "normal" A1/A1 genotype might be a factor of risk for endometrial carcinoma. Since this genetic variety may develop through an unconventional (nonsteroid) pathway, taking relevant preventive measures in high-risk groups should be recommended.

Topics: Biomarkers, Tumor; C-Peptide; Endometrial Neoplasms; Female; Genetic Markers; Genotype; Humans; Hyperinsulinism; Insulin; Polymorphism, Genetic; Risk Factors; Steroid 17-alpha-Hydroxylase

This study was designed to test the hypothesis that macrosomia in infants born to non-diabetic mothers is associated with an increased incidence of hyperinsulinemia and normal maternal glucose regulation in late pregnancy.. Twenty mothers and their macrosomic infants were chosen as the study group, and 20 mothers with their appropriate-for-gestational-age infants were chosen as the control group.. No difference in postpartum mean hemoglobin A1c levels was observed between the mothers of macrosomic infants and those of control infants. Cord plasma C-peptide levels were significantly higher in macrosomic than in control infants.. This study revealed that macrosomic infants of non-diabetic mothers were significantly more likely to have hyperinsulinemia than were normal-sized infants, and this hyperinsulinemia was not caused by dysregulation in glucose metabolism.

Topics: Blood Glucose; C-Peptide; Female; Fetal Blood; Fetal Macrosomia; Glycated Hemoglobin; Humans; Hyperinsulinism; Infant, Newborn; Male; Postpartum Period; Pregnancy; Pregnancy in Diabetics

Insulin release from the pancreatic beta-cells is controlled by ATP-sensitive K(+) (K(ATP)) channels, which consist of a hetero-octameric complex of four sulfonylurea receptor 1 (SUR1) and four Kir6.2 proteins. Mutations in the SUR1 gene are the major cause of congenital hyperinsulinemia (CHI). Despite the hereditary nature of CHI, studies of glucose homeostasis in heterozygous relatives of CHI patients are lacking. Theoretically, in the heterozygous state of the SUR1 gene mutation, only 1 of 16 K(ATP) channels consists of entirely normal subunits. The aim of our study was to investigate in vivo the glucose homeostasis of heterozygous SUR1 mutation carriers.. We studied 8 parents of CHI patients, all 8 of whom were heterozygous for the inactivating SUR1 mutation V187D, and 10 matched control subjects. We evaluated glucose tolerance and insulin secretory capacity with oral and intravenous glucose tests, rates of whole-body glucose uptake with hyperinsulinemic-euglycemic clamps, C-peptide response to hypoglycemia during hyperinsulinemic-hypoglycemic clamp, and function of the K(ATP) channels with intravenous tolbutamide test.. Carriers of the V187D substitution had normal glucose tolerance, normal tissue sensitivity to insulin, and no signs of inappropriate insulin secretion. The normal insulin response to tolbutamide indicated that heterozygosity for the V187D mutation did not impair K(ATP) channel function.. We conclude that the heterozygous carriers of the SUR1 mutation had normal glucose metabolism and insulin secretion, indicating that carriers of recessive K(ATP) channel mutations are unlikely to be at an increased risk of hypoglycemia or other disturbances in glucose metabolism.

Topics: Adult; Amino Acid Substitution; ATP-Binding Cassette Transporters; C-Peptide; Female; Genetic Carrier Screening; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mutation, Missense; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors; Tolbutamide

Abnormalities of glucose metabolism and hyperinsulinemia have been demonstrated in patients with end-stage renal disease and may contribute to the development of atherosclerotic complications in these patients. In the present study, we investigated the stage of renal failure in which abnormalities of glucose metabolism develop and whether these abnormalities were associated with an increased prevalence of cardiovascular events in patients with early renal failure. In 321 untreated essential hypertensive patients, we assessed renal function by measuring 24-h creatinine clearance, urinary protein excretion, and microalbuminuria; we assessed cardiovascular status by clinical and laboratory tests; and we measured plasma glucose, insulin, and C-peptide levels at fasting and after a 75-g oral glucose load. To evaluate insulin sensitivity, a hyperinsulinemic-euglycemic clamp was performed in a subgroup of 104 patients. Patients with creatinine clearance < 30 ml.min(-1).1.73 m(-2), severe hypertension, BMI < 30 kg/m(2), and diabetes or family history of diabetes were excluded. Hypertensive patients were found to be hyperinsulinemic when compared with 92 matched normotensive subjects. Early renal failure (creatinine clearance < 90 ml.min(-1).1.73 m(-2)) caused by hypertensive nephrosclerosis was detected in 116 of 321 patients. Analysis of patients with varying degrees of renal function impairment demonstrated increased plasma glucose and insulin response to oral glucose load, decreased fasting glucose-to-insulin ratio, and reduced sensitivity to insulin only in those patients with creatinine clearance < 50 ml.min(-1).1.73 m(-2). Parameters of glucose metabolism were not correlated with creatinine clearance and microalbuminuria. Prevalence of atherosclerotic cardiovascular events was significantly related to reduction of creatinine clearance, but parameters of glucose metabolism were comparable in patients with and without evidence of atherosclerotic damage. Thus, in patients with hypertensive nephrosclerosis and early impairment of glomerular filtration, alterations of glucose metabolism become evident only when creatinine clearance is < 50 ml.min(-1).1.73 m(-2) and are not related to microalbuminuria and cardiovascular complications.

Topics: Albuminuria; Blood Glucose; Body Mass Index; C-Peptide; Creatinine; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypertension; Insulin; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Reference Values; Smoking; Triglycerides

Several studies have linked low birth weight (LBW) and type 2 diabetes. We investigated hepatic and peripheral insulin action including intracellular glucose metabolism in 40 19-year-old men (20 LBW, 20 matched control subjects), using the hyperinsulinemic-euglycemic clamp technique at two physiological insulin levels (10 and 40 mU/m(2) per min), indirect calorimetry, and [3-(3)H]glucose. Insulin secretion was examined during an oral and intravenous glucose tolerance test. Fasting p-glucose was higher in the LBW group (5.6 +/- 0.1 vs. 5.4 +/- 0.1; P < 0.05). Basal plasma glycerol concentrations were significantly lower in the LBW group. Insulin-stimulated glycolytic flux was significantly reduced, and suppression of endogenous glucose production was enhanced in the LBW group. Nevertheless, basal and insulin-stimulated rates of whole-body peripheral glucose disposal, glucose oxidation, lipid oxidation, exogenous glucose storage, and nonoxidative glucose metabolism were similar in the two groups. Insulin secretion was reduced by 30% in the LBW group, when expressed relative to insulin sensitivity (disposition index = insulin secretion x insulin action). We propose that reduced insulin-stimulated glycolysis precedes overt insulin resistance in LBW men. A lower insulin secretion may contribute to impaired glucose tolerance and ultimately lead to diabetes.

Topics: 3-Hydroxybutyric Acid; Alanine; Birth Weight; Blood Glucose; C-Peptide; Denmark; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycerol; Humans; Hyperinsulinism; Infant, Low Birth Weight; Infant, Newborn; Insulin; Insulin Secretion; Lactates; Male; Reference Values; Registries; White People

In a cross-sectional study, we examined the association between hyperinsulinemia and hypertension, independent of body mass, among White non-Hispanic, Black non-Hispanic, and Mexican-American adults without diabetes.. Data are from 8,004 adults, aged > or = 20 years from the Third National Health and Nutrition Examination Survey, 1988-1994. Univariate differences in C-peptide levels (fasting) were examined in normotensives and hypertensives by racial or ethnic group. Multivariate logistic regression models were used to estimate the likelihood of hypertension across race-specific tertiles of C-peptide levels. Adjustments were made for age, sex, education, body mass index, and waist-to-hip ratio.. The prevalence of hypertension was 21.1% among non-Hispanic Whites, 24.6% among non-Hispanic Blacks, and 10.9% among Mexican Americans. The prevalence of hypertension increased significantly with C-peptide level for each racial or ethnic group. Mexican Americans with a C-peptide level in the upper tertile were 3.3 times (95% confidence interval [CI]=2.2-4.8) more likely to have hypertension than those with a C-peptide level in the lower tertile, after adjustment for age, sex, education, and BMI. Further adjustment for WHR resulted in a slightly lower odds ratio (OR=3.1; 95% CI=2.0-4.6). Among non-Hispanic Whites and Blacks, respectively, persons with a C-peptide level in the upper tertile were 1.6 times (95% CI=1.2-2.2) and 1.7 times (95% CI=1.1-2.6) more likely to have hypertension than those with a C-peptide level in the lower tertile, after multivariate (including WHR) adjustment.. These data suggest that high C-peptide levels, reflecting endogenous insulin secretion, are associated with hypertension, independent of body mass index and diabetes. This association was strongest among Mexican Americans. Our results also suggest that adjustment for waist-to-hip ratio as a confounding factor may be important in evaluation of the relationship between C-peptide level and hypertension.

Topics: Black or African American; C-Peptide; Comorbidity; Confidence Intervals; Cross-Sectional Studies; Female; Humans; Hyperinsulinism; Hypertension; Male; Mexican Americans; Obesity; Odds Ratio; White People

Acute elevations of plasma free fatty acid (FFA) levels augment glucose-stimulated insulin secretion (GSIS). Prolonged elevations of FFA levels reportedly impair GSIS, but no one has previously compared GSIS after prolonged exposure to saturated or unsaturated fat. Rats received a low-fat diet (Low-Fat) or one enriched with either saturated (Lard) or unsaturated fat (Soy) for 4 weeks. Insulin responses during hyperglycemic clamps were augmented by saturated but not unsaturated fat (580 +/- 25, 325 +/- 30, and 380 +/- 50 pmol x l(-1) x min(-1) in Lard, Soy, and Low-Fat groups, respectively). Despite hyperinsulinemia, the amount of glucose infused was lower in the Lard compared with the Low-Fat group. Separate studies measured GSIS from the perfused pancreas. Without fatty acids in the perfusate, insulin output in the Lard group (135 +/- 22 ng/30 min) matched that of Low-Fat rats (115 +/- 13 ng/30 min), but exceeded that of Soy rats (80 +/- 7 ng/30 min). When FFAs in the perfusate mimicked the quantity and composition of plasma FFAs in intact animals, in vivo insulin secretory patterns were restored. Because the GSIS of rats consuming Lard diets consistently exceeded that of the Soy group, we also assessed responses after 48-h infusions of lard or soy oil. Again, lard oil exhibited greater insulinotropic potency. These data indicate that prolonged exposure to saturated fat enhances GSIS (but this does not entirely compensate for insulin resistance), whereas unsaturated fat, given in the diet or by infusion, impairs GSIS. Inferences regarding the impact of fatty acids on GSIS that are based on models using unsaturated fat may not reflect the effects of saturated fat.

Topics: Animals; Blood Glucose; Body Composition; C-Peptide; Dietary Fats; Eating; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Linoleic Acid; Lipolysis; Male; Palmitic Acid; Pancreas; Rats; Rats, Sprague-Dawley; Soybean Oil; Stearic Acids; Triglycerides

To establish reference intervals for the pancreatic beta-cell response and the counterregulatory hormone response to prolonged fasting, we studied 33 healthy subjects (16 males, 17 females) during a 72-h fast. Glucose, insulin, C-peptide, and proinsulin levels decreased (P < 0.001), and the levels of counterregulatory factors increased during the fast [P < 0.05; glucagon and free fatty acids (FFA) with a linear increase and epinephrine, norepinephrine, and cortisol with a clear underlying circadian rhythm]. Growth hormone secretion increased from the first to third day of fasting (P < 0.05) but actually decreased from the second to third day of fasting (P = 0.03). Males had higher glucose and glucagon levels and lower FFA levels during the fast (P < 0.05), whereas no effect of gender on beta-cell polypeptides was observed. A high body mass index resulted in higher insulin and C-peptide levels during the fast (P < 0.05). In conclusion, we have provided reference intervals for glucoregulatory factors during a 72-h fast. We observed a diminished beta-cell response concomitant with an increased secretion of counterregulatory hormones. These results should be of clinical and scientific value in the investigation of hypoglycemic disorders.

Topics: Adult; Aged; B-Lymphocytes; Blood Glucose; Body Mass Index; C-Peptide; Chemistry, Clinical; Epinephrine; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Norepinephrine; Peptides; Proinsulin; Reference Values; Serum Albumin; Sex Factors

The negative-feedback control exerted by plasma insulin on beta-cell insulin release in normal-weight and obese subjects is still a matter of debate. Subjects submitted to a euglycemic insulin clamp undergo a suppression of insulin secretion that is due to both the infused insulin and the 2- to 3-hour fast during the procedure. We elected to elucidate the role of physiologic hyperinsulinemia per se in the insulin negative autofeedback in obese men. Ten men with massive uncomplicated obesity (age, 18 to 37 years; body mass index [BMI], 41 +/- 1.15 kg/m2) and 6 normal-weight healthy men (age, 22 to 30 years; BMI, 22 +/- 0.28 kg/m2) underwent 2 studies in random order: (1) a euglycemic-hyperinsulinemic glucose clamp with an insulin infusion rate of 1 mU/kg/min and (2) a control study with saline infusion. Serum C-peptide concentrations were significantly higher in obese versus control subjects at baseline (2.54 +/- 0.178 v 1.63 +/- 0.256 ng/mL, P < .05). Exogenous insulin infusion significantly suppressed serum C-peptide at steady state ([SS] last 30 minutes of insulin or saline infusion) in controls (mean of the last 4 measurements from 120 minutes to 150 minutes, 0.86 +/- 0.306 ng/mL, P < .05 vbaseline) but not in obese patients (2.03 +/- 0.26 ng/mL, nonsignificant [NS] v baseline). During the saline infusion studies, C-peptide levels slightly and similarly declined over time in both groups (2.71 +/- 0.350 at baseline v 2.31 +/- 0.300 ng/mL at SS in obese patients, NS, and 1.96 +/- 0.189 v 1.62 +/- 0.150 ng/mL in controls, NS). This study shows that in obese men hyperinsulinemia within the postprandial range is not superior to a 2.5-hour fast for the suppression of beta-cell activity, suggesting an impairment of the insulin negative autofeedback in this clinical condition.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Fasting; Fatty Acids, Nonesterified; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Male; Obesity

Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance.. Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y).. An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry.. The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation.. We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.

Topics: Adult; Body Composition; Body Mass Index; C-Peptide; Calorimetry, Indirect; Case-Control Studies; Electric Impedance; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Obesity, Morbid

Characterization of metabolically inadequate insulin secretion is essential for insulinoma diagnostics. Hyperinsulinaemic, eu- and hypoglycaemic clamp procedures have been used to suppress endogenous insulin secretion in healthy subjects. The use of exogenous insulin precluded the use of insulin as a parameter to be measured. We now suggest to use exogenous insulin lispro and an insulin-specific ELISA not cross reacting with insulin lispro. Thus, determination of insulin by ELISA in this experimental setting reflects endogenous insulin. A 39-year-old man with a surgically confirmed pancreatic insulinoma was studied under hyperinsulinaemic [lispro insulin 40 mU x m(-2) body surface x min(-1)] clamp conditions. Euglycaemia was achieved (3.8 +/- 0.5 mmol/L) for 1 h and hypoglycaemia (2.36 +/- 0.49 mmol/L) was achieved for another 30 min. Insulin was evaluated by ELISA (cross-reaction with lispro insulin < 0.006%, C-peptide < 0.01%, proinsulin < 0.001%) and by a nonselective RIA (cross-reaction with proinsulin 40%). In control subjects the euglycaemic hyperinsulinaemia suppressed C-peptide to 0.36 +/- 0.03 ng/ml and hypoglycaemic hyperinsulinaemia to 0.29 +/- 0.03 ng/ml. Endogenous insulin was suppressed to 2.8 +/- 0.03 mU/L under euglycaemia and to 2.6 +/- 0.03 mU/L under hypoglycaemia in control subjects. In the insulinoma patient apparently irregular but small changes in both C-peptide (1.43 +/- 0.1 ng/ml) and more pronounced changes in endogenous insulin concentrations 4.41 +/- 0.1 mU/l under euglycaemia and 5.35 +/- 0.3 mU/l under hypoglycaemic conditions, were observed. The basal level of insulin (ELISA insulin 4.6 mU/L) and C-peptide (1.7 ng/ml) were not markedly elevated. Determination of insulin allowed better characterization of irregular pulses because of the shorter half-life of insulin relative to C-peptide. The new modification of sequential eu- and hypoglycaemic clamp procedures should also be useful in pharmacological studies of insulinotropic substances. Direct measurement of peripheral insulin may be more sensitive than C-peptide to detect low levels of autonomous insulin secretion in small insulinomas.

Topics: Adult; C-Peptide; Enzyme-Linked Immunosorbent Assay; Fasting; Glucose; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Lispro; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Proinsulin

Microvascular angina has been found to be associated with insulin resistance. However, many factors known to affect insulin sensitivity were not excluded in patient selection. We aimed to evaluate whether microvascular angina is per se associated with insulin resistance.. We performed a Frequently Sampled Intravenous Glucose Tolerance Test (0.33 g kg(-1) b.w.) in 10 normal weight and normotensive patients with microvascular angina, with normal glucose tolerance and normal plasma lipids. Ten healthy subjects, comparable for age, sex, body mass index, blood pressure and plasma lipids, were used as control group.. Fasting serum glucose (4.49+/-0.2 SEM vs. 4.52+/-0.13 mmol L(-1), P = 0.9), insulin (39.46 +/-3.68 SEM vs. 47.12+/-4.6 pmol L(-1), P = 0.21) and C-peptide (0.56 +/-0.05 SEM vs. 0.53+/-0.05 nmol L(-1), P = 0. 68) values, as well as estimated parameters of insulin secretion and hepatic insulin extraction were similar in the two groups. Insulin sensitivity values (median, range) were also similar in the patients and control subjects (5.76 (3.39-12.30) vs. 7.54 (3.68-13.89. 10(-4) x min(-1)/(microU/mL), P = 0.97).. Microvascular angina per se is not associated with hyperinsulinaemia or insulin resistance when other confounding factors are excluded in patient selection.

Topics: Adult; Blood Glucose; C-Peptide; Cholesterol; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Male; Microvascular Angina; Middle Aged; Triglycerides

Hypothalamic neuropeptide Y is implicated in the aetiology of obesity and insulin resistance because of its hyperinsulinaemic, hyperphagic effects. We investigated the interaction of adrenal glucocorticoids and the parasympathetic nervous system in the hyperinsulinaemia caused by neuropeptide Y infusion in rats.. Neuropeptide Y was intracerebroventricularly given to normal or adrenalectomised rats for 3-6 days with pair-feeding, with or without subcutaneous dexamethasone infusion. We measured basal and intravenous glucose-induced insulinaemia and the effect of prior atropine injection.. Neuropeptide Y increased basal plasma insulin and C-peptide concentrations (380 +/- 90 and 1000 +/- 60 pmol/1, vs 190 +/- 20 and 590 +/- 50 pmol/1 in controls, p < 0.05). Neuropeptide Y also increased the plasma concentrations of these hormones as early as 60 s after glucose injection (1630 +/- 170 and 3200 +/- 170 pmol/1 for insulin and C peptide, respectively, vs 1080 +/- 80 and 1860 +/- 130 pmol/1 in controls, p < 0.05). Atropine reversed the effect of neuropeptide Y on basal plasma insulin and C-peptide concentrations but had no effect on post-glucose plasma concentrations. The hyperinsulinaemic effects of neuropeptide Y were prevented by adrenalectomy, but were restored by dexamethasone infusion. Dexamethasone in itself did not statistically significantly increase insulinaemia in adrenalectomised rats. As in intact rats, atropine attenuated the basal hyperinsulinaemia of adrenalectomised rats that had been infused with neuropeptide Y and dexamethasone but had no effect on post-glucose hyperinsulinaemia.. These data suggest firstly that neuropeptide Y infused centrally induces basal hyperinsulinaemia in rats through glucocorticoid-dependent parasympathetic activation to the pancreas. Secondly, neuropeptide Y potentiates glucose-induced insulinaemia through a pathway dependent on adrenal glucocorticoids that cannot be reversed by short-term blockade of the increased parasympathetic tonus.

Topics: Adrenalectomy; Animals; Atropine; Blood Glucose; C-Peptide; Cerebral Ventricles; Dexamethasone; Hyperinsulinism; Infusions, Parenteral; Insulin; Insulin Secretion; Kinetics; Male; Muscarinic Antagonists; Neuropeptide Y; Rats; Rats, Wistar; Reference Values

The present study was conducted in order to analyze the relationship existing between leptin and insulin levels in massive weight loss and weight recovery. Thirteen patients with severe obesity, 14 patients with anorexia nervosa and 13 healthy control subjects were studied. The patients with severe obesity underwent a vertical banded gastroplasty followed by an 800 kcal/day diet for 12 weeks. They were evaluated prior to (body mass index [BMI] 51.2 +/- 8.8 Kg/m2) and after drastic weight loss (BMI 40.6 +/- 6.7 Kg/m2). Patients with anorexia nervosa were treated exclusively with nutritional therapy during 12 weeks, and they were evaluated at their lowest weight status (BMI 16.2 +/- 2.2 Kg/m2) and after weight recovery (BMI 17.9 +/- 2.3 Kg/m2). The BMI of the normal subjects was in the normal range of 20 to 27 Kg/m2 (average 22.8 +/- 2.6 Kg/m2). BMI, percentage of body fat, waist circumference, and serum levels of leptin, insulin, and C-peptide were determined in each patient and normal subject. In severely obese patients, serum leptin and insulin decreased significantly after drastic weight reduction (leptin: from 51.8 +/- 22.3 to 23.7 +/- 10.2 ng/ml; insulin: from 27.1 +/- 13.3 to 17.2 +/- 7.2 mU/ml). In patients with anorexia nervosa, the mean serum leptin levels were significantly higher after weight recovery (5.5 +/- 3.2 vs 7.6 +/- 6 ng/ml). Serum leptin in the severe obesity group correlated positively with BMI, percentage body fat and waist circumference before and after weight loss. In those patients suffering from anorexia nervosa, serum leptin correlated positively with the BMI, percentage of body fat, and waist circumference in the low weight state and after weight recovery. In addition, their serum insulin correlated with BMI and waist circumference after weight recovery. These data reveal that serum leptin concentration correlates significantly with the BMI and body fat content 1) in subjects with a range of weight and caloric intake, 2) in obese patients after drastic weight loss; 3) in anorexic patients after weight gain; and that hyper- or normoinsulinemia do not seem to have any influence on the leptin changes caused by weight loss or gain.

Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Anthropometry; Body Mass Index; C-Peptide; Combined Modality Therapy; Female; Gastroplasty; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Weight Gain; Weight Loss

Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinemia. Both increased insulin secretion and decreased insulin clearance appear to contribute to hyperinsulinemia in cirrhotic patients. A decrease in hepatic insulin extraction rate may be due either to hepatocellular dysfunction or to portosystemic shunting with decreased first-pass insulin clearance.. To specifically address the contribution of portosystemic shunting to the pathogenesis of hyperinsulinemia in cirrhotic patients, we analyzed glycemic control and insulin levels in fasting serum in 23 cirrhotic patients before and after transjugular intrahepatic portosystemic shunt (TIPS).. Compared to respective values in healthy controls, C-peptide, insulin and proinsulin concentrations at baseline were increased by 340%, 120% and by 100% in cirrhotic patients (all p<0.05). In cirrhotic patients insulin levels before TIPS averaged 104+/-73 pmol/l and increased by more than 50% to 163+/-118 pmol/l after TIPS (p<0.01), whereas levels of C-peptide and proinsulin showed no significant change. Glucose and fructosamin levels also remained unchanged after TIPS.. Our data demonstrate that TIPS does not impair glycemic control in cirrhotic patients and that an increase in portosystemic shunting augments hyperinsulinemia, most likely by decreasing hepatic insulin clearance.

Topics: Ascites; Blood Glucose; C-Peptide; Female; Fructosamine; Hemorrhage; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Proinsulin; Reference Values

The magnitude of the counterregulatory response to insulin-induced hypoglycemia is primarily determined by the degree of hypoglycemia. We examined whether the route of acute insulin delivery (portal or peripheral venous) is also important in determining the magnitude of the counterregulatory response to hypoglycemia in nine healthy nondiabetic men. Pancreatic insulin secretion, stimulated by an i.v. tolbutamide infusion (portal insulin study), was matched with an exogenous insulin infusion into the peripheral vein 4-6 weeks later (peripheral insulin study). Each study consisted of a 150-min baseline tracer equilibration period, a 180-min euglycemic hyperinsulinemic (portal or peripheral insulin delivery) period, a 60-min hypoglycemic period in which insulin secretion diminished during tolbutamide or was reduced during exogenous insulin, and a 30-min recovery period. Peripheral venous glucose concentrations were well matched in the portal and peripheral studies during euglycemia and hypoglycemia (glucose nadir, 2.9 +/- 0.1 mmol/L in the portal and 2.7 +/- 0.1 mmol/L in the peripheral; mean +/- SEM; P = NS), and insulin concentrations were about 1.5-fold higher throughout the experiment in the peripheral vs. the portal insulin study due to the first pass extraction of insulin in the portal study. There was a much greater increment (P < 0.0001) in FFA in the portal vs. the peripheral study (area under the curve: portal, 19.5 +/- 3.9 mmol/L x 90 min; peripheral, 3.3 +/- 1.1 mmol/L x 90 min), whereas plasma glucagon and GH were higher in the peripheral study (P = 0.01 for glucagon; P = 0.015 for GH). There was no significant difference between studies in epinephrine and norepinephrine responses to hypoglycemia or stimulation of endogenous glucose production (area under the curve: portal, 636 +/- 103 micromol/kg x 90 min; peripheral, 705 +/- 69 micromol/kg x 90 min; P = NS). In summary, we have shown that the glucagon, GH, and FFA responses to hypoglycemia during insulin dissipation are affected by the route of insulin delivery and are not controlled exclusively by the nadir blood glucose level. The clinical importance of these observations in diabetic subjects as they relate to route of insulin delivery (portal or peripheral) during insulin dissipation remains to be determined.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Glucose; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Injections, Intravenous; Insulin; Lactic Acid; Male; Portal Vein; Reference Values; Tolbutamide; Veins

Hyperglycaemia slows gastric emptying in both normal subjects and patients with diabetes mellitus. The mechanisms mediating this effect, particularly the potential role of insulin, are uncertain. Hyperinsulinaemia has been reported to slow gastric emptying in normal subjects during euglycaemia. The purpose of this study was to evaluate the effect of euglycaemic hyperinsulinaemia on gastric emptying in Type I (insulin-dependent) and Type II (noninsulin-dependent) diabetes mellitus. In six patients with uncomplicated Type I and eight patients with uncomplicated Type II diabetes mellitus, measurements of gastric emptying were done on 2 separate days. No patients had gastrointestinal symptoms or cardiovascular autonomic neuropathy. The insulin infusion rate was 40 mU x m(-2) x min(-1) on one day and 80 mU x m(-2) x min(-1) on the other. Gastric emptying and intragastric meal distribution were measured using a scintigraphic technique for 3 h after ingestion of a mixed solid/liquid meal and results compared with a range established in normal volunteers. In both Type I and Type II patients the serum insulin concentration had no effect on gastric emptying or intragastric meal distribution of solids or liquids. When gastric emptying during insulin infusion rates of 40 mU x m(-2) x min(-1) and 80 mU x m(-2) x min(-1) were compared the solid T50 was 137.8+/-24.6 min vs. 128.7+/-24.3 min and liquid T50 was 36.7+/-19.4 min vs. 40.4+/-15.7 min in the Type I patients; the solid T50 was 94.9+/-19.1 vs. 86.1+/-10.7 min and liquid T50 was 21.8+/-6.9 min vs. 21.8+/-5.9 min in the Type II patients. We conclude that hyperinsulinaemia during euglycaemia has no notable effect on gastric emptying in patients with uncomplicated Type I and Type II diabetes; any effect of insulin on gastric emptying in patients with diabetes is likely to be minimal.

Topics: Adult; Amyloid; Blood Glucose; C-Peptide; Cholecystokinin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Islet Amyloid Polypeptide; Male; Peptide Fragments; Protein Precursors

In adults, endogenous hyperinsulinemic hypoglycemia is almost invariably due to insulinoma. In these patients with insulinoma, neuroglycopenic episodes exclusively after meal ingestion and negative 72-h fasts are extraordinarily rare. We describe five adults with neuroglycopenic episodes from hyperinsulinemic hypoglycemia within 4 h of meal ingestion and negative 72-h fasts. Each had negative transabdominal ultrasonography, spiral computed tomographic scanning, and celiac axis angiography of the pancreas. However, all showed positive selective arterial calcium stimulation tests indicative of pancreatic beta-cell hyperfunction. At pancreatic exploration, no insulinoma was detected by intraoperative ultrasonography and complete mobilization and palpation of the pancreas. Moreover, the resected pancreata showed islet hypertrophy and nesidioblastosis, but no insulinoma. No definite disease-causing mutation was detected in Kir6.2 and SUR1 genes, which encode the subunits of the pancreatic ATP-sensitive potassium channel responsible for glucose-induced insulin secretion. Four patients who underwent gradient-guided partial pancreatectomy have been free of hypoglycemic symptoms for up to 3 yr follow-up; the other, who underwent a limited distal pancreatectomy, has had brief recurrence of symptoms. The unique clinical features and responses to dynamic testing in these adults with hyperinsulinemic hypoglycemia in the absence of insulinoma may constitute a new syndrome of postprandial hypoglycemia from diffuse beta-cell hyperfunction.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Calcium; Female; Glycosyltransferases; Humans; Hyperinsulinism; Hypoglycemia; Islets of Langerhans; Male; Membrane Proteins; Mutation; Pancreas; Pancreatectomy; Postprandial Period; Potassium Channels; Potassium Channels, Inwardly Rectifying; Regional Blood Flow; Repressor Proteins; Saccharomyces cerevisiae Proteins; Syndrome; Tomography, X-Ray Computed; Ultrasonography

Sympathetic activation has been considered as a link between insulin resistance, hyperinsulinemia, and hypertension. However, little is known about the association between insulin sensitivity and autonomic regulation or about the effect of acute hyperinsulinemia on cardiac sympathovagal balance. The aim of this study was to investigate heart rate variability (HRV) during the euglycemic-hyperinsulinemic clamp in nondiabetic offspring of patients with type 2 diabetes. We studied 35 nondiabetic offspring of patients with type 2 diabetes and 19 control subjects. Probands were chosen from a 10-year follow-up study of patients with well-characterized type 2 diabetes according to their fasting C-peptide level (selected from both ends of the distribution) and from control subjects to form three groups: 1) a group including subjects who were offspring of type 2 diabetic patients with low C-peptide levels (deficient insulin secretion group [IS group], n = 17), 2) a group including subjects who were offspring of type 2 diabetic patients with high C-peptide levels (insulin-resistant group [IR group], n = 18), and 3) a control group without a history of type 2 diabetes in first-degree relatives (n = 19). HRV was assessed at baseline and at the steady state during the euglycemic-hyperinsulinemic clamp. Rates of whole-body glucose uptake (M value) were lower in the IR group than in the IS group and the control group (41+/-3 vs. 54+/-2 vs. 60+/-4 micromol x kg(-1) x min(-1), P < 0.01 and P < 0.01, respectively). In all groups, heart rate increased significantly during hyperinsulinemia. In the IR group, insulin infusion increased total power of HRV [from 7.70+/-0.15 to 8.05+/-0.15 ln(ms2), P < 0.01] and the low frequency-to-high frequency ratio (from 0.62+/-0.14 to 1.14+/-0.18, P < 0.01) and decreased power of the high frequency spectral component (from 5.73+/-0.17 to 5.43+/-0.16 ln(ms2), P < 0.05), whereas in other groups, changes in HRV were not significant. We conclude that the HRV response to acute hyperinsulinemia in the offspring of type 2 diabetic probands was likely to be modulated by the type 2 diabetic phenotype of the parent. In insulin-resistant subjects, autonomic dysfunction may be an earlier defect than hitherto acknowledged.

Topics: Adult; Autonomic Nervous System; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Heart Rate; Humans; Hyperinsulinism; Insulin Resistance; Male; Middle Aged; Phenotype; Smoking

Plasma leptin is considered to play a role in maintenance of energy balance and body weight by neuroendocrine mechanisms. Thyroid hormones are permissive for adrenergic activation, which in turn has been shown to decrease leptin expression. This study was therefore designed to test the hypothesis that hyperthyroidism results in lower leptin concentrations, whereas hypothyroidism leads to higher plasma leptin concentrations. In addition, the effects of normalization of thyroid function on plasma leptin were investigated.. Fasting plasma leptin concentrations and body fat mass (total body electrical conductivity) were measured in patients with overt hypothyroidism and hyperthyroidism before and after successful treatment. Plasma leptin, glucose, insulin and free fatty acid concentrations were monitored during an oral glucose tolerance test (OGTT 75 g).. Fasting plasma leptin concentrations were similar in lean patients, independently of their thyroid function (hyperthyroid 12.5 +/- 2 ng mL-1, hypothyroid 10.2 +/- ng mL-1, euthyroid 12.7 +/- 3 ng mL-1). In obese hypothyroid patients, plasma leptin was threefold higher (P < 0.0005) than in lean hypothyroid patients, twofold higher (P < 0.005) than in obese hyperthyroid patients matched for fat mass and 30% increased (P < 0.01) compared with obese euthyroid subjects. There were no differences between fasting and post-prandial (OGTT) leptin concentrations in any group. Normalization of thyroid function did not affect plasma leptin, which remained elevated (P < 0.005) in formerly obese hypothyroid patients. Plasma leptin was not associated with serum thyroid hormones but highly correlated with body mass index and body fat mass in all patients (r = 0.85, P < 0.001). Plasma leptin correlated with plasma insulin concentration only in hyperthyroid patients (P < 0.01, r = 0.64), who presented with blunted stimulation of insulin release and higher plasma glucose (P < 0.05) than hypothyroid subjects.. The results indicate that (a) the correlation of leptin with body fat mass is preserved in thyroid dysfunction, (b) plasma leptin is markedly increased in obese hypothyroid hyperinsulinaemic patients and (c) plasma leptin is not affected by oral glucose loading.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hydrocortisone; Hyperinsulinism; Hyperthyroidism; Hypothyroidism; Insulin; Leptin; Male; Middle Aged; Obesity; Proteins

Recent evidence suggests that hyperinsulinemia may contribute to the development of various risk factors of atherosclerosis. To examine the effects of energy intake on insulin secretion, 24-h urine C-peptide was measured in twelve women with rheumatoid arthritis who were not taking any medicine and stayed in Koda hospital for a diet therapy which lasted 55 days. They were basically placed on a 1200 kcal/day vegan diet combined with three 3-5-day fasting periods (200 kcal/day). Urine C-peptide excretion markedly decreased from 31-40 to 8-14 micrograms/day during the fasting periods. Among the anthropometric variables examined, the average level of urine C-peptide excretions measured in the fasting periods showed a significant correlation with the percentage and the amount of body fat. However, such correlation was not observed while the calorie intake was 1200 kcal. No clinical laboratory parameter showed a significant correlation with urinary C-peptide excretion. These results suggest that the major determinant of urine C-peptide excretion is food intake and that hyperinsulinemia could be easily improved by restricting energy intake.

Topics: Arthritis, Rheumatoid; C-Peptide; Energy Intake; Female; Humans; Hyperinsulinism

Topics: Adult; C-Peptide; Fatty Liver; Female; Hepatitis; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Lipids; Liver; Male; Obesity; Reference Values

The correlation between hypertension and related risk factors has been studied in 733 type 2 diabetic patients. Hypertension was more frequent in women (65.35%) than in men (50.35%) (p < 0.0001).. Hypertensive patients showed older age (p < 0.0001) and greater Body Mass Index (BMI) (p < 0.03) than normotensive. In the diabetic group on diet only basal insulinaemia was higher (p < 0.05) in hypertensive than in normotensive diabetic men, but not in women. Such a difference, was not seen in patients of both sexes treated with oral hypoglycaemic agents; besides there was no difference in fasting C-peptide levels between hypertensive and normotensive insulin treated patients. In both sexes hypertension was independently correlated with age, BMI, increased urinary albumin excretion, triglycerides. The strongest correlation was with the family history of hypertension. On the contrary there was no correlation between hypertension and waisthip ratio.. In conclusion, the association between hypertension and type 2 diabetes depends on various risk factors, but a relationship with insulin levels is not surely demonstrable.

Topics: Administration, Oral; Adult; Age Factors; Aged; Albuminuria; Blood Glucose; Body Constitution; Body Mass Index; C-Peptide; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Hyperinsulinism; Hypertension; Hypertriglyceridemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Italy; Male; Middle Aged; Obesity; Prevalence; Risk Factors

Insulin secretion in response to an oral glucose tolerance test (OGTT) and sex hormone levels (free testosterone, androstenedione, dehydroepiandrosterone sulfate [DHEAS], estradiol, and sex hormone-binding globulin [SHBG]) were evaluated in 49 healthy obese premenopausal women (body mass index [BMI], 30 to 50.6 kg/m2) and 21 control subjects (BMI, 17.8 to 24.0 kg/m2) with normal glucose tolerance and without signs of hyperandrogenism. Obese women were divided into two groups according to waist to hip ratio (WHR): 27 subjects with upper-body obesity (WHR > 0.85) and 22 subjects with lower-body obesity (WHR < 0.8). Both fasting and glucose-induced insulin levels were higher in women with upper-body obesity than in controls (P < .001) and those with lower-body obesity (P < .001). Hyperandrogenism was observed in women with upper-body obesity, as evident by significantly elevated free testosterone (P < .05 v controls and subjects with lower-body obesity) and decreased SHBG (P < .001 v controls). The most important independent determinants of fasting insulin levels were BMI (P < .01) and the ratio of DHEAS to free testosterone (P < .01). The most important determinants of cumulative insulin response were WHR (P < .0005), duration of obesity (P < .01), and androstenedione levels (P < .01). In conclusion, in healthy obese premenopausal women without clinical signs of hyperandrogenism, a high BMI and more pronounced upper-body fat localization resulted in hyperinsulinemia and hyperandrogenism. The duration of obesity exaggerated the glucose-induced insulin level and cumulative insulin response independently of the degree of obesity and obesity type. The ratio of DHEAS to free testosterone was an independent determinant of fasting insulin concentration. Furthermore, the ratio of DHEAS to free testosterone rather than either of these androgens alone may be important in the regulation of insulin action in women.

Topics: Adult; Androstenedione; Body Weight; C-Peptide; Dehydroepiandrosterone; Estradiol; Fasting; Female; Glucose; Glucose Tolerance Test; Gonadal Steroid Hormones; Humans; Hyperandrogenism; Hyperinsulinism; Insulin; Obesity; Premenopause; Regression Analysis; Sex Hormone-Binding Globulin; Testosterone

Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of polycystic ovarian disease (PCOD). On the other hand, being generally admitted that opioids may play a role in glycoregulation and that opioid tone is altered in PCOD, an involvement of the opioids in determining the hyperinsulinemia of PCOD patients could be suggested. The aim of this study was to evaluate the effect of a chronic opioid blockade on insulin metabolism and peripheral insulin sensitivity in PCOD hyperinsulinemic patients. Twenty-three women with PCOD were studied. An oral glucose tolerance test (OGTT) and a clamp study were performed at baseline (during the follicular phase) and after 6 weeks of naltrexone administration (50 mg/d orally). Based on the insulinemic response to the OGTT, 16 women were classified as hyperinsulinemic and seven as normoinsulinemic. Naltrexone treatment significantly reduced fasting (P < .05) and area under the curve (AUC) (P < .02) plasma insulin levels only in the hyperinsulinemic group. Moreover, hyperinsulinemic patients showed similar C-peptide incremental areas after naltrexone treatment, whereas in the same patients the fractional hepatic insulin extraction calculated from the incremental areas of insulin and C-peptide was found to be increased after chronic opioid blockade by naltrexone. For peripheral insulin sensitivity, the hyperinsulinemic group showed significantly lower (P < .01) total-body glucose utilization (M) compared with the normoinsulinemic group. No change in the M value was found after treatment in both groups. These data suggest that the insulin sensitivity and hyperinsulinemia after an OGTT are two distinct deranged features of the insulin disorder of PCOD patients.

Topics: Adolescent; Adult; C-Peptide; Female; Glucose; Humans; Hyperinsulinism; Insulin Resistance; Naltrexone; Opioid Peptides; Polycystic Ovary Syndrome

Topics: Adult; Angiography; Blood Glucose; C-Peptide; Cognition Disorders; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syncope; Tomography, X-Ray Computed

To study 1) whether abdominal adiposity was present in adult offspring of two NIDDM parents, 2) whether abdominal adiposity was associated with the development of glucose intolerance, and 3) the association of pancreatic beta-cell function with impaired glucose tolerance (IGT) and NIDDM in these groups.. One hundred offspring whose parents both had NIDDM were studied (60 men, 40 women, mean age 34 +/- 6.9 years, BMI 27.4 +/- 4.1 kg/m2). None had a history of glucose intolerance. Nondiabetic control subjects with no family history of diabetes were also studied for comparison (21 men, 19 women, age 36 +/- 10.3 years, BMI 26 +/- 3.7 kg/m2). A standard oral glucose tolerance test was done for all, and plasma glucose, C-peptide, and insulin responses were measured. Abdominal fat measurements at L4-L5 were made using a computed axial tomography scan. Subcutaneous fat (SF), visceral fat (VF), and total fat (TF) areas were measured and VF/SF ratio was calculated. An index of insulin secretion (delta I/G) was derived as the ratio of incremental insulin at 30 min divided by 30-min plasma glucose.. IGT was detected in 32 offspring and diabetes in 21 offspring. Diabetic men had a higher TF area than the other groups. SF, VF, and VF/SF ratios were similar in control men and in offspring with normal glucose tolerance (NGT), IGT, or diabetes. Among control subjects, women had significantly lower VF than men. Female offspring had higher VF than the control subjects, but intragroup variations were absent. Fasting insulin and all C-peptide responses were higher in NGT compared with control subjects (P < 0.02). The 2-h insulin and C-peptide responses were higher in IGT subjects (P < 0.005). In diabetic subjects, the insulin-to-glucose ratio, C-peptide-to-glucose ratio, and delta I/G were significantly low compared with all other groups (P < 0.005). Multiple logistic regression analysis showed that the area of insulin response had a positive association and delta I/G had a negative association with diabetes, while age, sex, BMI, waist-to-hip ratio, abdominal fat areas, fasting and 2-h insulin, area of insulin, and the C-peptide measurements did not show independent associations. Two-hour insulin showed a positive association with IGT, while increasing area of insulin showed a negative association.. Visceral adiposity seemed to precede glucose intolerance only in women, but it had no independent association with IGT or NIDDM. Insulin resistance, indicated by higher plasma insulin response, and insulin secretory defect, indicated by low delta I/G at 30 min, were associated with diabetes. beta-cell defect was not independently associated with IGT. Increased abdominal visceral adiposity does not appear to be a prerequisite for development of IGT or diabetes in Asian Indians with a strong genetic predisposition for diabetes.

Topics: Abdomen; Adipose Tissue; Adult; Blood Glucose; Body Constitution; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; India; Insulin; Islets of Langerhans; Male; Nuclear Family; Postprandial Period; Prediabetic State; Sex Characteristics; Tomography, X-Ray Computed

We aimed to evaluate gestational impaired glucose tolerance (GIGT) in untreated patients using umbilical cord blood insulin and connecting peptide (C-peptide) concentrations to indicate fetal hyperinsulinemia. A 75 g, 2-hour oral glucose tolerance test, evaluated using WHO criteria, was performed in 722 antenatal patients. Cord C-peptide (p = 0.001) and insulin (p = 0.008) concentrations were significantly higher in patients with GIGT in comparison to those with normal glucose tolerance. The WHO test failed to identify abnormal C-peptide concentrations (p = 0.057), but did identify abnormal insulin concentrations (p = 0.006) and cases where either or both were raised (p = 0.002), with a low Youden's index (range 8.1-11.3) in all 3 cases. A significant biochemical difference exists in patients with GIGT. The WHO criteria for GIGT predict abnormal biochemical outcomes, but they do so poorly.

Topics: Biomarkers; C-Peptide; Diabetes, Gestational; Female; Fetal Blood; Fetal Diseases; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Pregnancy; Pregnancy Complications

Hyperinsulinaemia and dyslipoproteinaemia are markers and risk factors for coronary artery disease (CAD) and non-insulin-dependent diabetes mellitus (NIDDM). We investigated the influence of a tumour necrosis factor beta (TNF-beta) gene polymorphism on serum parameters related to these metabolic disorders in patients with CAD.. A total of 199 patients with CAD and 81 control subjects with angiographically normal coronary arteries were studied. A digestion of amplified DNA with NcoI revealed three fragment patterns: homozygosity for TNF-beta *1 or TNF-beta *2 and heterozygosity (TNF-beta *1/*2).. Patients with CAD who had increased serum insulin or C-peptide (fasting and after glucose load) were predominantly heterozygous for TNF-beta (72% vs. 47%) and less frequently homozygous for TNF-beta *2 (22% vs. 43%, P = 0 x 0.03).. This study demonstrates an association of TNF-beta alleles with the risk factor hyperinsulinaemia in CAD. Genomic variants of TNF-beta may therefore contribute to the complex susceptibility for the metabolic syndrome in patients with CAD.

Topics: Alleles; C-Peptide; Coronary Disease; Gene Frequency; Glucose Tolerance Test; Heart Valve Diseases; Heterozygote; Homozygote; Humans; Hyperinsulinism; Insulin; Lymphotoxin-alpha; Male; Middle Aged; Polymorphism, Genetic

Plasma norepinephrine (NE) concentrations are a fallible index of sympathetic neural activity because circulating NE can be derived from sympathetic nerves, the adrenal medullas, or both and because of regional differences in sympathetic neural activity. We used isotope dilution measurements of systemic and forearm NE spillover rates (SNESO and FNESO, respectively) to study the sympathochromaffin system during prolonged standing, hyperinsulinemic euglycemia, and hyperinsulinemic hypoglycemia in healthy humans. Prolonged standing led to decrements in blood pressure without increments in heart rate, the pattern of incipient vasodepressor syncope. FNESO was not increased (0.58 +/- 0.20 to 0. 50 +/- 0.21 pmol. min-1. 100 ml tissue-1), suggesting that the approximately twofold increments in plasma NE and SNESO were derived from sympathetic nerves other than those in the forearm (with a possible contribution from the adrenal medullas). Hyperinsulinemia per se (euglycemia maintained) stimulated sympathetic neural activity, as evidenced by increments in FNESO (0.57 +/- 0.11 to 1.25 +/- 0.25 pmol. min-1. 100 ml tissue-1, P < 0.05), but not adrenomedullary activity. Hypoglycemia per se stimulated adrenomedullary activity (plasma epinephrine from 190 +/- 70 to 1720 +/- 320, pmol/l, P < 0.01). Although SNESO (P < 0.05) and perhaps plasma NE (P < 0.06) were raised to a greater extent during hyperinsulinemic hypoglycemia than during hyperinsulinemic euglycemia, FNESO was not. Thus these data do not provide direct support for the concept that hypoglycemia per se also stimulates sympathetic neural activity.

Topics: Adult; Blood Pressure; C-Peptide; Chromaffin System; Female; Forearm; Glucagon; Glucose Clamp Technique; Heart Rate; Hormones; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Infusions, Intravenous; Insulin; Male; Muscle, Skeletal; Norepinephrine; Pancreatic Polypeptide; Posture; Regional Blood Flow; Sympathetic Nervous System

In 18 patients with pernicious anaemia (PA) the authors assessed the blood glucose level, C-peptide level and immunoreactive insulin (IRI) during the oral glucose tolerance test (o-GTT). They calculated the body mass index (BMI), assessed the level of the thyroid-stimulating hormone (s-TSH), free thyroxine (fT4), triiodothyronine (T3) and took repeatedly blood pressure readings. In one female patient they confirmed the diagnosis of insulin dependent diabetes mellitus (IDDM), in another six subjects they detected non-insulin dependent diabetes mellitus (NIDDM), incl. two persons where it was detected newly. In four patients impaired glucose tolerance was revealed. In the remaining seven patients non-classifiable glucose tolerance was found, none of the patients had a quite normal o-GTT. In five patients, hitherto not diagnosed latent hypothyroidism was detected. Eleven subjects were obese, four patients suffered from hypertension, another six from systolic hypertension, in eight patients a significantly elevated C-peptide level on fasting was found, in the majority of patients an elevated, or protracted response of C-peptide and insulin to orally administered glucose was found. Patients with pernicious anaemia must be considered subjects with cumulation of risk factors for atherosclerosis; these risk factors must be actively sought and treated.

Topics: Aged; Aged, 80 and over; Anemia, Pernicious; Arteriosclerosis; Blood Glucose; C-Peptide; Diabetes Complications; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Risk Factors

Obesity is characterized by variable degrees of hyperinsulinaemia, which has been attributed to either beta-cell hypersecretion or reduced hepatic insulin extraction, or both. To investigate this controversial issue, a 4-h frequently sampled i.v. glucose tolerance test (glucose dose 12.8 g m(-2)) was performed in 13 normotolerant, grossly obese adolescents (10 F/3 M; 13+/-1 y; body mass index 32+/-0.9; pubertal stage 4-5; obesity duration 7.8+/-3 y) and in a comparable group of 8 healthy, normal-weight subjects. Glucose, insulin and C-peptide time-course were analysed by the minimal model technique, which estimates beta-cell secretion, insulin sensitivity (Si), glucose effectiveness (SG) and hepatic insulin extraction (HE). Despite similar fasting and after load glucose patterns (SG similar in the two groups), obese adolescents showed sustained peripheral hyperinsulinaemia (total insulin area under the concentration curve 67.2+/-10.8 vs 19.1+/-1.2 pmol l(-1) in 240 min; p <0.002) and a 71% reduction in Si (2.02+/-0.33 vs 6.95+/-1.03 x 10(4) min(-1) (microU ml(-1)); p < 0.001). Compared with control subjects, the total amounts of prehepatic insulin secretion and posthepatic insulin delivery were also increased significantly in obese adolescents by 30% and 46%, respectively; HE was reduced by 15% during the first 30 min of the test, but recovered within the normal range during the rest of the test. In conclusion, severely obese adolescents are insulin resistant and their hyperinsulinaemia is primarily caused by beta-cell hypersecretion, whereas the reduction in insulin hepatic extraction is a transient metabolic phenomenon.

Topics: Adolescent; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Obesity

Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic beta-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic beta-cell secretion in men with different body compositions. Eighteen young men (30.0 +/- 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P < 0.05), proinsulin (r = -0.47, P < 0.05), C-peptide (r = -0.55, P < 0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P < 0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P < 0.05). When subjects were divided into obese (BMI > 28 kg/m2, N = 8) and nonobese (BMI < or = 25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic beta-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic beta-cell demand.

Topics: Adult; Biomarkers; Body Mass Index; C-Peptide; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Islets of Langerhans; Male; Proinsulin; Sex Hormone-Binding Globulin

Exercise is known to decrease insulin secretion, but the effect on insulin clearance is unclear. We examined the effect of exercise in insulin clearance with euglycaemic insulin clamp in 28 healthy men either 12 h after a marathon run (n = 14) or 44 h after a 2-h treadmill exercise (n = 14), and in seven insulin-dependent diabetes mellitus (IDDM) patients 12 h after a marathon run, and after a resting, control day. During the post-exercise insulin infusion, steady-state plasma insulin concentration was reduced by 9% in healthy men after both types of exercise, and by 16% in the diabetic subjects compared with the control study (P < 0.05 in all). In healthy men, C-peptide concentrations were more than one-third lower during insulin infusion, both after the marathon run (P < 0.001) or treadmill exercise (P < 0.02) compared with the control study. Insulin clearance was significantly increased by exercise both in healthy men (9% P < 0.05) and in IDDM subjects (15%, P < 0.05). After exercise, endogenous insulin secretion in healthy men is reduced and insulin clearance is enhanced both in healthy men and in IDDM patients. Decreased insulin availability may allow enhanced muscle lipid utilization and spare glucose after long-term exercise.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Exercise; Fasting; Humans; Hyperinsulinism; Insulin; Male; Running; Triglycerides

We determined the metabolic effects of insulin derived from renal subcapsular islet grafts, either with systemic delivery of insulin through renal venous drainage (REN) or with portal delivery of insulin after renal vein-to-superior mesenteric vein anastomosis (RMA), in streptozotocin-induced diabetic Lewis rats, in comparison with normal rats. After gavage glucose, the plasma glucose responses were similar to normal in REN and RMA rats; however, hyperinsulinemia occurred in REN rats (area under the concentration curves [AUCs] of insulin, 27 +/- 3 nmol x 1(-l) min) in comparison with RMA (14 +/- 2) and normal rats (19 +/- 2), P < 0.003, with no difference in C-peptide responses. The ratio of AUC C-peptide to AUC insulin was lower in REN (2.0 +/- 0.2) than in RMA (3.4 +/- 0.3) and normal animals (3.2 +/- 0.3), P < 0.0005. In euglycemic-hyperinsulinemic clamp studies using the same insulin infusion rate (10 pmol x kg(-1) x min(-1), insulin resistance was found in REN animals (mean glucose infusion rate [GIR], REN: 7.5 +/- 1.2; RMA: 12.0 +/- 1.2; normal: 12.7 +/- 1.0 mg x kg(-1) x min(-1); P < 0.008), with higher steady-state insulin levels in REN (554 +/- 63 pmol/l) than in RMA (291 +/- 26) and normal rats (269 +/- 60), P < 0.0001. With matching steady-state insulin levels in RMA and REN rats during infusion of insulin at 20 pmol x kg(-1) x min(-1) in RMA rats (steady-state insulin 623 +/- 64 pmol/l), GIR was 15.7 +/- 0.7 mg x kg(-1) x min(-1). Thus, systemic delivery of insulin from islet grafts is associated with hyperinsulinemia, insulin resistance, and decreased metabolic clearance of insulin. These abnormalities are prevented by portal delivery of insulin from islet grafts in the same site. The findings are consistent with the hypothesis that portal delivery of insulin is important in maintenance of normal whole-body insulin sensitivity.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Glucagon; Glucose Clamp Technique; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans Transplantation; Liver; Male; Mesenteric Veins; Organ Size; Rats; Rats, Inbred Lew; Renal Veins

Topics: Adult; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Ultrasonography

To better characterize autonomous insulin secretory behaviour in insulinoma patients and to establish diagnostic criteria with high accuracy, hyper-insulinaemic, sequentially eu- and hypoglycaemic clamp tests were performed in insulinoma patients and control subjects. Ten patients with insulinoma (benign in nine, histologically proven in nine) and 10 patients with suspected episodes of hypoglycaemia, in whom thorough clinical evaluation excluded an insulinoma, were examined. Five insulinoma patients were restudied after successful extirpation of the tumour. Suppression of C-peptide during low-dose [2 pmol kg-1 min-1 (20 mU kg-1 h-1) for 90 min, plasma insulin approximately 120 pmol L-1 (20 mUL-1)] and high-dose [8 pmol kg-1 h-1 (80 mU kg-1 h-1) for 90 min, plasma insulin approximately 450 pmol L-1 (75 mU L-1)] insulin infusion under euglycaemic conditions [plasma glucose 4.4-5.0 mmol L-1 (80-90 mg dL-1)] and during high-dose insulin infusion under hypoglycaemic conditions [glucose 2-2.2 mmol L-1 (40-45 mg dL-1)] was evaluated by radioimmunoassay (RIA). Euglycaemic hyper-insulinaemia suppressed C-peptide in control subjects (P < 0.0001), whereas in insulinoma patients apparently irregular changes in C-peptide concentrations (with spontaneous or paradoxical increments, P = 0.0006 vs. controls) were observed. The combination of hyper-insulinaemia and controlled hypoglycaemia led to a nearly complete suppression of C-peptide in normal subjects (from basal, 0.76 +/- 0.08-0.06 +/- 0.01 nmol L-1; maximum observed value 0.10 nmol L-1), which was more pronounced than at the point of discontinuation of prolonged fasting (> 48 h; 0.26 +/- 0.16 nmol L-1; P = 0.005). In insulinoma patients, C-peptide remained elevated under all conditions (P = 0.51 vs. prolonged fasting). All these findings were reversible after successful surgical removal of the insulinoma. Insulinoma patients could be identified as abnormal by (a) non-suppression of C-peptide even under hyperinsulinaemic/hypoglycaemic conditions (10 out of 10 patients) and (b) irregular increments in C-peptide under conditions that led to at least partial suppression in all normal subjects (9 out of 10 patients) and/or by an apparent shift to the left of insulin secretion relative to glucose concentrations (7 out of 10 patients). Controlled exposure to hyperinsulinaemic/hypoglycaemic conditions can help to characterize autonomous secretion in insulinoma patients and may be used as a diagnostic procedure when convent

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

The objective of the study was to determine if male subjects with coronary atherosclerotic heart disease (CHD) without major CHD risk factors have hyperinsulinemia and related metabolic changes. Previous studies suggested that hyperinsulinemia is a CHD risk factor, but they did not entirely exclude concurrent metabolic abnormalities. A prospective, comparative, cross-sectional study in a tertiary care teaching hospital in Mexico City was conducted in 15 men who had suffered myocardial infarction 6 to 24 months before and had significant coronary occlusion on angiography. Control group was formed by 15 age-matched healthy men. None had hypertension, obesity, diabetes, gout, glucose intolerance or hyperlipidemia. Body mass index (BMI), waist/hip ratio (WHR), blood pressure (BP); oral glucose tolerance test (OGTT) with measurement of serum glucose, insulin and C-peptide every 30 min for 2 h, fasting serum cholesterol, triglycerides and uric acid, areas under curve (AUC) of glucose and insulin, insulin/glucose ratio and insulin sensitivity index were calculated. BMI, WHR and BP were similar in both groups. Fasting and post-load serum glucose and insulin concentrations were significantly higher in CHD than in control group (p < 0.01); fasting glucose 5.9 +/- 0.6 vs. 4.8 +/- 0.7 nmol/1, 2-h glucose 8.3 +/- 0.6 vs. 7.3 +/- 0.9 mmol/l, fasting insulin 17.5 +/- 1.2 vs. 15.3 +/- 1.7 pmol/l, 2 h insulin 448 +/- 108 vs. 282 +/- 87 pmol/l in CHD and control group, respectively. AUC of glucose, AUC of insulin, insulin/glucose ratio, post load C-peptide, serum cholesterol, triglycerides and uric acid levels were also significantly higher in CHD than in healthy controls. Insulin sensitivity index was significantly lower in patients with CHD (27.7 +/- 8.3) than in healthy control subjects (73.9 +/- 18) (p < 0.001). Patients with CHD have hyperinsulinemia and subtle metabolic abnormalities related with insulin resistance even in absence of overt risk factors.

Topics: Adult; Aged; Anthropometry; Blood Glucose; Blood Pressure; C-Peptide; Comorbidity; Convalescence; Coronary Artery Disease; Cross-Sectional Studies; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin Resistance; Lipids; Male; Mexico; Middle Aged; Myocardial Infarction; Prospective Studies; Risk Factors; Uric Acid

In idiopathic recurrent calcium urolithiasis (RCU) the state of insulin and carbohydrate metabolism, and relationships to minerals such as phosphate, are insufficiently understood. Therefore, in two groups of males with RCU (n = 30) and healthy controls (n = 8) the response to an oral carbohydrate- and calcium-rich test meal was studied with respect to glucose, insulin, and C-peptide in peripheral venous blood (taken before and up to 180 min post-load), and phosphate and glucose in fasting and post-load urine. In one RCU group (n = 16) the meal was supplemented with ascorbic acid (ASC; 5 mg/kg body weight). The mean age (RCU 29, RCU + ASC 30, controls 27 years) and mean body mass index [RCU 24.4, RCU + ASC 25.0, controls 24.0 kg/m2] were similar. Insulin resistance (synonymous sensitivity of peripheral organs to insulin) was calculated from insulin serum concentration, as was also integrated insulin, C-peptide, and glucose. Untreated stone patients (RCU) developed hyperinsulinaemia between 60 and 120 min post-load, increased integrated insulin, and insulin resistance (P < or = 0.05 vs controls), whereas the rise of C-peptide and glycaemia (absolute and integrated values) was only of borderline significance. Fasting phosphaturia was low in both RCU subgroups vs controls; however, phosphaturia in untreated RCU rose in response to the meal, contrasting sharply with a decrease in controls. ASC supplementation of the meal (in the RCU + ASC subgroup) normalized insulin, failed to normalize post-load phosphaturia, but reduced post-load glucosuria and urinary pH significantly (mean pH values 5.55 vs 5.93 in untreated RCU, controls 5.50). Postprandial urinary oxalate, calcium, protein, and supersaturation products were not changed. The postprandial changes in phosphaturia and insulin sensitivity were inversely correlated (n = 38, r = -0.44, P = 0.007). It was concluded that in younger RCU males: (1) postprandial hyperinsulinaemia, the failure to reduce phosphaturia and - within limits - glucosuria, appropriately, as well as poor urine acidification are important features of the metabolism; (2) these phenomena are probably caused by insulin resistance of organs, the kidney included; and (3) the addition of a supraphysiological dose of ASC to a meal, the subsequent abolition of hyperinsulinaemia, and the restoration of normal urine acidification suggest that this antioxidant is capable of counteracting some pre-existing basic abnormality of cell metabolism in RCU.

Topics: Adult; Ascorbic Acid; Blood Glucose; C-Peptide; Fasting; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Phosphates; Postprandial Period; Time Factors; Urinary Calculi; Urine

The long-term follow-up of chronic hyperinsulinemic seizures, epileptogenesis and other neurological complications in five patients who were treated with conservative therapy followed by pancreatectomy during the neonatal period and infancy, who were confirmed to have diffuse nesidioblastosis are described. The reaction pattern of the C-peptide (CPR) suppression test and its relation to the final extent of pancreatectomy was examined in four patients. The chronological change in electro-encephalography (EEG) and its epileptogenesis was also examined in each patient during hyperinsulinemic hypoglycemia, and during normoglycemia in a long-term post-pancreatectomy follow-up. All patients demonstrated several types of hypoglycemic seizures, ranging from apnea, erratic seizures, evolving to generalized/unilateral tonic-clonic or tonic seizures, myoclonic seizures and EEG abnormalities. Four of five patients still suffered from epilepsy at the age of 4-22 years. The reaction pattern of the CPR suppression test showed dichotomy, with a hyper-reactive pattern in two patients who required total pancreatectomy to control hypoglycemia, and a suppression pattern in two other patients treated with 90-95% pancreatectomy. Neonatal onset and subsequent myoclonic seizures were ominous signs of epileptogenesis to various types of intractable epilepsy and other neurological sequelae. A prompt diagnosis and pancreatectomy of a sufficient extent at the first operation are essential. The CPR suppression test may be useful for a prompt diagnosis and selection of the extent of pancreatectomy.

Topics: Blood Chemical Analysis; C-Peptide; Epilepsy; Female; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Male; Pancreatectomy; Pancreatic Diseases; Pancreatic Function Tests; Prospective Studies

To determine whether hyperinsulinism affects cytochrome P450c17 alpha activity by investigating the correlation between 17-hydroxyprogesterone (17-OHP) hyper-responsiveness to the gonadotropin-releasing hormone (GnRH) agonist, buserelin, and the insulin response to oral glucose in polycystic ovary syndrome (PCOS).. Ultrasound, clinical and hormonal parameters were used to define PCOS in this prospective clinical study. We investigated the correlation between the 17-OHP response to buserelin testing and the insulin response to oral glucose in PCOS.. Twenty-eight women with PCOS and eighteen normal women were included in the study. 17-OHP response to buserelin, and insulin and C-peptide responses to oral glucose were measured.. Twenty-five women with PCOS had an increased 17-OHP response. The PCOS patients showed significantly higher mean post-glucose load insulin and C-peptide levels than controls (P < 0.05). No significant correlations were found between basal 17-OHP and fasting insulin or fasting C-peptide, between peak 17-OHP and fasting insulin, peak insulin or peak C-peptide, between 17-OHP area under the curve (AUC) and insulin AUC or C-peptide AUC, and between percent increment in 17-OHP and insulin AUC or C-peptide AUC (P > 0.05).. Lack of a relationship between the 17-OHP response to the GnRH agonist buserelin and hyperinsulinism suggests that hyperinsulinism may not play a role in the dysregulation of the cytochrome P450c17 alpha enzyme seen in PCOS.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Buserelin; C-Peptide; Female; Follicle Stimulating Hormone; Glucose; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Hyperinsulinism; Insulin; Luteinizing Hormone; Polycystic Ovary Syndrome; Prolactin; Steroid 17-alpha-Hydroxylase; Testosterone; Time Factors

To examine the hypothesis that hyperinsulinaemia promotes atherosclerosis, cholesterol-fed rabbits were injected subcutaneously with 6 i.u. of human insulin (n = 16) or placebo (n = 20) daily for 24 weeks; injection of insulin resulted in hyperinsulinaemia for up to 16 h after injection. Compared to placebo rabbits, insulin-treated rabbits had higher levels of insulin antibodies in plasma, similar levels of intermediate density, low density and high density lipoprotein cholesterol and similar activities of hepatic and lipoprotein lipase in post-heparin plasma, but lower levels of plasma C-peptide, blood glucose, postprandial plasma triglycerides, plasma cholesterol and very low density lipoprotein cholesterol. On univariate analysis, with and without adjustment for differences in plasma cholesterol levels between the two groups, there were no significant differences in extent or severity of atherosclerosis between insulin and placebo rabbits. Furthermore, after combining the results from all the rabbits to examine plasma insulin levels and the other variables mentioned above as predictors of atherosclerosis severity, plasma insulin level was not a predictor, on univariate or multiple linear regression analysis; the first ranked independent predictors were postprandial intermediate density lipoprotein cholesterol in the arch, and postprandial plasma triglyceride in both the thoracic and abdominal aorta. These results suggest that exogenous hyperinsulinaemia does not promote atherogenesis in cholesterol-fed rabbits, but that postprandial levels of intermediate density lipoprotein cholesterol or plasma triglycerides may be involved in atherogenesis.

Topics: Animals; Aorta; Arteriosclerosis; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Female; Humans; Hyperinsulinism; Insulin; Insulin Antibodies; Lipase; Lipoprotein Lipase; Lipoproteins; Lipoproteins, HDL; Lipoproteins, IDL; Liver; Placebos; Predictive Value of Tests; Rabbits; Recombinant Proteins; Time Factors; Triglycerides

Topics: Acanthosis Nigricans; C-Peptide; Female; Humans; Hyperinsulinism; Insulin Resistance; Lupus Erythematosus, Systemic; Middle Aged; Syndrome

Increasing attention is being paid to disturbances in glucose metabolism as key explanatory factors for the development of coronary artery disease. We studied the prevalence of impaired glucose tolerance and non-insulin-dependent diabetes and the levels of plasma insulin after an oral glucose tolerance test in 99 men with heart disease but without a history of diabetes referred to coronary arteriography; we also compared the outcome with a matched control group (n = 116). The severity of atherosclerosis in coronary angiograms was evaluated according to glucose tolerance status. Among the 99 patients with coronary artery disease, 37.4% had an abnormal oral glucose tolerance test result, whereas only 18.1% of the control group had an abnormal result (p < 0.01). Moreover, patients with heart disease and normal glucose tolerance were hyperinsulinemic compared with the control group (p < 0.01). By analysis of variance no statistically significant difference in severity of coronary atherosclerosis on coronary angiograms was found. In conclusion, we demonstrated frequent disturbances in glucose metabolism indicating insulin resistance in patients with ischemic heart disease without a history of diabetes, but we could not demonstrate a relation between these disturbances and degree of coronary atherosclerosis.

Topics: Adult; Aged; Albuminuria; Analysis of Variance; Blood Glucose; C-Peptide; Case-Control Studies; Coronary Angiography; Coronary Artery Disease; Coronary Disease; Diabetes Mellitus, Type 1; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Myocardial Ischemia; Prevalence; Proinsulin

We have shown previously in humans that insulin partly suppresses hepatic glucose production (HGP) by an extrahepatic (indirect) mechanism. In the present study, we investigated the role of free fatty acids (FFAs) in mediating the extrahepatic effects of insulin in humans and determined the extent to which insulin can regulate HGP by a non-FFA-mediated effect. Sixteen healthy men received an intravenous tolbutamide infusion for 3 h, and pancreatic insulin secretion was calculated by deconvolution of peripheral C-peptide levels. On a subsequent occasion, equimolar exogenous insulin was infused by peripheral vein. In both studies, glucose was clamped at euglycemia. We have previously validated this method and shown no independent insulin-like activity of tolbutamide. During the clamp, 9 of the 16 subjects received a low dose of heparin and Intralipid to prevent the insulin-induced suppression of FFAs, while 7 subjects received a high dose of heparin and Intralipid to raise FFAs approximately 2.5-fold. In both the high- and low-dose groups, peripheral insulin was higher and calculated portal insulin lower with peripheral versus portal insulin delivery. In the low-dose group, HGP decreased by 68.3 +/- 2.1% with portal insulin delivery and 64.7 +/- 3.7% with peripheral insulin delivery (NS). In the high-dose group, HGP decreased by 58.0 +/- 4.5% with portal insulin and 48.3 +/- 5.0% with peripheral insulin (P < 0.05). Four individuals who participated in the high-dose group underwent an additional peripheral insulin study in which the same dose of exogenous insulin was infused as in the high-dose group but in the absence of heparin and Intralipid. During this latter study, FFA levels declined by approximately 90% during hyperinsulinemia, and HGP was suppressed by 71.8 +/- 5.6%, which was a much greater suppression (P < 0.01) than when FFA levels were raised in these subjects during the equivalent rate insulin infusion. In summary, the previously observed greater suppression of HGP with equimolar peripheral versus portal insulin is eliminated or reversed, depending on plasma FFA levels, if FFAs are prevented from decreasing, suggesting an important role of FFAs in mediating the extrahepatic effects of insulin on HGP. However, the effect of FFA clamping is relatively small with a significant degree of suppression of HGP (by approximately 50%), which remains even when FFAs are elevated above basal levels, suggesting that in the physiological range FFAs only parti

Topics: Adult; C-Peptide; Cohort Studies; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Heparin; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Liver; Male; Time Factors; Tolbutamide; Triglycerides; Tritium

These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group (n = 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group (n = 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 +/- 1 microU/ml vs 7 +/- 1 microU/ml), but not in the hepatic vein (5 +/- 1 microU/ml vs 7 +/- 1 microU/ml) and in the portal vein (10 +/- 2 microU/ml vs 12 +/- 2 microU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 +/- 0.02 ng/ml vs 0.42 +/- 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 +/- 0.9 vs 3.4 +/- 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 +/- 11 pg/ml vs 323 +/- 65 pg/ml), portal vein (221 +/- 27 pg/ml vs 495 +/- 69 pg/ml), and hepatic vein (142 +/- 15 pg/ml vs 395 +/- 58 pg/ml). The estimate of pancreatic secretion of insulin (115 +/- 28 microU/kg.min) vs 71 +/- 21 microU/kg.min) and glucagon (2.0 +/- 0.4 ng/kg.min vs 2.7 +/- 0.7 ng/kg.min) and the fractional hepatic extraction rate of insulin (35 +/- 8% vs 32 +/- 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 +/- 5% vs 11 +/- 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.

Topics: Animals; Body Weight; C-Peptide; Glucagon; Hyperinsulinism; Insulin; Liver; Liver Circulation; Liver Transplantation; Metabolic Clearance Rate; Regional Blood Flow; Swine

To investigate whether fasting hyperinsulinemia is associated with a clustering of cardiovascular disease (CVD) risk factors, manifesting as the insulin resistance syndrome (IRS), in a population of native Hawaiians.. A total of 574 native Hawaiians > or = 30 years of age were examined for blood pressure, waist-to-hip ratio (WHR), BMI, oral glucose tolerance, and fasting lipid, insulin, and C-peptide concentrations. All statistical analyses (n = 384) excluded 190 individuals who had NIDDM or who were taking hypertension medication. Using logistic regression analysis, fasting insulin and C-peptide levels were compared with CVD risk factors (glucose intolerance, hypertension, central adiposity, elevated triglyceride levels, and low HDL cholesterol levels) after adjusting for age and obesity.. Sixty-six percent of native Hawaiians were overweight or obese, and 70% were found to have central adiposity. Fasting insulin concentrations were correlated with BMI, WHR, blood pressure, and triglyceride, HDL cholesterol, and glucose concentrations. Fasting insulin was also significantly associated with an increasing number of CVD risk factors in each participant (P < 0.001). Fasting insulin and C-peptide concentrations were independently associated with glucose intolerance, high triglyceride levels, and low HDL cholesterol levels. However, only fasting C-peptide concentrations were independently associated with hypertension and central adiposity. Apparent differences in the correlates of fasting insulin and C-peptide may be related to multiple factors and warrant further evaluation.. This study provides cross-sectional data confirming the existence of the IRS in native Hawaiians. However, further longitudinal studies are needed to examine the relationship of insulin resistance and/or surrogate markers to increased rates of NIDDM and CVD mortality in native Hawaiians.

Topics: Adult; Asian; Body Constitution; C-Peptide; Cardiovascular Diseases; Cross-Sectional Studies; Fasting; Female; Hawaii; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Logistic Models; Male; Middle Aged; Obesity; Odds Ratio; Prevalence; Risk Factors; Sex Characteristics; Syndrome

The diagnosis of hypoglycemia caused by hyperinsulinism may be difficult because insulin levels are not uniformly elevated at the time of hypoglycemia. Insulin-like growth factor binding protein-1 (IGFBP-1) is a 28 kd protein whose secretion is acutely inhibited by insulin. We hypothesized that serum levels of IGFBP-1 would be a useful marker of hyperinsulinism. We measured IGFBP-1 levels during the course of standardized fasting studies in hospitalized children; 36 patients became hypoglycemic during the fasting studies, and samples obtained at the point of hypoglycemia were analyzed. On the basis of the currently used diagnostic criteria, 13 children had hyperinsulinism, 16 had ketotic hypoglycemia or no disorder, 3 had hypopituitarism or isolated growth hormone deficiency, 2 had glycogen storage disease type 1 and 2 had fatty acid oxidation disorders. In control subjects (children with ketotic hypoglycemia or no disorder), IGFBP-1 levels rose during fasting to a mean of 343.8 +/- 71.3 ng/ml in the sample drawn at the time of hypoglycemia. Mean IGFBP-1 levels at hypoglycemia for the entire group with hyperinsulinism were 52.4 +/- 11.5 ng/ml, significantly different from levels seen in control subjects (p < 0.0001). In children with moderately controlled hyperinsulinism (fasting tolerance > 4 hours), mean IGFBP-1 levels at the time of hypoglycemia were 71.5 +/- 16.9 ng/ml. IGFBP-1 levels in the children with poorly controlled hyperinsulinism (fasting tolerance < 4 hours) failed to rise during fasting, with a mean of 30.1 +/- 10.4 ng/ml in the final sample. IGFBP-1 levels were inversely correlated with serum insulin and C-peptide levels (r = -0.71 and -0.72, respectively; p < 0.0001). Patients with other endocrinologic or metabolic diseases that result in fasting hypoglycemia demonstrated a rise in IGFBP-1 levels similar to that seen in ketotic hypoglycemia. Low serum levels of IGFBP-1 at the time of hypoglycemia provide an additional marker of insulin action that might help to differentiate hyperinsulinism from other hypoglycemic disorders.

Topics: Adolescent; Biomarkers; C-Peptide; Child; Child, Preschool; Fasting; Fatty Acids; Female; Glycogen Storage Disease Type I; Human Growth Hormone; Humans; Hyperinsulinism; Hypoglycemia; Hypopituitarism; Infant; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Ketosis; Lipid Metabolism, Inborn Errors; Male

Epidemiological studies have suggested an association among chronic hyperinsulinemia, insulin resistance, and hypertension. However, the causality of this relationship remains uncertain. In this study, chronically catheterized conscious rats were made hyperinsulinemic for 7 days (approximately 90 mU/l, i.e., threefold over basal), while strict euglycemia was maintained (approximately 130 mg/dl, coefficient of variation < 10%) by using a modification of the insulin/glucose clamp technique. Control rats received vehicle infusion. Baseline mean arterial pressure and heart rate were 125 +/- 5 mmHg and 427 +/- 12 beats/min and remained unchanged during the 7-day infusion of insulin (127 +/- 7 mmHg; 401 +/- 12 beats/min) or vehicle (133 +/- 4 mmHg; 411 +/- 10 beats/min). Baseline plasma epinephrine (88 +/- 15 pg/ml), norepinephrine (205 +/- 31 pg/ml), and sodium balance (0.34 +/- 0.09 mmol) remained constant during the 7-day insulin or vehicle infusion. After 7 days of insulin or vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-3H]glucose infusion to quantitate whole-body glucose uptake, glycolysis, glucose storage (total glucose uptake minus glycolysis), and hepatic glucose production. Compared with vehicle-treated rats, 7 days of sustained hyperinsulinemia resulted in a reduction (P < 0.01) in insulin-mediated glucose uptake, glucose storage, and glycolysis by 39, 62, and 26%, respectively. Hepatic glucose production was normally suppressed after 7 days of hyperinsulinemia. Neither insulin-stimulated glucose uptake nor glucose storage correlated with blood pressure or heart rate. In conclusion, 7 days of euglycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but does not increase blood pressure, catecholamine levels, or sodium retention. This indicates that hyperinsulinemia-induced insulin resistance is not associated with the development of hypertension in rats who do not have a genetic predisposition for hypertension. Because hyperinsulinemia was initiated in normal rats under euglycemic conditions, additional (inherited or acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.

Topics: Animals; Blood Glucose; Blood Pressure; C-Peptide; Catecholamines; Glucagon; Glucose; Glucose Clamp Technique; Glycolysis; Heart Rate; Hyperinsulinism; Hypertension; Insulin Resistance; Liver; Male; Rats; Rats, Sprague-Dawley; Sodium

Several investigations have presented evidence that amylin inhibits insulin secretion and induces insulin resistance both in vitro and in vivo. However, basal and postmeal amylin concentrations proved similar in non-insulin-dependent diabetes mellitus (NIDDM) patients and controls. Since hyperglycemia may alter both amylin and insulin secretion, we examined basal and glucose-stimulated amylin secretion in eight glucose-tolerant, insulin-resistant Mexican-American subjects with both parents affected with NIDDM (offspring) and correlated the findings with the insulin sensitivity data acquired by an insulin clamp. Eight offspring and eight Mexican-Americans without any family history of diabetes (controls) underwent measurement of fat free mass (3H2O dilution method), 180-minutes, 75-g oral glucose tolerance test (OGTT), and 40-mU/m2, 180-minute euglycemic insulin clamp associated with 3H-glucose infusion and indirect calorimetry. Fasting amylin was significantly increased in offspring versus controls (11.5 +/- 1.4 v 7.0 +/- 0.8 pmol/L, P < .05). After glucose ingestion, both total (3,073 +/- 257 v 1,870 +/- 202 pmol.L-1.min-1, P < .01) and incremental (1,075 +/- 170 v 518 +/- 124 pmol.L-1.min-1, P < .05) areas under the curve (AUCs) of amylin concentration were significantly greater in offspring. The amylin to insulin molar ratio was similar in offspring and controls at all time points. Basal and postglucose insulin and C-peptide concentrations were significantly increased in the offspring. No correlation was found between fasting amylin, postglucose amylin AUC or IAUC, and any measured parameter of glucose metabolism during a euglycemic-hyperinsulinemic clamp (total glucose disposal, 7.21 +/- 0.73 v 11.03 +/- 0.54, P < .001; nonoxidative glucose disposal, 3.17 +/- 0.59 v 6.33 +/- 0.56, P < .002; glucose oxidation, 4.05 +/- 0.46 v 4.71 +/- 0.21, P = NS; hepatic glucose production, 0.29 +/- 0.16 v 0.01 +/- 0.11, P = NS; all mg.min-1.kg-1 fat-free mass, offspring v controls). In conclusion, these data do not support a causal role for amylin in the genesis of insulin resistance in NIDDM.

Topics: Adult; Amyloid; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Male; Mexican Americans; Nuclear Family; United States

To assess the effects of GH treatment on carbohydrate and protein metabolism, we studied eight patients with short stature before and after the commencement of GH treatment. The hyperglycemic clamp procedure was employed to produce a hyperglycemic stimulus of 50 mg/dL above fasting levels for 120 min. These patients were then treated with 0.3 mg/kg. week GH for 6 months, after which they were restudied. Patients were compared to eight healthy control children matched for age, sex, and Tanner stage. Fasting plasma glucose did not change significantly, but fasting plasma insulin levels were higher after GH therapy (P < 0.005). Despite identical glucose increments during the glucose clamp procedure, both first, and second phase insulin responses were markedly greater after instituting GH treatment. Even in the face of higher mean plasma insulin levels after GH treatment, the rate of insulin-stimulated glucose metabolism did not differ during the last 60 min of both studies. Hence, the rate of insulin-stimulated glucose metabolism/mean plasma insulin ratio (an index of insulin sensitivity) was sharply reduced after GH treatment (P < 0.01). During the clamp, the fall in circulating branched chain amino acid levels was significantly greater after GH therapy (P < 0.02). We conclude that glucose-stimulated insulin responses are increased in short children treated with GH and that such hyperinsulinemic responses compensate for reductions in insulin sensitivity. The compensatory hyperinsulinemic responses induced by GH therapy may serve a beneficial role by augmenting insulin's anabolic effects on protein metabolism.

Topics: Adaptation, Physiological; Adolescent; Amino Acids, Branched-Chain; Body Height; C-Peptide; Child; Female; Glucose Clamp Technique; Growth Disorders; Human Growth Hormone; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male

The aim of this study was to evaluate the impact of reduced peripheral insulin sensitivity, beta cell hypersecretion and reduced hepatic insulin clearance in the hyper-insulinaemia of lean and obese PCOS patients. A total of 35 women with polycystic ovary syndrome (PCOS) and 10 lean normo-ovulatory controls underwent an oral glucose tolerance test and an euglycaemic-hyper-insulinaemic clamp study. PCOS patients were classified into four groups according to their BMI and insulin secretion (normo-lean; normo-obese; hyper-lean; hyper-obese), and results were compared between groups and with the controls. All the PCOS groups showed significantly higher insulin secretion than controls; there were no differences in insulin response to glucose load between lean and obese normo- and hyper-insulinaemic patients. Secretion of c-peptide was greater in PCOS groups than controls. All the hyper-insulinaemic PCOS patients had lower values of hepatic insulin clearance, independent of BMI, when compared either with controls (P < 0.001) or with PCOS normo-insulinaemic women (P < 0.01). Normo- and hyper-insulinaemic obese patients had similar total body glucose utilization (M value), which was lower than in lean PCOS subjects and controls. Our results suggest that evaluation of insulin resistance alone does not fully characterize the PCOS population; differences in liver metabolism of insulin are present in obese insulin resistant subjects and in lean patients with normal insulin sensitivity when divided into normo- and hyper-insulinaemic subgroups. Insulin resistance and hyper-insulinaemia may represent two distinct features of the insulin disorder in PCOS: the former appear to reflect the presence of obesity, while the latter may be a primary feature of PCOS.

Topics: Adolescent; Adult; Body Mass Index; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Obesity; Polycystic Ovary Syndrome

To examine the relationships between pituitary-adrenal cortical (PA) function, abdominal obesity, hyperinsulinaemia, and dyslipidaemia.. A prospective study.. Helsinki University Central Hospital, Finland.. Seventy-one healthy males aged 30-55 years.. Insulin sensitivity was assessed by the oral glucose tolerance test (OGTT). Basal PA activity was examined by measuring urinary and serum concentrations of hormones, followed by dexamethasone suppression and corticotrophin (ACTH) stimulation tests to determine functional PA activity.. The means of waist-to-hip ratio (WHR), body-mass index (BMI), HDL-cholesterol and triglyceride levels, and insulin and C-peptide measurements during the OGTT were significantly different across the tertiles for insulin:glucose ratio. The ratio of 12-h urinary cortisol excretion to BMI, preceding the OGTT, and the mean basal cortisol level during the OGTT were decreased, while the net increments of cortisol and 17-hydroxyprogesterone (17-OHP) from 0 to 60 min, as well as the ratio of net 17-OHP to 11-deoxycortisol increments, after ACTH, were elevated in the upper compared with the lower tertile. The mean cortisol during the OGTT, and the ratio of urinary cortisol to BMI were negatively related, while absolute DHEA and cortisol responses to ACTH were positively related to fasting and mean insulin levels. Hormonal variables, WHR, insulin, and triglycerides were successfully integrated into a tentative mathematical model by the use of covariance structure (path) analyses.. Several alterations in the PA function, suggestive of decreased 21-hydroxylase activity, mild cortisol deficiency and slight adrenal hyperplasia, are associated with abdominal obesity which, in turn, appears to be an important prelude to insulin resistance and dyslipidaemia.

Topics: 17-alpha-Hydroxyprogesterone; Abdomen; Adrenal Cortex; Adult; Body Constitution; Body Mass Index; C-Peptide; Cholesterol, HDL; Dehydroepiandrosterone; Glucose Tolerance Test; Humans; Hydrocortisone; Hyperinsulinism; Hyperlipidemias; Insulin; Life Style; Male; Middle Aged; Obesity; Pituitary-Adrenal System; Prospective Studies; Risk Factors; Triglycerides

High insulin levels are a recognized risk factor for atherosclerosis. Microvascular endothelium is more susceptible to metabolic and mitogenic effects of insulin than large-vessel endothelium. Besides their atherogenic effect, high insulin levels impair fibrinolysis by enhancing plasminogen activator inhibitor-1. We undertook this study to evaluate the hypothesis that elevated serum insulin and C-peptide levels are related to cerebral small-vessel disease rather than large-vessel pathology.. One hundred ninety-four consecutive patients presenting with symptomatic cerebrovascular disease were assigned to three subgroups that were differentiated by clinical presentations, brain imaging studies, and extracranial as well as transcranial vascular ultrasound findings: (1) patients with lacunes (n = 20), (2) patients with subcortical arteriosclerotic encephalopathy (n = 35), and (3) patients with strokes due to large-vessel disease (n = 99). Patients who had suffered a cryptogenic (n = 9) or cardioembolic (n = 16) stroke or who showed characteristics of the microangiopathy and macroangiopathy groups (n = 15) were not further evaluated. Thirty patients without manifestations of cerebrovascular disease were also examined. Fasting blood glucose, insulin, and C-peptide levels were determined in all subjects.. There were no significant differences in age or sex among the three groups and control patients. Insulin levels were significantly higher in the lacunar group compared with the subcortical arteriosclerotic encephalopathy group, the macroangiopathy group, and the control patients (median [interquartile range]: 103.8 [198.6], 72.0 [103.2], 66.0 [57.0], and 52.2 [57.0] pmol/L, respectively; all P < .05, Mann-Whitney test). There was a statistically significant difference in insulin concentrations between the microangiopathy group (subcortical arteriosclerotic encephalopathy and lacunes) and the macroangiopathy and control groups (81.0 [110.4], 66.0 [57.0], and 55.2 [57.0] pmol/L, respectively; all P < .05, Mann-Whitney). The same was true for the distribution of C-peptide levels and to a minor extent blood glucose values, but these differences failed to reach statistical significance.. Elevated insulin levels potentially represent a pathogenetic factor in the development of cerebral small-vessel disease, predominantly in patients presenting with lacunes. Whether this is due solely to atherosclerotic changes of the small penetrating arteries or whether changes in hemorheology are operative as well remains to be evaluated.

Topics: Aged; Arteriosclerosis; Blood Glucose; C-Peptide; Cerebrovascular Circulation; Cerebrovascular Disorders; Diabetes Mellitus; Female; Humans; Hyperinsulinism; Hypertension; Insulin; Male; Microcirculation; Middle Aged; Prevalence; Risk Factors

Circulating growth hormone, insulin, C-peptide, and glucose levels were compared during the sleep state in adults with acromegaly and healthy control subjects. Growth hormone secretion was episodic in both groups, with the sleep-related growth hormone peak noticeably absent in the acromegalic subjects. The mean nocturnal plasma insulin concentration was greater in the acromegalics. There was no significant difference in the C-peptide between the two groups. Insulin and glucose levels did not show an early morning rise in either acromegalics or healthy subjects. The authors conclude that there is a marked difference in the circulating levels of growth hormone and insulin between the acromegalic and the healthy groups during the sleep state, and there is no sleep-related nocturnal growth hormone peak in the acromegalic subjects. The hyperinsulinism of patients with acromegaly cannot be attributed to excess secretion of insulin.

Topics: Acromegaly; Adult; Blood Glucose; Body Mass Index; C-Peptide; Circadian Rhythm; Fasting; Female; Glucose Tolerance Test; Growth Hormone; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Male; Pancreas; Pituitary Gland, Anterior; Secretory Rate; Sleep

To test the hypothesis that hyperinsulinemia and glucose intolerance are present at an early age in australian aborigines and can be used to predict the eventual development of NIDDM.. Baseline anthropometric, pubertal stage, and blood pressure data were collected for 100 Australian aboriginal children and adolescents in 1989. Plasma concentrations of glucose, insulin, C-peptide, triglycerides, and LDL, HDL, and total cholesterol were measured before and during an oral glucose tolerance test. All measurements were repeated in 74 individuals from the original study population in 1994. Results were compared among hyperinsulinemic and normoinsulinemic subjects, and subjects with normal or abnormal glucose tolerance.. The percentage of subjects who were overweight increased from 2.7% at baseline to 17.6% 5 years later. At a mean age of 18.5 years, 8.1% of the population had impaired glucose tolerance (IGT), 2.7% had diabetes, and 21.6% had elevated cholesterol concentrations in plasma. Dyslipidemia was particularly prevalent among male subjects in the population: 34.4% had elevated plasma cholesterol and 21.9% had elevated LDL cholesterol values. Of the eight subjects who had diabetes or IGT in 1994, four were classified as hyperinsulinemic in 1989 and four were not.. The major finding of this study is the high prevalence of risk factors for NIDDM and cardiovascular disease in this population of aboriginal children and adolescents. Abnormalities of carbohydrate and lipid metabolism were well established by late in the second decade of life. Although many subjects had high insulin levels and there was evidence of insulin resistance in the population, hyperinsulinemia did not predict the development of abnormal glucose tolerance 5 years later.

Topics: Adolescent; Anthropometry; Australia; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Cardiovascular Diseases; Child; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Hyperlipidemias; Insulin; Male; Native Hawaiian or Other Pacific Islander; Obesity; Risk Factors; Sex Characteristics; Sex Factors; Time Factors; Triglycerides

Previous studies have documented the association of insulin resistance and hyperandrogenism in adult women with functional ovarian hyperandrogenism (FOH) or polycystic ovary syndrome (a form of FOH). However, the possible impact of adrenal hyperandrogenism development during childhood in premature pubarche (PP) patients on postpubertal insulin secretion patterns remains unclear. The fasting insulin to glucose ratio, C peptide, early insulin response to glucose (IRG), mean blood glucose, mean serum insulin (MSI), glucose uptake rate in peripheral tissues (M), and insulin sensitivity indexes (SI) in response to a standard oral glucose tolerance test were evaluated in 13 PP girls with FOH (group A; age, 17.2 +/- 0.5 yr), 11 eumenorrheic nonhirsute PP girls (group B; age, 16.6 +/- 0.5 yr), and 21 age-matched controls (group C). Body mass indexes (BMI) were similar in the 3 groups (group A, 23.3 +/- 0.8; group B, 22.5 +/- 0.6; group C, 20.6 +/- 0.5 kg/m2). MSI values were significantly higher in FOH patients than in controls (74.7 +/- 17.6 vs. 45.7 +/- 4.1 mU/L; P < 0.01), but were not different from those in group B (63.3 +/- 11.1 mU/L). Thirty-eight percent of FOH patients (group A) and 27% of non-FOH patients (group B), all of whom had normal BMI, showed MSI levels well above the upper normal limit for controls (> 83.3 mU/L). MSI correlated with the degree of ovarian hyperandrogenism [defined by an abnormal 17-hydroxyprogesterone response to challenge with the GnRH analog leuprolide acetate; group A] and with the free androgen index [testosterone (nanomoles per L)/sex hormone-binding globulin (nanomoles per L) x 100; groups A and B)]. Although IRG, glucose uptake rate in peripheral tissues, mean blood glucose, and SI values were not significantly different in the 3 groups, 3 patients in group A and 1 patient in group B showed decreased insulin sensitivity and/or an enhanced early IRG. Among others, significant correlations between MSI and free androgen index values (r = 0.6; P < 0.002; groups A and B) and between BMI and SI (r = -0.53; P < 0.05; groups A and B) were found. Peak 17-hydroxyprogesterone responses to ACTH at PP diagnosis correlated positively with SI in both groups of patients (r = 0.53; P < 0.007). Hyperinsulinemia is a common feature in adolescent PP patients with FOH and appears to be directly related to the degree of androgen excess. Long term follow-up of PP patients into adulthood is warranted to ascertain whether hyperinsulinemia actuall

Topics: Adolescent; Androgens; Blood Glucose; C-Peptide; Female; Hair; Humans; Hyperandrogenism; Hyperinsulinism; Insulin; Insulin Secretion; Medical Records; Ovary; Puberty; Sexual Maturation

The contribution of dietary amino acids and endogenous hyperinsulinemia to prandial protein anabolism still has not been established. To this end, leucine estimates ([1-14C]leucine infusion, plasma alpha-ketoisocaproic acid [KIC] specific activity [SA] as precursor pool SA) of whole-body protein kinetics and fractional secretory rates (FSRs) of albumin, fibrinogen, antithrombin III, and immunoglobulin G (IgG) were measured in three groups of healthy volunteers during intragastric infusion of water (controls, n = 5), liquid glucose-lipid-amino acid (AA) meal (meal+AA, n = 7), or isocaloric glucose-lipid meal (meal-AA, n = 7) that induced the same insulin response as the meal+AA. The results of this study demonstrate that 1) by increasing (P < 0.01) whole-body protein synthesis and decreasing (P < 0.01) proteolysis, dietary amino acids account for the largest part (approximately 90%) of postprandial protein anabolism; 2) the ingestion of an isocaloric meal deprived of amino acids exerts a modest protein anabolic effect (10% of postprandial protein anabolism) by decreasing amino acid oxidation and increasing (P < 0.01) albumin synthesis; 3) albumin FSR is increased (approximately 20%) by postprandial hyperinsulinemia (meal-AA) and additionally increased (approximately 50%) by amino acid intake (meal+AA); 4) IgG FSR is stimulated (approximately 40%) by amino acids, not by insulin; and 5) fibrinogen and antithrombin III FSR are not regulated by amino acids or insulin.

Topics: Administration, Oral; Adult; Amino Acids; Antithrombin III; Blood Glucose; C-Peptide; Carbon Radioisotopes; Eating; Fatty Acids, Nonesterified; Female; Fibrinogen; Glucagon; Glucose; Humans; Hyperinsulinism; Immunoglobulin G; Insulin; Intestinal Absorption; Keto Acids; Kinetics; Leucine; Lipid Metabolism; Lipids; Male; Protein Biosynthesis; Proteins; Radioisotope Dilution Technique; Serum Albumin

We investigated the contributions made by the entero-insular axis, proinsulin and the fractional hepatic extraction of insulin to the hyperinsulinaemia characteristic of polycystic ovarian syndrome (PCOS). We measured plasma glucose, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (7-36 amide) (GLP-1(7-36) amide), immunoreactive insulin (IRI), intact proinsulin (IPI), and C-peptide concentrations during a 75 g oral glucose tolerance test in seven normal weight women with PCOS and eight healthy women. Women with PCOS had higher fasting (P = 0.05) and integrated (P < 0.01) IRI concentrations than controls. Fasting C-peptide levels were similar in both groups but integrated C-peptide (P < 0.05) concentrations were greater in PCOS subjects than controls. Fasting and integrated concentrations of glucose, GIP and GLP-1(7-36) amide were similar in subjects with PCOS and controls. Although fasting IPI concentrations were similar in both groups, integrated IPI concentrations were higher (P = 0.05) in patients with PCOS. Women with PCOS had similar fasting but higher (P < 0.05) integrated IRI:C-peptide molar ratios than controls. Fasting and integrated IPI:IRI molar ratios were similar in both groups. These results confirm that lean women with PCOS have peripheral hyperinsulinaemia. The mild fasting hyperinsulinaemia is due to increased pancreatic secretion, whereas the stimulated hyperinsulinaemia is due to both pancreatic hypersecretion and reduced fractional hepatic extraction of insulin. Hyperproinsulinaemia is modest and appropriate in PCOS, GIP and GLP-1(7-36) amide do not contribute to the stimulated hyperinsulinaemia in PCOS.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Neurotransmitter Agents; Peptide Fragments; Polycystic Ovary Syndrome; Proinsulin

To investigate the rheological properties of RBC in obese subjects and the factors associated with their changes.. Two consecutive studies of non diabetic obese subjects.. Filtration index of RBC using the Hanss hemorheometer, RBC filterability using a cell transit time analyser and RBC aggregation measured on the Myrenne aggregometer.. In both studies an increase in the filtration index of RBC, namely a reduction in their deformability, was found. In the first study the filtration index correlated negatively with hematocrit and positively with plasma C peptide levels. In the second study RBC filterability was also studied by the cell transit time analyzer in which there is no aggregate formation. The RBC transit time was not found to be different in the obese patients and in the controls, but RBC aggregation was increased and correlated significantly with body weight and BMI. RBC aggregation worsened after four days of hypocaloric diet.. (1) obesity, independently of the other cardiovascular risk factors, is associated with significant changes in RBC rheology; (2) these changes are probably related for the most part to plasma factors, possibly via hyperinsulinemia, even if changes in the chemical composition of the RBC membrane are not excluded, (3) RBC aggregation worsens during the first days of a hypocaloric diet; (4) rheological changes in RBC seem to be another component of the insulin resistance syndrome.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Creatinine; Erythrocyte Deformability; Female; Hemorheology; Humans; Hyperinsulinism; Male; Obesity; Uric Acid

We investigated the response of the glucose transport system to insulin, in the presence of ambient glucose concentrations, in isolated skeletal muscle from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) (age, 55 +/- 3 years, BMI 27.4 +/- 1.8 kg/m2) and seven healthy control subjects (age, 54 +/- 3 years, BMI 26.5 +/- 1.1 kg/m2). Insulin-mediated whole body glucose utilization was similar between the groups when studied in the presence of ambient glucose concentrations (approximately 10 mmol/l for the NIDDM patients and 5 mmol/l for the control subjects). Samples were obtained from the vastus lateralis muscle, by means of an open muscle biopsy procedure, before and after a 40-min insulin infusion. An increase in serum insulin levels from 54 +/- 12 to 588 +/- 42 pmol/l, induced a 1.6 +/- 0.2-fold increase in glucose transporter protein (GLUT4) in skeletal muscle plasma membranes obtained from the control subjects (p < 0.05), whereas no significant increase was noted in plasma membrane fractions prepared from NIDDM muscles, despite a similar increase in serum insulin levels. At concentrations of 5 mmol/l 3-O-methylglucose in vitro, insulin (600 pmol/l) induced a 2.2-fold (p < 0.05) increase in glucose transport in NIDDM muscles and a 3.4-fold (p < 0.001) increase in the control muscles. Insulin-stimulated 3-O-methylglucose transport was positively correlated with whole body insulin-mediated glucose uptake in all participants (r = 0.78, p < 0.001) and negatively correlated with fasting plasma glucose levels in the NIDDM subjects (r = 0.93, p < 0.001). Muscle fibre type distribution and capillarization were similar between the groups. Our results suggest that insulin-stimulated glucose transport in skeletal muscle from patients with NIDDM is down-regulated in the presence of hyperglycaemia. The increased flux of glucose as a consequence of hyperglycaemia may result in resistance to any further insulin-induced gain of GLUT4 at the level of the plasma membrane.

Topics: 3-O-Methylglucose; Analysis of Variance; Biological Transport; Biopsy; Body Mass Index; C-Peptide; Cell Membrane; Diabetes Mellitus, Type 2; Glucose; Glucose Clamp Technique; Glucose Transporter Type 4; Humans; Hyperinsulinism; In Vitro Techniques; Insulin; Kinetics; Male; Middle Aged; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Oxygen Consumption; Reference Values

Earlier we found elevated insulin levels in obese children and adolescents. The present study examines whether alterations in insulin secretion and/or clearance contribute to hyperinsulinemia in obese adolescents.. Fasting circulating insulin and C-peptide concentrations were examined in 1157 adolescents, aged 11-18 y, from a biracial (black/white) community. In this epidemiologic study, plasma C-peptide was used as a noninvasive measure of insulin secretion by beta cells, C-peptide to insulin ratio as an indicator of hepatic insulin extraction, and insulin to glucose ratio as a measure of insulin sensitivity. Body mass index (BMI) was used as an index of obesity, since it is strongly associated with insulin levels and the C-peptide to insulin ratio more so than with measures of skinfolds and percent body fatness.. Obese individuals (BMI > 90th P) had higher levels of plasma insulin (23.7 mu/ml vs 11.7 mu/ml), C-peptide (2.7 ng/ml vs 1.7 ng/ml), and insulin to glucose ratio (0.29 vs 0.15), and lower C-peptide to insulin ratio (0.13 vs 0.16) than non-obese adolescents (all P < 0.001). Elevated C-peptide and decreased C-peptide to insulin ratio were noted in subjects with both obesity and hyperinsulinemia (insulin > 90th P) versus those without these conditions (P < 0.001). Individuals with obesity and low insulin clearance (C-peptide/insulin < 10th P) had 18-fold higher prevalence of hyperinsulinemia versus those without these conditions. Although black adolescents, despite their lower percent body fat, had higher insulin and lower C-peptide and C-peptide to insulin ratio than their white counterparts, BMI related positively to insulin and C-peptide, and inversely with C-peptide to insulin ratio in both races.. These data suggest that both increased insulin secretion and decreased insulin clearance contribute to hyperinsulinema in obese adolescents.

Topics: Adolescent; Black People; Blood Glucose; Body Mass Index; C-Peptide; Child; Female; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Louisiana; Male; Metabolic Clearance Rate; Obesity; White People

To determine the time course of changes in insulin action and secretion that occur early during the development of obesity, we studied children before the onset of puberty. The reason for choosing the prepubertal stage of development is that it is metabolically characterized by both a high sensitivity to insulin and low glucose stimulated insulin responses. Fifteen obese preadolescents (8 male/7 female, age 10 +/- 0.4 years, body mass index (BMI) 31 +/- 1.2 kg/m2 Tanner Stage I) with a duration of obesity of less than 5 years and 10 non-obese preadolescents (6 male/4 female, age 10 +/- 0.4 years, BMI 18 +/- 0.9 kg/m2) matched for gender were studied. In a cross-sectional analysis, we compared responses in obese preadolescents, with those in obese adolescents and obese adults with a longer duration of obesity. The euglycaemic hyperinsulinaemic clamp with 1-13C-glucose (Hot Ginf) and indirect calorimetry were used to quantitate insulin action and the hyperglycaemic clamp used to assess beta-cell function. Insulin-stimulated glucose uptake measured at two physiological levels of hyperinsulinaemia (approximately 180 and 480 pmol) was reduced by 20 and 45% in all three groups of obese compared to non-obese subjects (p < 0.01). Defects in oxidative and non-oxidative glucose metabolism were observed in all three groups of obese subjects at the higher insulin infusion rate. The ability of insulin to inhibit lipid oxidation was impaired in all three obese groups at both levels of hyperinsulinaemia. Increases in basal and glucose-stimulated insulin levels during the hyperglycaemic clamp mirrored the reductions in glucose uptake during the insulin clamp in all obese groups. These results indicate that insulin resistance and hyperinsulinaemia co-exist in preadolescent children with moderate to severe obesity.

Topics: Adolescent; Adult; C-Peptide; Calorimetry, Indirect; Child; Cohort Studies; Cross-Sectional Studies; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Lipid Metabolism; Male; Obesity; Oxidation-Reduction; Time Factors

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Glucagon; Humans; Hyperinsulinism; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay

A boy affected by severe obesity (kg 117, Body Mass Index 37 kg/m2) and acanthosis nigricans, was treated with octreotide for 150 days (50 micrograms x three daily subcutaneous administrations). Before treatment the patient showed an exaggerated insulin (IRI) and C-peptide (CPR) response to a standard meal with a lowering in after-meal CPR/IRI molar ratio. During octreotide treatment both IRI and CPR response was reduced but CPR/IRI molar ratio rised after meal indicating an increase in hepatic insulin removal. Body weight and acanthosis nigricans were sharply reduced during treatment and the reduction was still maintained six months after the cessation of therapy. Furthermore, IRI and CPR response, as well as the behaviour of CPR/IRI molar ratio, remained within normal range. In conclusion long-term octreotide treatment has been able to correct hyperinsulinemia and to reduce body weight and acanthosis nigricans.

Topics: Acanthosis Nigricans; Adolescent; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Hormones; Humans; Hyperinsulinism; Insulin; Male; Obesity, Morbid; Octreotide

The author describe a rare case of pancreatic beta-cell hyperplasia. The patient was referred to us because of serious hypoglycemic crises. During hospitalization, endogenous hyperinsulinism was confirmed by hematochemical and instrumental tests. AngioCT of the pancreas evidenced a small lesion of the corpus, suspected of insulinoma. The patient underwent a corpus caudalis pancreatectomy: a small nodule with histologic neuroendocrine traits was ablated. A few days after the operation, new symptomatic hypoglycemia appeared. The hormonal tests confirmed a recurrence of endogenous hyperinsulinism. The patient underwent a new operation for pancreaticoduodenectomy: histological examination confirmed a pancreatic beta-cells hyperplasia. This condition has to be taken into account in the differential diagnosis of post prandial hypoglycemia. Besides, the observation of an insulinoma doesn't exclude the presence of a diffused disorder of islet cells as in the case above described.

Topics: C-Peptide; Diagnosis, Differential; Female; Humans; Hyperinsulinism; Hyperplasia; Hypoglycemia; Insulinoma; Islets of Langerhans; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy

The C-peptide suppression test employing the euglycemic hyperinsulinemic clamp technique has been proposed as a useful diagnostic measure for insulinoma. To examine the specificity of the C-peptide suppression, we applied this test to subjects with symptoms suggesting reactive hypoglycemia. Five subjects studied had never experienced fasting hypoglycemia, and were negative in ultrasound, CT and MRI of the pancreas. Plasma C-peptide was not suppressed by physiological (50-100 microU/ml) and supraphysiological (200-500 microU/ml) hyperinsulinemia (% of baseline: 97.3 +/- 8.6% and 90.6 +/- 10.4%, +/- SEM, respectively, both NS). Three subjects were re-examined one year later, when their hypoglycemic episodes were noticeably attenuated. No significant suppression was found. Significant suppression was observed when plasma glucose was clamped at 50-60 mg/dl in four of five subjects (61.7 +/- 11.5%, P < 0.05), but one subject responded to neither higher plasma insulin nor low-normal glucose. In contrast, normal glucose tolerance (n = 13), IGT (n = 12) and obese NIDDM (n = 31) subjects showed highly significant suppression during euglycemic and physiological hyperinsulinemia (37.1 +/- 3.8%, 46.3 +/- 5.6%, 39.9 +/- 2.6%, respectively, all P < 0.001). In conclusion, the results of the present study indicate that a failure of hyperinsulinemic suppression of C-peptide in euglycemia is not specific for insulinoma, and that suppression of C-peptide by insulin at lower plasma glucose levels (50-60 mg/dl) would be a better diagnostic test.

Topics: Adolescent; Adult; Aged; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Obesity

The acute effects of hyperinsulinemia on androgen homeostasis and a possible association of androgens to insulin sensitivity, serum lipids and lipoproteins and to lipid oxidation were examined in 19 healthy males (27 +/- 1 yrs, body mass index 24 +/- 1 kg/m2). In each subject, a 240 min euglycemic hyperinsulinemic clamp was performed and glucose and lipid oxidation were determined by indirect calorimetry. During hyperinsulinemia serum sex hormone-binding globulin (SHBG) concentration decreased by 5% (P < 0.01), insulin-like growth factor binding protein (IGFBP-1) by 88% (P < 0.001) and dehydroepiandrosterone sulphate (DHEAS) by 12% (P < 0.001), with no change in total or free testosterone concentrations. In the basal state, IGFBP-1 and C-peptide were inversely related (r = -0.54, P < 0.05). Fasting concentrations of serum free testosterone (r = 0.59, P < 0.01) and DHEAS (r = 0.47, P < 0.05) correlated positively with serum free fatty acid (FFA) concentrations during hyperinsulinemia, but not with fasting FFA level. Lipid oxidation rate in the basal state correlated positively to the decline in SHBG (r = 0.61, P < 0.01) and DHEAS concentrations (r = 0.62, P < 0.01) during hyperinsulinemia. While the fasting serum high density lipoprotein cholesterol level correlated positively with the insulin-induced decline in DHEAS level (r = 0.58, P < 0.01), no associations were found between serum androgens and total cholesterol, low density lipoprotein cholesterol or triglyceride concentrations. Insulin sensitivity was not related to SHBG, IGFBP-1, DHEAS or testosterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adult; Androgens; C-Peptide; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Lipid Peroxidation; Male; Sex Hormone-Binding Globulin; Somatomedins; Testosterone

The peripheral hyperinsulinaemia of hypertriglyceridaemic subjects has only been defined using insulin immunoassays in which proinsulin and proinsulin fragments cross-react. Relative contributions of pancreatic secretion and hepatic extraction of insulin to this hyperinsulinaemia have not been studied. We, therefore, reassessed the hyperinsulinaemia of hypertriglyceridaemia by measuring fasting plasma concentrations of intact proinsulin, glucose, insulin, and C-peptide in 24 hypertriglyceridaemic subjects with normal glucose tolerance (n = 14) and with impaired glucose intolerance (n = 10) and in normal subjects (n = 14). Hypertriglyceridaemic subjects had higher (p < 0.01) fasting concentrations of insulin and C-peptide and greater (p < 0.01) fasting insulin: C-peptide molar ratios than in control subjects. Fasting intact proinsulin concentrations were similar in hypertriglyceridaemic subjects with normal glucose tolerance and control subjects but these were lower (p < 0.01) than in hypertriglyceridaemic subjects with impaired glucose tolerance. These results suggest that the fasting peripheral hyperinsulinaemia of hypertriglyceridaemic subjects is due to increased pancreatic secretion and reduced hepatic fractional extraction of insulin. The peripheral hyperinsulinaemia of hypertriglyceridaemia appears to reflect peripheral insulin resistance and is not attributable to elevated proinsulin concentrations which are characteristic of impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetes mellitus.

Topics: Adult; Blood Glucose; C-Peptide; Cholesterol; Cohort Studies; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypertriglyceridemia; Insulin; Male; Middle Aged; Proinsulin; Reference Values; Triglycerides

We have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbA1C (p=0.001) and fasting plasma glucose (p=0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU x kg-1 x min-1) in combination with indirect calorimetry, a 35% (p=0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased non-oxidative glucose metabolism (p=0.02) was demonstrated in teh gliclazide-treated patients when compared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half-maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p=0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide-treated obese NIDDM patients has no impact on the gene expression of muscle glycogen synthase.

Topics: Adult; Aged; Animals; Base Sequence; Biopsy; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; DNA Primers; DNA, Complementary; Female; Gene Expression; Gliclazide; Globins; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen Synthase; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Middle Aged; Molecular Sequence Data; Muscle, Skeletal; Polymerase Chain Reaction; Rabbits; RNA, Messenger

The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU.kg-1.min-1) and a high-dose (1.20 mU.kg-1.min-1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means +/- SE) 60.0 +/- 2.4, 165.6 +/- 1.8, and 455.4 +/- 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 +/- 10.1, 73.7 +/- 12.8, and 73.4 +/- 10.3 pmol/kg, whereas second phase was 266.1 +/- 46.0, 143.1 +/- 33.5, and 133.0 +/- 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Glucagon; Glucose Clamp Technique; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Secretion; Kinetics; Male; Reference Values; Somatostatin; Time Factors

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Proinsulin

The effects of two low-energy diets on serum insulin concentrations and weight loss in obese hyperinsulinemic females were compared during a 12-wk period. The first diet (n = 15) was designed to evoke a low insulin response (ID), and the second (n = 15) was a conventionally balanced diet (ND). After a 12-wk washout period, seven and nine subjects who had been on the ID and ND, respectively, changed to the alternative diet for 12 wk. Variables studied were basal and 30- and 120-min concentrations of blood glucose, insulin, and C-peptide after an oral glucose load; body weight; and energy intake. Mean (+/- SD) weight was significantly reduced after ID and ND (9.35 +/- 2.49 and 7.41 +/- 4.23, respectively). The mean weight loss was more after ID. Fasting insulin concentrations decreased more after ID compared with ND (91.3 +/- 61.8 vs 21.0 +/- 71.5 pmol/L; P < 0.05). We conclude that ID significantly reduces serum insulin concentrations and weight in obese hyperinsulinemic females.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Complications; Diabetes Mellitus; Diet, Diabetic; Energy Intake; Fasting; Female; Humans; Hyperinsulinism; Insulin; Obesity; Weight Loss

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Retrospective Studies

The relation of dietary factors and physical activity to hyperinsulinemia was examined in 389 men aged 70-89 years who participated in the Zutphen Elderly Study in 1990. Information about the usual diet was obtained using a cross-check dietary history, and habitual physical activity was assessed using a validated questionnaire. Known and newly diagnosed diabetic patients were excluded from this study, since serum insulin and C-peptide levels are indicators of insulin resistance and hyperinsulinemia in non-diabetics only. Insulin levels during the oral glucose tolerance test were lowest in men with the highest physical activity. This inverse association was independent of age, body mass index, the ratio of subscapular to triceps skinfold thickness, cigarette smoking, and energy intake (p < 0.001). In addition, insulin levels were inversely associated with the intake of dietary fiber and polyunsaturated fatty acids, which could not be accounted for by variables such as energy intake, body mass index, physical activity, prescribed diets, or the presence of coronary heart disease. In contrast, insulin levels increased with the increasing intake of saturated fatty acids and alcohol. The fasting C-peptide level was independently associated with the intake of total fat, saturated and monounsaturated fatty acids, and alcohol, whereas an inverse relation with the intake of total carbohydrates and dietary fiber was seen. Besides overweight, physical activity and dietary factors such as the intake of fatty acids, fiber, carbohydrates, and alcohol, were independently associated with hyperinsulinemia and insulin resistance. Therefore, these behavioral factors may partly determine the occurrence of non-insulin-dependent diabetes mellitus and coronary heart disease and play a role in the prevention of these disorders.

Topics: Aged; Aged, 80 and over; C-Peptide; Diet; Diet Surveys; Exercise; Fasting; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Longitudinal Studies; Male; Netherlands; Risk Factors

Cockayne syndrome is a rare autosomal recessive disorder of childhood characterized by cachectic dwarfism with senile-like appearance, mental retardation, photosensitive dermatitis, loss of adipose tissue, pigmentary degeneration of retina, microcephaly, deafness, skeletal and neurologic abnormalities. We describe here an 18 year old boy with Cockayne syndrome who had, in addition to the typical features of the disorder, fasting hyperinsulinemia and growth hormone deficiency.

Topics: Adolescent; C-Peptide; Cockayne Syndrome; Growth Disorders; Growth Hormone; Humans; Hyperinsulinism; Insulin; Male; Optic Atrophy; Retinal Degeneration

To determine whether pancreas transplantation alters lipid and lipoprotein concentrations and whether peripheral hyperinsulinemia is always associated with altered lipid levels.. We assessed the lipid profiles of seven pancreas-kidney recipients with insulin-dependent diabetes mellitus, seven kidney recipients without diabetes who received the same immunosuppressive agents, and eight normal subjects.. In the three study groups, fasting and postprandial plasma glucose, insulin, C-peptide, cholesterol, triglyceride, free fatty acid, and apolipoprotein A-I, A-II, C-II, and C-III concentrations were determined.. Fasting and postprandial glucose concentrations did not differ between the two transplant groups; however, peripheral insulin concentrations were twice as high (P < 0.05) in the pancreas-kidney recipients as in the kidney recipients both before (102 +/- 15 versus 53 +/- 6 pmol/L) and after (123 +/- 22 versus 61 +/- 6 nmol/L per 6 hours) ingestion of a meal. Preprandial and postprandial insulin levels in both transplant groups also were greater (P < 0.05) than those in normal subjects (35 +/- 6 pmol/L and 40 +/- 7 nmol/L per 6 hours, respectively). Despite significant differences in insulin concentrations, no differences were noted in total cholesterol, high-density or low-density lipoprotein cholesterol, plasma free fatty acids, or apolipoprotein A-I, A-II, C-II, and C-III concentrations among the study groups. Plasma triglyceride concentrations in the two transplant groups were similar (114 +/- 20 versus 142 +/- 18 mg/dL) and were slightly more than those in the normal subjects (80 +/- 7 mg/dL).. Despite peripheral hyperinsulinemia, pancreas transplantation can result in normal or near-normal lipid and lipoprotein concentrations. Thus, systemic delivery of insulin does not invariably produce an atherogenic lipid profile.

Topics: Adult; Apolipoproteins; Blood Glucose; C-Peptide; Case-Control Studies; Cholesterol; Diabetes Mellitus, Type 1; Eating; Fasting; Fatty Acids, Nonesterified; Female; Humans; Hyperinsulinism; Insulin; Kidney Transplantation; Male; Pancreas Transplantation; Triglycerides

Beta cell hypersecretion is associated with the syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans. It is unknown whether concomitant alpha cell secretory dysfunction occurs in patients with this syndrome. The authors evaluated the gastroenteropancreatic hormones in four family members with varying degrees of the hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome. Gastroenteropancreatic hormones were measured during oral glucose tolerance test with and without subcutaneous octreotide injection. The study revealed that the administration of subcutaneous octreotide resulted in suppression of beta cell function (insulin and c-peptide) but had no effect or a delayed effect on alpha cell secretion (glucagon). Furthermore, the severity of glucagon abnormalities paralleled that of beta cell hypersecretion and the clinical and phenotypic manifestations of acanthosis nigricans in our four patients. We speculate that this alpha cell aberration could potentially be involved in the altered glucose homeostasis and perhaps the skin manifestations of this syndrome. Therefore, glucagon levels should be evaluated in the hormonal studies in patients with hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome.

Topics: Acanthosis Nigricans; Adolescent; Adult; C-Peptide; Child; Female; Glucagon; Glucose Tolerance Test; Hirsutism; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Male; Octreotide; Pancreas

This study was conducted to compare the insulin responses to an oral glucose load in healthy volunteers and patients with syndrome X and patients with coronary artery disease.. An abnormal coronary flow reserve has been reported in syndrome X by several investigators. However, its cause is not known. Recently, it has been suggested that elevated insulin levels in syndrome X may contribute to microvascular dysfunction.. Insulin responses to an oral glucose load (75 g) were compared in 17 patients with coronary artery disease, 17 patients with chest pain, positive exercise test findings, normal coronary arteries and impaired coronary flow reserve (syndrome X) and 17 healthy volunteers (control subjects). All were matched for age, gender and body weight. Patients with overt diabetes mellitus or hypertension were excluded. Venous blood samples were taken during fasting and at 30, 60, 90 and 120 min after the glucose load. Samples were analyzed for glucose, immunoreactive insulin and C peptides.. There was no significant difference in the glucose levels at all sampling points among the three groups. The C peptide and immunoreactive insulin levels were significantly higher than values in the control group at 60, 90 and 120 min in the groups with syndrome X and coronary artery disease. The peak responses and the areas under the curve were also significantly greater in the latter two groups. There was no significant difference at all sampling points between the group with syndrome X and the group with coronary artery disease.. Patients with syndrome X have stimulated hyperinsulinemia, which may contribute to the pathophysiology of syndrome X.

Topics: Blood Flow Velocity; Blood Glucose; C-Peptide; Cardiac Catheterization; Coronary Circulation; Coronary Disease; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Lipids; Male; Microvascular Angina; Middle Aged

Many obese middle-aged rhesus monkeys (Macaca mulatta) spontaneously develop noninsulin dependent diabetes mellitus (NIDDM). Basal hyperinsulinemia and increased stimulated plasma insulin levels are associated with this obesity and precede the onset of overt diabetes. The present studies sought to determine the relative contributions of enhanced insulin secretion and of reduced insulin clearance to this early obesity-associated hyperinsulinemia. Direct simultaneous measurement of portal and jugular vein insulin levels in two normal monkeys showed a constant rate of hepatic insulin extraction of 56+/-3% over the range of peripheral insulin levels from 351+/-113 to 625+/-118 pmol/L. In 33 additional monkeys ranging from normal to diabetic, basal C-peptide levels were examined as an indicator of beta-cell secretion and the molar ratio of plasma C-peptide to insulin (C/I ratio) under basal steady state conditions calculated as an index of hepatic insulin extraction. Well in advance of overt diabetes, there was a progressive decline of 67% in the apparent hepatic insulin extraction rate in association with increased obesity and plasma insulin levels. Basal insulin levels and hepatic insulin extraction returned toward normal in monkeys with impaired glucose tolerance and in those with overt diabetes. We conclude that reduced insulin disposal, probably due to reduced hepatic extraction of insulin, in addition to increased beta-cell activity, contributes to the development of basal hyperinsulinemia in obese rhesus monkeys progressing toward NIDDM. In addition, in overt diabetes, normal hepatic insulin extraction in the presence of limited beta-cell secretion may exacerbate the hypoinsulinemic state.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Jugular Veins; Liver; Macaca mulatta; Male; Metabolic Diseases; Obesity; Portal Vein; Receptor, Insulin; Time Factors

Aim of this study was to verify the existence of a correlation between the insular hormones and the atrial natriuretic factor (ANF). We studied 70 subjects (20 control, 20 obese, 20 non insulin-dependent diabetic obese, 10 insulin-dependent diabetic subjects) submitted to a glucagon test (1 mg i.v.). Blood samples were collected at -15, 0, 3, 6, 12, 15, 30, 60, 120, 150 minutes to assay insulin, C-peptide, serum electrolytes and ANF levels. The results to point out are: the ANF basal values are significantly higher (p < 0.01) in non insulin-dependent obese patients than in controls; the obese subjects also present a significant difference (p < 0.05). After glucagon injection no variations have been found in the ANF values until the 15th minute; then the controls, the obese and, above all, the non insulin-dependent diabetic obese subjects showed a significant increase of the ANF values between 60' and 90' (basal values 38 +/- 4 ng/ml; 90' values 85 +/- 7 ng ml). As these high values appear only after the induction of hyperinsulinism in our experiment and are not present in the type-1 diabetic subjects, it's probable that insulin, rather than glucagon, stimulates, directly or indirectly, the ANF secretion. If this hypothesis is confirmed, the correlation between insulin and ANF should deserve attention from a therapeutic point of view in subjects with glycometabolic imbalance.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Potassium; Secretory Rate; Sodium

Blood glucose(BG), insulin(IS), C-peptide(CP), glucagon(GC) and their area under the curve(AUC), the CP:IS molar ratio and IS:GC molar ratio were measured and calculated in 31 hypertensives and 23 weight control normotensives. Compared with the normotensives, the patients showed higher fasting serum IS, CP and the IS:GC ratio, and exhibited increased BG, IS, CP and their AUC and the IS:GC ratio, and a lower CP:IS molar ratio after the oral glucose load. No significant difference was found in the fasting CP:IS molar ratio, BG, GC between normotensive and hypertensive subjects. The results indicate that there are impaired glucose tolerance, hyperinsulinemia and IS resistance in essential hypertensive subjects. The hyperinsulinemia may be caused by a beta-cell hypersecretory response to the defective peripheral action of the hormone and by a decreased hepatic insulin clearance. The study also suggests that IS resistance in essential hypertensive subjects usually involve other abnormalities of metabolism and associate with increased risk factors for coronary artery disease.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Glucagon; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged

To report studies on an elderly patient with moderate NIDDM associated with marked fasting hyperinsulinemia.. The propositus and several family members were studied by a combination of clinical, biochemical, and molecular genetic approaches to define the underlying genetic defect.. Fasting levels of contrainsulin hormones were normal, and resistance to exogenous insulin was absent. Gel filtration and reverse-phase high-performance liquid chromatography revealed elevated amounts of a structurally abnormal proinsulin intermediate (AC proinsulin). A study of the family of the propositus showed the same abnormality in 4 of 5 members in 3 successive generations. Genetic analysis revealed a point mutation affecting residue 65 of human proinsulin (Arg-->His) in one allele of the insulin gene in the propositus, a defect similar to that described previously in 3 other apparently unrelated lineages.. This family exhibits a clear-cut relationship between increasing age and metabolic decompensation in all the hyperproinsulinemic members, suggesting that (inherited) metabolic stress and age both contribute to development of diabetes mellitus.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; DNA Primers; Exons; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Molecular Sequence Data; Polymerase Chain Reaction; Proinsulin

Insulin resistance and dyslipidaemia associated with smoking may result from increased secretion of anti-insulin hormones. We compared the pituitary-adrenocortical function using oral glucose tolerance, dexamethasone suppression and ACTH stimulation tests in smoking (n = 22) and non-smoking (n = 22) healthy males matched for age, body mass index, and waist-to-hip ratio. Smokers had lower HDL-cholesterol (p < 0.02), and higher triglyceride (p < 0.001), basal cortisol (p < 0.05), insulin (p < 0.05), and C-peptide (p < 0.02) levels, and a higher response of insulin and C-peptide to oral glucose (p < 0.005) than non-smokers, while the ACTH, cortisol, 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione responses to oral glucose were similar in both groups. No differences were found in the response of cortisol, 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione to dexamethasone. In contrast, the response of 17-hydroxyprogesterone (p = 0.04), dehydroepiandrosterone (p = 0.007), and androstenedione (p = 0.001) to ACTH was higher in smokers than non-smokers, while the increase in cortisol was of marginal significance (p = 0.07). In multiple regression analyses the dehydroepiandrosterone response to ACTH was a significant determinant of insulin, C-peptide, and triglyceride levels independent of physical activity, waist-to-hip ratio and HDL-cholesterol. Thus, smoking inhibits the adrenal 21-hydroxylase resulting in an increase in the production of adrenal androgens, which might contribute to the insulin resistance and dyslipidaemia in smokers.

Topics: 17-alpha-Hydroxyprogesterone; Adrenocorticotropic Hormone; Adult; Alcohol Drinking; Androstenedione; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol, HDL; Dehydroepiandrosterone; Dexamethasone; Glucose; Glucose Tolerance Test; Humans; Hydrocortisone; Hydroxyprogesterones; Hyperinsulinism; Insulin; Male; Middle Aged; Pituitary-Adrenal System; Reference Values; Smoking; Triglycerides

The purpose of this investigation was to determine whether there is a relation between impaired insulin-stimulated glucose utilization, or insulin resistance, and blood pressure (BP) in a young adult black population. Clinically well, young black men and women, including normotensive (BP < 135/85 mm Hg, n = 23) and borderline hypertensive (BP > or = 135/85 mm Hg, n = 27) individuals, were studied. Each subject had an oral glucose tolerance test (OGTT) and underwent a euglycemic hyperinsulinemic clamp procedure. A two-way analysis of variance demonstrated a significantly greater fasting insulin plasma concentration (P < .02) and sum of insulin levels during the OGTT (P = .04) in the borderline hypertensive compared with normotensive subjects. In both BP groups, women had significantly higher fasting plasma insulin levels than men (P < .02 and P = .009). Body mass index was a significantly covariate of the plasma insulin concentration. Data obtained from the clamp demonstrated significant insulin resistance in borderline hypertensive compared with normotensive subjects (4.69 +/- 0.50 versus 6.57 +/- 0.63 mg/kg per minute, P = .002). A stepwise multiple linear regression analysis demonstrated that there are significant multiple correlations of insulin resistance with body mass index, clamped insulin level, BP group, and systolic BP (multiple R = .7862, P < .001). Application of this analysis to the nonobese sample (n = 33) found significant correlations of insulin resistance with sex, BP group, and systolic BP (multiple R = .6817, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Black People; Blood Pressure; Body Mass Index; C-Peptide; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Male; Regression Analysis; Sex Factors

Peripheral hyperinsulinism is said to be associated and perhaps implicated in the pathogenesis of hypertension. There is however some inconsistency in the evidence of the relationship between insulin and blood pressure. We prospectively investigated glucose metabolism, insulin and C-peptide values and serum lipids in a large sample of hypertensive as compared with age and body habitus-matched normotensive subjects. As a group, the 145 hypertensives (blood pressure: 160/99 +/- 8.5/6.5 mmHg, mean +/- SD) had significantly elevated fasting plasma insulin (p < 0.02), total and LDL-cholesterol (p < 0.01) than 132 normotensive control subjects. The fasting HbA1c (glycated hemoglobin A1c)/insulin ratio, an estimate of insulin sensitivity, was significantly lower (5.15 +/- 1.45) in the hypertensives than normotensives (5.8 +/- 1.5, p < 0.001). Hypertensives had normal fasting C-peptide levels and lower C-peptide/insulin molar ratios, indicating low hepatic insulin extraction. There was no correlation between mean blood pressure (1/3 systolic + 2/3 diastolic) and fasting serum C-peptide (p = 0.14), insulin (p = 0.11), HbA1c/insulin ratio (p = 0.6), C-peptide/insulin ratio (p = 0.22) and HbA1c (p = 0.19), even after adjusting for age, BMI and family history of diabetes. The differences between hypertensives and normotensives persisted after dividing the subjects according to the presence/absence of either obesity or impaired glucose tolerance, but the significance was lost due to the smaller samples of the subgroups. The obese hypertensives with impaired glucose tolerance had the lowest values of insulin sensitivity and clearance in the fasting state.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; C-Peptide; Diabetes Complications; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Secretion; Lipids; Male; Metabolic Clearance Rate; Middle Aged; Obesity; Prospective Studies

Topics: Albuminuria; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glycated Hemoglobin; Humans; Hyperinsulinism; Triglycerides

C-Peptide, a marker for insulin secretion, is purported to be elevated in patients with insulinoma but diagnostic criteria have not been established. Thirty-seven patients with histologically confirmed insulinoma studied preoperatively, 19 normal subjects, and 2 patients who subsequently acknowledged self-administration of insulin underwent the prolonged fast (< or = 72 h) according to a standard protocol. Plasma glucose, C-peptide, and insulin were measured every 6 h until plasma glucose was less than or equal to 3.3 mmol, then hourly until Whipple's triad was demonstrated or until 72 h without symptoms was reached. At the termination of the fasts, plasma was analyzed for sulfonylurea. Statistical analysis was by rank sum test. Data are expressed as median (range). The durations of fasts were 20 (2.5-68) h for patients with insulinomas and 72 h for normal subjects. At the end of fasts plasma glucose, C-peptide, and insulin concentrations were 2.2 (1.4-2.9) vs. 3.6 (2.7-5.5) mmol, P < 0.001; 0.60 (0.20-1.92) vs. 0.13 (0.07-0.43) nmol, P < 0.001; and 126 (35-840) vs. 35 (35-126) pmol, P < 0.001, respectively, for insulinoma patients and normal subjects. All plasma samples were negative for sulfonylurea. Insulinoma patients had C-peptide values at the end of the fasts greater than or equal to 0.20 nmol whereas normal subjects and patients with insulin factitial hypoglycemia had C-peptide concentrations less than or equal to 0.10 nmol when plasma glucose was less than or equal to 2.8 mmol. Insulinoma is confirmed in a sulfonylurea negative patient with Whipple's triad during the prolonged fast and a concomitant C-peptide concentration greater than or equal to 0.20 nmol.

Topics: Adolescent; Adult; Aged; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay; Reference Values

The existence of insulin feedback inhibition is a controversial issue. The present study adopted a novel approach to determine whether insulin feedback inhibition exists in vivo during physiologic hyperinsulinemia and if it could contribute to enhanced insulin secretion in obesity. Serial plasma insulin and C-peptide levels were determined during a basal state and a hyperinsulinemic clamp (287 pmol/min/m2) and following discontinuation of the insulin infusion under euglycemic conditions. Insulin secretion rates were derived from plasma C-peptide levels and individual C-peptide kinetics using a two-compartment model. Eight non-obese and nine obese men were recruited for the studies, which were performed in random order. Men with significant variations in glucose levels during hyperinsulinemia were excluded from the analysis. Plasma glucose levels were similar between the non-obese and obese groups during all phases of the study, and similar plasma insulin levels were achieved in both groups during euglycemic hyperinsulinemia. In obese men, C-peptide levels were significantly greater compared with non-obese men during euglycemic hyperinsulinemia (P < .05). However, neither the non-obese nor the obese group demonstrated significant suppression of insulin secretion rates during euglycemic hyperinsulinemia. Expressing the data in absolute terms or as a percent of basal did not alter the results. Moreover, there was no significant change between the non-obese and the obese group during the rapid onset and cessation of hyperinsulinemia. Under euglycemic conditions, physiologic hyperinsulinemia does not induce suppression of endogenous insulin secretion in non-obese or obese men.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Feedback; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Male; Obesity

Previous studies have shown that hyperinsulinism is associated with hyperandrogenism in patients with the polycystic ovary syndrome, a form of functional ovarian hyperandrogenism (FOH). Although many studies have documented insulin resistance and hyperinsulinemia in polycystic ovary syndrome, the relative roles of insulin secretion and clearance in the pathogenesis of the hyperinsulinism remain uncertain. In this study, using individually derived C-peptide kinetic parameters, insulin secretion rates were calculated directly from plasma C-peptide concentrations in 10 patients with FOH and 7 weight-matched control subjects. All subjects were studied during a 24-h period when they ate a standardized diet consisting of 3 mixed meals. On a separate occasion, insulin sensitivity was calculated during a hyperinsulinemic euglycemic clamp. Although glucose concentrations in both groups were within the normal range, the FOH group had higher basal (P < 0.01) and 24-h insulin (P < 0.04) concentrations. The increased insulin concentrations reflected both a reduced clearance (P < 0.02) and an increased secretion of insulin. Basal insulin secretion rates were significantly increased (P < 0.04) in the FOH patients. By contrast, their incremental insulin secretory response to meals was markedly reduced. This reduction in the postprandial responses resulted from a reduction in the relative amplitude of meal-related (P < 0.007) secretory pulses, rather than from a reduction in the number of pulses present. Insulin sensitivity was also lower in those with FOH. Thus, women with FOH have significantly higher basal insulin secretory rates and attenuated secretory responses to meals. These secretory patterns resemble those of noninsulin-dependent diabetes mellitus more than they do those of simple obesity.

Topics: Adult; Androgens; Blood Glucose; C-Peptide; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Osmolar Concentration; Ovarian Diseases

Microalbuminuria predicts cardiovascular events in diabetic and nondiabetic patients. For a better understanding of the physiopathological importance of microalbuminuria in atherosclerotic disease, we evaluated the relation between urinary albumin excretion and arterial blood pressure, left ventricular mass, insulin, and lipid levels. The studies were conducted in patients with atherosclerotic peripheral vascular disease. Urinary albumin excretion (studied by nephelometry; an average of triplicate collections from 8 PM to 8 AM), causal blood pressure, echocardiographic left ventricular mass index and wall thickness, plasma immunoreactive insulin and C-peptide (both basally and after a 75-g oral glucose load), blood lipids, and fibrinogen were studied in eight normal subjects and 20 nonobese, nondiabetic male patients with angiographically documented atherosclerotic peripheral vascular disease and preserved renal function, 12 of whom were either hypertensive or on antihypertensive treatment. Eight patients were microalbuminuric (urinary albumin > 20 micrograms/min) and 12 were not. Ankle-arm index and calf and foot transcutaneous oxygen tension were reduced in comparison with normal control subjects but superimposable between the two patient groups to indicate a comparable clinical progression of the vascular disease. In the microalbuminuric subjects, left ventricular mass index was greater, interventricular septum was thicker, and cardiac hypertrophy was more frequent than in nonmicroalbuminuric patients. The prevalence of hypertension tended to be greater and systolic blood pressure values were higher in the presence of microalbuminuria. Overall, a highly significant relation existed between urinary albumin excretion and left ventricular mass. Systolic blood pressure was greater and a history of arterial hypertension was more frequent among microalbuminurics, whereas diastolic blood pressure values showed a statistically significant correlation with both variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aged; Albuminuria; Angiography; Arteriosclerosis; Blood Glucose; Blood Pressure; C-Peptide; Echocardiography; Fibrinogen; Glucose; Humans; Hyperinsulinism; Hypertrophy, Left Ventricular; Insulin; Lipids; Male; Middle Aged; Peripheral Vascular Diseases

We examined the mechanism by which an increase in blood insulin concentration inhibits insulin secretion by the pancreas. To this end, we determined plasma C-peptide concentrations during euglycemic-hyperinsulinemic (approximately 500 pmol/L) clamps in five patients with insulin-dependent diabetes mellitus (IDDM) after combined pancreas and kidney (P/K) transplantation, in five nondiabetic patients after kidney transplantation (K), and in six normal control subjects. Hyperinsulinemia decreased C-peptide concentrations in K patients (by 60%, P < .01) and controls (by 35%, P < .05), but not in P/K patients (653 +/- 115 v 702 +/- 197 pmol/L before and after 4 hours of hyperinsulinemia, respectively). The main difference between K patients and controls and P/K patients was that the pancreas in K patients and controls was innervated, whereas the transplanted pancreas of K/P patients was denervated. The data therefore suggested that the inhibition of pancreatic insulin secretion by hyperinsulinemia was neurally mediated.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Feedback; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Kidney Transplantation; Male; Pancreas; Pancreas Transplantation

Treatment for hyperinsulinism in infants and children can be difficult and has included numerous treatment modalities. This paper reports 16 months of palliative treatment with cyproheptadine and diazoxide in a child with hyperinsulinism initially diagnosed at 6 months of age (her insulin level was 80 microU/mL while her glucose level was 38 mg/dL). She continued to have episodes of staring and alteration in level of consciousness while receiving her usual doses of diazoxide (12 mg/kg) alone. Mean nocturnal glucose values, which were quite low during treatment with diazoxide alone, improved significantly with the addition of cyproheptadine to her therapeutic regimen. Fasted C-peptide values, elevated during diazoxide alone, returned to the normal range with combination treatment for 16 months. Cyproheptadine and diazoxide in combination may be useful for treatment of hyperinsulinism that presents after the neonatal period.

Topics: Blood Glucose; C-Peptide; Cyproheptadine; Diazoxide; Drug Combinations; Female; Humans; Hyperinsulinism; Infant; Insulin; Palliative Care

Persistent neonatal hyperinsulinaemic hypoglycaemia due to nesidioblastosis is a rare condition probably transmitted by an autosomal recessive inheritance. Recurrent hypoglycaemic episodes become evident after birth and cause severe neurological damage without intensive treatment. The intrauterine detection of hypoglycaemia and hyperinsulinism in newborns subsequently diagnosed as affected by nesidioblastosis has not yet been reported. We describe a case of familial nesidioblastosis in which an intrauterine diagnosis could be suggested by high levels of insulin and C-peptide and low values of glucose in the amniotic fluid.

Topics: Amniocentesis; Blood Glucose; C-Peptide; Humans; Hyperinsulinism; Infant, Newborn; Insulin; Male; Pancreatic Diseases; Pedigree; Prenatal Diagnosis

First-degree relatives of patients with NIDDM manifest severe insulin resistance despite normal glucose tolerance test. To examine the mechanisms underlying the normal glucose tolerance, we evaluated the serum glucose/C-peptide/insulin dynamics and free fatty acid (FFA) as well as substrate oxidation rates and energy expenditure (EE) (indirect calorimetry) in nine young offspring of NIDDM patients (mean +/- SEM age 30 +/- 2.3 years, body mass index 24.2 +/- 1.2 kg/m2). Nine age-, sex- and weight-matched, normal subjects with no family history of diabetes served as the controls. Metabolic parameters were measured before, during and after a two-step glucose infusion (2 and 4 mg/kg.min) for 120 min. Mean basal serum glucose, insulin and C-peptide levels were similar in both groups. During 2 mg/kg.min glucose infusion, mean serum insulin and C-peptide rose to significantly (P less than 0.05-0.02) greater levels in the offspring vs. controls, while serum glucose levels were similar. With the 4 mg/kg.min glucose infusion, mean serum glucose, insulin and C-peptide levels were significantly (P less than 0.02-0.001) greater in the offspring at 100-120 min. Isotopically-derived (D[3-3H]glucose), basal hepatic glucose output (HGO) was not significantly different between the offspring vs. controls (1.86 +/- 0.30 vs. 1.78 +/- 0.06 mg/kg.min). During glucose infusion, basal HGO was partially suppressed by 66% at 60 min and by 100% at 120 min in the offspring. In contrast, HGO was completely (100%) suppressed at both times in the controls. Following cessation of glucose infusion, HGO rose to 1.64 +/- 0.12 mg/kg.min in the offspring and 1.46 +/- 0.05 mg/kg.min in the controls (P less than 0.05) between 200 and 240 min. These were 88% and 82% of the respective basal HGO values. At low glucose infusion (t = 0-60 min), the mean absolute, non-oxidative glucose disposal remained 1.5-fold greater in the offspring while at higher glucose infusion, nonoxidative glucose metabolism was not different in both groups. Throughout the study period, oxidative glucose disposal rate was not significantly different in both groups. The mean basal FFA was significantly greater in the offspring vs. controls (865 +/- 57 vs. 642 +/- 45 microEq/l). It was appropriately suppressed during glucose infusion to a similar nadir in both groups (395 +/- 24 vs. 375 +/- 33 microEq/l). The mean basal lipid oxidation was also significantly greater in the offspring than controls (1.06 +/- 0.05 vs. 0.75 +/- 0

Topics: Adult; Blood Glucose; Body Temperature; C-Peptide; Calorimetry; Child of Impaired Parents; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids, Nonesterified; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Metabolic Clearance Rate; Tritium

Serum C-peptide immunoreactivity (CPR)/immunoreactive insulin (IRI) molar ratio was determined in 136 subjects without renal, hepatic and thyroid disorders, at fasting, and during the initial period of 75 g-oral glucose tolerance test. The subjects were divided into 4 groups based on their body weight and age; Group A, young (< 55 years) and normal body weight (body mass index [BMI, kg/m2] < or = 25) subjects; Group B, young and overweight (BMI > 25) subjects; Group C, aged (> or = 55 years) and normal body weight (BMI < or = 25) subjects; Group D, aged and overweight subjects. Fasting CPR/IRI ratio and absolute CPR level negatively correlated in Groups B and D but not in A and C. After oral glucose load with elevation of insulin, CPR/IRI ratio invariably declined in all groups and significant negative correlation between CPR/IRI and CPR was found in Groups A, B and D but not in C. Slope of the regression lines obtained for correlation between CPR/IRI ratio and CPR were significantly steeper at fasting compared to the post-stimulation phase. CPR/IRI ratio is affected by hyperinsulinemia and oral glucose load but not by obesity alone. Assuming that CPR/IRI ratio reflects hepatic extraction of insulin, the insulin clearance at fasting is progressively reduced with increasing insulin secretion in overweight subjects: failure to detect such phenomenon in normal body weight subjects may be due to a narrower CPR range in this population. Insulin metabolism at fasting and during glucose stimulation is likely to be regulated by distinct factors.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Female; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity

Several studies have demonstrated that patients with hypertension have greater plasma insulin levels than normotensive subjects. The aim of the present study was to clarify if hyperinsulinemia in hypertension is a consequence of either increased pancreatic secretion or decreased hepatic clearance, and to determine whether abnormalities of glucose metabolism are equally present in essential and secondary hypertension. In an observational cross-sectional study, fasting blood glucose, plasma insulin, and plasma C-peptide levels were measured in five patient groups: 34 lean normotensive, 19 overweight normotensive, 25 lean essential hypertensive, 27 overweight essential hypertensive, and 20 secondary hypertensive subjects. The blood glucose/plasma insulin and plasma insulin/plasma C-peptide ratios were calculated as indexes of insulin sensitivity and hepatic insulin clearance, respectively. Subjects with essential hypertension and, to a greater extent, those who were overweight, exhibited significantly higher fasting insulin and C-peptide levels and significantly lower glucose/insulin ratios as compared with lean normotensive subjects. In contrast, no differences were observed between secondary hypertensive and control subjects. Mean blood pressure was significantly and independently correlated to body mass index, plasma insulin and plasma C-peptide levels, and the glucose/insulin ratio. In lean essential hypertensive and secondary hypertensive subjects, the insulin/C-peptide ratios were comparable to controls, indicating normal hepatic insulin clearance. In both overweight groups, a trend to increased insulin/C-peptide ratios was observed. This study shows that in essential hypertensive subjects, hyperinsulinemia is caused by insulin hypersecretion, whereas in overweight subjects, both increased insulin secretion and decreased hepatic insulin clearance might be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Hypertension; Male; Middle Aged; Obesity

Obesity is characterized by peripheral hyperinsulinemia, for which either beta-cell hypersecretion, diminished hepatic insulin extraction, or both may be responsible. To clarify this issue, we investigated insulin secretion and hormone hepatic extraction in 18 nondiabetic obese patients (body mass index [BMI], 39 +/- 1.3 kg/m2) and 18 healthy, lean control subjects (BMI, 21.3 +/- 0.7 kg/m2). Body fat distribution was calculated by measuring the waist to hip ratio (WHR). A highly reduced tissue insulin sensitivity (2.4 +/- 0.5 v 9.5 +/- 1.5 10(4).min-1/[microU/mL], P > .0005) and glucose effectiveness, ie, glucose's ability to stimulate its own disappearance at basal insulin (16 +/- 2 v 30 +/- 3 10(3).min-1, P > .005), were found in the overweight subjects compared with the controls. The basal (76 +/- 14 v 37 +/- 4 pmol/L/min) and total (377,848 +/- 5,562 v 16,864 +/- 1,850 pmol/L) prehepatic insulin secretion and the basal (15 +/- 2 v 7 +/- 0.7 pmol/L/min) and total (8,286 +/- 2,009 v 2,840 +/- 210 pmol/L) posthepatic insulin delivery were significantly higher in the overweight subjects compared with the controls (P < .005), whereas the mean hepatic insulin extraction did not differ (77.8% +/- 2.6% v 79.5% +/- 2.6%). A significant inverse correlation was found between the hepatic insulin extraction and the WHR (r = .5, P > .04), signifying the importance of fat distribution in insulin metabolism. The obese patients were subdivided into two subgroups according to their glucose tolerance; eight patients exhibited a normal tolerance and the remaining 10 were intolerant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abdomen; Adult; Blood Pressure; C-Peptide; Cholesterol; Diabetes Complications; Diabetes Mellitus; Female; Glucose Tolerance Test; Hip; Humans; Hyperinsulinism; Insulin; Islets of Langerhans; Liver; Male; Models, Biological; Obesity; Time Factors; Triglycerides

to investigate whether differences in the glucose-insulin axis are present at birth in neonates from ethnic groups at high risk of diabetes.. fructosamine samples were taken from Maori, European and Pacific Island expectant mothers at their 28 week appointment at the public outpatients clinic at National Women's Hospital, Auckland. Umbilical cord samples for insulin, C-peptide and fructosamine assay were taken at delivery and babies had their subscapular skinfold fat thickness measured by callipers.. the mean maternal 28 week fructosamine was similar in the three populations in spite of a higher prevalence of gestational diabetes among Pacific Islanders. Of the 1066 deliveries, cord samples were available for 207 Europeans, 81 Maoris and 113 Pacific Islanders. Both Pacific Island and Maori babies had higher cord fructosamine concentrations than European babies. However, Pacific Island babies were also heavier, and had higher cord insulin concentrations and subscapular skinfold thickness than European babies.. the elevated cord fructosamine concentrations suggest that Maori and Pacific Island babies, who share a high risk of noninsulin dependent diabetes mellitus later in life, are hyperglycaemic at birth. The paradoxical insulin results and the cause for the relative neonatal hyperglycemia warrant further investigation.

Topics: Adult; Anthropometry; Birth Weight; Body Height; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Ethnicity; Europe; Female; Fetal Blood; Fructosamine; Head; Hexosamines; Hospitals, Maternity; Hospitals, Public; Humans; Hyperinsulinism; Infant, Newborn; Insulin; New Zealand; Parity; Polynesia; Pregnancy; Prevalence; Risk Factors; Skinfold Thickness

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

Chronic in utero hyperinsulinemia in the fetal rhesus monkey produces a number of changes in the fetus that are similar to those found in the human infant of the diabetic mother, including macrosomia, selective organomegaly, and altered insulin secretion during the neonatal period. The chronically hyperinsulinemic fetal rhesus model has been used to test the hypothesis that the effects of chronic hyperinsulinemia persist beyond the neonatal period into later life and may, in part, be responsible for the increased prevalence of impaired glucose tolerance or diabetes found in the human infant of the diabetic mother. We report that infant rhesus monkeys that had plasma insulin concentrations of approximately 10 times basal levels (2176 +/- 808 pmol compared to 172 +/- 101 pmol) exhibited reduced insulin secretion during the first 5 months of life. The integrated incremental change in plasma insulin and immunoreactive C-peptide (IRCP) concentration was significantly reduced by approximately 50% in response to i.v. glucose, arginine, and tolbutamide when given at 3, 4, and 5 months of age. The response to glucagon at 2 months of age was equivocal with a significantly reduced insulin response but without the corresponding IRCP reduction. There was no difference between groups in insulin sensitivity as measured at 6 months of age by an i.v. insulin tolerance test. The glucagon and glucose tolerance tests were repeated annually in both groups until the animals were 3 yr of age with no differences in insulin or IRCP secretion being observed. We conclude that chronic in utero euglycemic hyperinsulinemia results in impaired insulin secretion that persists beyond the neonatal period.

Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; C-Peptide; Disease Models, Animal; Female; Fetal Blood; Fetal Diseases; Fetal Macrosomia; Gestational Age; Hyperinsulinism; Insulin; Insulin Secretion; Macaca mulatta; Pregnancy; Umbilical Arteries; Umbilical Veins

Glucose and insulin responses to a glucose load in 11 patients with angina attributed to microvascular coronary dysfunction were compared with those in 11 healthy subjects matched for age, sex, and body mass. Stimulated hyperinsulinaemia was demonstrated in the microvascular angina group. The findings suggest a role for increased concentrations of insulin in coronary microvascular dysfunction.

Topics: Adult; Angina Pectoris; Blood Glucose; C-Peptide; Coronary Circulation; Evaluation Studies as Topic; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Microcirculation; Middle Aged; Syndrome

Much research has demonstrated that in late pregnancy glucose administration causes a marked increase of peripheral insulin levels. To ascertain whether this particular increase is due to increased insulin secretion and/or to reduced hepatic insulin removal, we measured blood glucose, plasma C-peptide and plasma insulin during OGTT in 7 nonpregnant women and in 20 nondiabetic women at third trimester of gestation and 60-90 days after delivery. The C-peptide/insulin molar ratio was calculated for all subjects. Data obtained showed that both plasma insulin and C-peptide response to oral glucose is considerably higher in women at third trimester of pregnancy as compared with that observed in the same subjects after delivery and in nonpregnant women. The basal (overnight fasting) C-peptide/insulin molar ratio did not differ significantly between pregnant and nonpregnant women. After the oral glucose load the molar ratio was sharply reduced in all groups of subjects, but the overall decrease in the pregnant women in the three hours following oral glucose was considerably greater than in postpartum and in nonpregnant women. The increased plasma C-peptide response clearly indicates that in pregnancy oral glucose-induced hyperinsulinism is caused by increased insulin release from pancreatic B-cells. Moreover, the marked overall decrease of the C-peptide/insulin molar ratio suggests, even if it does not definitely prove, that hyperinsulinism after glucose in late pregnancy may be a consequence not only of increased insulin secretion, but also of decreased hepatic extraction of insulin.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Liver; Obesity; Pancreas; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third

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

Hyperinsulinemia is a well-recognized entity of simple obesity. It is demonstrated that hyperinsulinemia is associated with upper body fat and fat cell hypertrophy. Androgen excess and lower levels of sex hormone binding globulin (SHBG) may produce fat cell hypertrophy and hyperinsulinemia as well. We measured serum insulin and C-peptide levels during an OGTT in two groups of obese premenopausal women to determine whether the hyperinsulinemia is due to hypersecretion or due to a diminished hepatic extraction of insulin. In this study, we found no correlation between the insulin and C-peptide levels or their ratio and the degree of obesity. However, a significant correlation was found between the waist-to-hip circumference ratio (WHR), used as an index of body fat distribution, and the areas of insulin (r = 0.55; P less than 0.001) and C-peptide (r = 0.51; P less than 0.001). SHBG and free androgen index (FAI) were also significantly related to these areas. The peripheral C-peptide/insulin molar ratio has been assumed to reflect changes in hepatic insulin extraction while the corrected C-peptide response reflects beta-cell function. WHR was negatively related to this ratio (r = -0.44; P less than 0.005) and SHBG showed a positive correlation (r = 0.34; P less than 0.05). Stepwise multiple regression analysis revealed that the 2-h insulin and C-peptide values and both curve areas can be explained up to 40-80% by sex hormones and anthropometric variables. Also the C-peptide/insulin molar ratio is dependent in a first step on WHR (r2 = 0.23; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abdomen; Adipose Tissue; Adult; Blood Glucose; Body Mass Index; C-Peptide; Female; Follicular Phase; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Obesity, Morbid; Sex Hormone-Binding Globulin; Testosterone

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Glucagon; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Radioimmunoassay; Reference Values

Inhibition of C-Peptide secretion by exogenous insulin was studied during euglycemic clamp in 13 patients with histologically verified causes of organic hyperinsulinaemia (10 with beta cell adenoma; 2 with beta cell carcinoma and 1 with beta cell hyperplasia) and in 10 healthy controls. Euglycemic clamps were performed using artificial endocrine pancreas (Clamp Mode 9:1) while insulin infusion (Humulin Normal-Lilly) rate was 0.1 U/kg BW/h. Blood samples for serum insulin (RIA INEP) and C-Peptide (RIA-Biodata) were taken at 0; 30; 60; 90 and 120 min. Statistical analysis was done using SPSS on IBM-PC with Wilcoxon sum rank test and one way ANOVA. All the patients were studied before the operation and in four of them clamp studies were repeated after the operation. Statistically significant suppression of C-Peptide values in 120 min was established in the control group (p less than 0.05) while there was no significant suppression in insulinoma group (p greater than 0.05), except in one patient with beta cell hyperplasia. Various types of responses (suppression, no change, paradoxical increase) were observed after the operation in the insulinoma group. Possible mechanisms and the meanings of the absence of insulin induced C-Peptide suppression in insulinoma group are discussed. It is concluded that euglycemic hyperinsulinemic clamp study could be useful and a complementary test to other established tests for the confirmation of the diagnosis of insulinoma. Further work on beta cell response after the operation in patients with insulinoma is necessary.

Topics: Adenoma; Adenoma, Islet Cell; Adult; Aged; Analysis of Variance; Body Mass Index; C-Peptide; Carcinoma; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hyperplasia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

Hypertensive subjects who have received no treatment have been found to be hyperinsulinaemic in previous studies using different populations. The present study was carried out to further examine the metabolic disturbances in carefully treated hypertensive subjects [diastolic blood pressure (DBP) less than 90 mmHg] of both sexes from the Dalby population. Three hundred and ten subjects who had been hypertensive for more than 5 years [DBP 88.1 +/- 0.5 (mean +/- s.e.m.)] were compared with 288 normotensive controls, matched for sex and age and chosen from the same population. After an overnight fast and with no medication for 24 h, an oral glucose tolerance test was carried out. P-insulin and P-C-peptide were analysed and insulin sum (P-insulin at start + after 2 h of oral glucose tolerance test) and C-peptide sum were calculated. Insulin and C-peptide sums were higher (P less than 0.001) in the hypertensive than in the normotensive subjects; 0.69 +/- 0.03, 3.36 +/- 0.08 and 0.41 +/- 0.02, 2.74 +/- 0.06, respectively. The diagnosis of hypertension, not the attained blood pressure level, correlated with insulin and C-peptide sums in multivariate analyses; F-values 20.96 (n = 598; P less than 0.001) and 6.68 (P less than 0.01), respectively. Hypertensive subjects under treatment, using calcium antagonists as monotherapy (n = 21), did not differ in age or body mass index from other hypertensives, but they had lower values for insulin and C-peptide sums; 0.45 +/- 0.05 and 2.63 +/- 0.18. Angiotensin converting enzyme inhibitors were not frequently used for monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antihypertensive Agents; C-Peptide; Cohort Studies; Female; Humans; Hyperinsulinism; Hypertension; Insulin; Male; Middle Aged; Sweden

Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemic effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemic effect of pulsatile insulin administration, in particular, whether prolonged pulsatile hyperinsulinemia induces insulin insensitivity. Basally and 1 h after cessation of a 20-h pulsatile infusion of insulin (0.5 mU.kg-1.min-1), eight nondiabetic human subjects were assessed for 1) glucose turnover with [3-3H]glucose, 2) insulin sensitivity by minimal-model analysis of intravenous glucose tolerance tests, and 3) monocyte insulin-receptor binding. The time-averaged plasma insulin levels were 30 +/- 5 mU/L (mean +/- SE) during the infusion, which was similar to the levels achieved in our previous continuous hyperinsulinemia study. However, the average rate of glucose infusion to maintain euglycemia was 55% greater than in the previous study. Hepatic glucose production was -5.2 +/- 1.4 mumol.kg-1.min-1 during the infusion but returned to preinfusion levels 1 h after the infusion was stopped. Insulin sensitivity (Sl) and glucose tolerance (rate of glucose disappearance, Kg) showed changes opposite in direction to our previous continuous hyperinsulinemia study (pre- vs. postinfusion Kg 1.5 +/- 0.1 vs. 1.7 +/- 0.2 min-1 x 10(2), NS; pre- vs. postinfusion Sl 8.4 +/- 2.3 vs. 11.8 +/- 3.7 min-1.mU-1.L x 10(4), P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Computer Simulation; Drug Administration Schedule; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Kinetics; Liver; Male; Norepinephrine; Time Factors

Plasma insulin-like growth factor 1 (IGF-1) concentrations were measured in a group of patients with hypoglycaemia due to endogenous hyperinsulinism, and compared with those in a group of patients matched for age and sex with hypoglycaemia and appropriately suppressed insulin levels. Insulin-like growth factor 1 concentrations were significantly higher in the hyperinsulinaemic hypoglycaemic group than in either the hypoinsulinaemic hypoglycaemia group or a group of euglycaemic control subjects. These data provide further evidence that insulin promotes IGF-1 production and release from the liver.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Male; Middle Aged; Somatomedins

To evaluate the metabolic consequences of pancreas transplantation with systemic venous drainage on beta-cell function, we examined insulin and C-peptide responses to glucose and arginine in type I (insulin-dependent) diabetic pancreas recipients (n = 30), nondiabetic kidney recipients (n = 8), and nondiabetic control subjects (n = 28). Basal insulin levels were 66 +/- 5 pM in control subjects, 204 +/- 18 pM in pancreas recipients (P less than 0.0001 vs. control), and 77 +/- 17 pM in kidney recipients. Acute insulin responses to glucose were 416 +/- 44 pM in control subjects, 763 +/- 91 pM in pancreas recipients (P less than 0.01 vs. control), and 589 +/- 113 pM in kidney recipients (NS vs. control). Basal and stimulated insulin levels in two pancreas recipients with portal venous drainage were normal. Integrated acute C-peptide responses were not statistically different (25.3 +/- 4.3 nM/min in pancreas recipients, 34.2 +/- 5.5 nM/min in kidney recipients, and 23.7 +/- 2.1 nM/min in control subjects). Similar insulin and C-peptide results were obtained with arginine stimulation, and both basal and glucose-stimulated insulin-C-peptide ratios in pancreas recipients were significantly greater than in control subjects. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first-pass hepatic insulin clearance, although insulin resistance secondary to immunosuppressive therapy (including prednisone) probably plays a contributing role. To avoid hyperinsulinemia and its possible long-term adverse consequences, transplantation of pancreas allografts into sites with portal rather than systemic venous drainage should be considered.

Topics: Adult; Arginine; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucose; Humans; Hyperinsulinism; Insulin; Islets of Langerhans; Male; Pancreas Transplantation; Portal Vein

The secretion of insulin by the pancreas of the newborn rhesus monkey that had been made experimentally hyperinsulinemic in utero was studied in 18 animals. Chronic in utero hyperinsulinemia was produced by the continuous subcutaneous delivery of 4.75 units of insulin per day for 18 +/- 1 days. After delivery, the insulin-containing pump was removed to allow neonatal insulin levels to drop to normal levels. By 6.5 +/- 1.0 hr after pump removal, plasma glucose, insulin, and C-peptide immunoreactivity (CPIR) were comparable in the control and experimental animals. At that point 300 micrograms of glucagon/kg body weight was given iv to stimulate insulin secretion. After 30 min a significant elevation (expressed as the percentage of basal levels) in plasma glucose by 250%, insulin by 200%, and CPIR by 200% was observed in the control animals. In contrast, no changes in plasma insulin or CPIR concentrations occurred, with an attenuated glucose response that was only one-fifth of the control response, in the experimental animals. These results along with the observed lowered concentrations of CPIR in the plasma and insulin in the pancreas at birth can be interpreted as evidence that insulin is an inhibitor of its synthesis and secretion in utero and that this abnormal intrauterine environment causes changes that persist into extrauterine life.

Topics: Animals; Animals, Newborn; Blood Glucose; C-Peptide; Female; Fetal Diseases; Glucagon; Hyperinsulinism; Infusion Pumps, Implantable; Insulin; Insulin Secretion; Islets of Langerhans; Macaca mulatta; Pregnancy; Pregnancy in Diabetics

Blood glucose concentrations were measured prospectively in 27 small for dates infants in the first 48 hours after birth: 10 infants became hypoglycaemic. Of these, five had inappropriately raised plasma insulin concentrations. Plasma free fatty acids were lower and carbohydrate intake higher in these five infants, further supporting the diagnosis of hyperinsulinism. The hypoglycaemia recurred in four of the five hyperinsulinaemic infants, but in none of those who were not hyperinsulinaemic. Hyperinsulinism is common in small for dates babies. It is important to recognise this because hypoglycaemia is likely to recur and appropriate treatment is needed to prevent long term sequelae.

Topics: C-Peptide; Dietary Carbohydrates; Fatty Acids, Nonesterified; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Prospective Studies

Investigation of patients with suspected or proven hypoglycemia is often a time-consuming and expensive process. We describe a glucose reduction challenge test which may be useful as an out-patient screening procedure. Insulin is infused for 3 h at 40 mU/kg.h. Plasma glucose was monitored at the bedside during the test, and blood samples were collected for measurement of C-peptide. Responses were examined in 17 normal controls, and 6 patients with insulinomas. In normal subjects, mean plasma glucose fell to a plateau value of 3.2 +/- 0.2 mmol/L (57 +/- 2.6 mg/dL) and remained at that level with few symptoms. In contrast, five of six patients with insulinomas developed severe hypoglycemia, with plasma glucose levels between 1.9 (34 mg/dL) and 2.2 mmol/L (39 mg/dL). Plasma C-peptide concentrations were suppressed to 0.08 pmol/mL or less in normal subjects, but in insulinoma patients remained at 0.32-1.6 pmol/mL i.e. outside the normal range, and diagnostic of nonsuppressible insulin secretion. These data demonstrate that moderate reduction of serum glucose maintained for a prolonged period results in marked suppression of plasma C-peptide, permitting improved discrimination between normal subjects and patients with insulinomas. This glucose reduction challenge can, therefore, be used as a test of glucose-regulating ability, where failure (hypoglycemia) per se represents a measurable abnormality. C-Peptide measurements will determine whether the cause of hypoglycemia is due to hyperinsulinemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Resistance; Male; Middle Aged

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Pancreatic Neoplasms

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Humans; Hyperinsulinism; Pancreatic Function Tests; Proinsulin; Reference Values

Decreased food intake and weight loss are seen in eating and depressive disorders. No satisfactory pathophysiological mechanisms have been proposed to explain those findings. While it should be kept in mind that the etiology of those diseases is still unclear, it seems reasonable to propose that the maintenance of anorectic behavior in the eating disorders as well as the decreased food intake of major depression, leading to continued weight loss seen in both conditions, are either caused or mediated by insulin in levels which are elevated but insufficient to cause hypoglycemia. A brief review is made of the role of insulin in satiety and in the control of body weight, and of the newly available techniques to accurately quantify secretion, hepatic extraction, and post-hepatic delivery rates of insulin. Neural, metabolic, and endocrine stimuli affect insulin secretion. The hypothesis is therefore compatible with several etiologic factors leading to hyperinsulinemia in anorexia nervosa and major depression, and resulting in decreased food intake and weight loss.

Topics: Anorexia Nervosa; C-Peptide; Depressive Disorder; Eating; Humans; Hyperinsulinism; Insulin; Liver; Weight Loss

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

Plasma glucose, immunoreactive insulin (IRI) and C-peptide responses during an oral glucose tolerance test (oGTT) were assessed in 11 non-obese patients with polycystic ovarian disease (PCOD) and 11 reference subjects matched for age, height and weight. Also, 6 patients with PCOD and 6 normal women were subjected to intravenous glucose tolerance testing (ivGTT) On oGTT, all subjects exhibited normal glucose tolerance; however, PCOD patients had significantly higher mean plasma glucose levels at 30, 60, 90 and 120 min and higher mean incremental glucose areas. In addition the patients with polycystic ovaries showed higher mean basal IRI and C-peptide levels, higher mean glucose stimulated IRI and C-peptide levels and higher mean incremental IRI and C-peptide values. The molar ratios of C-peptide/IRI were significantly lower in the PCOD group at all time intervals after glucose stimulation when compared to the normal women. During ivGTT, there were significantly higher mean glucose levels at 5, 40, 50 and 60 min in the PCOD group when compared to the reference group. The IRI response to intravenous glucose in the PCOD women was similar to the reference group. The findings on oGTT suggest that non-obese patients with PCOD have increased pancreatic IRI secretion as well as impaired hepatic extraction of the hormone.

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Female; Glucose; Humans; Hyperinsulinism; Injections, Intravenous; Insulin; Polycystic Ovary Syndrome

We are investigating human insulin gene expression in transgenic mice. An 8.8 kilobase (kb) human genomic DNA fragment, including the insulin gene (1.4 kb) and 2 kb of 5' human flanking sequences, was introduced into mouse embryos by pronuclear microinjection. Two lines of transgenic mice have been established, both of which carry the intact human gene in multiple copies. Animals from both lines have significantly higher insulin levels than control mice, and the degree of hyperinsulinemia shows a positive correlation with human gene copy number in the two lines. Expression of the human gene is confirmed by the detection of human C-peptide in plasma. Tissue specificity of expression is maintained, with human insulin mRNA detectable only in the pancreas. The transgenics maintain normal fasting blood glucose in spite of their high insulin levels, but preliminary studies show them to be glucose intolerant when given a glucose load. These mice provide a model system for further studies on the regulation of insulin gene expression and on the effects of chronic hyperinsulinemia on glucose homeostasis.

Topics: Animals; Blood Glucose; C-Peptide; Gene Expression; Genes, Dominant; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Mice; Mice, Transgenic; Organ Specificity; Pancreas; Plasmids; Transfection

To investigate the hypothesis that insulin resistance is concerned in the pathogenesis of essential hypertension fasting glucose/insulin and fasting insulin/C-peptide ratios were measured in non-obese normotensive and hypertensive diabetic and non-diabetic subjects. Patients with essential hypertension had normal fasting serum insulin values and normal fasting glucose/insulin ratios; by contrast, the hypertensive non-insulin-dependent diabetic subjects had higher fasting serum insulin and lower glucose/insulin ratios than either normotensive diabetic or non-diabetic patients. Both hypertensive and normotensive diabetic subjects had higher fasting C-peptide values than those without diabetes. Hypertensive diabetic patients had the highest insulin/C-peptide ratios, indicating low hepatic insulin extraction rates. These findings suggest that hyperinsulinaemia is not causally related to essential hypertension but that it may contribute to the hypertension of non-insulin-dependent diabetes in association with low hepatic insulin clearance.

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged

To assess the contribution of gastric inhibitory polypeptide (GIP) to the postprandial hyperinsulinemia of obesity, secretion rates of GIP (generated from kinetic analyses from infusions of porcine GIP) and insulin (from C-peptide applied to a validated kinetic model) to meals of 3 sizes were determined in 10 obese (5 male and 5 female) and 10 lean, sex- and age-matched healthy subjects. Although the postprandial secretion rates of GIP were greater in obese subjects (P = 0.03), postprandial concentrations of GIP were not. The latter may be explained by the greater volume of distribution of GIP in obese subjects (P = 0.036). Secretion rates and volume of distribution of GIP were correlated (r = 0.652, P less than 0.01). Despite excessive integrated postprandial (P = 0.010) insulin concentrations, insulin secretion was not significantly different between obese and lean subjects. We conclude that 1) although postprandial plasma GIP concentrations are normal, GIP secretion is increased in obesity, 2) the postprandial hyperinsulinemia of obesity is not due to excessive insulin secretion but is likely secondary to altered insulin clearance, and 3) GIP cannot account for the hyperinsulinemia of obesity through its insulinotropic action.

Topics: Adult; Blood Glucose; C-Peptide; Female; Food; Gastric Inhibitory Polypeptide; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Kinetics; Male; Obesity; Sex Factors

The purpose of the present study was to elucidate the interrelationship between pancreatic polypeptide (PP) and other pancreatic endocrine hormones. For this purpose, a radioimmunoassay (RIA) system of plasma PP was established and the changes in plasma PP, plasma immunoreactive insulin (IRI), plasma C-peptide reactivity (CPR) and plasma immunoreactive glucagon (IRG) following oral administration of glucose were examined in ten normal subjects and twenty-five patients with liver cirrhosis. Patients with liver cirrhosis were classified into a normal glucose tolerance group (NGT), an impaired glucose tolerance group (IGT), and a diabetes mellitus group (DM) on the basis of the glucose tolerance curves obtained after the oral administration of glucose. In the IGT and DM groups, fasting plasma PP levels were significantly elevated when compared with those in the control and NGT groups. Also oral administration of 75g glucose elicited an exaggerated rise in plasma PP in the IGT and DM groups when compared with the response in the control and NGT groups. On the other hand, PP response to glucose in the NGT group was similar to that in the control group. Plasma IRI increased markedly before and after oral administration of glucose in the IGT and DM groups when compared with the control groups. In these patients, plasma levels of CPR almost paralleled those of IRI. No significant difference was noted between the NGT group and the control group with regard to plasma IRI and CPR levels before and after oral glucose loading. Accordingly, insufficient insulin action was considered to exist in the IGT and DM groups. This insufficiency in insulin action was expressed in terms of the indices of increase in plasma IRI and CPR, delta IRI/delta BS and delta CPR/delta BS, which corresponded to the elevated blood glucose levels, being significantly lower in the IGT and DM groups than in the control and NGT groups 30 minutes after oral administration of glucose. No significant difference was noticeable between the NGT group and control group with regard to these indices. In the patients with liver cirrhosis, the delta PP value, obtained by subtracting the plasma PP level during fasting from the PP level 30 minutes after oral glucose loading, was inversely correlated with the values of both delta IRI/delta BS and delta CPR/delta BS.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: C-Peptide; Diabetes Complications; Diabetes Mellitus; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Liver Cirrhosis; Middle Aged; Pancreatic Hormones; Pancreatic Polypeptide; Radioimmunoassay

The diagnosis of insulinoma on the basis of persistent hypoglycemia requires further confirmation. The insulin suppression test has been used to support this diagnosis prior to surgical intervention. In this study the euglycemic clamp technique was used to compare five control volunteers with four hypoglycemic patients with suspected insulinoma. Insulin was infused over successive two-hour periods at 2, 4, and 8 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dL (4.4 mmol/L) using an artificial pancreas. High insulin levels were measured in all subjects, ranging from 225 +/- 30 microU/mL (1614 +/- 215 pmol/L) to 1018 +/- 239 microU/mL (7304 +/- 1714 pmol/L). Levels of C peptide fell to 0.1 ng/mL (0.028 nmol/L) in control subjects but remained at high levels in the patients. Insulinoma was confirmed on laparotomy in all four patients. In two patients tested after removal of the tumor the results were found to have returned to normal.

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulinoma; Pancreatic Neoplasms

Surreptitious self-administration of insulin is an important cause of hypoglycemia. A 28-year-old female hospital ward clerk presented with hypoglycemia associated with an elevated plasma insulin level and a low plasma C-peptide concentration. Factitious illness was denied by the patient until it was definitively proven by using a species-specific insulin radioimmunoassay that the type of insulin circulating at the time of hypoglycemia was of animal rather than of human origin. The differential diagnosis of hypoglycemia associated with hyperinsulinemia and the current laboratory methods which may be employed to distinguish between factitious hypoglycemia and endogenous hyperinsulinism are discussed.

Topics: Adult; Animals; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Radioimmunoassay; Species Specificity; Sulfonylurea Compounds

We recently reported a new case of abnormal insulinemia with LeuA3 insulin. Herein, we measured urinary insulin clearance during oral glucose tolerance tests in proband with abnormal insulinemia (44-yr-old female), three affected family members, two unaffected family members, two other hyperinsulinemic patients with obesity, five non-insulin-dependent diabetic patients, and five normal control subjects. Urinary insulin-to-creatinine clearance ratio in the proband and her affected family members was 0.22 X 10(-3) +/- 0.07 (mean +/- SD, n = 4) and was markedly reduced compared with those of other groups: 1.73 X 10(-3) in two unaffected family members, 2.77 X 10(-3) in two other hyperinsulinemic patients with obesity, 2.99 X 10(-3) +/- 1.48 in five non-insulin-dependent diabetic patients, and 2.54 X 10(-3) +/- 0.67 in five normal control subjects. In contrast, urinary C-peptide clearance in these groups was not significantly different from controls. Binding of immunopurified insulins extracted from urine of the patients with abnormal insulinemia to guinea pig kidney membrane was slightly decreased (71% of standard insulin), in contrast with the observation that serum insulin of the proband had much less receptor-binding activity. Reverse-phase HPLC analysis of the immunopurified insulin of the proband revealed that the ratios of normal insulin to abnormal insulin were 8:3 in urine and 1:7 in serum, respectively. These results suggest that excretion of abnormal insulin in urine is much less than that of normal insulin.

Topics: Adult; Animals; C-Peptide; Creatinine; Diabetes Mellitus, Type 1; Female; Glucose Tolerance Test; Guinea Pigs; Humans; Hyperinsulinism; Insulin; Kidney; Male; Metabolic Clearance Rate; Obesity; Radioimmunoassay; Radioligand Assay

We describe a family from Japan displaying the mutant insulin syndrome with hyperinsulinaemia and an increased insulin: C-peptide molar ratio. Serum insulin isolated from several family members showed reduced in vitro biological activity, and analysis by high performance liquid chromatography revealed a peak co-eluting with human insulin and a second species of increased hydrophobicity co-migrating with the previously reported Insulin Wakayama. The insulin genes from the propositus were cloned and sequenced, revealing one normal allele; the second allele, encoding a leucine for valine amino acid substitution at position 3 of the insulin A chain, was similar to that previously described for Insulin Wakayama. Synthesized [LeuA3] insulin showed 0.14% of receptor binding activity on rat adipocytes and a 10-fold prolonged half-life in a somatostatin-infused dog compared with human insulin. The finding of the same mutant gene in two unrelated Japanese families suggests that Insulin Wakayama may be discovered in additional Japanese families with hyperinsulinaemia and/or diabetes.

Topics: Adult; Aged; Amino Acid Sequence; Animals; C-Peptide; Chromatography, High Pressure Liquid; Dogs; Female; Half-Life; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Pedigree; Rats; Receptor, Insulin; Syndrome

Plasma clearance of endogenous and intravenously administered insulin was studied in three sibs with severe insulin resistance secondary to an affinity defect of their insulin receptors, and in five healthy controls. Intravenous infusion of somatostatin was used to inhibit the insulin secretion. 0.3 U of insulin/kg body weight was administered as an intravenous bolus. Plasma glucose, immunoreactive insulin and C-peptide were determined subsequently at constant intervals. We found a prolonged plasma half-life of insulin in the three patients, being 33.5 +/- 11.8 min vs 8.2 +/- 2.2 min in controls, P less than 0.002, but a normal half-life of C-peptide. The result indicates, that the plasma insulin clearance is predominantly mediated by intact insulin receptors. We conclude, that insulin has a prolonged half-life in all patients with insulin resistance secondary to an impaired receptor function.

Topics: Adult; Blood Glucose; C-Peptide; Female; Half-Life; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Male; Metabolic Clearance Rate; Middle Aged; Receptor, Insulin; Somatostatin

A 45-yr-old muscular nonobese white man who had a 9-yr history of syncopal episodes was studied on several occasions between April 1979 and August 1984. Fasting glucose concentrations ranged between 74-115 mg/dl, and those of insulin ranged between 14-64 microU/ml. Reactive hypoglycemia 3-4 h after ingestion of glucose occurred in the first 2 yr. Glucose tolerance was impaired in 1979, from February 1982 through September 1983, and again in August 1984. The maximum plasma insulin response to glucose ranged between 475-1630 microU/ml. When studied in November 1982, insulin (0.1 U/kg) caused a fall in blood glucose concentration of only 25% (normal, greater than 50%), and maximal glucose utilization during the euglycemic hyperinsulinemic clamp was 7.5 mg/kg . min (normal, greater than 12 mg/kg . min). Plasma counterregulatory hormone concentrations were normal, and antibodies to insulin and the insulin receptor were absent. Binding of exogenous insulin to the patient's cellular receptors (monocytes, red blood cells, and skin fibroblasts) was normal. Insulin was purified from plasma by immunoaffinity and molecular sieve chromatography and was found to elute later than human insulin on reversed phase high performance liquid chromatography. It was more hydrophobic than normal human insulin and had only 10% of the activity of normal insulin in terms of ability to bind to and stimulate glucose metabolism in isolated rat adipocytes. The abnormal insulin was identified in two of three sons and a sister, but not in the mother, brother, or niece. Sensitivity to insulin was normal in the two sons who had abnormal insulin. These results suggest that in this family the abnormal insulin was due to a biosynthetic defect, inherited as an autosomal dominant trait. The hyperinsulinemia was not associated with diabetes in family members who had no insulin resistance.

Topics: Blood Glucose; C-Peptide; Chromatography, Gel; Chromatography, High Pressure Liquid; Diabetes Complications; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Receptor, Insulin

According to our previous study, hyperinsulinism develops not before 10 years of age despite the presence of obesity but during the maturation years of 10-20. We aimed here at examining the growth-related islet B-cell change together with pituitary activity in non-familial juvenile obesity. Measurement of 24 h urine hormones was shown to be useful for evaluation of the diurnal hormones in plasma. In 56 non-obese and obese juveniles, a significantly positive correlation was found between age (6-18 years) and 24 h urine insulin and c-peptide, thus indicating that the age-related absolute value of body weight significantly affects insulin and c-peptide excretions both in non-obese and obese subjects. Consequently, urinary insulin and c-peptide excretions per kg of body weight were highly similar between obese and non-obese juveniles. However, when the lower specific gravity of fat mass compared with lean body mass and the relative shortage of circulating plasma in fat tissues are taken into consideration, it is obvious that obesity by itself specifically augments this physiologic B-cell maturation between 10 and 20 years of age. The possible interactions of growth hormone and pituitary gonadotropin in hyperinsulinism are discussed.

Topics: Adolescent; Aging; Body Height; Body Weight; C-Peptide; Child; Female; Gonadotropins, Pituitary; Growth Hormone; Humans; Hyperinsulinism; Insulin; Islets of Langerhans; Male; Obesity; Pituitary Gland

The clinical usefulness of calcium antagonists was studied in four patients with reactive hypoglycemia including two with alimentary and two with idiopathic. All patients had hyperresponses of plasma insulin (IRI) and C-peptide (CPR) during an oral glucose tolerance test (OGTT). A calcium antagonist (diltiazem 90 mg/d, or nifedipine 30 mg/d, or nicardipine 60 mg/d) was administered orally for about two months. After two months of treatment, plasma IRI and CPR responses during the OGTT were clearly suppressed in all patients and symptomatic reactive hypoglycemia disappeared. One month after the discontinuation of the treatment in two patients, plasma IRI and CPR responses during the OGTT became higher again and symptomatic reactive hypoglycemia recurred. In addition, an intravenous glucose tolerance test was performed before and after two months of the treatment with calcium antagonists in the two patients with reactive hypoglycemia and seven patients with hypertension, who were free from glucose intolerance and were also treated with a calcium antagonist. In these patients, plasma IRI and CPR responses were also reduced after the treatment compared with those before the treatment. These results suggest that calcium antagonists are useful as therapeutic agents for the treatment of reactive hypoglycemia associated with hyperinsulinemia, and that one of the main mechanisms of action of calcium antagonists is a direct action on the pancreatic B-cell to inhibit glucose-induced insulin release.

Topics: Adult; Aged; C-Peptide; Calcium Channel Blockers; Diltiazem; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Male; Middle Aged; Nicardipine; Nifedipine

The diagnosis of an insulin producing tumour can be confirmed by a minimum of biochemical investigations. Its preoperative localisation is more difficult. Sonogram, Computertomogram, selective angiography and percutaneous transhepatic collecting of blood samples for insulin analysis from the portal system were preoperative measured to localize the tumours in 32 of 37 patients of our series. In 2 patients intraoperative tumour localisation by measurement of incorporated p32 proved to be effective. In B-cell-carinomas pancreas resection is the adequate therapy. With regard to the therapeutic effects a high risk is involved in the 'blind' left or right sited resection of non-localized tumours.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Blood Glucose; C-Peptide; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Hyperinsulinism; Infant; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Postoperative Complications

We have characterized the molecular forms of circulating insulins in patients with hyperinsulinemia of diverse etiology. We have also compared the efficacy of various chromatographic conditions using reversed-phase (RP) HPLC. Using 0.2% trifluoroacetic acid (TFA) and triethylamine (TEA) with acetonitrile as the organic modifier, at an elution rate of 0.17%/min, porcine, bovine, and human insulins could be easily separated as well as abnormal insulins in the plasma of a patient (J.R.) with hyperinsulinemia of unknown etiology. When the reversed-phase C18 column was changed and a gradient of 0.33%/min was used, the abnormal insulin in patient J.R. could not be separated. By changing the solvent system to acetonitrile and isopropanol (vol:vol, 3:1) containing 0.1% TFA, omitting the TEA, and using a gentle gradient of 0.1%/min, various semisynthetic analogues of human insulin could be easily separated and the abnormal insulin could be identified in the plasma of the patient J.R. Abnormal insulin was also found in a patient with MEN-I, but in contrast, the insulins in eight patients with benign sporadic insulinomas appeared to be normal. These results suggest that certain hyperinsulinemic states may be associated with an abnormal insulin and that RP-HPLC is useful for identification of insulin variants in the circulation. However, the conditions of RP-HPLC may be critical if the abnormalities of the insulin are subtle.

Topics: C-Peptide; Chromatography, High Pressure Liquid; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Depression, Chemical; Female; Glucose; Humans; Hyperinsulinism; Infusions, Parenteral; Insulin; Male; Nonsuppressible Insulin-Like Activity; Obesity

Peripheral hyperinsulinaemia usually found in conventionally treated Type 1 (insulin-dependent) diabetic patients may have deleterious metabolic effects. We have used a hyperinsulinaemic model to examine intermediary metabolism in two key peripheral tissues, aorta and muscle. Nine pigs were immunized with crystalline insulin. Subsequently, they showed an insulin-binding capacity of 86.2 +/- 25.0 pmol/l and fasting total serum insulin of 3.9 +/- 3.1 nmol/l (control range 0.034-0.072 nmol/l), impaired glucose tolerance after oral glucose tolerance testing, significantly elevated levels of peripheral venous serum free insulin and C-peptide, and increased mean post-prandial free insulin/glucose ratios. The immunized pigs showed marked elevation of aorta and muscle triglycerides compared with control pigs (n = 15) but similar levels of non-esterified fatty acids. The glucose-6-phosphate-dehydrogenase, malic enzyme and 3-hydroxyacyl-CoA-dehydrogenase activities were all increased significantly (by 50%-300%) in both aorta and muscle. Phosphofructokinase was decreased in both tissues. Hexokinase was increased in muscle alone whereas pyruvate kinase was significantly decreased in aorta. Glyceraldehyde-3-phosphate dehydrogenase activity was not significantly different in aorta and muscle. Thus in insulin immunized pigs with normal beta-cell function and pronounced peripheral hyperinsulinaemia there was increased peripheral lipogenic activity. These findings have potentially important implications with regard to macrovascular disease in diabetes.

Topics: Animals; Aorta; Blood Glucose; C-Peptide; Cattle; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Hyperinsulinism; Insulin; Male; Muscles; Swine; Triglycerides

Persistent hyperinsulinism in the newborn may warrant surgical intervention to prevent neurologic sequelae. Subtotal pancreatectomy may not be adequate, necessitating near-total pancreatectomy with subsequent development of diabetes mellitus. We report an infant with hyperinsulinemic hypoglycemia who underwent near-total pancreatectomy. The postoperative period was characterized by insulin-dependency and extreme insulin sensitivity. Clinical follow-up and C-peptide determinations showed a return of insulin secretory capacity permitting the discontinuation of insulin therapy after five months. This experience reaffirms the potential for a favorable outcome after near-total pancreatectomy in the newborn period for severe hyperinsulinism.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hyperinsulinism; Infant; Infant, Newborn; Insulin; Pancreatectomy; Remission, Spontaneous

The authors have studied insulin receptors on peripheral blood monocytes and insulin sensitivity, evaluated by simultaneous infusion of glucose, insulin and somatostatin in 10 control subjects and in 20 obese patients with normal glucose tolerance. The obese patients have been divided into two groups, normo (NO) and hyperinsulinemic (HO), according to the total insulin response during OGTT. We considered HO patients with insulin response higher than M + 2DS of controls. Obese patients showed, in comparison to the controls, a lower specific binding and higher degree of insulin resistance. The subdivision of obese patients allowed us to distinguish two groups. The first was characterized by basal hyperinsulinemia, normal insulin response to the stimulus, reduced number of insulin receptors and normal or slightly reduced sensitivity. The second group showed high basal and after stimulus insulinemic values, reduced number of insulin receptors and high level of insulin resistance. When we compared the two groups of obeses we found that the first has a shorter duration of obesity and lower blood glucose values after OGTT. However both groups show the same reduction of insulin bound and the same degree of basal hyperinsulinemia. These data suggest that a reduction of insulin receptors is not the main factor responsible for insulin resistance in obesity. Furthermore, the presence of basal hyperinsulinemia and normal insulin sensitivity in our first group suggests that the modification of basal insulin concentrations is not dependent on the presence of insulin resistance.

Topics: Adult; Blood Glucose; C-Peptide; Glucagon; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Middle Aged; Obesity; Receptor, Insulin

The effects of prior high-intensity cycle exercise (85% VO2 max) to muscular exhaustion on basal and insulin-stimulated glucose metabolism were studied in obese, insulin-resistant, and normal subjects. Six obese (30.4% fat) and six lean (14.5% fat) adult males underwent two separate, two-level hyperinsulinemic-euglycemic clamp studies (100-min infusions at 40 and 400 mU/m2/min), with and without exercise 12 h earlier. Carbohydrate oxidation was estimated by indirect calorimetry using a ventilated hood system, and endogenous glucose production by D-(3-3H)-glucose infusion. Glycogen content and glycogen synthase activity (GS %l) were measured in vastus lateralis muscle biopsies before and at the end of each insulin clamp procedure. After exercise, the obese and lean subjects had comparably low muscle glycogen concentrations (0.10 versus 0.08 mg/g protein, respectively), and equal activation of muscle GS activity (54.4 versus 45.3 GS %l, respectively). In the obese subjects, insulin-stimulated glucose disposal was increased significantly, but not totally corrected to normal. In both groups there was a comparable increase in nonoxidative glucose disposal (NOGD), whereas glucose oxidation was decreased and lipid oxidation was increased. Thus, the major effect of prior exercise was to increase insulin-stimulated glucose disposal in the obese subjects and to alter the pathways of glucose metabolism to favor NOGD and decrease glucose oxidation. No correlation was found between the exercise-induced increase in GS %l and NOGD, except in the normal subjects during maximal insulin stimulation. Thus, glycogen synthase activity does not appear to be rate-limiting for NOGD at physiologic insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Glucose; Glucose Tolerance Test; Glycogen; Glycogen Synthase; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Muscles; Obesity; Oxidation-Reduction; Physical Exertion; Urea

Increased cord blood C-peptide levels in neonates born to mothers with gestational diabetes (GD) were directly correlated with the increased relative birth weight ratio (BWR) of these neonates. In addition, the percentage oxygen saturation of the cord blood was inversely correlated with cord blood C-peptide levels and with the relative BWR. These correlations were absent in neonates delivered to normal mothers. The results indicate the presence of both hyperinsulinaemia and mild hypoxaemia in neonates of mothers with GD. In poorly controlled diabetic pregnancy this hypoxaemia may constitute an important fetal risk factor.

Topics: Birth Weight; C-Peptide; Female; Fetal Blood; Humans; Hyperinsulinism; Hypoxia; Infant, Newborn; Oxygen; Partial Pressure; Pregnancy; Pregnancy in Diabetics

Familial hyperproinsulinemia, a hereditary syndrome in which individuals secrete high amounts of 9,000-mol wt proinsulin-like material, has been identified in two unrelated cohorts. Separate analysis of the material from each of the two cohorts had suggested that the proinsulin-like peptide was a conversion intermediate in which the C-peptide remained attached to the insulin B-chain in one case, whereas it was a conversion intermediate in which the C-peptide remained attached to the insulin A-chain in the other. To reinvestigate this apparent discrepancy, we have now used chemical, biochemical, immunochemical, and physical techniques to compare in parallel the structures of the immunoaffinity chromatography-purified, proinsulin-like peptides isolated from the serum of members of both families. Our results show that affected individuals in both cohorts secrete two-chained intermediates of proinsulin conversion in which the COOH-terminus of the C-peptide is extended by the insulin A-chain and from which the insulin B-chain is released by oxidative sulfitolysis. Analysis of the conversion intermediates by reverse-phase high-performance liquid chromatography using two different buffer systems showed that the proinsulin-related peptides from both families elute at a single position very near that of the normal intermediate des-Arg31, Arg32-proinsulin. Further, treatment of these peptides with acetic anhydride prevented trypsin-catalyzed cleavage of the C-peptide from the insulin A-chain, a result demonstrating the presence of Lys64 and the absence of Arg65 in both abnormal forms. We conclude that individuals from both cohorts with familial hyperproinsulinemia secret very similar or identical intermediates of proinsulin conversion in which the C-peptide remains attached to the insulin A chain and in which Arg65 has been replaced by another amino acid residue.

Topics: Acetic Anhydrides; Arginine; C-Peptide; Carboxypeptidase B; Carboxypeptidases; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Humans; Hyperinsulinism; Insulin; Proinsulin; Radioimmunoassay; Trypsin

To elucidate the mechanisms controlling the response of glucagon to hypoglycemia, a vital component of the counterregulatory hormonal response, the role of intraislet insulin was studied in seven normal subjects and five subjects with insulin-dependent diabetes mellitus (IDDM) (of less than 15-mo duration). In the normal subjects, hypoglycemia (arterial plasma glucose [PG] 53 +/- 3 mg/dl) induced by an intravenous insulin infusion (30 mU/m2 X min for 1 h, free immunoreactive insulin [FIRI] 58 +/- 2 microU/ml) elicited a 100% fall in insulin secretion and an integrated rise in glucagon of 7.5 ng/ml per 120 min. When endogenous insulin secretion was suppressed by congruent to 50 or congruent to 85% by a hyperinsulinemic-euglycemic clamp (FIRI 63 +/- 1.5 or 147 +/- 0.3 microU/ml, respectively) before hypoglycemia, the alpha cell responses to hypoglycemia were identical to those of the control study. When the endogenous insulin secretion was stimulated by congruent to 100% (hyperinsulinemic-hyperglycemic clamp, FIRI 145 +/- 1.5 microU/ml, PG 132 +/- 2 mg/dl) before hypoglycemia, the alpha cell responses to the hypoglycemia were also superimposable on those of the control study. Finally, in C-peptide negative diabetic subjects made euglycemic by a continuous overnight intravenous insulin infusion, the alpha cell responses to hypoglycemia were comparable to those of normal subjects despite absent beta cell secretion, and were not affected by antecedent hyperinsulinemia (hyperinsulinemic-euglycemic clamp for 2 h, FIRI 61 +/- 2 microU/ml). These results indicate that the glucagon response to insulin-induced hypoglycemia is independent of the level of both endogenous intraislet and exogenous arterial insulin concentration in normal man, and that this response may be normal in the absence of endogenous insulin secretion, in contrast to earlier reports. Thus, loss of beta cell function is not responsible for alpha cell failure during insulin-induced hypoglycemia in IDDM.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucagon; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Islets of Langerhans

Exaggerated insulin response to oral glucose was demonstrated in peripheral blood of patients with chronic hepatic diseases. High peripheral insulin levels may be the result of pancreatic hypersecretion or decreased hepatic removal of insulin. The simultaneous assay of insulin and C-Peptide concentrations in peripheral blood enables the determination of both beta-cell activity and hepatic fractional insulin extraction. We have measured peripheral insulin and C-Peptide levels during OGTT in a group of subjects with chronic active hepatitis (CAH). These subjects showed glucose levels and incremental areas significantly higher than controls, but still in the upper range of normality. Insulin response to oral glucose was significantly greater in CAH patients than in controls, whereas C-Peptide levels and areas were quite similar in the two groups. The C-Peptide to insulin molar ratios before and after glucose, and the relations between C-Peptide and insulin incremental areas were lower in CAH patients than in controls. We conclude that the peripheral hyperinsulinemia observed in subjects with CAH is due to diminished insulin removal by the diseased liver rather than pancreatic hypersecretion.

Topics: Adult; Blood Glucose; C-Peptide; Glucose Tolerance Test; Hepatitis, Chronic; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Liver; Male; Middle Aged

We have identified a patient with mild diabetes, marked fasting hyperinsulinemia (89 to 130 microU of insulin per milliliter), and a reduced fasting C-peptide: insulin molar ratio of 1.11 to 1.50 (normal, greater than 4). The patient responded normally to exogenous insulin. However, her endogenous immunoreactive insulin showed reduced biologic activity during a glucose-clamp study with hyperglycemia and a reduced ability to bind to the insulin receptor and stimulate glucose transport in vitro. Family studies showed that five additional relatives in three generations had variable degrees of glucose intolerance, marked hyperinsulinemia, and a reduced peripheral C-peptide:insulin molar ratio. Restriction-endonuclease cleavage of DNA isolated from circulating leukocytes in the patient and in family members with hyperinsulinemia revealed loss of the MboII recognition site in one allele of the insulin gene--consistent with a point mutation at position 24 or 25 in the insulin B chain. Other studies using high-pressure liquid chromatography and detailed gene analysis have identified the defect as a serine for phenylalanine substitution at position 24 of the insulin B chain. The secretion of a structurally abnormal insulin should be considered in patients with hyperinsulinemia who respond normally to exogenous insulin and have a reduced C-peptide:insulin molar ratio. Glucose tolerance may range from relatively normal to overtly diabetic.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Mutation; Receptor, Insulin

Ten severely obese women were subjected to physical training for three months on ad libitum diet. Under metabolic ward conditions oral glucose tolerance test was performed before and after the training period with the same energy intake quantitatively and qualitatively, and glucose, insulin, connecting (C)-peptide, gastric inhibitory polypeptide (GIP) and pancreatic polypeptide (PP) were determined. In confirmation of previous work, physical training caused no decrease in body fat in these severely obese subjects, and no change in body cell mass or glucose tolerance, while insulin and blood pressure decreased. The control of dietary conditions demonstrated that the latter phenomena were not due to quantitative or qualitative changes in the diet. C-peptide concentrations decreased also, indicating effects of physical training in obesity on insulin production. GIP is believed to be a gastrointestinal factor facilitating insulin secretion (Incretin). Previous work has indicated that gastrointestinal factor(s) are involved in the insulin lowering effect seen after physical training. It is possible that GIP is contributing to this phenomenon.

Topics: Adipose Tissue; Blood Glucose; Body Composition; C-Peptide; Cholesterol; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Obesity; Pancreatic Polypeptide; Physical Exertion; Triglycerides

This study investigated early alterations of glucose metabolism in idiopathic haemochromatosis. Circulating concentrations of glucose, insulin, C-peptide, glucagon, and gastric inhibitory polypeptide (GIP) were measured after a 100-g oral glucose load in 10 men with idiopathic haemochromatosis in the non-cirrhotic stage of the disease. All had normal glucose tolerance and normal body weight. Ten matched healthy subjects were studied as controls. Insulin concentrations increased to significantly higher levels in patients with idiopathic haemochromatosis than in the control subjects from 30 to 180 min after the glucose load (p less than or equal to 0.01), while fasting insulin concentrations were not significantly different (p greater than 0.05). Concentrations of glucose, glucagon, C-peptide, and GIP were not significantly different at any time (p greater than 0.05). Thus, patients with idiopathic haemochromatosis show hyperinsulinaemia and hence insulin resistance without impaired glucose tolerance in the non-cirrhotic stage. Since pancreatic insulin secretion (C-peptide), glucagon secretion, and the entero-insulinar axis (GIP) are not impaired in these non-cirrhotic patients with idiopathic haemochromatosis, iron accumulation in the hepatocytes may be responsible for the impaired insulin effect and may cause impaired hepatic insulin extraction.

Topics: Adult; Blood Glucose; C-Peptide; Gastric Inhibitory Polypeptide; Glucagon; Hemochromatosis; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Male; Middle Aged

The possible contribution of hepatocellular damage and portal-systemic shunting to hyperinsulinism in cirrhosis was studied in 23 cirrhotics, 8 of whom had a surgical portacaval shunt, and 16 controls by measuring insulin and the connecting peptide (C-peptide) concentrations in simultaneous samples of peripheral arterial and hepatic venous blood. The fractional hepatic insulin extraction (0.48 +/- 0.06, mean +/- SE) was normal in cirrhosis. The hepatic insulin elimination rate was directly related to arterial insulin levels (r = 0.91, P less than 0.001) even at very high circulating levels. Extrahepatic insulin metabolism was measured across the kidney and lower limb. There were no significant differences between cirrhotics and control subjects in relation to renal (0.25 +/- 0.05 vs. 0.23 +/- 0.04) and lower limb insulin extraction (0.14 +/- 0.07 vs. 0.19 +/- 0.04). While in the control group hepatic venous insulin (0.143 +/- 0.018 pmol/ml) markedly exceeded the peripheral insulin concentration (0.083 +/- 0.009 pmol/ml, P less than 0.01), the contrary was found in cirrhotics with end-to-side portacaval shunt in whom all the pancreatic venous effluent is shunted to the systemic circulation (hepatic venous insulin, 0.130 +/- 0.028 pmol/ml; peripheral, 0.234 +/- 0.037 pmol/ml; P less than 0.01). Portal-hypertensive cirrhotics without a surgical portacaval shunt also had hepatic venous insulin levels (0.132 +/- 0.029 pmol/ml) below peripheral arterial insulin concentrations (0.205 +/- 0.041 pmol/ml, P less than 0.01). The study suggests that hyperinsulinism in cirrhosis is not the result of an intrinsic defect of hepatic insulin metabolism but of the spontaneous shunting of portal blood to the systemic circulation.

Topics: C-Peptide; Humans; Hyperinsulinism; Hypertension, Portal; Insulin; Kidney; Liver; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Portal System; Portasystemic Shunt, Surgical

Insulin and C-peptide levels in peripheral blood in the fasting state and after an oral glucose load were measured in 65 nondiabetic, obese subjects and 65 age- and sex-matched nondiabetic normal weight subjects. Fasting insulin and C-peptide levels were significantly higher in obese than in nonobese subjects, whereas 1 and 2 h after the oral glucose load only insulin concentrations were significantly higher in the obese subjects. C-peptide to insulin molar ratios, as well as the relation between the incremental areas of the two peptides, were used as relative measures of hepatic insulin extraction. In the fasting state the ratios between C-peptide and insulin were similar in obese and nonobese subjects, whereas after glucose they were significantly lower in the obese individuals. Similarly, the relations between C-peptide and insulin incremental areas were significantly lower in obese than in nonobese subjects. The comparison of the corresponding plasma levels and areas of C-peptide and insulin after glucose showed that for the same C-peptide value, the insulin value was higher in the obese group. Last, in obese subjects the parameter used as an estimate of hepatic removal of insulin after oral glucose inversely correlated with the fasting insulin concentration and the insulin incremental area after glucose. These results suggest that in obesity peripheral hyperinsulinemia depends on pancreatic hypersecretion of insulin in the fasting state and impaired hepatic insulin metabolism after oral glucose loading.

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Liver; Male; Middle Aged; Obesity

Hypoglycemia when associated with hyperinsulinemia is usually a consequence of an insulinoma or the administration of either insulin or an insulin secretagogue. This report describes 14 patients with hypoglycemia whose diagnosis was clarified by the use of a species-specific insulin radioimmunoassay. Eleven of the 14 patients had elevated levels of animal insulin due to surreptitious accidental or malicious administration of insulin. Three of the 14 patients had hyperinsulinemia as the result of excessive human insulin release and were found to have either intrinsic pancreatic disease or secretagogue-mediated insulin release.

Topics: Adolescent; Adult; Aged; C-Peptide; Child; Diagnosis, Differential; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Male; Middle Aged; Radioimmunoassay

We describe two children with hypoglycaemia due to pancreatic beta cell hyperactivity. Both had low serum insulin but raised plasma C peptide concentrations when hypoglycaemic. Measurement of C peptide is valuable in the diagnosis of hyperinsulinaemic hypoglycaemia in children.

Topics: C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Insulin; Islets of Langerhans; Male

The hyperinsulinemia of obesity could result from a decrease in the metabolic clearance rate of insulin (MCR-I), an increase in the secretory rate of insulin (SR-I), or a combination of both these processes. Because C-peptide and insulin are secreted in an equimolar ratio, the plasma concentrations of C-peptide (C) and insulin (I) are inversely proportional to their rates of metabolic clearance (C/I = MCR-I/MCR-C). We obtained 24-h integrated concentrations (IC) of insulin (IC-I) and C-peptide (IC-C) in 23 obese and 45 nonobese subjects over a period of normal activity and food intake. The IC-I was 69% higher in the obese subjects (P less than 0.0001). A 13% increase in the IC-C (P = 0.04), with a constant rate of C-peptide clearance, indicates a proportionate increase in SR-I. A 33% decrease in the IC-C/IC-I in the obese group (P less than 0.005) reflects a decrease in MCR-I; hence, 75% of the hyperinsulinemia is due to a decrease in the clearance of insulin. Because peripheral MCR-I (pMCR-I) is similar in obese and nonobese subjects, the decrease in MCR-I may be due to a decrease in the hepatic clearance of insulin. This conclusion was supported by our comparison of 24-h IC-C/IC-I ratios in the obese and nonobese subjects. Whereas the 24-h IC-C/IC-I of the nonobese resembled the fasting state, the 24-h IC-C/IC-I of the obese resembled the postprandial state, when insulin removal by the liver is known to be suppressed. These data are consistent with a decreased 24-h hepatic MCR-I (hMCR-I) as the cause of the hyperinsulinemia of obesity.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Height; Body Weight; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Insulin; Male; Metabolic Clearance Rate; Middle Aged; Obesity

Glucose metabolism was investigated in four infants aged 3-32 months with persistent hypoglycemia and hyperinsulinism of neonatal onset. Fasting hypoglycemia was found to be due both to an insulin-induced decrease in hepatic glucose output to 3.95 +/- 0.30 (SEM) mg/kg X min, a value about two thirds of normal, and to a glucose utilization rate of 4.25 +/- 0.32 mg/kg X min, which exceeded glucose production by about 8%. Simultaneously, and despite hypoglycemia, fasting plasma D-beta-hydroxybutyric acid concentrations were inappropriately low: 406 +/- 146 microM, presumably the result of elevated circulating insulin levels. The infusion of sodium DL-beta-hydroxybutyrate resulted in an increase of plasma glucose (48 +/- 7 vs. 32 +/- 7 mg/dl, P less than 0.01) and lactate (1704 +/- 217 vs. 964 +/- 149 microM, P less than 0.005), without detectable changes in insulin secretion estimated from circulating C-peptide values. Unexpectedly, the increase of plasma glucose was due to the restoration of glucose production up to 6.7 +/- 0.2 mg/kg X min. The individual increments of plasma lactate and glucose production rate were linearly correlated (P less than 0.01). These results together with the known inhibitory effect of ketone bodies on pyruvate dehydrogenation, suggest both increased production of lactate from peripheral recycling of glucose carbon and an increased conversion of this gluconeogenic precursor into glucose.

Topics: 3-Hydroxybutyric Acid; Blood Glucose; C-Peptide; Fasting; Humans; Hydroxybutyrates; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Insulin; Male; Metabolic Clearance Rate

Patients with hepatic cirrhosis often have demonstrable glucose intolerance. We studied 21 patients with cirrhosis of the liver. Oral glucose tolerance tests (OGTT), intravenous arginine stimulation tests (IVAST), and intravenous insulin tolerance tests (IVITT) were performed, and timed blood samples were obtained for the assay of glucose immunoreactive insulin (IRI), C-peptide (C-P), and immunoreactive glucagon (IRG). The 125I-insulin binding to circulating monocytes was studied in some of the patients. All results were compared to those of similar studies performed on healthy controls. During OGTT significant glucose intolerance was demonstrable in the patients with cirrhosis (2 hr plasma glucose 198.8 +/- 14.3 mg/dl in cirrhosis and 116.4 +/- 4.2 in controls; p less than 0.001). Two-hour plasma IRI, C-P, and IRG were significantly higher in the cirrhotic patients than in controls (p less than 0.001; less than 0.001; less than 0.025). In response to IVAST, the patients with cirrhosis showed a greater first-phase insulin secretion and controls had a slightly better second-phase insulin release. Plasma IRG rose from a basal value of 446 pg/ml to 1100 in the patients with cirrhosis and from 171 pg/ml to 494 in controls. After intravenous insulin administration, there was only a 40% decline in plasma glucose concentration from basal values in the patients with cirrhosis whereas the controls showed a 60% decline, demonstrating that the patients with cirrhosis had significant insulin resistance. Moreover, the half-life of insulin was prolonged in the patients with cirrhosis (t 1/2 = 15.5 min in cirrhosis and 10.3 in controls; p less than 0.001); and the ratio of C-P to insulin during OGTT was also reduced, indicating that the patients with cirrhosis have reduced hepatic clearance of insulin. The specific binding of 125I-insulin to circulating monocytes was 2.7% in cirrhosis, 2% in obese controls, and 4% in lean controls. There was a significant negative correlation between the fasting plasma insulin values and the specific binding of insulin. In conclusion, patients with hepatic cirrhosis have significant glucose intolerance characterized by hyperinsulinemia, hyperglucagonemia, insulin resistance, and down-regulation of insulin receptors. Although hyperinsulinemia is probably caused by reduced hepatic clearance of insulin, hyperglucagonemia is primarily due to increased pancreatic secretion.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Glucagon; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Monocytes

The finding of hypoglycemia after the surgical removal of a pheochromocytoma in two patients in a previous study led to monitoring of the serum glucose and plasma C-peptide levels in two other patients with a pheochromocytoma and one with unilateral adrenocortical hyperplasia. In the two patients with a pheochromocytoma endogenous insulin secretion, as measured by a C-peptide assay, was suppressed before removal of the tumours and resumed immediately after removal. The serum glucose levels decreased in these patients, but sufficient intravenous administration of glucose prevented postoperative hypoglycemia. In the patient with adrenocortical hyperplasia the plasma C-peptide level was not decreased before tumour removal, nor did it increase abruptly following removal. It therefore seems likely that the rapid fall in the serum glucose level following removal of a pheochromocytoma is caused by prompt resumption of beta-cell activity, with rebound hyperinsulinism.

Topics: Adrenal Cortex Diseases; Adrenal Gland Neoplasms; Blood Glucose; C-Peptide; Female; Humans; Hyperinsulinism; Hyperplasia; Male; Middle Aged; Pheochromocytoma; Postoperative Complications

Two cases of hyperinsulinism from insulin self-administration are described, both patients being admitted to hospital with a diagnosis of insulinoma. In the first case, the diagnosis was clarified after a left pancreatectomy elsewhere, thanks to the discovery of a bottle of insulin. In the second case, the diagnosis was confirmed by the measurement of C-peptide during a hypoglycemic attack. The simultaneous sharp decrease in glucose levels, an exceptional increase in insulinaemia and a reduction or disappearance of serum C-peptide is indicative of this particular type of hyperinsulinism. The two cases described here were remarkably similar. Apart from the most common features, both reported a severe hypoglycemic syndrome of recent onset; negative tolbutamide and calcium tests; a frequent relapse shortly after glucose administration.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Munchausen Syndrome; Pancreatic Neoplasms; Recurrence; Self Administration

To differentiate peripheral and hepatic insulin resistance in hyperinsulinaemic overweight Type 2 (non-insulin-dependent) diabetic patients (n = 17; 143 +/- 4% ideal body weight; mean +/- SEM) arterial concentrations and splanchnic exchange of glucose, pyruvate, lactate, non-esterified fatty acids, beta-hydroxybutyrate and acetoacetate, as well as the insulin production rate, were determined before and during oral glucose loads of 25 g or 100 g. Insulin production rate, hepatic insulin retention and splanchnic exchange of glucose and metabolites were estimated by means of the hepatic venous catheter technique. In the basal state insulin production rate was greater in overweight Type 2 diabetic patients (2.57 +/- 0.28 pmol.kg-1. min-1) than in healthy control subjects (1.68 +/- 0.17 pmol.kg-1.min-1; p less than 0.01). After ingestion of 25 g glucose, the cumulative insulin production rate exceeded normal values (p less than 0.05), but was below normal with 100 g glucose (p less than 0.01). Relative insulin trapping by the splanchnic bed in the diabetic patients was 54 +/- 3%, not different from normal. Following a 100 g glucose load, splanchnic insulin retention fell by 20% in the patients, and less consistently so in healthy controls. Splanchnic glucose output was normal in the diabetic patients both in the basal state and after glucose ingestion although the induced arterial blood glucose levels were greater in the diabetic patients than in control subjects (p less than 0.005). Splanchnic output of pyruvate (p less than 0.025), lactate (p less than 0.01), and beta-hydroxybutyrate (p less than 0.005) were greater in the basal state in the diabetic patients than in healthy subjects. However, no difference in splanchnic exchange was seen between the two groups in their metabolites' respective response to glucose ingestion. These data suggest that obese hyperinsulinaemic Type 2 diabetic patients may represent a subgroup of diabetic patients with predominantly peripheral, but compensated hepatic, insulin resistance being associated with an increased basal insulin production rate which only exhausts after ingestion of a large glucose load.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Male; Middle Aged; Obesity; Splanchnic Circulation

Topics: Adult; C-Peptide; Carbohydrate Metabolism; Danazol; Endometriosis; Female; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Long-Term Care; Pregnadienes; Prospective Studies

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

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Female; Humans; Hyperinsulinism; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Humans; Hyperinsulinism; Insulin; Insulinoma; Male; Middle Aged; Peptides; Proinsulin

On the basis of results of simultaneous determinations of plasma free insulin and free c-peptide, episodes of hypoglycemia in an insulin-dependent diabetic were attributed to surreptitious self-administration of insulin. Immunoreactive c-peptide values were falsely increased and diagnostically misleading when measured in unextracted plasma. After preliminary removal of antigen/antibody complexes from the plasma by extraction with polyethylene glycol, the c-peptide values, referred to as "free c-peptide," were suppressed. We suggest that insulin antibodies formed complexes with proinsulin-like material in the plasma of this patient, which accounted for most of the c-peptide immunoreactivity in her unextracted plasma. These complexes must be removed if c-peptide measurements are to be accurate.

Topics: Adolescent; C-Peptide; Diabetes Complications; Diabetes Mellitus; Female; Humans; Hyperinsulinism; Insulin; Peptides; Radioimmunoassay; Self Medication

Topics: Adolescent; C-Peptide; Carbohydrate Metabolism; Child; Child, Preschool; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Obesity; Peptides

In 64 patients suffering from chronic inflammatory liver disease (alcoholic hepatitis, chronic active hepatitis, chronic persistent hepatitis) significantly increased values of blood glucose and insulin, free fatty acids and C-peptide were observed during a 100 g oral glucose load. Fasting values of blood glucose, free fatty acids and C-peptide were also increased, while serum growth hormone remained unchanged. In patients with chronic active hepatitis the C-peptide/insulin-ratio, a measure for hepatic insulin degradation, was significantly lowered after glucose uptake. During oral load there were no discernible differences between the different types of chronic inflammatory liver disease concerning blood glucose, serum insulin and free fatty acids. In normal weight and in overweight patients suffering from liver disease blood glucose and serum insulin values were increased to the same extent. As it is known from the liver cirrhosis chronic inflammatory liver disease lead to an insulin resistance, to which elevated free fatty acid levels contribute. Increased body weight has no influence on the insulin resistance observed in chronic liver inflammation. From the changes of the C-peptide and the C-peptide/insulin-ratio it can be deduced, that the hyperinsulinism in patients with chronic inflammatory liver disease is due to both insulin hypersecretion and diminished hepatic insulin degradation.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Chronic Disease; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Hepatitis; Humans; Hyperinsulinism; Male; Middle Aged

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

Cirrhosis is complicated by numerous abnormalities of carbohydrate metabolism although these are seldom of clinical importance. Carbohydrate intolerance is extremely common and is accompanied by hyperinsulinaemia, hyperglucagonaemia and elevated levels of gluconeogenic precursors. The hyperinsulinaemia results from impaired hepatic degradation of insulin while recent evidence suggests that pancreatic hypersecretion is responsible for the elevated levels of glucagon in cirrhosis. The role of hepatocellular damage and portal-systemic shunting in the pathogenesis of these abnormalities is controversial but the derangements in carbohydrate metabolism probably reflect hepatocellular damage rather than portal-systemic shunting.

Topics: C-Peptide; Carbohydrate Metabolism; Glucagon; Gluconeogenesis; Glucose; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis; Pancreas

Basal and reactive peripheral hyperinsulinism recorded in alcoholic hepatic disease may result from decreased hepatic breakdown or pancreatic hypersecretion. C-peptide (CPR) and insulin (IRI) concentrations were measured in 3 groups of 8 alcoholic patients--steatosis, compensated and decompensated cirrhosis--and compared with 8 normal subjects in order to determine the importance of these two possibilities. At basal state, the molar ratio CPR/IRI was near the normal (8.7 +/- 0.9) but is diminished in the 8 hyperinsulinaemic patients (5.9 +/- 0.6). After i.v. glucose tolerance test and tolbutamide stimulations, an hyperreactivity of IRI and CPR may be noted in cirrhotics. A relative insensitivity of the B-cell to glucose appeared after comparison with the effect of tolbutamide. Thus basal hyperinsulinism resulted of decreased hepatic breakdown and stimulated hyperinsulinism resulted of hypersecretion. Glucose intolerance and anomalies of the insulin secretion were more apparent with severe hepatic disease.

Topics: Adolescent; Adult; C-Peptide; Fatty Liver, Alcoholic; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Peptides; Tolbutamide

The breakdown of proinsulin in the pancreatic beta cell yields insulin and C-peptide which are secreted in equimolar amounts. Unlike insulin, C-peptide is not degraded significantly by the liver, so that its measurement should give a better assessment of insulin secretion than estimation of peripheral insulin levels alone; particularly in the presence of hepatic dysfunction. Plasma C-peptide and insulin response to an oral glucose load have therefore been assessed in 14 cirrhotic and 7 normal subjects. Cirrhotic patients were divided into hyperinsulinaemic and normoinsulinaemic groups based on fasting plasma-insulin concentrations. Fasting blood-blucose and plasma-C-peptide concentrations were the same in normal and cirrhotic subjects, suggesting that basal pancreatic insulin secretion was the same in all subjects. Thus the C-peptide/insulin ratio was significantly decreased in hyperinsulinaemic subjects (2-13 +/- 0-31, compared with 4-63 +/- 0-48 in controls). After oral glucose, the two groups of cirrhotic patients showed the same glucose intolerance. C-peptide concentrations were also the same but insulin concentrations were markedly increased in the hyperinsulinaemic group. It is suggested that pancreatic insulin secretion is not increased in cirrhosis and that the peripheral hyperinsulinism is due solely to decreased hepatic insulin degradation secondary to either spontaneous portal-systemic shunting or to parenchymal damage.

Topics: Administration, Oral; Adult; Aged; Biodegradation, Environmental; Blood Glucose; C-Peptide; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Liver; Liver Cirrhosis; Male; Middle Aged