c-peptide and Body-Weight

Despite advances in the characterization of partial clinical remission (PR) of type 1 diabetes, an accurate definition of PR remains problematic. Two recent studies in children with new-onset T1D demonstrated serious limitations of the present gold standard definition of PR, a stimulated C-peptide (SCP) concentration of >300 pmol/L. The first study employed the concept of insulin sensitivity score (ISS) to show that 55% of subjects with new-onset T1D and a detectable SCP level of >300 pmol/L had low insulin sensitivity (IS) and thus might not be in remission when assessed by insulin-dose adjusted A1c (IDAA1c), an acceptable clinical marker of PR. The second study, a randomized controlled trial of vitamin D (ergocalciferol) administration in children and adolescents with new-onset T1D, demonstrated no significant difference in SCP between the ergocalciferol and placebo groups, but showed a significant blunting of the temporal trend in both A1c and IDAA1c in the ergocalciferol group. These two recent studies indicate the poor specificity and sensitivity of SCP to adequately characterize PR and thus call for a re-examination of current approaches to the definition of PR. They demonstrate the limited sensitivity of SCP, a static biochemical test, to detect the complex physiological changes that occur during PR such as changes in insulin sensitivity, insulin requirements, body weight, and physical activity. These shortcomings call for a broader definition of PR using a combination of functional markers such as IDAA1c and ISS to provide a valid assessment of PR that reaches beyond the static changes in SCP alone.

Topics: Adolescent; Biomarkers; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Ergocalciferols; Exercise; Glycated Hemoglobin; Health Status Indicators; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Randomized Controlled Trials as Topic; Remission Induction

Despite improvements in the pharmacodynamics of injectable insulin and better insulin delivery systems, glucose control remains suboptimal in the majority of individuals with Type 1 diabetes. Profound defects in the physiological processes that normally maintain glucose homeostasis contribute to the difficulty in achieving glycaemic targets. Non-insulin-based adjunct treatments offer a potential means of complementing intensive insulin therapy in Type 1 diabetes through addressing some of the physiological disturbances that result from endogenous β-cell destruction, particularly through preservation of β-cell mass and prevention of apoptosis, and suppression of α-cell glucagon release in the postprandial state. The former approach applies most readily to newly diagnosed C-peptide-positive Type 1 diabetes, while the latter to established C-peptide-negative Type 1 diabetes. This review focuses primarily on the clinical trial data available on the use of non-insulin-based therapies in longer-duration Type 1 diabetes. We conclude that metformin may prove useful in macrovascular disease reduction, while pramlintide, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors and leptin co-therapies may reduce HbA(1c) , glucose variability, postprandial glucose excursions and body weight. These early studies are encouraging and offer novel and potentially very effective approaches to the treatment of Type 1 diabetes, but the evidence is largely restricted to small, often uncontrolled trials. As such, these therapies cannot be currently recommended for routine clinical practice. There is a clear need to support large, multi-centre randomized controlled trials designed to establish whether adjunct insulin therapy has a place in the modern management of Type 1 diabetes.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Male; Metformin; Randomized Controlled Trials as Topic

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

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

The effects were investigated of weight loss on the relationship between hyperinsulinemia, body weight and body fat distribution in two groups of women with central-type obesity (CTO) (waist-to-hip ratio WHR greater than 0.85) or peripheral-type obesity (PTO) (WHR less than 0.85). An oral glucose tolerance test was carried out before and after a hypocaloric nutritional treatment lasting 4 months. Both groups were matched for age, body mass index and amount of body fat. At the basal condition, group CTO had fasting and glucose-stimulated insulin levels significantly higher than group PTO; fasting (but not stimulated) C peptide levels were also higher in CTO compared with PTO. Weight and fat loss were significantly higher in CTO than in PTO women. Moreover, unlike PTO, CTO subjects significantly reduced their WHR values. In both groups weight loss led to a significant drop in fasting and glucose-stimulated insulin and C peptide levels. However, PTO women reduced their C peptide levels significantly less than CTO. In conclusion, weight loss only modified body fat distribution in women with CTO, who appeared to be prone to a greater weight loss than the PTO women. Compared to PTO, CTO women were characterized by higher insulin levels and peripheral insulin resistance, which improved during hypocaloric feeding probably due to the combined effect of weight loss and the change in body fat distribution.

Topics: Adipose Tissue; Adult; Body Weight; C-Peptide; Energy Intake; Female; Humans; Insulin; Insulin Secretion; Obesity; Weight Loss

Excess body weight and insulin resistance lead to type 2 diabetes and other major health problems. There is an urgent need for dietary interventions to address these conditions.. To measure the effects of a low-fat vegan diet on body weight, insulin resistance, postprandial metabolism, and intramyocellular and hepatocellular lipid levels in overweight adults.. This 16-week randomized clinical trial was conducted between January 2017 and February 2019 in Washington, DC. Of 3115 people who responded to flyers in medical offices and newspaper and radio advertisements, 244 met the participation criteria (age 25 to 75 years; body mass index of 28 to 40) after having been screened by telephone.. Participants were randomized in a 1:1 ratio. The intervention group (n = 122) was asked to follow a low-fat vegan diet and the control group (n = 122) to make no diet changes for 16 weeks.. At weeks 0 and 16, body weight was assessed using a calibrated scale. Body composition and visceral fat were measured by dual x-ray absorptiometry. Insulin resistance was assessed with the homeostasis model assessment index and the predicted insulin sensitivity index (PREDIM). Thermic effect of food was measured by indirect calorimetry over 3 hours after a standard liquid breakfast (720 kcal). In a subset of participants (n = 44), hepatocellular and intramyocellular lipids were quantified by proton magnetic resonance spectroscopy. Repeated measure analysis of variance was used for statistical analysis.. Among the 244 participants in the study, 211 (87%) were female, 117 (48%) were White, and the mean (SD) age was 54.4 (11.6) years. Over the 16 weeks, body weight decreased in the intervention group by 5.9 kg (95% CI, 5.0-6.7 kg; P < .001). Thermic effect of food increased in the intervention group by 14.1% (95% CI, 6.5-20.4; P < .001). The homeostasis model assessment index decreased (-1.3; 95% CI, -2.2 to -0.3; P < .001) and PREDIM increased (0.9; 95% CI, 0.5-1.2; P < .001) in the intervention group. Hepatocellular lipid levels decreased in the intervention group by 34.4%, from a mean (SD) of 3.2% (2.9%) to 2.4% (2.2%) (P = .002), and intramyocellular lipid levels decreased by 10.4%, from a mean (SD) of 1.6 (1.1) to 1.5 (1.0) (P = .03). None of these variables changed significantly in the control group over the 16 weeks. The change in PREDIM correlated negatively with the change in body weight (r = -0.43; P < .001). Changes in hepatocellular and intramyocellular lipid levels correlated with changes in insulin resistance (both r = 0.51; P = .01).. A low-fat plant-based dietary intervention reduces body weight by reducing energy intake and increasing postprandial metabolism. The changes are associated with reductions in hepatocellular and intramyocellular fat and increased insulin sensitivity.. ClinicalTrials.gov Identifier: NCT02939638.

Topics: Absorptiometry, Photon; Adult; Aged; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet, Fat-Restricted; Diet, Vegan; Energy Intake; Energy Metabolism; Female; Glycated Hemoglobin; Hepatocytes; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Middle Aged; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Overweight; Postprandial Period; Proton Magnetic Resonance Spectroscopy; Triglycerides

Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period.. One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels.. From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide.. The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Weight; C-Peptide; Clozapine; Denmark; Fasting; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipid Metabolism; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Overweight; Placebos; Prediabetic State; Schizophrenia; Young Adult

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

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

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

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

The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads.. The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water.. Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects.. It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance.. ClinicalTrials.gov NCT01875575.

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Double-Blind Method; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Young Adult

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

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

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

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

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

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

To examine associations of baseline insulin dynamics with changes in body composition and resting energy expenditure (REE) following weight loss.. Twenty-one participants with overweight or obesity achieved 10-15% weight loss and then received 3 weight loss maintenance diets (high-carbohydrate, moderate-carbohydrate, and low-carbohydrate) in random order, each for 4 weeks. Body composition was measured at baseline and after weight loss. Insulin 30 min after glucose consumption (insulin-30; insulin response), C-peptide deconvolution analysis, HOMA, hepatic insulin sensitivity (IS), and REE were assessed at baseline and after each maintenance diet.. Insulin-30, but not maximal insulin secretion, hepatic IS, or HOMA, predicted changes in fat mass (standardized β = 0.385, 1.7 kg difference between 10th and 90th centile of insulin-30, P = 0.04) after weight loss. Insulin-30 (β = -0.341, -312 kcal day(-1) , P = 0.008), maximal insulin secretion (β = -0.216, -95 kcal day(-1) , P = 0.0002), HOMA (β = -0.394, -350 kcal day(-1) , P = 0.002), and hepatic IS (β = 0.217, 225 kcal day(-1) , P = 0.0003) predicted change in REE during weight loss maintenance, independent of changes in body composition. The inverse relationship between insulin-30 and REE was substantially attenuated when the low-carbohydrate diet was consumed first.. These findings distinguish a novel phenotype, characterized by high insulin response, at risk for weight regain, and identify a dietary approach to ameliorate this risk.

Topics: Adult; Body Composition; Body Weight; C-Peptide; Diet, Carbohydrate-Restricted; Diet, Reducing; Energy Metabolism; Female; Humans; Insulin; Insulin Resistance; Male; Obesity; Overweight; Rest; Weight Loss; Young Adult

Adaptive thermogenesis (AT) is the fat-free mass (FFM)-independent reduction of resting energy expenditure (REE) to caloric restriction (CR). AT attenuates weight loss and favors weight regain. Its variance, dynamics, and control remain obscure.. Our aims were to address the variance and kinetics of AT, its associations with body composition in the context of endocrine determinants, and its effect on weight regain.. Thirty-two nonobese men underwent sequential overfeeding (1 wk at +50% of energy needs), CR (3 wk at -50% of energy needs), and refeeding (2 wk at +50% of energy needs). AT and its determinants were measured together with body composition as assessed with the use of quantitative magnetic resonance, whole-body MRI, isotope dilution, and nitrogen and fluid balances.. Changes in body weight were +1.8 kg (overfeeding), -6.0 kg (CR), and +3.5 kg (refeeding). CR reduced fat mass and FFM by 114 and 159 g/d, respectively. Within FFM, skeletal muscle (-5%), liver (-13%), and kidneys (-8%) decreased. CR also led to reductions in REE (-266 kcal/d), respiratory quotient (-15%), heart rate (-14%), blood pressure (-7%), creatinine clearance (-12%), energy cost of walking (-22%), activity of the sympathetic nervous system (SNS) (-38%), and plasma leptin (-44%), insulin (-54%), adiponectin (-49%), 3,5,3'-tri-iodo-thyronine (T3) (-39%), and testosterone (-11%). AT was 108 kcal/d or 48% of the decrease in REE. Changes in FFM composition explained 36 kcal, which left 72 kcal/d for true AT. The decrease in AT became significant at ≤3 d of CR and was related to decreases in insulin secretion (r = 0.92, P < 0.001), heart rate (r = 0.60, P < 0.05), creatinine clearance (r = 0.79, P < 0.05), negative fluid balance (r = 0.51, P < 0.01), and the free water clearance rate (r = -0.90, P < 0.002). SNS activity and plasma leptin, ghrelin, and T3 and their changes with CR were not related to AT.. During early weight loss, AT is associated with a fall in insulin secretion and body fluid balance. This trial was registered at clinicaltrials.gov as NCT01737034.

Topics: Adaptation, Physiological; Adiponectin; Adult; Basal Metabolism; Body Composition; Body Mass Index; Body Weight; C-Peptide; Caloric Restriction; Creatinine; Energy Metabolism; Ghrelin; Heart Rate; Humans; Insulin; Insulin Secretion; Leptin; Male; Minnesota; Starvation; Testosterone; Thermogenesis; Triiodothyronine; Young Adult

Whey protein (WP), when consumed in small amounts prior to a meal, improves post-meal glycemic control more than can be explained by insulin-dependent mechanisms alone. The objective of the study was to identify the mechanism of action of WP beyond insulin on the reduction of post-meal glycemia. In a randomized crossover study, healthy young men received preloads (300 ml) of WP (10 and 20 g), glucose (10 and 20 g) or water (control). Paracetamol (1.5 g) was added to the preloads to measure gastric emptying. Plasma concentrations of paracetamol, glucose, and β-cell and gastrointestinal hormones were measured before preloads (baseline) and at intervals before (0-30 min) and after (50-230 min) a preset pizza meal (12 kcal/kg). Whey protein slowed pre-meal gastric emptying rate compared to the control and 10 g glucose (P<.0001), and induced lower pre-meal insulin and C-peptide than the glucose preloads (P<.0001). Glucose, but not WP, increased pre-meal plasma glucose concentrations (P<.0001). Both WP and glucose reduced post-meal glycemia (P=.0006) and resulted in similar CCK, amylin, ghrelin and GIP responses (P<.05). However, compared with glucose, WP resulted in higher post-meal GLP-1 and peptide tyrosine-tyrosine (PYY) and lower insulin concentrations, without altering insulin secretion and extraction rates. For the total duration of this study (0-230 min), WP resulted in lower mean plasma glucose, insulin and C-peptide, but higher GLP-1 and PYY concentrations than the glucose preloads. In conclusion, pre-meal consumption of WP lowers post-meal glycemia by both insulin-dependent and insulin-independent mechanisms.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cholecystokinin; Cross-Over Studies; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Islet Amyloid Polypeptide; Male; Milk Proteins; Peptide YY; Whey Proteins; Young Adult

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

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

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

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

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

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

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

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

This participant-blinded parallel-group randomized placebo-controlled study demonstrated that alfacalcidol (vitamin D analogue) preserves beta cell function in newly diagnosed type 1 diabetes (T1DM) in children.. Subjects from outpatient clinic were randomized to intervention and control groups. Inclusion: (1) age 8-15, (2) T1DM, (3) duration <8 weeks, (4) no chronic diseases, (5) stable diet. Exclusion: (1) vitamin D, calcium supplements or fortified foods, (2) hypercalcemia. Intervention group received alfacalcidol 0.25 μg twice daily, while control group received placebo. Insulin given physician-titrated to blood glucose. Safety monitored by serum calcium and phosphate. Beta cell function assessed at 0, 3, 6 months using fasting C-peptide (FCP) and daily insulin dosage per body weight (DID). Primary outcome measured using multivariate repeated measures GLM-ANOVA, with FCP and DID as primary measures and age, gender, sunlight exposure, 25-hydroxy vitamin D, and HbA1c as covariates.. Of 61 subjects, 7 dropped out. GLM-ANOVA showed that groups were different (p=0.019, Eta-squared=0.087), with no significant covariates. FCP was higher and DID lower in the intervention group, with males having stronger responses to alfacalcidol (p=0.001). No adverse effects were observed.. The study confirmed that alfacalcidol can safely preserve beta cell function in newly diagnosed T1DM in children, with a stronger effect in males.. IRCT201205159753N1.

Topics: Adolescent; Blood Glucose; Body Weight; C-Peptide; Calcium, Dietary; Child; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hydroxycholecalciferols; Hypercalcemia; Insulin; Insulin-Secreting Cells; Linear Models; Male; Multivariate Analysis; Single-Blind Method

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

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

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

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

The intake of wholemeal foods is consistently associated with reduced risk of type 2 diabetes and cardiovascular diseases in epidemiological studies, although the mechanisms of this association are unclear. Here we aim to compare in healthy subjects the metabolic effects of a diet rich in wholemeal wheat foods versus one based on the same products in refined form.. Fifteen healthy individuals (12 M/3 F), mean age 54.5+/-7.6 years, BMI 27.4+/-3.0 kg/m(2) (mean+/-SD), participated in a randomized sequential crossover study. After 2 weeks run-in, participants were randomly assigned to two isoenergetic diets with similar macronutrient composition, one rich in wholemeal wheat foods and the other with the same foods but in refined form (cereal fibre 23.1 vs. 9.8 g/day). After the two treatment periods (each lasting 3 weeks) plasma glucose and lipid metabolism, antioxidant activity, acetic acid, magnesium, adipokines, incretins and high-sensitivity C-reactive protein (hs-CRP) were measured at fasting and for 4h after a standard test meal (kcal 1103, protein 12%, CHO 53%, fat 35%) based on wholemeal or refined wheat foods, respectively. After the two diets there were no differences in fasting nor in postprandial plasma parameter responses; only glucose was slightly but significantly lower at 240 min after the refined wheat food meal compared to the wholemeal wheat food meal. Conversely, after the wholemeal diet both total (-4.3%; p<0.03) and LDL (-4.9%; p<0.04) cholesterol levels were lower than after the refined wheat diet at fasting.. Consumption of wholemeal wheat foods for 3 weeks reduces significantly fasting plasma cholesterol as well as LDL cholesterol levels in healthy individuals without major effects on glucose and insulin metabolism, antioxidant status and sub-clinical inflammation markers.

Topics: Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Diet; Fasting; Female; Food Handling; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors; Triticum

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by (31)P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.

Topics: Adipokines; Administration, Oral; Adult; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cross-Over Studies; Dietary Fats; Gastric Inhibitory Polypeptide; Gene Expression; Glucose; Glucose Clamp Technique; Glycolysis; Heat-Shock Proteins; Humans; Insulin; Insulin Resistance; Lipids; Liver; Male; Muscle, Skeletal; Oxidative Phosphorylation; Pancreatic Polypeptide; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphates; Phosphocreatine; Transcription Factors

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

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

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

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

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

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

The present study was to investigate the sex difference in effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.. One hundred twelve patients with schizophrenia were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index, waist-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol and triglyceride levels. All measures were collected at baseline and at the end of the 8-week treatment.. After treatment, waist-hip ratio and triglyceride and IRI levels of men were increased higher than that of women in clozapine and olanzapine groups. In sulpiride group, body mass index and triglyceride, insulin, and IRI levels of women increased higher than those of men. There was no significant sex difference for all assessments in risperidone group. Insulin, C-peptide, and IRI, but not fasting glucose levels, were significantly increased in the 4 groups. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride.. These results suggest that clozapine, olanzapine, and sulpiride had effects on glucose and lipid metabolism in first-episode schizophrenia with sex difference. Clozapine and olanzapine seem to have the greatest potential to induce glucose and lipid metabolism abnormalities, and risperidone has the least.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Female; Homeostasis; Humans; Insulin; Lipid Metabolism; Longitudinal Studies; Male; Prospective Studies; Schizophrenia; Sex Characteristics; Triglycerides

Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation due to fear of adiposity. Ghrelin, gastric peptide with potent orexigenic, adipogenic, GH-releasing and metabolic properties, is elevated in AN. We have previously shown that intervention with exogenous ghrelin is not effective in terms of inducing neuroendocrine and appetite responses in AN. In this arm of the same study protocol we investigated glucose metabolism responses to 5 h i.v. infusion of active ghrelin in a) 9 severely malnourished AN patients, b) 6 AN patients who partially recovered body weight (PRAN), c) 10 constitutionally thin female subjects with regular menstrual cycles. At baseline, no significant differences were observed in blood glucose, insulin, c-peptide, adiponectin, and homeostasis model assessment index values, between the studied groups. During ghrelin infusions, blood glucose levels significantly increased in all groups although significantly less in low-weight AN; insulin levels were not significantly affected, while c-peptide levels were significantly suppressed only in the constitutionally thin and PRAN subjects. In addition to our previous findings of impaired neuroendocrine and appetite responses in patients with AN, we conclude that metabolic responses to ghrelin are attenuated in these patients, which tend to recover with weight gain.

Topics: Adult; Anorexia Nervosa; Blood Glucose; Body Weight; C-Peptide; Eating; Female; Ghrelin; Humans; Infusions, Intravenous; Insulin; Thinness

Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulin-like growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased (P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period.

Topics: Adolescent; Anticonvulsants; Blood Glucose; Body Height; Body Mass Index; Body Weight; C-Peptide; Child; Child, Preschool; Epilepsy; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Puberty; Valproic Acid; Weight Gain

Increased intake of dietary fiber reduces the risk of obesity and type 2 diabetes. We assessed the effects of a fiber-rich diet on body weight, adipokine concentrations, and the metabolism of glucose and lipids in non-obese and obese subjects in Korea, where rice is the main source of dietary carbohydrates.. Eleven healthy, non-obese and 10 obese subjects completed two 4-week phases of individual isoenergetic food intake. During the control diet phase, subjects consumed standard rice; during the modified diet phase, subjects consumed equal proportions of fiber-rich Goami No. 2 rice and standard rice. We used a randomized, controlled, crossover study design with a washout period of 6 weeks between the two phases.. After the modified diet phase, body weight was significantly lower in both the non-obese and obese subjects (non-obese, 57.0 +/- 2.9 vs. 56.1 +/- 2.8 kg, p = 0.001; obese, 67.7 +/- 2.1 vs. 65.7 +/- 2.0 kg, p < 0.001 for before vs. after). The BMI was significantly lower in obese subjects (26.9 +/- 0.5 vs. 26.0 +/- 0.6 kg/m2, p < 0.001). The modified diet was associated with lower serum triacylglycerol (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.05), and C-peptide (p < 0.05) concentrations in the obese subjects.. These results indicate that fiber-rich Goami No. 2 rice has beneficial effects and may be therapeutically useful for obese subjects.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Cross-Over Studies; Dietary Carbohydrates; Dietary Fiber; Female; Glycated Hemoglobin; Humans; Leptin; Lipid Metabolism; Male; Obesity; Oryza; Resistin; Triglycerides

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

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

Despite the demonstrated benefits of glycemic control, patient acceptance of basal/bolus insulin therapy for type 1 diabetes has been slow. We investigated whether a basal/bolus insulin regimen involving rapid-acting, dry powder, inhaled insulin could provide glycemic control comparable with a basal/bolus subcutaneous regimen.. Patients with type 1 diabetes (ages 12-65 years) received twice-daily subcutaneous NPH insulin and were randomized to premeal inhaled insulin (n = 163) or subcutaneous regular insulin (n = 165) for 6 months.. Mean glycosylated hemoglobin (A1C) decreased comparably from baseline in the inhaled and subcutaneous insulin groups (-0.3 and -0.1%, respectively; adjusted difference -0.16% [CI -0.34 to 0.01]), with a similar percentage of subjects achieving A1C <7%. Although 2-h postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group (adjusted difference -39.5 mg/dl [CI -57.5 to -21.6]). Inhaled insulin was associated with a lower overall hypoglycemia rate but higher severe hypoglycemia rate. The overall hypoglycemia rate (episodes/patient-month) was 9.3 (inhaled) vs. 9.9 (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91-0.97]), and the severe hypoglycemia rate (episodes/100 patient-months) was 6.5 vs. 3.3 (RR 2.00 [CI 1.28-3.12]). Increased insulin antibody serum binding without associated clinical manifestations occurred in the inhaled insulin group. Pulmonary function between the groups was comparable, except for a decline in carbon monoxide-diffusing capacity in the inhaled insulin group without any clinical correlates.. Inhaled insulin may provide an alternative for the management of type 1 diabetes as part of a basal/bolus strategy in patients who are unwilling or unable to use preprandial insulin injections.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Male; Middle Aged; Respiratory Function Tests

Studies have demonstrated that proinsulin C-peptide stimulates the activities of Na(+),K(+)-ATPase and endothelial nitric oxide synthase, both of which are enzyme systems of importance for nerve function and known to be deficient in type 1 diabetes. The aim of this randomized double-blind placebo-controlled study was to investigate whether C-peptide replacement improves nerve function in patients with type 1 diabetes. Forty-nine patients without symptoms of peripheral neuropathy were randomized to either 3 months of treatment with C-peptide (600 nmol/24 h, four doses s.c.) or placebo. Forty-six patients (15 women and 31 men, aged 29 years, diabetes duration 10 years, and HbA(1c) 7.0%) completed the study. Neurological and neurophysiological measurements were performed before and after 6 and 12 weeks of treatment. At baseline the patients showed reduced nerve conduction velocities in the sural nerve (sensory nerve conduction velocity [SCV]: 50.9 +/- 0.70 vs. 54.2 +/- 1.2 m/s, P < 0.05) and peroneal nerve (motor nerve conduction velocity: 45.7 +/- 0.55 vs. 53.5 +/- 1.1 m/s, P < 0.001) compared with age-, height-, and sex-matched control subjects. In the C-peptide treated group there was a significant improvement in SCV amounting to 2.7 +/- 0.85 m/s (P < 0.05 compared with placebo) after 3 months of treatment, representing 80% correction of the initial reduction in SCV. The change in SCV was accompanied by an improvement in vibration perception in the patients receiving C-peptide (P < 0.05 compared with placebo), whereas no significant change was detectable in cold or heat perception. In conclusion, C-peptide administered for 3 months as replacement therapy to patients with early signs of diabetic neuropathy ameliorates nerve dysfunction.

Topics: Adult; Age of Onset; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Insulin; Male; Neural Conduction; Neurologic Examination; Patient Selection; Peripheral Nervous System Diseases; Placebos; Time Factors

In this open-label, randomized study we compared the influence of a new oral contraceptive containing 30 microg ethinylestradiol and 3 mg drospirenone (Yasmin) with a reference preparation containing 30 microg ethinylestradiol and 150 microg desogestrel (Marvelon) on variables of carbohydrate metabolism by means of oral glucose tolerance tests at baseline and in the 6th and 13th treatment cycle. The mean levels of fasting glucose and insulin were similar at baseline and after 13 treatment cycles, whereas C-peptide and free fatty acid levels decreased slightly in both groups. All blood glucose and insulin values measured in the oral glucose tolerance tests were within normal ranges, despite a slight increase in the mean areas under the curves of 0-3 h [AUCs (0-3 h)] of both variables from baseline to treatment cycle 13. Differences between both treatments were not statistically significant. The mean AUCs (0-3 h) for C-peptide were not markedly changed in any treatment group. Free fatty acid levels decreased by 42% in the drospirenone group and increased by 48.9% in the desogestrel group, in terms of means of individual changes. Both preparations were well tolerated and equally efficacious regarding contraception and cycle control. The mean body weight was slightly decreased in most cycles during treatment with the drospirenone combination, as compared to baseline, while it was slightly increased versus baseline in all cycles during treatment with the desogestrel combination. The combination with drospirenone had less impact on blood pressure than the combination with desogestrel. In conclusion, Yasmin, a combined low-dose oral contraceptive with 30 microg ethinylestradiol and 3 mg of the novel progestogen drospirenone, as well as the reference Marvelon, containing 30 microg ethinylestradiol and 150 microg desogestrel had little impact on carbohydrate metabolism when used for 1 year. The observed changes were small and not suggestive of a clinically relevant deterioration of carbohydrate metabolism.

Topics: Adolescent; Adult; Androstenes; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Carbohydrate Metabolism; Contraceptives, Oral, Combined; Desogestrel; Ethinyl Estradiol; Fasting; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Insulin; Kinetics

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

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

Oral contraceptives slightly deteriorate insulin sensitivity. The present study investigated whether they may further unbalance the glucose metabolism of lean women with polycystic ovary syndrome (PCOS). Women with PCOS were assigned to receive for 6 months the biphasic association of 40/30 micro g ethinyl estradiol (EE) and 25/125 micro g desogestrel (DSG; n = 10) or the monophasic association of 35 micro g EE and 2 mg cyproterone acetate (CPA; n = 10). Glucose tolerance was investigated by an oral glucose tolerance test (OGTT). Glucose utilization dependent [insulin sensitivity (SI)] or independent (Sg) of insulin was investigated by the minimal model method applied to a frequently sampled iv glucose tolerance test. EE/DSG increased the response of C peptide to OGTT (1413 +/- 113 vs. 2053 +/- 213 area under the curve; P < 0.009) and the C peptide/insulin ratio (0.085 +/- 0.01 vs. 0.134 +/- 0.01 area under the curve; P < 0.003). It also increased the Sg (0.026 +/- 0.002 vs. 0.034 +/- 0.003; P < 0.04) and decreased the SI (2.40 +/- 0.26 vs. 1.68 +/- 0.27; P < 0.01). EE/CPA did not modify responses to OGTT of glucose, insulin, C peptide, or C peptide/insulin ratio. It did not modify Sg and significantly increased SI (1.47 +/- 0.38 vs. 3.27 +/- 0.48; P < 0.04). The present study indicates that EE/CPA improves SI, whereas EE/DSG impairs SI, but improves insulin clearance. The long-term metabolic effects of these two compounds on women with PCOS require further investigations.

Topics: Adult; Anthropometry; Blood Glucose; Body Weight; C-Peptide; Contraceptives, Oral, Hormonal; Cyproterone Acetate; Desogestrel; Ethinyl Estradiol; Female; Glucose; Glucose Tolerance Test; Hormones; Humans; Insulin; Insulin Resistance; Polycystic Ovary Syndrome

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

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

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

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

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

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

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

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

A weight-reducing effect of metformin has been demonstrated in obese subjects with and without diabetes. The mechanisms of this action are unclear, which may be partly due to the fact that in obese and diabetic patients the substance's effects result from a complex interaction with the distinct endocrine and metabolic disturbances in these patients. To dissociate primary from secondary action of metformin, we examined effects of the substance in normal-weight healthy subjects. Fifteen normal-weight men were treated with metformin (850 mg twice daily) or placebo for a 15-day period in a double-blind, placebo-controlled, cross-over study. Anthropometric, psychologic, cardiovascular, endocrine, and metabolic parameters were assessed before and at the end of the treatment period. Metformin did not affect body weight (P =.838) and body fat mass (P =.916). Yet, serum leptin concentration was distinctly reduced after metformin (P <.001). Also, metformin reduced the concentration of plasma glucose (P =.011), serum insulin (P=.044), and serum insulin-like growth factor -1 (IGF-1) (P=.013), while it increased serum glucagon concentration (P <.001). There were no effects of metformin on feelings of hunger, blood pressure, heart rate, resting energy expenditure, the respiratory quotient, free fatty acids, beta-hydroxybutyrate, glycerol, triglycerides, cholesterol, and uric acid (all P >.1). Data indicate that metformin decreases the serum leptin concentration even without affecting body weight and body composition in normal-weight men.

Topics: Adipose Tissue; Adult; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus; Glucagon; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Metformin; Obesity; Reference Values

To examine the effects of improved glycaemic control over 20 weeks on the type and distribution of weight change in patients with type 2 diabetes who at baseline have poor glycaemic control.. Forty-three patients with type 2 diabetes and HbA1c > 8.9% were randomised to either intensive glycaemic control (IC) n = 21 or usual glycaemic control (UC) n = 22 for 20 weeks. Dual energy X-ray absorptiometry was used to assess the type and distribution of weight change during the study.. After 20 weeks HbA1c was significantly lower in patients randomised to IC than UC (HbA1c IC 8.02 +/- 0.25% vs. UC 10.23 +/- 0.23%, p < 0.0001). In the IC group weight increased by 3.2 +/- 0.8 kg after 20 weeks (fat-free mass increased by 1.8 +/- 0.3 kg) compared to 0.02 +/- 0.70 kg in UC (p = 0.003). The gain in total body fat mass comprised trunk fat mass (IC 0.94 +/- 0.5 kg vs. UC 0.04 +/- 0.4 kg, p = 0.18) and peripheral fat mass (total body fat - trunk fat) (IC 0.71 +/- 0.32 kg vs. UC -0.21 +/- 0.28 kg, p = 0.04). Blood pressure and serum lipid concentrations did not change over time in either group.. Intensive glycaemic control was associated with weight gain which was distributed in similar proportions between the central and peripheral regions and consisted of similar proportions of fat and fat-free mass. Blood pressure and serum lipid concentrations were not adversely affected.

Topics: Absorptiometry, Photon; Adipose Tissue; Blood Glucose; Body Composition; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Electrocardiography; Ethnicity; Female; Humans; Lipids; Male; Middle Aged; New Zealand; Weight Gain

Bedtime ingestion of slow-release carbohydrates leads to sustained nocturnal fatty acid suppression and improved glucose tolerance in type 2 diabetic patients.. This study assessed the effects of 2 different doses of bedtime carbohydrate supplement (BCS) on morning glycemic control and glycated hemoglobin (Hb A(1c)) in type 2 diabetic patients. In addition, the effects of the high-dose BCS on insulin sensitivity and postprandial glucose and triacylglycerol concentrations were assessed.. Two BCS doses were studied separately in 7-wk randomized, placebo-controlled, double-blind studies with either a parallel (low-dose BCS; n = 24 patients) or crossover (high-dose BCS; n = 14 patients) design. The effects of the low and high doses (0.30 and 0.55 g uncooked cornstarch/kg body wt, respectively) were compared with those of a starch-free placebo.. Compared with the starch-free placebo, the high-dose BCS ( approximately 45 g) produced enhanced nocturnal glucose (P < 0.01) and insulin (P < 0.01) concentrations as well as a 32% suppression of fatty acid concentrations (P < 0.01). Moreover, glucose tolerance (P < 0.05) and C-peptide response (P < 0.05) improved after breakfast the next morning. The low-dose BCS ( approximately 25 g) improved fasting blood glucose concentrations (P < 0.05). However, there were no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or Hb A(1c) after 7 wk.. Nocturnal fatty acid suppression by BCS improved fasting and postprandial blood glucose concentrations in type 2 diabetic patients the next morning. In contrast, no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or long-term glycemic control assessed by Hb A(1c) were seen after BCS supplementation.

Topics: Blood Glucose; Body Weight; C-Peptide; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lactic Acid; Male; Middle Aged; Starch; Triglycerides

Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy.

Topics: Body Mass Index; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipoproteins; Male; Metformin; Middle Aged; Obesity; Placebos; Triglycerides

Patients with type 2 diabetes are often obese and require large doses of insulin to achieve glycemic control. Weight gain often accompanies insulin therapy and results in increasing insulin requirements.. To evaluate the efficacy of metformin in combination with insulin in patients with type 2 diabetes poorly controlled with insulin therapy alone.. Randomized, double-blind, placebo-controlled trial.. Outpatient diabetes clinic at a university medical center.. 43 patients with poorly controlled type 2 diabetes who were receiving insulin therapy.. Patients were randomly assigned to receive placebo or metformin in combination with insulin for 24 weeks.. Hemoglobin A1c levels decreased by 2.5 percentage points (95% CI, 1.8 to 3.1 percentage points) in the metformin group, a significantly greater change (P = 0.04) than the decrease of 1.6 percentage points in the placebo group. Average final hemoglobin A1c levels were 6.5% in the metformin group and 7.6% in the placebo group (difference, 11%). For patients who received placebo, the insulin dose increased 22.8 units (CI, 11 to 44 units) or 29% more than did the dose for patients who received metformin (P = 0.002); for these patients, the insulin dose decreased slightly. Patients in the placebo group gained an average of 3.2 kg of body weight (CI, 1.2 to 5.1 kg); patients in the metformin group gained an average of 0.5 kg of body weight (P = 0.07). Total cholesterol and low-density lipoprotein cholesterol levels decreased in both groups. High-density lipoprotein cholesterol and triglyceride levels did not change.. The addition of metformin to insulin therapy resulted in hemoglobin A1c concentrations that were 10% lower than those achieved by insulin therapy alone. This improvement in glycemic control occurred with the use of 29% less insulin and without significant weight gain. Metformin is an effective adjunct to insulin therapy in patients with type 2 diabetes.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Energy Intake; Hemoglobin A; Humans; Hypoglycemic Agents; Insulin; Lipids; Metformin; Obesity; Statistics, Nonparametric

In the present study we assessed and compared the effectiveness and safety of preconstituted, fixed, combinations of low-dose glyburide plus metformin with higher-dose glyburide monotherapy in patients with type 2 diabetes. This randomized, double-blind, cross-over study comprised 40 patients. After a 30-day run-in period of dietary treatment, patients received combined glyburide (5, 7.5 or 10 mg/day) and metformin (800, 1,200 or 1,600 mg/day) as preconstitued, fixed combinations, or glyburide alone (5, 10 or 15 mg/day). The dose was increased stepwise so as to have 1 (T1), 2 (T2) and 3 (T3) months of treatment for any given regimen (6 months in total). After 2 weeks of washout (T4), the groups were then crossed over (T5, T6, T7 periods). Body weight, fasting plasma glucose, HbA(1c), blood lactate, total cholesterol and HDL-cholesterol, and triglycerides were measured at the beginning and end of T1 and T5, and end of T2, T3, T6 and T7; postprandial plasma glucose, fasting and postprandial plasma insulin and C-peptide were evaluated at the beginning of T1 and T5, and end of T3 and T7. At these latter time points additional assessments included routine clinical chemistry measurements, ECG, and ophthalmoscopic examination. Statistical analysis was performed by the paired Student's t-test and analysis of variance for cross-over studies. Thirty-three patients completed the study. Fasting plasma glucose, postprandial plasma glucose and HbA(1c) levels improved significantly during combined treatment with glyburide at lower doses plus metformin. This effect was achieved without any major change of insulin and C-peptide concentrations. Circulating lactate concentrations increased during the regimen including metformin, but they remained well within the reference values for normal subjects. Plasma total cholesterol and triglycerides levels remained substantielly unchanged throughout the study, whereas HDL-cholesterol concentrations increased slightly, but significantly, with glyburide plus metformin therapy. Routine clinical chemistry measurements, ECG and ophthalmoscopic examinations did not change during the study. These results demonstrate that improved metabolic control can be achieved with preconstituted, fixed combinations of low-dose glyburide plus metformin in patients with type 2 diabetes, compared to higher doses of the sulphonylurea alone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Postprandial Period; Time Factors

Troglitazone and metformin lower glucose levels in diabetic patients without increasing plasma insulin levels. We compared the insulin sparing actions of these two agents and their effects on insulin sensitivity and insulin secretion in 20 type 2 diabetic patients. To avoid the confounding effect of improved glycemic control on insulin action and secretion, patients were first rendered euglycemic with 4 weeks of continuous subcutaneous insulin infusion (CSII) before randomization to CSII plus troglitazone (n = 10) or CSII plus metformin (n = 10); euglycemia was maintained for another 6-7 weeks. Insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp 1) at baseline, 2) after 4 weeks of CSII, and 3) after CSII plus either troglitazone or metformin. The 24-h glucose, insulin, and C-peptide profiles were performed on the day before the second and third glucose clamps. Good glycemic control was achieved with CSII alone and was maintained with CSII plus an oral agent (mean 24-h glucose: troglitazone, 6.2+/-0.6 mmol/l; metformin, 6.2 +/-0.3 mmol/l). Insulin requirements decreased 53% with troglitazone compared with CSII alone (48+/-4 vs. 102+/-13 U/day, P < 0.001), but only 31% with metformin (76+/-13 vs. 110+/-18 U/day, P < 0.005). The 24-h C-peptide profiles were similar. Normal fasting hepatic glucose output was maintained with both agents despite lower insulin levels than on CSII alone. Insulin sensitivity did not change significantly with CSII alone or with CSII plus metformin, but improved 29% with CSII plus troglitazone (P < 0.005 vs. CSII alone) and was then 45% higher than in the CSII plus metformin patients (P < 0.005). In conclusion, metformin has no effect on insulin-stimulated glucose disposal independent of glycemic control in type 2 diabetes. Troglitazone (600 mg/day) has greater insulin-sparing effects than metformin (1,700 mg/day) in CSII-treated euglycemic patients. This is probably explained by the peripheral tissue insulin-sensitizing effects of troglitazone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Chromans; Circadian Rhythm; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Fructosamine; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Male; Metformin; Middle Aged; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone

Rosiglitazone is the most potent of the thiazolidinediones, a novel class of oral antidiabetic agents that reduce blood glucose levels by sensitizing peripheral tissues to insulin. This study was designed to identify doses of rosiglitazone that would lower fasting plasma glucose (FPG) in patients with type 2 diabetes.. In this 12-week, double-blind, multicentre study, 380 patients with FPG values > or =7.8 mmol/L (140 mg/dL) and < or =13.3 mmol/L (240 mg/dL) were randomly assigned to receive treatment with placebo or rosiglitazone, 0.05, 0.25, 1.0, or 2.0 mg twice daily. The primary efficacy parameter was changed in FPG from baseline after 12 weeks of treatment. Secondary endpoints were changes in HbA1c, fructosamine, C peptide, insulin, lipid levels, and body weight (b.w.). Safety monitoring included clinical laboratory evaluations, electrocardiography, and echocardiography.. Rosiglitazone 1.0 and 2.0 mg b.i.d. produced significant decreases in FPG (p=0.0001). Fructosamine also decreased in patients treated with these two dosages (p=0.003 in the 2.0 mg b.i.d. group). Rosiglitazone 2.0 mg b.i.d. significantly reduced plasma insulin levels (p=0.0044) and free fatty acids (p=0.0014) compared with placebo. Total cholesterol (p=0.0001), HDL (p=0.0009), and LDL (p=0.0001) increased in the rosiglitazone 2.0 mg b.i.d. group, but there was no significant change in the total cholesterol/HDL ratio or triglyceride levels in any rosiglitazone treatment group. Clinically insignificant dose-dependent increases in b.w. were observed in the rosiglitazone 1.0 and 2.0 mg b.i.d. treatment groups.. Twelve weeks of treatment with rosiglitazone 2.0 mg b.i.d. significantly decreases fasting plasma glucose, fructosamine, plasma insulin, and free fatty acids in patients with type 2 diabetes. Longer studies using higher doses will be needed to assess the efficacy and safety of rosiglitazone in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fructosamine; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Middle Aged; Placebos; Rosiglitazone; Thiazoles; Thiazolidinediones

To determine the effect of benfluorex on glycaemic control in obese insulin-requiring Type 2 diabetes, 76 patients (aged 53.8 +/- 12.8 years) receiving insulin (> or = 0.5 IU/kg) and an appropriate low-calorie diet were evaluated after a 1-month run-in followed by a 3-month double-blind treatment period (3 tablets daily) with benfluorex (B; n = 37) vs placebo (P; n = 39). At inclusion, the B and P groups respectively did not differ in body weight (80.9 +/- 10.3 vs 77.2 +/- 9.1 kg), body mass index (BMI) (30.1 +/- 4.6 vs 29.0 +/- 2.3 kg/m2) or fasting blood glucose (11.22 +/- 4.33 vs 10.35 +/- 4.42 mmol/l). However, daily insulin dose and HbA1c levels were higher in the B group (59.9 +/- 18.6 vs 50.4 +/- 12.8 IU, p = 0.012; and 7.72 +/- 1.60 vs 6.96 +/- 1.27%, p = 0.025, respectively). After 3 months of treatment, the decrease in daily insulin dose was greater in the B group (8.7 +/- 10.1 vs 2.7 +/- 8.1 IU; p = 0.032), with a decrease in HbA1c (-0.73 +/- 1.74%, p = 0.026), vs no change in the P group (+0.01 +/- 1.65%, NS) and a tendency towards a greater decrease in fasting blood glucose (-1.43 +/- 5.41 vs +0.42 +/- 3.78 mmol/l respectively). Body weight and BMI were also lower in the B group (1.77 ñ 2.27 vs 0.21 ñ 2.68 kg, p = 0.013; and 0.64 +/- 0.84 vs 0.07 +/- 1.07 kg/m2, p = 0.019, respectively) in parallel with the decrease in insulin dose. Triglycerides decreased in the B group vs an increase in the P group (-0.54 +/- 2.04 vs +0.21 +/- 0.70 mmol/l p = 0.06). Total cholesterol decreased within the B group (-0.47 +/- 1.01 mmol/l; p = 0.013) and vs the P group (intergroup p = 0.006). Adverse events were reported in 11 patients in the B group vs 5 in the P group (NS), causing dropout in only one case (intercurrent illness, P group). Addition of benfluorex in obese insulin-requiring Type 2 diabetes thus enhances glycaemic control and lowers both daily insulin requirement and body weight. Benfluorex + insulin is a valid alternative for obese patients who remain poorly controlled despite insulin or who require high doses of insulin.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Fenfluramine; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Monitoring, Physiologic; Obesity; Postprandial Period

Insulin sensitivity is impaired in overweight subjects with IGT and is accompanied by hyperinsulinemia, a condition, that might promote early B-cell exhaustion. Twelve subjects were recruited for a double-blind trial using either 100 mg of acarbose or placebo for three months. Insulin sensitivity was measured by hyperglycemic clamp and with the minimal model. Baseline characteristics such as body weight, BMI, blood glucose, HB-A1c and serum lipids did not change throughout the study period. The steady state glucose infusion rate (SSGIR) improved significantly following acarbose. The insulin sensitivity as measured by clamp (MI) or minimal model, (SI), however, increased only descriptively (p = 0.08). The fasting proinsulin was raised in all subjects during pretreatment. Following acarbose, the proinsulin dropped from 20.3 +/- 12.9 to 13.6 +/- 7.1 ng/ml, but remained unchanged in the placebo group. Due to the high variability of values and the low number of subjects in this study, differences were only descriptive and did not reach significance (p = 0.08). The proinsulin/insulin ratio, however, significantly decreased after 3 months of acarbose treatment. Acarbose might therefore be considered recommendable for the protection of the B-cell function and for delaying the transition of IGT to overt NIDDM.

Topics: Acarbose; Adult; Analysis of Variance; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Double-Blind Method; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Proinsulin; Trisaccharides

To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone.. There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed.. Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy. Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.

Topics: Blood Glucose; Body Weight; C-Peptide; Chromans; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Treatment Outcome; Troglitazone

It is difficult to treat obese non-insulin-dependent diabetic patients (NIDDs) whose glycaemic control remains poor despite maximal oral antidiabetic therapy. We studied the effect of a continuous subcutaneous insulin infusion (CSII) associated with a low-calorie diet and metformin 1,700 mg/day on glycaemic control and basal and stimulated insulin secretion in a series of 82 overweight NIDD before (T1), during CSII (T2), and after CSII withdrawal (T3). Patients were treated for 8 to 23 days with a mean amount of 0.50 +/- 0.02 IU/kg/day. Glycaemic control was very good after 3-5 days of CSII and remained good at T3. At T2, fasting and postprandial plasma C peptide levels decreased significantly. At T3, fasting C peptide was very similar to T1, and postprandial C peptide was significantly higher than at T1. The molar fasting and postprandial plasma C peptide/glycaemia ratios increased significantly at T3. After glucagon injection, the molar delta C peptide/glycaemia ratio was significantly increased at T2 and even higher at T3. At T2, as at T1 and T3, there were significant correlations between fasting and postprandial C peptide levels and between the glucagon-induced C peptide peak and fasting and postprandial C peptide levels. Between T1 and T3 weight changes correlated significantly with the molar fasting C peptide/glycaemia ratio at T1. Twenty-nine of the 30 patients for whom this ratio was > 6.6 x 10(-8) lost weight. The length of CSII treatment did not correlate with weight changes or other biological parameters. This study shows that CSII with moderate amounts of insulin associated with a low-calorie diet and metformin provided rapid glycaemic control, led to weight loss, maintained regulation of insulin secretion and seemed to improve insulin secretion and sensitivity. These results were obtained in only 8 to 10 days.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Infusions, Parenteral; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Secretory Rate; Time Factors

Most obese patients with noninsulin-dependent diabetes mellitus (NIDDM) are initially treated with diet, then with oral hypoglycemic agents, eventually with insulin. However several reports indicate that in these patients insulin therapy has little chance to control glucose metabolism, promotes weight gain and arterial hypertension, and is likely to aggravate insulin resistance. In this randomized, double-blind trial vs. placebo (P) we evaluated in 29 obese NIDDM patients poorly controlled by insulin (daily insulin doses 48.7 +/- 4.0 U/day, HbA1c 10 +/- 0.27%, mean daily blood glucose levels 12.3 +/- 0.3 mmol/L, fasting C-peptide 1.8 +/- 0.2, C-peptide after 1 mg iv glucagon 3.2 +/- 0.3 ng/mL, means +/- SE), the clinical and metabolic effects of benfluorex (B), a lipid-lowering drug able to improve insulin sensitivity. After a 2-3 week run-in period (1 tablet P at dinner and diet 800 cal/day to lose 5% of the initial body weight (BWi), patients received a 1000 kcal/day diet and were randomized to B, 150 mg/ tablet, or P (3 tablets/day); the time limit was set at a 10% decrease of BWi or at 90 days. At the end of run-in there was a significant reduction of BWi (P < 0.001), fasting (P = 0.002) and mean daily blood glucose levels (P < 0.001), triglycerides (P = 0.02), cholesterol (P < 0.001) and daily insulin doses (P < 0.001). At the end of the double-blind trial, weight-loss was greater (P < 0.05), faster (P = 0.018), and more frequent (P < 0.05) with B than with P, and systolic blood pressure (P < 0.05) decreased only with B. Considering only patients with a 10% decrease of BWi (B = 15, P = 10), HbA1c (P < 0.001) decreased only with B, while fasting insulin levels decreased with both B (P < 0.01) and with P (P < 0.05). Insulin sensitivity was evaluated by means of a double infusion test (LDIGIT, insulin 25 mU/Kg/h plus glucose 4 mg/kg/min, lasting 150 min) at the end of run-in and at the end of the double-blind trial; at the end of the double-blind trial steady state blood glucose (SSBG, P < 0.05), free fatty acids (FFA, P < 0.05) and blood beta-hydroxybutyrate (P < 0.05) decreased only with B, while blood glycerol decreased both with both P (P < 0.05) and B (P < 0.06). At the end of the double-blind trial, C-peptide release was unchanged with either P or B. In conclusion, benfluorex potentiates the effects of hypocaloric diet on weight loss and on glycemic control in obese NIDDM patients treated with insulin, and this effect seems to be the result of an

Topics: 3-Hydroxybutyric Acid; Appetite Depressants; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Fenfluramine; Glucose; Glycerol; Humans; Hydroxybutyrates; Insulin; Insulin Resistance; Insulin Secretion; Middle Aged; Obesity; Placebos

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

To examine the safety and overall clinical effects of normalizing the fasting plasma glucose (FPG) level with bedtime NPH insulin alone in patients with non-insulin-dependent diabetes mellitus (NIDDM) that is poorly controlled with maximal doses of sulfonylureas.. Twelve obese male NIDDM subjects were treated for 16 weeks with bedtime insulin after a 4-week sulfonylurea washout. The insulin dosage was increased until the FPG level was normalized. The 24-h plasma glucose profiles and lipid and HbA1c levels were measured at the beginning and end of the study, and the incidence and severity of hypoglycemic episodes were closely monitored. In addition, hyperglycemic clamp studies were performed to assess insulin secretion and provide an indirect measurement of insulin sensitivity.. FPG (14.6 +/- 0.9 mmol/l at week 0) was normalized ( < 6.4 mmol/l) within 6 weeks (5.9 +/- 0.6 mmol/l) and remained at target levels until the end of the study (4.0 +/- 0.03 mmol/l at week 16, P < 0.001). The insulin dose was 80 +/- 9 U/day (0.86 +/- 0.10 U/kg). Improved glycemic control was confirmed by a reduction in HbA1c (10.9 +/- 0.05 vs. 7.2 +/- 0.2%, P < 0.001) and mean 24-h glucose (17.2 +/- 0.2 vs. 7.4 +/- 0.2 mmol/l, P < 0.001). The incidence of mild or moderate hypoglycemic episodes was 3.4 +/- 1/patient for the entire 16-week study, and no patient experienced severe hypoglycemia. Bedtime insulin significantly improved total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglyceride levels (P < 0.01). Weight gain was 2.4 +/- 0.7 kg, and blood pressure was unchanged. During the hyperglycemic clamp, there was an improvement in the first phase (P < 0.001) and in the second phase (P < 0.01) of insulin secretion. There also was an increase in the rate of exogenous glucose infused (M) (P < 0.01) and in the M/C-peptide ratio (P < 0.02), suggesting enhanced insulin sensitivity.. NPH insulin given at bedtime in amounts sufficient to achieve a normal FPG level does not cause excessive or severe hypoglycemia and does lead to good glycemic and lipid control in NIDDM. Bedtime insulin therapy also is accompanied by improved insulin secretion and insulin sensitivity. We conclude that a single dose of insulin alone at bedtime merits consideration as a therapeutic strategy in patients with poorly controlled NIDDM.

Topics: Analysis of Variance; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Glucose; Glycated Hemoglobin; Humans; Insulin, Isophane; Liver; Male; Middle Aged; Obesity; Reference Values; Time Factors; Triglycerides

To compare the effect of bedtime NPH insulin or preprandial regular insulin combined with glibenclamide on metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure to sulfonylurea therapy.. Eighty NIDDM patients were randomized to treatment with either three preprandial doses of regular insulin (daytime group D) or a bedtime dose of NPH insulin (nocturnal insulinization, group N), both regimens being combined with 10.5 mg of glibenclamide. Metabolic profiles were obtained at 0, 6, 16 weeks.. Glycemic control had improved significantly in both groups after 4 months. Fasting blood glucose was significantly lower compared with baseline in both groups. The mean change +/- SD in group D was -2.8 +/- 3.5 mmol/l and in group N -6.4 +/- 3.0 mmol/L, the reduction being more pronounced in group N compared with group D (P < 0.0001). HbA1c was lowered similarly, from 9.2 +/- 1.4 to 7.1 +/- 1.2% in group D (P < 0.0001) and from 9.1 to 1.1 to 7.5 +/- 1.5% in group N (P < 0.0001). The total daily insulin doses were similar, 29 +/- 11 U in group D and 26 +/- 9 U in group N, and the circulating insulin levels during daytime were higher in group D than in group N. Total serum cholesterol and triglycerides were similarly and significantly lowered compared with baseline in both groups. Weight gain was more pronounced in group D (3.4 +/- 0.3 kg) than in group N (1.9 +/- 1.9 kg; D vs. N, P < 0.002), and the change was inversely correlated with initial eight but not with the improvement in HbA1c.. The two insulin regimens exert similar effect on glucose metabolism and serum lipids in NIDDM patients on combination therapy. Weight gain is more pronounced in patients given insulin during the daytime when preprandial doses of short-acting insulin are used.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Eating; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin, Isophane; Middle Aged; Time Factors; Treatment Failure; Triglycerides

Exercise enhances insulin sensitivity in people with non-insulin-dependent diabetes mellitus (NIDDM), but the intensity of exercise necessary to optimize the effect is unknown. Eight women with NIDDM were studied on a metabolic ward in each of three conditions: 1) low-intensity exercise (LO) that consisted of treadmill walking at 50% of maximal O2 consumption on days 1 and 2, 2) high-intensity exercise (HI) that consisted of walking at 75% of maximal O2 consumption, and 3) no exercise (NX). The duration of exercise was adjusted so that energy expenditure was equal in both exercise conditions. On day 3, glucose, [6,6-2H]glucose, and insulin were infused at fixed rates for 3 h. Insulin sensitivity was determined both by steady-state plasma glucose concentration and rate of glucose disposal per unit plasma insulin. Steady-state plasma glucose concentration and rate of glucose disposal per unit plasma insulin were almost identical after LO or HI; values were significantly greater than after NX. Plasma glucose response to a test meal was the same among the three conditions, but plasma insulin response was lower for HI and LO compared with NX. We conclude that under these conditions LO is as effective as HI in enhancing insulin sensitivity in people with NIDDM.

Topics: Adult; Blood Glucose; Body Composition; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet; Exercise; Female; Humans; Insulin; Middle Aged; Oxidation-Reduction

Combination therapy with insulin and sulphonylurea has gained acceptance in management of subjects with Type 2 (non-insulin-dependent) diabetes mellitus. However, its role in management of Type 1 (insulin-dependent) diabetes mellitus remains controversial. In this study, the effect of combination therapy with insulin and glibenclamide on metabolic control, daily insulin dosage, and insulin sensitivity was assessed in subjects with Type 1 diabetes mellitus. Ten men with Type 1 diabetes mellitus participated in a randomized, double-blind, crossover, clinical trial with three treatment regimens, namely (1) insulin alone, (2) insulin and placebo, (3) insulin and glibenclamide, each lasting 3 months. Combination therapy induced: (1) reduction in daily insulin dosage; (2) more uniform blood glucose control as reflected by a lower average 24 h blood glucose level, a smaller difference between mean preprandial and 2 h postprandial blood glucose concentrations, decreased 24 h urine glucose excretion, and a decline in number of hypoglycaemic events; (3) improved insulin sensitivity as expressed by more rapid plasma glucose disappearance rate, without a significant alteration in fasting plasma glucagon and 1h postprandial serum C-peptide levels; when compared with treatment with either insulin alone or with insulin and placebo. Therefore, it is apparent that the addition of glibenclamide to insulin reduces daily insulin dosage and renders a greater uniformity to diurnal blood glucose control, most probably secondary to enhancement of insulin sensitivity.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Glucagon; Glyburide; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Placebos; Triglycerides

To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM).. Of 165 patients (fasting blood glucose [FBG] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, with FBG < 6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration.. The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups.. Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Lipids; Male; Metformin; Middle Aged

To determine if the use of indwelling catheters for insulin injections affects the long- and short-term metabolic control of insulin-dependent diabetes mellitus (IDDM).. Sixteen children and adolescents 9-20 years of age were included in a randomized 10-week crossover study using indwelling catheters (Insuflon, Pharma-Plast, Lynge, Denmark; CHRONIMED, Minnetonka, Minnesota) for insulin injections. Their diabetes duration was 7.5 +/- 3.3 years (range 2-14), and they used multiple injection therapy with 4-5 doses/day. C-peptide was < or = 0.15 nM fasting and < or = 0.30 nM postprandial.. We found no significant difference between those with and without Insuflon in degree of metabolic control reflected by HbA1c (with Insuflon, 7.3 +/- 2.6%; without, 7.1 +/- 2.2%), 24-h profiles of blood glucose and free insulin, 24-h samples of glucosuria, or ketonuria. Weight, insulin doses per kilogram per 24 h, and insulin antibodies were all the same in the two groups.. The long- and short-term metabolic control of IDDM was not altered by the use of indwelling catheters for insulin injections. Insuflon can be offered as an alternative to patients with IDDM who find regular injections uncomfortable.

Topics: Adolescent; Blood Glucose; Body Weight; C-Peptide; Catheters, Indwelling; Child; Cross-Over Studies; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Insulin; Insulin Antibodies; Insulin Infusion Systems

To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas.. A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment.. Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients.. The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Eating; Fasting; Glyburide; Glycated Hemoglobin; Humans; Insulin, Isophane; Metformin; Middle Aged; Obesity

Twenty-two NIDDM patients completed an open randomized cross-over study comparing metformin and glibenclamide over 1 year. The drugs had an equivalent effect on glycaemic control, but, in contrast to glibenclamide, metformin reduced body weight. Neither drug affected triglycerides, total- and LDL-cholesterol or C-peptide. Metformin caused a slight elevation of HDL-cholesterol (P less than 0.05). No serious adverse effects were observed. The results show that oral hypoglycaemic agents are not associated with undesirable effects on lipids and lipoproteins.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Insulin; Insulin Secretion; Lipids; Lipoproteins; Male; Metformin; Middle Aged; Prospective Studies; Triglycerides

The effects of different protein intakes on wt gain, insulin secretion, and plasma concentrations of amino acids have been evaluated in a prospective study involving 30 normal term infants. The infants were studied from 4.0 to 6.0 mo of age. Ten infants were breast-fed (BF), the others were randomly divided into two groups of 10 infants. One group was fed a formula containing 1.3 g protein/100 mL (F 1.3), the other a formula with 1.8 g protein/100 mL (F 1.8). The formulas were isocaloric (72 kcal/100 mL), and the fat concentrations were 3.5 g/100 mL (F 1.3) and 3.2 g/100 mL (F 1.8). All infants received the same supplementary foods. The urinary C-peptide excretion in the infants fed the F 1.8-formula was 4.4 +/- 2.1 nmol/mmol creatinine or 19.4 +/- 12.9 nmol/m2, significantly higher than that in the infants fed the F 1.3-formula (2.6 +/- 1.5 and 7.9 +/- 5.1) or the BF infants (1.7 +/- 1.4 and 6.3 +/- 6.0). Gain in wt was 18.0 +/- 4.3, 19.9 +/- 3.9, 22.8 +/- 1.6 g/kg/wk and corresponded to protein intakes of 1.3 +/- 0.2, 1.9 +/- 0.3, and 2.6 +/- 0.2 g/kg/d, in the BF, F 1.3, and F 1.8 groups, respectively. Gain in length was 6.7 +/- 1.8 (BF-group), 6.2 +/- 2.5 (F 1.3-group), and 7.6 +/- 2.2 (F 1.8-group) mm/m/wk. Wt gain correlated with urinary C-peptide excretion at 6.0 mo (r = 0.51, p less than 0.01) and with protein intake (r = 0.43, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Body Weight; C-Peptide; Dietary Proteins; Female; Growth; Humans; Infant; Insulin; Insulin Secretion; Male; Prospective Studies; Randomized Controlled Trials as Topic

Eight patients with noninsulin-dependent diabetes underwent two 2-wk study periods in random order during which they were provided with carbohydrate foods with either a high or low glycemic index (GI). Over both high-GI and low-GI periods there were significant reductions in body weight, serum fructosamine, and cholesterol. Reductions in fasting blood glucose, HbA1c, and urinary c-peptide-to-creatinine ratio were significant only over the low-GI period despite a smaller mean weight loss. Reductions in triglyceride were significant only over the high-GI diet. Inclusion of low-GI foods into diets of patients with diabetes may be an additional measure that favorably influences carbohydrate metabolism without increasing insulin demand.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; Male; Middle Aged

20 patients with non insulin dependent diabetes mellitus (NIDDM), and within 20% of their ideal body weight were studied. They had failed to achieve adequate diabetic control following 3 months of dietary therapy. They were randomly allocated to insulin or sulphonylurea therapy for 3 months and then "crossed over" for the same period of time. Patients were maintained at euglycaemia (plasma glucose 4-7 mmol/l) for 24 hr using an open-loop intravenous insulin infusion, and then underwent a standard 75 gm oral glucose tolerance test (OGTT) following each mode of therapy. Mean glycosylated haemoglobin and preprandial blood glucose were 8.7% and 7.7 mmol/l respectively after sulphonylurea, and 7.8% (p less than 0.05) and 6.6 mmol/l (p less than 0.05) after insulin therapy. There was no significant difference in change in body weight. Following a 75 gm OGTT mean plasma insulin at 1/2 hr and 1 hr was 14.0 mu/l and 16.5 mu/l after sulphonylurea, and 23.4 mu/l (p less than 0.05) and 22.1 mu/l (p less than 0.05) after insulin therapy. Plasma C-peptide responses were also improved at 1/2, 1 and 1 1/2 hr after a period of insulin therapy being 0.61 nmol/l, 0.65 nmol/l and 0.59 nmol/l respectively. After sulphonylurea therapy comparable plasma C-peptide responses were 0.31, 0.41 and 0.37 nmol/l respectively (p less than 0.05). There was no significant difference in the total amount of intravenous insulin required for 24 hr euglycaemia. Our study shows that short term insulin therapy in patients with NIDDM who had failed on diet alone has advantages over sulphonylurea therapy in that it achieves better diabetic control and an improved B-cell response to glucose stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diet, Diabetic; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Middle Aged; Tolbutamide

A double-blind, placebo-controlled investigation has been made into the effects of 8 weeks of glipizide treatment in diabetics previously classified as Type 2 but with subsequent attenuation of insulin secretion and thence maintained on exogenous insulin. Although all patients were exposed to therapeutic plasma concentrations of glipizide, fasting blood glucose, haemoglobin A1 and plasma lipoproteins (HDL, LDL, total cholesterol and triglycerides) did not show any consistent improvement following this treatment. It appears unlikely that SU (glipizide) has any primary effect on insulin action or on plasma lipoproteins. Its primary action is to augment insulin release and availability, so, its use should be restricted to Type 2 diabetics who retain insulin secretion.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Glipizide; Glycated Hemoglobin; Humans; Insulin; Lipids; Lipoproteins; Male; Middle Aged; Random Allocation; Sulfonylurea Compounds

We have studied the effect of the combination of a sulfonylurea (Hb 420 or glibenclamide) with insulin in 22 type II diabetic patients, treated with insulin and with residual insulin secretion (fasting plasma C peptide level greater than 0.2 pmol/ml). After a 3 week run-in period, the patients received either glibenclamide (7 mg of Hb 420 before breakfast and 3.5 mg before supper) or placebo in double blind fashion. Clinical and biological parameters (body weight, number of hypoglycemic episodes, daily insulin dose, fasting and postprandial glucose and C peptide levels after a standard meal) were collected during the basal (run-in) period and after 8 and 16 weeks of treatment. In the glibenclamide group, a significant increase in the number of hypoglycemic episodes was observed in spite of a 8 to 10% reduction in insulin requirements. A 18% reduction of both fasting and postprandial plasma glucose levels was found after 8 and 16 weeks of glibenclamide therapy. Concomitantly, a 35% increase of fasting and postprandial plasma C peptide levels occurred. The data suggest that the use of combined sulfonylurea and insulin therapy may be beneficial to type II diabetic patients with residual insulin secretion and poor glycemic control under insulin therapy alone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glyburide; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Triglycerides

This study was performed in two randomly defined groups of obese patients with polycystic ovaries to investigate the overall effects of hypocaloric diet combined (group 2) or not combined (group 1) with an antiandrogenic therapy (cyproterone acetate, 50 mg/day, plus ethinyl estradiol, 0.05 mg/day) on sex hormone plasma levels, insulin secretion and resistance, and body weight loss and on their reciprocal interrelationships. All obese patients with polycystic ovaries showed elevated luteinizing hormone and androgen levels, hyperinsulinemia, and marked insulin resistance. After an average period of 3 months both groups showed a similar weight loss and a similar reduction in the insulin-resistant state. During treatment in group 1 three patients had a greater frequency of menstrual bleeding, and in one of them an ovulatory cycle was documented. Whereas, no changes in gonadotropin and sex steroid levels were found in group 1, a significant fall was observed in group 2. No relationships were observed between these changes and those which occurred on insulin levels. We conclude that hyperandrogenism in obese patients with polycystic ovaries does not appear to be a primary factor leading to the insulin-resistant state.

Topics: Adolescent; Adult; Androgen Antagonists; Body Weight; C-Peptide; Energy Intake; Female; Glucose Tolerance Test; Gonadal Steroid Hormones; Humans; Insulin; Insulin Resistance; Male; Obesity; Polycystic Ovary Syndrome

In a double-blind cross-over study we compared the effects of insulin plus glibenclamide, 5 mg twice daily, with insulin plus placebo during 8-week periods on metabolic parameters in 13 non-insulin dependent diabetic (NIDDM) patients poorly controlled with insulin alone. The combination therapy improved diabetic control as assessed by fasting blood glucose (p less than 0.001), 24-hour urinary glucose (p less than 0.01) and glycohemoglobin (HbA1) concentrations (p less than 0.05 at week 12). The effect tended to cease with time. Significantly higher C-peptide values were found during combination treatment than during insulin-placebo (p less than 0.01) and the changes in fasting C-peptide concentrations correlated positively with the changes in HbA1 concentrations (r = 0.56, p less than 0.05). There was no difference in glucagon concentrations, insulin binding to erythrocytes or insulin sensitivity between the two study periods. Neither did the combination therapy influence blood lipids significantly. The present study shows that the combination of insulin and glibenclamide may be of limited value in the treatment of NIDDM patients poorly controlled with insulin alone. However, thus far the long-term results are uncertain. In the absence of significant effects on insulin binding and insulin sensitivity, the improved diabetic control seems to be explained, at least partly, by glibenclamide-induced stimulation of insulin secretion.

Topics: Blood Glucose; Body Weight; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon; Glyburide; Glycated Hemoglobin; Glycosuria; Humans; Insulin; Lipids; Male; Middle Aged

A double-blind crossover study was undertaken to determine whether glibenclamide could improve glycaemic control in patients not adequately controlled by insulin. Nine elderly outpatients with non-insulin dependent (type 2) diabetes participated in the study. In addition to their regular insulin treatment, the patients were given either glibenclamide 5 mg twice daily or placebo tablets for 2 months followed by the opposite combination for a further 2 months. The fasting plasma glucose concentrations were lower during the insulin plus glibenclamide period than during the insulin plus placebo period and the difference tended to increase at the end of each study period (p less than 0.01 and 0.001). The level of haemoglobin A, (HbA1) decreased significantly from 13.8 +/- 0.6% (mean +/- SE) to 12.4 +/- 0.6% during the insulin + glibenclamide period (p less than 0.01); in contrast, there was no change during the insulin + placebo period. The 24-hour urinary glucose excretion was reduced during the insulin + glibenclamide period compared with insulin + placebo (p less than 0.05). Basal and glucagon stimulated C-peptide concentrations did not significantly differ between the two treatment regimens. The results suggest that glibenclamide can improve the glycaemic control in insulin-treated elderly diabetics by mechanisms which still are to be elucidated.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Male

Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol. Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter. On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide. Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment. Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide. Plasma glucagon and GIP concentrations were not significantly affected. Insulin sensitivity was increased by glibenclamide but not by glipizide. Neither therapy affected insulin binding to erythrocytes. It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide. Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels. The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Erythrocytes; Female; Gastric Inhibitory Polypeptide; Glipizide; Glucagon; Glyburide; Glycosuria; Humans; Insulin; Insulin Resistance; Kinetics; Male; Middle Aged; Random Allocation; Sulfonylurea Compounds

A high-carbohydrate-(HC)-modified fat diet was compared with a standard low-carbohydrate (LC) diabetic diet in 11 insulin-dependent diabetics. Basal and preprandial plasma glucose concentrations were appreciably lower when the patients received the HC diet derived chiefly from readily available cereal and vegetable sources (mean (+/- SE of mean) basal concentrations 6.7 +/- 1.2 mmol/l (121 +/- 22 mg/100 ml) with the LC diet and 4.3 +/- 0.7 mmol/l (77 +/- 13 mg/100 ml) with the HC diet; mean preprandial concentrations 11.1 +/- 1.2 mmol/l (200 +/- 22 mg/100 ml) LC diet and 8.9 +/- 1.3 mmol/l (160 +/- 23 mg/100 ml) HC diet). total and low-density lipoprotein cholesterol concentrations were lower when patients took the HC diet (mean 4.4 +/- 0.2 and 2.4 +/- 0.2 mmol/l (189 +/- 8 and 124 +/- 8 mg/100 ml) respectively), and the ratio of high-density lipoprotein cholesterol to total cholesterol tended to rise. The average percentage of glycosylated haemoglobin did not differ between the two diets. Thus several measures of carbohydrate and lipid metabolism appear to be more satisfactory when patients receive a HC diet, which is an acceptable alternative to that still recommended to most insulin-requiring patients.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus; Diet, Diabetic; Dietary Carbohydrates; Female; Humans; Insulin; Male; Middle Aged; Triglycerides

The prevalence of obesity in general pediatric population increases without sparing children with T1D. We intended to find factors associated with the possibility of preserving endogenous insulin secretion in individuals with long-standing T1D. At onset, higher BMI is associated with higher C-peptide level, which may indicate to be one of the favorable factors involved in preserving residual β-cell function. The study determines the influence of BMI on C-peptide secretion in children newly diagnosed with T1D in two years observation.. We assessed the possible relationship between selected pro- and anti-inflammatory cytokines, body mass at recognition and β-cell function status. 153 pediatric patients with newly diagnosed T1D were divided into quartiles according to BMI-SDS index. We separated a group consisted of patients with BMI-SDS >1. Participants were followed up for two years and examined for changes in body weight, HbA1c, and insulin requirement. C-peptide was assessed at baseline and after two years. We evaluated the patients' levels of selected inflammatory cytokines at baseline.. Subjects with higher BMI-SDS presented higher serum C-peptide levels and lower insulin requirements at diagnosis than children with lower body weight. The two-year follow-up showed that C-peptide levels of obese patients dropped more rapidly than in children with BMI-SDS within normal limits. The group with BMI-SDS >1 showed the greatest decrease in C-peptide level. Despite statistically insignificant differences in HbA1c at diagnosis between the study groups, in the fourth quartile and BMI-SDS >1 groups, HbA1c as well as insulin requirements increased after two years. The levels of cytokines varied the most between BMI-SDS <1 and BMI-SDS >1 groups and were significantly higher within BMI-SDS >1 group.. Higher BMI, associated with enhanced levels of inflammatory cytokines, relates to preservation of C-peptide at T1D recognition in children but is not beneficial in the long term. A decrease in C-peptide levels combined with an increase in insulin requirements and in HbA1c among patients with high BMI occur, which may indicate a negative effect of excessive body weight on the long term preservation of residual β-cell function. The process seems to be mediated by inflammatory cytokines.

Topics: Body Mass Index; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Insulin; Obesity; Weight Gain

This study sought to examine the impacts of a high dietary fiber cereal meal in comparison to conventional dietary management for diabetes on body weight, distribution of adipose tissue, and cardiovascular risk among individuals diagnosed with type 2 diabetes (T2DM).. A cohort of 120 patients diagnosed with T2DM was enlisted as the study population and divided into two groups using a ratio of 2:1-namely, the W group (n=80) and the U group (n=40). The U group (control) received usual diet, while the W group (intervention) incorporated a high dietary fiber cereal meal in place of their regular staple food in addition to adhering to conventional diabetes dietary recommendations. The high dietary fiber cereal meal was based on whole grains, traditional Chinese medicinal foods, and prebiotics. A subsequent follow-up period of 3 months ensued, during which diverse parameters such as body mass index (BMI),waist-hip ratio (WHR), glycated hemoglobin (HbA1c),fasting blood glucose(FBG),C-peptide levels, blood pressure, blood lipids, high-sensitivity C-reactive protein (hsCRP),10-year cardiovascular disease (CVD) risk, and Lifetime CVD risk were assessed before and after the intervention.. Among the participants, a total of 107 successfully completed the intervention and follow-up, including 72 individuals from the W group and 35 from the U group. Following the intervention, both cohorts exhibited decrease in BMI, WHR, HbA1c, FBG, blood pressure, and blood lipid levels in contrast to their initial measurements. Remarkably, the improvements in BMI, WHR, HbA1c, FBG, total cholesterol (TC), triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C), and the ratio of 2-hour C-peptide (2hCP) to fasting C-peptide (FCP) were more marked within the W group, exhibiting statistically significant disparities (. The intervention centred on a cereal-based dietary approach showcased favourable outcomes with regard to body weight, adipose distribution, and cardiovascular risk in overweight individuals grappling with T2DM.

Topics: Body Weight; C-Peptide; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dietary Fiber; Edible Grain; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Lipids; Obesity; Risk Factors; Triglycerides

The aim of this study was to analyze the clinical characteristics and the pattern of long-term changes of fasting plasma C-peptide in patients with mitochondrial diabetes (MD), and to provide guidance for the diagnosis and treatment of MD.. We retrieved MD patients with long-term follow-up at Peking Union Medical College Hospital from January 2005 to July 2021 through the medical record retrieval system and retrospectively analyzed their clinical data, biochemical parameters, fasting plasma C-peptide, glycosylated hemoglobin and treatment regimens. Non-parametric receiver operating characteristic (ROC) curves were used to assess the relationship between exercise test-related plasma lactate levels and suffering from MD.. A total of 12 MD patients were included, with clinical characteristics of early-onset, normal or low body weight, hearing loss, maternal inheritance, and negative islet-related autoantibodies. In addition, patients with MD exhibited significantly higher mean plasma lactate levels immediately after exercise compared to patients with type 1 diabetes mellitus (T1DM) (8.39 ± 2.75 vs. 3.53 ± 1.47 mmol/L, p=0.003) and delayed recovery time after exercise (6.02 ± 2.65 vs. 2.17 ± 1.27 mmol/L, p=0.011). The optimal cut-off points identified were 5.5 and 3.4 mmol/L for plasma lactate levels immediately after and 30 minutes after exercise, respectively. The fasting plasma C-peptide levels decreased as a negative exponential function with disease progression (Y= 1.343*e. The increased level of plasma lactate during exercise or its delayed recovery after exercise would contribute to the diagnosis of MD. Changes of fasting plasma C-peptide in MD patients over the course of the disease indicated a rapid decline in the early stages, followed by a gradual slowing rate of decline.

Topics: Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Exercise Test; Fasting; Follow-Up Studies; Humans; Lactic Acid; Retrospective Studies

Cistanche tubulosa (Schrenk) R. Wight (Orobanchaceae) is a frequently prescribed component in many traditional herbal prescriptions which are used to treat diabetes in China. In recent studies, the antidiabetic activity of Cistanche tubulosa extracts have been confirmed. However, no systematic investigation has been reported on the total glycosides of Cistatnche tubulosa (TGCT).. The present study aimed to investigate the hypoglycemic and hypolipidemic effects of TGCT and the potential mechanisms in diet/streptozotocin (STZ)-induced diabetic rats, and to chemically characterize the main constituents of TGCT.. The major constituents of TGCT were characterized by HPLC/Q-TOF-MS and the analytical quantification was performed with HPLC-DAD. Type 2 diabetic rats were induced by high-fat high-sucrose diet (HFSD) and a single injection of STZ (30 mg/kg). TGCT (50 mg/kg, 100 mg/kg and 200 mg/kg) or metformin (200 mg/kg) were orally administered for 6 weeks. Body weight and calorie intake were monitored throughout the experiment. Fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), area under curve of glucose (AUC-G), glycosylated hemoglobin (HbA1c), fasting insulin, serum C-peptide, glycogen content and insulin sensitivity index were tested. The levels of phosphorylated protein kinase B and phosphorylated glycogen synthase kinase 3β, the activities of hexokinase and pyruvate kinase were assayed. Meanwhile, the changes in serum lipid profiles, superoxide dismutase, glutathione peroxidase, malondialdehyde and inflammatory factors were measured. Histological of pancreas were also evaluated by haematoxylin-eosin stain.. Our investigation revealed the presence of phenylethanoid glycosides (PhGs): echinacoside (500.19 ± 11.52 mg/g), acteoside (19.13 ± 1.44 mg/g) and isoacteoside (141.82 ± 5.78 mg/g) in TGCT. Pharmacological tests indicated that TGCT significantly reversed STZ-induced weight loss (11.1%, 200 mg/kg); decreased FPG (56.4%, 200 mg/kg) and HbA1c (37.4%, 200 mg/kg); ameliorated the OGTT, AUC-G and insulin sensitivity; increased glycogen content (40.8% in liver and 52.6% in muscle, 200 mg/kg) and the activities of carbohydrate metabolizing enzymes; regulated lipid profile changes and the activities of antioxidant enzymes; diminished serum markers of oxidative stress and inflammation in a dose-dependent manner (p < 0.05).. This study confirmed that TGCT was an effective nutritional agent for ameliorating hyperglycemia and hyperlipidemia in diet/STZ-induced diabetic rats, which might be largely attributed to the activities of TGCT on inhibitions of oxidative stress and inflammation.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cistanche; Diabetes Mellitus, Experimental; Diet; Eating; Glycated Hemoglobin; Glycogen; Glycosides; Hypoglycemic Agents; Hypolipidemic Agents; Inflammation; Insulin; Male; Oxidative Stress; Pancreas; Phosphotransferases; Plant Extracts; Rats, Sprague-Dawley; Streptozocin

One of the therapeutic approaches in the treatment of obesity is the use of histamine H. Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored.. Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders.. The presented study proves that search among the active histamine H

Topics: Adipose Tissue; Animals; Body Weight; C-Peptide; Carrier Proteins; Cholesterol; Energy Intake; Feeding Behavior; Female; Glucose Tolerance Test; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Insulin; Insulin Resistance; Leptin; Ligands; Metformin; Models, Animal; Obesity; Rats, Wistar; Receptors, Histamine H3; Triglycerides

To investigate the association of body mass index (BMI) or BMI z-score (BMIz) at diagnosis with β-cell function in new-onset type 1 diabetes (T1D) patients in children and adults.. This was a retrospective cohort study; 256 children (<18 years) and 245 adults (≥18 years) with less than 1-year duration were recruited and followed for 4 years with an interval of 12 months. Smooth curve fitting, a two-piecewise linear model, and Cox proportional hazards models were utilized to investigate the influence of BMI/BMIz on C-peptide levels.. Association between BMI/BMIz and C-peptide in T1D followed a complicated J curve pattern, and heavier patients had greater C-peptide at diagnosis and a lower risk of β-cell failure at 4 years, suggesting that baseline BMI is a useful predictor for β-cell function in patients with T1D.

Topics: Adolescent; Adult; Age of Onset; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Humans; Male; Prognosis; Retrospective Studies

This study aims to investigate the characteristics of sheep pancreatic mesenchymal stem cells (PSCs) and therapeutic potential of differentiated β-like cells in streptozotocin-induced diabetic mice.. Pancreatic mesenchymal stem cells were isolated from 3- to 4-month-old sheep embryos, and their biological characteristics were explored. The function and therapeutic potential of differentiated β-like insulin-producing cells were also investigated in vitro and in vivo. Differentiated cells were identified through dithizone staining and immunofluorescence staining. Insulin secretion was analyzed using an enzyme-linked immunosorbent assay kit. The preliminary therapeutic potential of induced β-like cells in diabetic mice was detected by blood glucose and body weight.. Primary PSCs were isolated and subcultured up to passage 36. Immunofluorescence staining presented PSC-expressed important markers such as Pdx1, Nkx6-1, Ngn3, and Nestin. Primary PSCs could be induced into functional pancreatic β-like islet cells with a 3-step protocol. The induced β-like islet cells could ameliorate blood glucose in diabetic mice.. The method proposed for generating pancreatic islet β cells provided a preliminary phenotypic investigation of induced cell treatment in diabetic mice, and also laid a foundation in the identification of pharmaceutical targets to treat insulin-dependent diabetes.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon; Glucose; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Sheep

The fructooligosaccharide 1-kestose cannot be hydrolyzed by gastrointestinal enzymes, and is instead fermented by the gut microbiota. Previous studies suggest that 1-kestose promotes increases in butyrate concentrations in vitro and in the ceca of rats. Low levels of butyrate-producing microbiota are frequently observed in the gut of patients and experimental animals with type 2 diabetes (T2D). However, little is known about the role of 1-kestose in increasing the butyrate-producing microbiota and improving the metabolic conditions in type 2 diabetic animals. Here, we demonstrate that supplementation with 1-kestose suppressed the development of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, possibly through improved glucose tolerance. We showed that the cecal contents of rats fed 1-kestose were high in butyrate and harbored a higher proportion of the butyrate-producing genus Anaerostipes compared to rats fed a control diet. These findings illustrate how 1-kestose modifications to the gut microbiota impact glucose metabolism of T2D, and provide a potential preventative strategy to control glucose metabolism associated with dysregulated insulin secretion.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cecum; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Drinking; Fasting; Gastrointestinal Microbiome; Glucose; Insulin; Organ Size; Rats; Trisaccharides

The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized β- and α-cell function, in cretin hormone release and insulin sensitivity in individuals with (remitters) or without (non-remitters) diabetes remission after RYGB.. This is a cross-sectional study of two distinct cohorts of individuals with or without diabetes remission at least 2 years after RYGB. Each individual underwent-either an oral glucose (remitters) or a mixed meal (non-remitters) test; glucose, proinsulin, insulin, C-peptide, glucagon, incretins and leptin were measured.. Compared to remitters (n = 23), non-remitters (n = 31) were older (mean [±SD] age 56.1 ± 8.2 vs. 46.0 ± 8.9 years, P < 0.001), had longer diabetes duration (13.1 ± 10.1 vs. 2.2 ± 2.4 years, P < 0.001), were further out from the surgery (5.6 ± 3.3 vs. 3.5 ± 1.7 years, P < 0.01), were more insulin resistant (HOMA-IR 4.01 ± 3.65 vs. 2.08 ± 1.22, P < 0.001), but did not differ for body weight. As predicted, remitters had higher β-cell glucose sensitivity (1.95 ± 1.23 vs. 0.86 ± 0.55 pmol/kg/min/mmol, P < 0.001) and disposition index (1.55 ± 1.75 vs 0.33 ± 0.27, P = 0.003), compared to non-remitters, who showed non-suppressibility of glucagon during the oral challenge (time × group P = 0.001). Higher proinsulin (16.55 ± 10.45 vs. 6.62 ± 3.50 PM, P < 0.0001), and proinsulin: C-peptide (40.83 ± 29.43 vs. 17.13 ± 7.16, P < 0.001) were strongly associated with non-remission status, while differences in incretins between remitters and non-remitters were minimal.. Individual without diabetes remission after gastric bypass have poorer β-cell response and lesser suppression of glucagon to an oral challenge; body weight and incretins differ minimally according to remission status.. 背景: 目前尚未完全明确2型糖尿病(T2D)患者接受胃旁路术(RYGB)后病情缓解或复发的决定因素。这项研究描述了RYGB术后糖尿病缓解或未缓解个体的β-与α-细胞功能、肠促胰岛素激素释放及胰岛素敏感性。 方法: 这是一项横断面研究, 对RYGB术后至少2年后糖尿病缓解或未缓解的不同队列个体进行了研究。每个个体均进行口服葡萄糖(缓解者)或者混合餐(非缓解者)耐量试验；测量血糖、胰岛素原、胰岛素、C肽、胰高血糖素、肠促胰岛素以及瘦素水平。 结果: 与缓解者(n=23)相比, 未缓解者(n=31)年龄更大(平均[±SD]年龄56.1±8.2 vs. 46.0±8.9岁, P<0.001)、糖尿病病程更长(13.1±10.1 vs. 2.2±2.4年, P<0.001)、距离手术时间更长(5.6±3.3 vs. 3.5±1.7年, P<0.01)、胰岛素抵抗更严重(HOMA-IR为4.01±3.65 vs. 2.08±1.22, P<0.001), 但体重无差异。正如预期, 与未缓解者相比, 缓解者具有较高的β细胞葡萄糖敏感性(1.95±1.23 vs. 0.86±0.55 pmol/kg/min/mmol, P<0.001)以及处置指数(1.55±1.75 vs. 0.33±0.27, P=0.003), 后者在口服耐量试验期间的胰高血糖素水平并未受到抑制(时间×分组, P=0.001)。较高水平的胰岛素原(16.55±10.45 vs. 6.62±3.50PM, P<0.0001)以及胰岛素原:C肽比值(40.83±29.43与17.13±7.16, P<0.001)与未缓解状态密切相关, 但是缓解者与未缓解者之间的肠促胰岛素差异非常小。 结论: 胃旁路术后糖尿病无缓解的个体对口服耐量试验中β细胞的应答较差, 对胰高血糖素的抑制也较小；根据糖尿病缓解状态进行分组, 发现体重与肠促胰岛素的差异非常小。.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Recurrence

We aimed to test the hypothesis that addition of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to insulin in C-peptide-positive patients with type 1 diabetes (T1D) will result in a reduction in glycated haemoglobin (HbA1c) with reduced insulin requirements and a rise in C-peptide concentrations. We conducted a retrospective analysis of 11 normal-weight patients with T1D consecutively treated with a GLP-1RA in addition to insulin. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, and C-peptide concentrations prior to and 12 ± 1 weeks after GLP-1RA therapy. At the end of 12 ± 1 weeks of GLP-1RA therapy, HbA1c fell from 10.74 ± 0.96% (95 ± 10.5 mmol/mol) to 7.4 ± 0.58% (58 ± 6.3mmol/mol) (P < 0.01), body weight fell from 71 ± 2.0 to 69 ± 2 kg (P = 0.06), and total insulin dose was reduced by 64% from 33 ± 6 to 11 ± 5 units (P < 0.01). Five out of 10 patients did not require any insulin. C-peptide concentrations increased significantly from 0.43 ± 0.09 ng/ml (0.14 ± 0.02 nmol/L) to 1.42 ± 0.42ng/ml (0.47 ± 0.13 nmol/L) (P = 0.01). Addition of GLP-1RA therapy to insulin in normal-weight patients with T1D led to a reduction in HbA1c with reduced insulin requirements, a 3.5-fold increase in C-peptide concentrations and freedom from insulin therapy in 50% of patients who tolerated the GLP-1RA therapy over a period of 12 ± 1 weeks.

Topics: Adult; Autoantibodies; Body Weight; C-Peptide; Deprescriptions; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Male; Middle Aged; Recombinant Fusion Proteins; Retrospective Studies; Treatment Outcome; Weight Loss

The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve β-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of <12 months duration.. All three active treatments produced on-treatment reductions in weight and improvements in HbA. In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved β-cell function during active treatment failed to produce persistent benefits after treatment withdrawal. These observations suggest that continued intervention may be required to alter the progressive β-cell dysfunction in IGT or early type 2 diabetes.

Topics: Adult; Arginine; B-Lymphocytes; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin Resistance; Liraglutide; Male; Metformin; Middle Aged; Withholding Treatment

This retrospective study investigated the effect of adding metformin to pharmacologic insulin dosing in type 1 diabetics on insulin therapy 1 year after treatment compared with patients on insulin therapy alone.. Twenty-nine adults with type 1 diabetes who had metformin added to their insulin therapy for 12 months were compared with 29 adults with type 1 diabetes who remained on insulin-alone therapy.. Fifty-eight patients with C peptide negative-type 1 diabetics (26 females, mean age: 29.01 ± 7.03 years, BMI: 24.18 ± 3.16 kg/m2) were analyzed. Age, sex, body weight, insulin dose requirement, plasma glucose (PG), blood pressure (BP), and lipids did not differ between groups before treatment (p > 0.05). Metabolic syndrome (44.8 vs 41.4%, p > 0.05) did not differ between the metformin-insulin and insulin alone groups before treatment. Metabolic syndrome was more decreased in the metformin-insulin group than in the insulin alone group after treatment (-8.9 ± 1.3 vs. 2.5 ± 0.6%, p = 0.028). Insulin dose requirement was lower in the metformin-insulin group than in the insulin alone group (-0.03 vs. 0.11 IU/kg/d, p = 0.006). Fasting PG (-26.9 ± 54.2 vs. 0.7 ± 29.5 mg/dL, p = 0.022) and postprandial PG (-43.1 ± 61.8 mg/dL vs. -3.1 ± 40.1 mg/dL, p = 0.010) was more decreased in the metformin-insulin group than in the insulin alone group. Body weight, lipids, and HbA1c did not differ between the groups (p > 0.05).. Metformin decreased glucose concentrations, reduced metabolic syndrome, as well as insulin dose requirement more than insulin therapy alone, 1 year after treatment. These results were independent of blood lipid improvement or weight loss, although on average weight remained decreased with metformin-insulin therapy, whereas the average weight increased with insulin therapy alone.

Topics: Adult; Biomarkers; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metabolic Syndrome; Metformin; Prognosis; Retrospective Studies

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

Topics: Adenosine Triphosphatases; Animals; bcl-2-Associated X Protein; Blood Glucose; Blood Proteins; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Ginkgo biloba; Glucokinase; Glucose Tolerance Test; Glycated Serum Proteins; Glycoproteins; Islets of Langerhans; Male; Physical Conditioning, Animal; Polysaccharides; Proto-Oncogene Proteins c-bcl-2; Rats

BACKGROUND The aim of this study was to compare the effects of liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, and insulin glargine, a long-acting insulin analog, on glycemic control and pancreatic β-cell function in db/db mice. MATERIAL AND METHODS Eight-week-old male db/db mice (n=40) were divided into five groups: the vehicle-treated group (VG) (n=8); the insulin glargine-treated group (GG) (dose, 450 mg/kg) (n=8), the low-dose liraglutide-treated group (LLG) (dose, 75 μg/kg) (n=8), the mid-dose liraglutide-treated group (MLG) (150 μg/kg) (n=8), and the high-dose liraglutide-treated group (HLG) (300 μg/kg) (n=8), treated with subcutaneous injection once daily, from 8-14 weeks-of-age. Body weight, pancreatic weight, levels of blood glucose, triacylglycerol, C-peptide, and the intraperitoneal glucose tolerance test (IPGTT) were used. Expression levels of the INS1 gene were measured using reverse transcription polymerase chain reaction (RT-PCR), and pancreatic and duodenal homeobox 1 (Pdx1), paired box 4 (Pax4), and paired box 6 (Pax6) mRNA expression were measured. RESULTS Both insulin glargine and liraglutide improved glycemic control of db/db mice when compared with vehicle. The following were significantly increased in the HLG compared with the GG: the receiver operating characteristic (ROC) area under the curve (AUC) for the IPGTT; C-peptide levels; the pancreas to body weight coefficient; expression levels of the INS1 gene and pancreatic transcription factors Pdx1, Pax4 and Pax6. Liraglutide treatment was without hypoglycemic effects. CONCLUSIONS Liraglutide acted in a dose-dependent manner on glycemic control of db/db mice, and was more effective than insulin glargine, when administered at a high dose.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Glargine; Insulin-Secreting Cells; Liraglutide; Male; Mice; RNA, Messenger; Triglycerides; Up-Regulation

We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor-deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice.. In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured.. The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels.. High-protein, low-carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients.

Topics: Albuminuria; Animals; Blood Glucose; Body Weight; C-Peptide; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Dietary Proteins; Insulin; Insulin Secretion; Leptin; Male; Maltose; Mice; Mice, Inbred C57BL; Mice, Knockout; Starch

The aim of this study was to identify the risk factors for presence and severity of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in Korean children and adolescents. A retrospective chart review of children and adolescents newly diagnosed with T1DM was conducted in seven secondary and tertiary centers in Korea. Eligible subjects were < 20 years of age and had records on the presence or absence of DKA at the time of T1DM diagnosis. DKA severity was categorized as mild, moderate, or severe. Data were collected on age, height, body weight, pubertal status, family history of diabetes, delayed diagnosis, preceding infections, health insurance status, and parental education level. A total of 361 patients (male 46.3%) with T1DM were included. Overall, 177 (49.0%) patients presented with DKA at T1DM diagnosis. Risk factors predicting DKA at T1DM diagnosis were age ≥ 12 years, lower serum C-peptide levels, presence of a preceding infection, and delayed diagnosis. Low parental education level and preceding infection increased the severity of DKA. These results suggest that alertness of the physician and public awareness of diabetes symptoms are needed to decrease the incidence and severity of DKA at T1DM diagnosis.

Topics: Adolescent; Asian People; Body Weight; C-Peptide; Child; Child, Preschool; Delayed Diagnosis; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Male; Republic of Korea; Retrospective Studies; Risk Factors; Severity of Illness Index; Tertiary Care Centers

Obesity and late-night food consumption are associated with impaired glucose tolerance. Late-night carbohydrate consumption may be particularly detrimental during late pregnancy because insulin sensitivity declines as pregnancy progresses. Further, women who were obese (Ob) prior to pregnancy have lower insulin sensitivity than do women of normal weight (NW). The aim of this study is to test the hypothesis that night-time carbohydrate consumption is associated with poorer glucose tolerance in late pregnancy and that this association would be exacerbated among Ob women. Forty non-diabetic African American women were recruited based upon early pregnancy body mass index (NW, <25 kg m(-2) ; Ob, ≥30 kg m(-2) ). Third trimester free-living dietary intake was assessed by food diary, and indices of glucose tolerance and insulin action were assessed during a 75-g oral glucose tolerance test. Women in the Ob group reported greater average 24-h energy intake (3055 kcal vs. 2415 kcal, P < 0.05). Across the whole cohort, night-time, but not day-time, carbohydrate intake was positively associated with glucose concentrations after the glucose load and inversely associated with early phase insulin secretion (P < 0.05). Multiple linear regression modelling within each weight group showed that the associations among late-night carbohydrate intake, glucose concentrations and insulin secretion were present only in the Ob group. This is the first study to report an association of night-time carbohydrate intake specifically on glucose tolerance and insulin action during pregnancy. If replicated, these results suggest that late-night carbohydrate intake may be a potential target for intervention to improve metabolic health of Ob women in late pregnancy.

Topics: Adolescent; Adult; Black or African American; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diet; Diet Records; Dietary Carbohydrates; Feeding Behavior; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Linear Models; Metabolic Diseases; Nutrition Assessment; Obesity; Pregnancy; Time Factors; Young Adult

To assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes.. We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with β-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change.. Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C-peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P ≤ 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ≤0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol [-0.5 vs. -1.4%], P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol [-0.2 vs. -1.4%], P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change.. Clinical markers of low β-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Postprandial Period; Prospective Studies

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 objective was to determine the value of clinical and analytical maternal factors to predict birth weight and umbilical cord biochemical markers of diabetic fetopathy.. Prospective evaluation of gestational diabetes pregnancies (n = 50). Maternal weight-related clinical and analytical factors were collected during pregnancy. After birth, an umbilical cord sample was taken.. Univariate linear regression analysis showed relationship between maternal weight, glycated hemoglobin (HbA1c) and insulin-like growth factor 1 (IGF1) with birth weight percentile. A significant association was found between maternal weight and cord insulin and C-peptide. Maternal HbA1c, leptin and insulin during pregnancy showed a positive linear association to cord leptin, insulin and C-peptide. In multivariate analysis models, final maternal BMI showed an independent positive association with cord C-peptide.. Maternal weight-related and analytical parameters show diagnostic value to birth weight and cord markers.

Topics: Adult; Birth Weight; Body Weight; C-Peptide; Diabetes, Gestational; Female; Fetal Blood; Fetal Diseases; Glycated Hemoglobin; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Pregnancy

Obesity is a major risk factor for several cancers, including female cancers. Endogenous hormones and inflammatory factors may mediate the association between anthropometric measures and cancer risk, although these associations have been studied mainly in Caucasians. The aim of the current study was to explore the association of circulating hormones, adipokines, and inflammatory factors with obesity and overweight in premenopausal Mexican women.. We conducted a cross-sectional analysis of 504 premenopausal women from the large Mexican Teachers' Cohort (MTC, ESMaestras) study to determine the association of insulin-like growth factor I (IGF-I), its major circulating binding protein (IGFBP-3), leptin, adiponectin, C-peptide, and C-reactive protein with comprehensive measures of body size. Biomarkers were measured by immunoassays. Multivariate regression analyses were performed to compare geometric mean biomarker concentrations with measured markers of body size and adiposity.. Mean IGF-I and IGFBP-3 concentrations significantly increased with increasing height and leg length. Concentrations of IGF-I, adiponectin, and the IGF-I/IGFBP-3 ratio strongly decreased with increasing BMI, weight, waist and hip circumferences, waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR), while CRP, leptin, C-peptide concentrations, and the leptin/adiponectin ratio strongly increased. Adiponectin and the leptin/adiponectin ratio remained significantly related to measures of central adiposity (waist circumference, WHpR, and WHtR) after adjustment by body mass index.. The results of our study suggest a strong relation between biomarkers and body size in this study population and suggest that different fat depots may have different metabolic properties.

Topics: Adiposity; Adult; Biomarkers; Body Mass Index; Body Size; Body Weight; C-Peptide; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Female; Humans; Immunoassay; Inflammation; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Mexico; Middle Aged; Multivariate Analysis; Obesity; Overweight; Premenopause; Waist Circumference; Waist-Hip Ratio

Circulating levels of the adipokine adipocyte fatty acid-binding protein (AFABP) are increased in obesity. However, the influence of circulating AFABP on insulin sensitivity in vivo remains unclear.. C57BL/6NTac mice (10 weeks) were treated over 8 weeks i.p. with saline (control) or recombinant AFABP (0.5 mg/kg/d). A comprehensive characterization of metabolic parameters, body composition, and energy expenditure was performed. Furthermore, the effect of AFABP on pancreatic β-cell responsiveness, hepatic glycogen content, and peroxisome proliferator-activated receptor (PPAR) γ protein expression was elucidated.. In male mice, AFABP treatment induced insulin resistance with significantly increased fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance. In female animals, a similar trend was observed. In both genders, no difference in body weight, lipid parameters, body composition, or energy expenditure could be detected between AFABP-treated and control mice. Insulin resistance in male AFABP-treated mice was accompanied by decreased PPARγ protein content in perigonadal adipose tissue and diminished circulating adiponectin. AFABP treatment did not affect pancreatic β-cell responsiveness and hepatic glycogen content.. Circulating AFABP induces insulin resistance in male mice. AFABP-mediated degradation of PPARγ in adipose tissue and subsequently decreased expression of insulin-sensitizing adiponectin are potential mechanisms for this effect.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; C-Peptide; Fatty Acid-Binding Proteins; Female; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma

Shubat, probiotic fermented camel milk, has been used both as a drink with ethnic flavor and a medicine among Kazakh population for diabetic patients. Kazakh people have lower diabetic prevalence and impaired fasting glucose (IFG) than do other ethnic groups living in Xinjiang China, which might be related to the beneficial properties of shubat. We therefore prepared shubat in laboratory and tested anti-diabetic activity and evaluated its possible hypolipidemic and renoprotective effects in type 2 diabetic rats.. Type 2 diabetic rats were induced by an administration of high-glucose-fat diet for 6 weeks and an intraperitoneal injection of streptozotocin (STZ, 30mg/kg). Diabetic rats were divided randomly into four groups and treated for 28 days with sitagliptin (30mg/kg) or shubat (6.97×10(6) lactic acid bacteria+2.20×10(4) yeasts) CFU/mL, (6.97×10(7) lactic acid bacteria+2.20×10(5) yeasts) CFU/mL and (6.97×10(8) lactic acid bacteria+2.20×10(6) yeasts) CFU/mL. In addition, a normal control group and a diabetic control group were used for comparison. All drugs were given orally once daily 10mL/kg for 4 weeks. Fasting blood glucose (FBG) and body weight (BW) were measured before treatment and every week thereafter. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), serum creatinine (SCr), blood urea nitrogen (BUN), C-peptide, glycated hemoglobin (HbAlc), glucagon-like peptide-1 (GLP-1) levels and pancreas tissue sections were tested after 4 weeks.. Shubat demonstrated positive hypoglycemic activity on FBG, HbAlc, C-peptide and GLP-1 levels, high dose shubat decreased FBG (P<0.01) and HbAlc (P<0.05), increased C-peptide (P<0.05) and GLP-1 (P<0.01), decreased serum TC, TG, LDL-c (P<0.05), increased HDL-c (P<0.01), and improved the reduction of body weight as well as decreased SCr and BUN levels (P<0.01) compared to diabetic controls. Histological analysis showed shubat protected the function of islets of type 2 diabetic rats.. The results of this study indicate that shubat has significant hypoglycemic potential in T2D rats and may modulate lipid metabolism and protect renal function in the type 2 diabetic condition, which might be related to various probiotics acting through promoting the release of GLP-1 and improving the function of β-cells.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cultured Milk Products; Diabetes Mellitus, Experimental; Diet, High-Fat; Dietary Carbohydrates; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Hypertrophy; Hypoglycemic Agents; Kidney; Male; Pancreas; Probiotics; Rats; Sitagliptin Phosphate; Streptozocin

To investigate the effects of transplantation of insulin-producing cells (IPCs) in the treatment of diabetic rats after 90% pancreatectomy.. Human umbilical cord mesenchymal stem cells (UCMSCs) were isolated and induced into IPCs using differentiation medium. Differentiated cells were examined by dithizone (DTZ) staining, reverse transcription-polymerase chain reaction (RT-PCR), and real-time RT-PCR. C-peptide release, both spontaneously and after glucose challenge, was measured by ELISA. IPCs were then transplanted into Sprague-Dawley rats after 90% pancreatectomy and blood glucose levels and body weight were measured.. The differentiated cells were positive for DTZ staining and expressed pancreatic β-cell related genes. C-peptide release by the differentiated cells increased after glucose challenge (380.6 ± 15.32 pmol/L vs 272.4 ± 15.32 pmol/L, P < 0.05). Further, in the cell transplantation group, blood sugar levels were significantly lower than in the sham group 2 wk after transplantation (18.7 ± 2.5 mmol/L vs 25.8 ± 1.25 mmol/L, P < 0.05). Glucose tolerance tests showed that 45 min after intraperitoneal glucose injection, blood glucose levels were significantly lower on day 56 after transplantation of IPCs (12.5 ± 4.7 mmol/L vs 42.2 ± 9.3 mmol/L, P < 0.05).. Our results show that UCMSCs can differentiate into islet-like cells in vitro under certain conditions, which can function as IPCs both in vivo and in vitro.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cell Differentiation; Cell Proliferation; Cell Shape; Cells, Cultured; Cord Blood Stem Cell Transplantation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Expression Regulation; Glucose Tolerance Test; Humans; Insulin-Secreting Cells; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pancreatectomy; Rats, Sprague-Dawley; Time Factors; Umbilical Cord; Wharton Jelly

Global disruption of the GH receptor in mice (GHR-/-) produces a large and reproducible extension in lifespan. Since lack of GH action in muscle resulting in improved glucose homeostasis is potentially a mechanism by which GHR-/- mice are long-lived, and since no information on muscle-specific GHR disruption in females is available, we generated and characterized a line of muscle-specific GHR disrupted (MuGHRKO) mice. As expected, male MuGHRKO mice had improved fasting blood glucose, insulin, c-peptide, and glucose tolerance. In contrast, female MuGHRKO mice exhibited normal glucose, insulin, and glucose tolerance. Body weight was mildly but significantly altered in opposite directions in males (decreased) and females (increased) compared to controls. Grip strength and treadmill endurance were unchanged with advanced age in both sexes, suggesting that the direct action of GH on muscle has minimal effect on age-related musculoskeletal frailty. Longevity was unchanged in both sexes at Ohio University and significantly increased for males at University of Michigan. These data suggest that removal of GHR in muscle of male MuGHRKO mice replicates some of the health benefits seen in global GHR-/- mice including improvements to glucose homeostasis and smaller body weight in males, which may explain the trends observed in lifespan.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; C-Peptide; Carrier Proteins; Energy Metabolism; Female; Glucose Intolerance; Health Status; Insulin; Longevity; Male; Mice; Mice, Knockout; Muscle Strength; Muscle, Skeletal; Physical Endurance; Sex Characteristics

Genome-wide association studies have revealed an association of the transcription factor ETS variant gene 5 (ETV5) with human obesity. However, its role in glucose homeostasis and energy balance is unknown.. Etv5 knockout (KO) mice were monitored weekly for body weight (BW) and food intake. Body composition was measured at 8 and 16 weeks of age. Glucose metabolism was studied, and glucose-stimulated insulin secretion was measured in vivo and in vitro.. Etv5 KO mice are smaller and leaner, and have a reduced BW and lower fat mass than their wild-type controls on a chow diet. When exposed to a high-fat diet, KO mice are resistant to diet-induced BW gain. Despite a greater insulin sensitivity, KO mice have profoundly impaired glucose tolerance associated with impaired insulin secretion. Morphometric analysis revealed smaller islets and a reduced beta cell size in the pancreatic islets of Etv5 KO mice. Knockdown of ETV5 in an insulin-secreting cell line or beta cells from human donors revealed intact mitochondrial and Ca(2+) channel activity, but reduced insulin exocytosis.. This work reveals a critical role for ETV5 in specifically regulating insulin secretion both in vitro and in vivo.

Topics: Animals; Body Composition; Body Weight; C-Peptide; Diet, High-Fat; DNA-Binding Proteins; Eating; Exocytosis; Genome-Wide Association Study; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Insulin Secretion; Mice; Mice, Knockout; Transcription Factors

The ZAC1 gene, mapped to the 6q24 region, is part of a network of co-regulated imprinted genes involved in the control of embryonic growth. Loss of methylation at the ZAC1 differentially methylated region (DMR) is associated with transient neonatal diabetes mellitus, a developmental disorder involving growth retardation and diabetes in the first weeks of post-natal life. We assessed whether the degree of methylation of the ZAC1 DMR in leukocytes DNA extracted from cord blood is associated with fetal, birth and post-natal anthropometric measures or with C-peptide concentrations in cord serum. We also searched for an influence of dietary intake and maternal parameters on ZAC1 DMR methylation. We found positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). However, there were no significant correlations between the ZAC1 DMR MI and cord blood C-peptide levels. Maternal intakes of alcohol and of vitamins B2 were positively correlated with ZAC1 DMR methylation (respectively, r = 0.2 and 0.14; P = 0.004 and 0.04). The influence of ZAC1 seems to start in the second half of pregnancy and continue at least until the first year of life. The maternal environment also appears to contribute to the regulation of DNA methylation.

Topics: Adult; Age Factors; Alcohol Drinking; Anthropometry; Body Weight; C-Peptide; Cell Cycle Proteins; Cohort Studies; Diet; DNA Methylation; Female; Fetal Blood; Fetal Development; Genomic Imprinting; Humans; Infant; Infant, Newborn; Male; Pregnancy; Smoking; Transcription Factors; Tumor Suppressor Proteins; Young Adult

The leaf of Malus toringoides (Rehd.) Hughes is a traditional folk medicine in Tibet, China, which is called "E Se" in Tibetan language. This original plant grows on snow mountains at an attitude of 3000 to 3700 m. It is primarily used to treat hypertension, hyperlipidemia, hyperglycemia, indigestion and other diseases. This study aimed to evaluate the antidiabetic effect of flavonoids extracted from E Se (ESF) and to explore the potential mechanism in streptozotocin (STZ) or alloxan (ALX) induced diabetic mice and STZ-induced diabetic rats.. 72 h after the establishment of a diabetic model, STZ or ALX induced diabetic mice and STZ-induced diabetic rats were treated daily with ESF at doses of 45, 90, 180 mg/kg and 37.5, 75, 150 mg/kg, respectively. Both mice and rats were fasted for 5h before administration and the blood glucose (BG) levels were tested 1h after treatment. Body weight was determined every other day. For STZ-induced rats, glycosylated hemoglobin (Hb1Ac), serum insulin and c-peptide, hepatic glycogen, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in liver were assessed on the fourth day after BG level detection.. Compared with the model group, the general behavior of mice treated with ESF (90, 180 mg/kg) and rats treated with ESF (75, 150 mg/kg) became better and BG levels were significantly reduced (P<0.05). Significant decrease (P<0.05) in Hb1Ac level was observed in ESF-treated rats compared with diabetic rats. Significant increase (P<0.05 ) in serum insulin and c-peptide were detected in ESF-treated rats. The treatment also significantly (P<0.05) elevated SOD activity and reduced MDA level in the liver of diabetic rats. Besides, ESF 150 mg/kg had a trend of rising hepatic glycogen content of diabetic rats.. The findings of this study suggest that flavonoids from the Malus toringoides (Rehd.) Hughes leaves may possess an antidiabetic activity in animals with established diabetes.

Topics: Animals; Behavior, Animal; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Female; Flavonoids; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Liver; Male; Malondialdehyde; Malus; Mice; Phytotherapy; Plant Leaves; Rats, Sprague-Dawley; Superoxide Dismutase

This study was designed to evaluate the impact of fructose-rich diet and chronic kidney disease (CKD) on the in vitro function of pancreatic islets.. Fifty-four rats were divided into 3 equal groups as follows: control, rats with CKD 1/2 that underwent surgical uninephrectomy, and rats with CKD 5/6 that underwent uninephrectomy and kidney cortex mass resection. Each group was further assigned to 3 diet protocols--regular diet, regular diet with 10% fructose (F10), and 60% fructose-rich diet (F60). After 8 weeks of insulin administration, C-peptide, glycated hemoglobin level, serum urea nitrogen, creatinine clearance, and homeostasis model assessment of insulin resistance were evaluated. Static glucose insulin stimulation test of isolated pancreatic islets and histologic analysis of pancreatic tissue were performed.. The F10 diet increased the levels of insulin and C-peptide in all groups. Homeostasis model assessment of insulin resistance was increased in all animals fed with fructose. The elevated levels of creatinine and diminished creatinine clearance were detected in CKD 5/6 rats fed with 60% fructose-rich diet. The F10 diet resulted in high levels of serum insulin and C-peptide and glucose-stimulated insulin secretion. Fructose-rich diet increased the islet size and number, with irregular morphology and exocrine tissue fibrosis.. The fructose-rich diet accelerates the progression of CKD and affects the pancreatic islet function.

Topics: Animals; Body Weight; C-Peptide; Creatinine; Dietary Carbohydrates; Fructose; Glucose; Hypoglycemic Agents; In Vitro Techniques; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Kidney Failure, Chronic; Male; Rats, Wistar

Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition.

Topics: Amino Acids, Branched-Chain; Analysis of Variance; Animals; Biomarkers; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Gene Expression Profiling; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Ketones; Rats, Sprague-Dawley; Retina; Retinitis; Synapses

The encapsulation of porcine islets is an attractive methodology for the treatment of Type I diabetes. In the current study, the use of pravastatin as a mild anti-inflammatory agent was investigated in pancreatectomized diabetic canines transplanted with porcine islets encapsulated in agarose-agarose macrobeads and given 80 mg/day of pravastatin (n = 3) while control animals did not receive pravastatin (n = 3). Control animals reached preimplant insulin requirements on days 18, 19, and 32. Pravastatin-treated animals reached preimplant insulin requirements on days 22, 27, and 50. Two animals from each group received a second macrobead implant: control animals remained insulin-free for 15 and 21 days (AUC = 3003 and 5078 mg/dL/24 hr days 1 to 15) and reached preimplant insulin requirements on days 62 and 131. Pravastatin treated animals remained insulin-free for 21 and 34 days (AUC = 1559 and 1903 mg/dL/24 hr days 1 to 15) and reached preimplant insulin requirements on days 38 and 192. Total incidence (83.3% versus 64.3%) and total severity (22.7 versus 18.3) of inflammation on tissue surfaces were higher in the control group at necropsy. These findings support pravastatin therapy in conjunction with the transplantation of encapsulated xenogeneic islets for the treatment of diabetes mellitus.

Topics: Animals; Anticholesteremic Agents; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Dogs; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Pancreas; Pravastatin; Sepharose; Swine; Time Factors; Transplantation, Heterologous

We have previously described the use of a double coated agarose-agarose porcine islet macrobead for the treatment of type I diabetes mellitus. In the current study, the long-term viral safety of macrobead implantation into pancreatectomized diabetic dogs treated with pravastatin (n = 3) was assessed while 2 dogs served as nonimplanted controls. A more gradual return to preimplant insulin requirements occurred after a 2nd implant procedure (days 148, 189, and >652) when compared to a first macrobead implantation (days 9, 21, and 21) in all macrobead implanted animals. In all three implanted dogs, porcine C-peptide was detected in the blood for at least 10 days following the first implant and for at least 26 days following the second implant. C-peptide was also present in the peritoneal fluid of all three implanted dogs at 6 months after 2nd implant and in 2 of 3 dogs at necropsy. Prescreening results of islet macrobeads and culture media prior to transplantation were negative for 13 viruses. No evidence of PERV or other viral transmission was found throughout the study. This study demonstrates that the long-term (2.4 years) implantation of agarose-agarose encapsulated porcine islets is a safe procedure in a large animal model of type I diabetes mellitus.

Topics: Animals; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dogs; Insulin; Islets of Langerhans; Male; Pravastatin; Sepharose; Swine; Time Factors

To evaluate whether preoperative measurement of fasting plasma C-peptide levels is useful to predict diabetes outcome after Roux-en-Y gastric bypass (RYGB) surgery.. Diabetes outcome after RYGB was evaluated in 126 obese patients: 41 non-diabetic controls (NDC), 29 with impaired glucose tolerance (IGT) and 56 had type 2 diabetes mellitus (T2DM). Body weight, fasting plasma glucose, fasting C-peptide levels, and HbA1c were measured at baseline and 3.6 ± 0.16 years after GBS. Complete resolution of diabetes was defined as: fasting glucose <7.0 mmol/l, HbA1c <6.5 %, achieved without anti-diabetic medication.. Patients with complete resolution of diabetes had a more recent diagnosis of T2DM, lower preoperative HbA1c levels and lower daily doses of metformin and insulin use. These parameters were related to postoperative HbA1c levels but they failed to mark the specific patients who had not reached complete resolution of T2DM. Fasting preoperative C-peptide levels had better predictive power: 90 % of T2DM patients with preoperative fasting C-peptide levels >1.0 nmol/l achieved a postoperative HbA1c <6.5 %, and 74 % achieved complete resolution of their diabetes. In contrast, none of the T2DM patients with a preoperative fasting C-peptide <1.0 nmol/l attained these goals.. A preoperative fasting plasma C-peptide level <1.0 nmol/l in severely obese T2DM patients indicates partial β-cell failure, and is associated with a markedly reduced chance of complete resolution of T2DM after RYGB. We therefore advocate measuring C-peptide levels in all diabetic patients up for bariatric surgery to improve the prediction of outcome.

Topics: Adult; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Follow-Up Studies; Gastric Bypass; Glycated Hemoglobin; Humans; Male; Middle Aged; Netherlands; Obesity, Morbid; Postoperative Period; Predictive Value of Tests; Preoperative Period; Remission Induction; Retrospective Studies; Treatment Outcome; Weight Loss

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

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

Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy.. Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy.. In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated.. The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines.

Topics: Adiponectin; Anticonvulsants; Body Mass Index; Body Weight; C-Peptide; Child; Epilepsy; Female; Fructose; Humans; Insulin; Leptin; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Resistin; Topiramate; Valproic Acid

This study was done to characterize the natural course of C-peptide levels in patients with type 1 diabetes and identify distinguishing characters among patients with lower rates of C-peptide decline. A sample of 95 children with type 1 diabetes was analyzed to retrospectively track serum levels of C-peptide, HbA1c, weight, BMI, and diabetic complications for the 15 yr after diagnosis. The clinical characteristics were compared between the patients with low and high C-peptide levels, respectively. The average C-peptide level among all patients was significantly reduced five years after diagnosis (P < 0.001). The incidence of diabetic ketoacidosis was significantly lower among the patients with high levels of C-peptide (P = 0.038). The body weight and BMI standard deviation scores (SDS) 15 yr after diagnosis were significantly higher among the patients with low C-peptide levels (weight SDS, P = 0.012; BMI SDS, P = 0.044). In conclusion, C-peptide level was significantly decreased after 5 yr from diagnosis. Type 1 diabetes patients whose beta-cell functions were preserved might have low incidence of diabetic ketoacidosis. The declines of C-peptide level after diagnosis in type 1 diabetes may be associated with changes of body weight and BMI.

Topics: Adolescent; Body Mass Index; Body Weight; C-Peptide; Child; Child, Preschool; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Diabetic Retinopathy; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Incidence; Infant; Male; Peripheral Nervous System Diseases; Retrospective Studies

We have previously reported that C-peptide modulates insulin-mediated inhibition of lipolysis and glucose consumption but has no significant effects per se on adipose tissue of normal rats. It has been repeatedly observed that certain actions of C-peptide are restricted to the diabetic states. In the present study, therefore, we examined whether C-peptide alters lipolysis in adipose tissue of diabetic rats. Rats were rendered diabetic by streptozotocin and divided into 2 groups; insulin treated and untreated. Retroperitoneal adipose tissue was excised aseptically, subjected to organ culture and incubated with rat C-peptide, insulin, or a combination of both peptides in the presence or absence of isoproterenol. Tissue lipolysis was assessed by the rate of glycerol release into the culture media. The cultures were pretreated with cilostamide, a phosphodiesterase-3B enzyme inhibitor, when the role of this enzyme was to be examined. C-Peptide on its own, like insulin, significantly inhibited isoproterenol-stimulated lipolysis in the adipose tissue of untreated diabetic rats. The effect was enhanced by a combination of C-peptide and insulin. Notably, the C-peptide's effect was totally blocked in the presence of cilostamide. In the adipose tissue of insulin treated rats, however, C-peptide failed to show any significant antilipolytic effects. These data show that C-peptide has the potential to act, conditionally, as an antilipolytic hormone by activating phosphodiesterase-3B and suggest that the action may contribute to the C-peptide's beneficial effects on diabetes-induced complications.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; C-Peptide; Cyclic Nucleotide Phosphodiesterases, Type 3; Diabetes Mellitus, Experimental; Drinking; Enzyme Activation; Humans; Lipolysis; Male; Rats; Rats, Sprague-Dawley

This study was designed to investigate the effect of aging on the glucose metabolism on cynomolgus (Macaca fascicularis) monkeys. A total of 33 cynomolgus monkeys in three aged groups were monitored for glucose levels, serum parameters in fasting state and somatometric measurements. Intravenous glucose tolerance test (IVGTT) and insulin tolerance test (ITT) were also performed. Aging associated changes lies in the less secretion of insulin and C-peptide during IVGTT in cynomolgus monkeys. It was also found that impaired insulin sensitivity occurred in female monkeys during aging based on HOMA-IR and K(ITT) value. In addition, triglyceride level also rose with the increase of age. Less insulin secretion and impaired insulin sensitivity in female were the characteristic during the aging of cynomolgus monkeys in this study. Body mass index, weight and waist hip rate may be the relevant factors in insulin resistance of cynomolgus monkeys.

Topics: Age Factors; Aging; Animals; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Fasting; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Macaca fascicularis; Male; Models, Animal; Sex Factors; Time Factors; Triglycerides; Waist-Hip Ratio

The role of leptin in regulating physical activity is varied. The behavioral effects of leptin signaling depend on the type of activity and the animal's physiological state. We used mice from lines selectively bred for high voluntary wheel running to further study how leptin regulates volitional exercise. Mice from four replicate high runner (HR) lines typically run ~3-fold more revolutions per day than those from four non-selected control (C) lines. HR mice have altered dopamine function and differences from C in brain regions known to be important in leptin-mediated behavior. Furthermore, male HR mice have been found to dramatically increase running when administered Western diet, an effect possibly mediated through leptin signaling. Male mice from generation 61 (representing three HR lines and one C line) were allowed wheel access at 24 days of age and given either Western diet (high in fat and with added sucrose) or standard chow. After four weeks, Western diet significantly increased circulating leptin, insulin, C-peptide, gastric inhibitory polypeptide, and inflammatory hormone resistin concentrations in HR mice (C mice not measured). Western diet increased running in HR mice, but did not significantly affect running in C mice. During the fifth week, all mice received two days of intra-peritoneal sham injections (physiological saline) followed by three days of murine recombinant leptin injections, and then another six days of sham injections. Leptin treatment significantly decreased caloric intake (adjusted for body mass) and body mass in all groups. Wheel running significantly increased with leptin injections in HR mice (fed Western or standard diet), but was unaffected in C mice. Whether Western diet and leptin treatment stimulate wheel running in HR mice through the same physiological pathways awaits future study. These results have implications for understanding the neural and endocrine systems that control locomotor activity, food consumption, and body weight, and how they may vary with genetic background.

Topics: Animals; Body Weight; C-Peptide; Diet, High-Fat; Dietary Fats; Energy Intake; Gastric Inhibitory Polypeptide; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Motor Activity; Recombinant Proteins; Resistin

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

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

Total or partial pancreatectomy followed by autologous islet transplantation is a therapeutic option for the treatment of refractory chronic pancreatitis (CP). Maximization of islet yields from fibrotic and inflamed organs is crucial for prevention of posttransplant diabetes. We adapted technical advancements developed for islet allotransplantation toward islet autotransplantation. Eight patients (two men, six women; ages 24-58 years) underwent total (n = 7) or partial (n = 1) pancreatectomy for the treatment of CP refractory to maximal medical management. Pancreata were preserved in UW solution (UW group) in initial three cases and the last five pancreata were preserved with pancreatic ductal injection followed by ET-Kyoto/oxygenated PFC solutions (DI+TLM group). Islets were isolated by modified Ricordi method and were purified only in one case. All islet infusions were performed under general anesthesia via direct vein injection into the portal venous system with pressure monitoring. Total islet yields (129,314 ± 51,627 vs. 572,841 ± 116,934 IEQ, p < 0.04), islet yield/pancreas weight (1,233 ± 359 vs. 6,848 ± 847 IEQ/g, p < 0.003), and islet yield/patient body weight (1,951 ± 762 vs. 7,305 ± 1,531 IEQ/kg, p < 0.05) were significantly higher in the DI+TLM group when compared to the UW group. Pellet size was also higher (5.3 ± 0.3 vs. 13.5 ± 3.4 ml) in the DI+TLM group, suggesting that this method of preservation effectively protected pancreatic tissue against autolysis. First month posttransplant basal C-peptide and the secretory unit of islet transplant objects (SUITO) index were also higher in the DI+TLM group when compared to the UW group (2.0 ± 0.3 vs. 1.4 ± 0.4 ng/ml and 42.6 ± 12.7 vs. 14.6 ± 5.6, respectively). There were no technical complications related to the infusion. Our results suggest that higher islet yields can be achieved even from chronically inflamed and fibrotic organs using DI+TLM. The techniques applied for islet isolations from normal pancreata are showing promise for fibrotic pancreata from CP patients.

Topics: Adenosine; Adult; Allopurinol; Body Weight; C-Peptide; Epoprostenol; Female; Fluorocarbons; Follow-Up Studies; Glutamine; Glutathione; Humans; Hydroxyethyl Starch Derivatives; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Magnesium Sulfate; Male; Middle Aged; Niacinamide; Organ Preservation; Organ Preservation Solutions; Pancreatitis, Chronic; Raffinose; Transplantation, Autologous; Trehalose

To assess the effects of intrahepatic autotransplantation of bone-derived Beagle canine mesenchymal stem cells (BcMSCs) containing human insulin and EGFP in diabetic Beagle dogs.. BcMSCs were isolated from Beagle canine bone marrow, expanded, and transfected with a recombinant retrovirus MSCV carrying human insulin and EGFP. Animals were made diabetic by an intravenous administration of streptozotocin (STZ, 30 mg/kg) and alloxan (50 mg/kg), followed by intrahepatic autotransplantation of transfected BcMSCs. The variations of body weight, blood glucose, serum insulin levels, and plasma C-peptide were determined after autotransplantation. BcMSCs' survival and human insulin expression in liver and serum were examined by fluorescent microscopy, radioimmunoassay (RIA), and immunohistochemistry (IHC).. The body weight of diabetic Beagle dogs received BcMSCs transplantation increased by 11.09% within 16 wk after treatment, and the average blood glucose levels were 19.80±3.13 mmol/L (d 7) and 9.78±3.11 mmol/L (d 112), while in untreated animals, the average values were 21.20±3.26 mmol/L (d 7) and 22.5±3.22 mmol/L (d 112), showing a significant difference (P<0.05). The detection of C-peptide excluded the possible function of regenerative β cells. However, glucose tolerance test revealed BcMSCs group response was not as efficient as that of normal islets, although they could respond to the glucose challenge.. Experimental diabetes could be relieved effectively for up to 16 wk by intrahepatic autotransplantation of BcMSCs expressing human insulin, which implies a novel approach of gene therapy for type I diabetes.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cell Differentiation; Diabetes Mellitus, Experimental; Dogs; Fluorescent Antibody Technique; Genetic Therapy; Genetic Vectors; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liver; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Recombinant Proteins; Retroviridae; Transplantation, Autologous

Uremic type 2 diabetic patients on hemodialysis need various types of antidiabetic therapies. The aim of the present study was to identify differences between patients on oral antidiabetic drug therapy or insulin substitution or diet therapy alone during their first year of hemodialysis.. Sixty-four type 2 diabetic patients who had started hemodialysis (HD) at our dialysis center between 2003 and 2007 were included in the study. Kidney-transplanted patients (n = 1) and those with chronic infectious or malignant diseases (n = 4) were excluded. Patients were divided into three groups according to their antidiabetic therapy: group 1 consisted of patients on oral antidiabetic drug therapy (n = 12), group 2 of those on insulin therapy (n = 42), and group 3 of those being treated with diet alone (n = 10). At the start of HD and 12 months later, we measured fasting plasma glucose (FPG), HbA1c, the incidence of hypoglycemia (n/patient/month), cholesterol, triglycerides, body weight, and insulin requirements in the insulin-treated group. C-peptide was only measured at the start of dialysis. We evaluated changes in antidiabetic therapy during the first year on dialysis, and the prevalence of vascular disease in each group at the start of HD.. FPG and HbA1c values were similar in all groups at the start of HD and after 1 year. Hypoglycemia occurred more frequently in insulin-treated patients; however, the difference was not significant. Cholesterol levels were similar in all groups, whereas triglycerides were significantly lower in insulin-treated patients (138 ± 28 vs. 176 ± 46 mg/dl; P < 0.05). Body weight was similar in all groups. No significant change in body weight was observed in any group after 12 months on dialysis. At the start of HD, C-peptide levels were lower in insulin-treated patients than in the other groups (1.8 ± 0.9 ng/ml vs. 2.2 ± 1.1 and 2.4 ± 1.1 ng/ml; P < 0.05). During the first 12 months on HD, two patients from group 1 were shifted to group 3 (diet alone), while four patients could reduce their drug dosage (33%). However, two subjects became insulin-dependent. In group 2, insulin therapy could be terminated in two cases, while the insulin dose could be reduced in 20 patients (48%). In group 3, one patient was switched to oral antidiabetic therapy. The prevalence of vascular disease was slightly higher in group 3 (NS).. Within 1 year after the start of HD, the dose of sulfonylurea as well as insulin could be reduced in a large majority of patients. Metabolic control was similar in all groups. Only triglycerides were significantly lower in group 2. The frequency of hypoglycemia and the prevalence of vascular disease were just slightly higher in the group on insulin therapy.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Sulfonylurea Compounds; Triglycerides; Vascular Diseases

Insulin therapy induces remission in subjects with newly diagnosed type 2 diabetes mellitus (T2DM). This study assessed the insulin and C-peptide levels in newly diagnosed T2DM subjects during low-dose insulin therapy.. Twenty newly diagnosed, drug-naive, T2DM patients without acute or chronic complications were the subjects for this study. Premixed insulin (70/30), 16 units, as two divided doses, was started for all subjects after preliminary investigations. The same dose of insulin was continued until normoglycemia was achieved. Subsequently the insulin dose was down-titrated. Plasma insulin, C-peptide, and blood glucose (both fasting and after breakfast) were measured at baseline and monthly for 6 months. Body weight and glycosylated hemoglobin (HbA1c) were measured every 3 months and the lipid profile was obtained at baseline and at 6 months.. Blood glucose levels showed a rapid decreasing trend and reached the near-normoglycemic range by 3 months, whereas plasma insulin and C-peptide showed a slow and steady increase until the fourth month and remained the same during the next 2 months of follow-up. HbA1c was 11.3 ± 1.4% (range, 8.6-13.5%) and 7.05 ± 0.54% (range, 6.3-8.1%) at the time of diagnosis and at the end of 6 months, respectively. The mean weights of the study subjects at baseline and 3 and 6 months were 70 ± 16 kg (range, 44-95 kg), 68 ± 13 kg, and 68 ± 13 kg (P = 0.083), respectively. Total cholesterol, low-density lipoprotein-cholesterol, and triglycerides decreased, whereas high-density lipoprotein-cholesterol was higher at 6 months.. Low-dose insulin therapy in newly diagnosed T2DM leads to β-cell recovery (as documented by plasma insulin and C-peptide levels) by 3-4 months.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Pilot Projects; Statistics, Nonparametric; Triglycerides

Studies of the nutritional status of wild animals are important in a wide range of research areas such as ecology, behavioural ecology and reproductive biology. However, they have so far been strongly limited by the indirect nature of the available non-invasive tools for the measurement of individual energetic status. The measurement of urinary C-peptide (UCP), which in humans and great apes shows a close link to individual nutritional status, may be a more direct, non-invasive tool for such studies in other primates as well and possibly even in non-primate mammals. Here, we test the suitability of UCPs as markers of nutritional status in non-hominid primates, investigating relationships between UCPs and body-mass-index (BMI), skinfold fatness, and plasma C-peptide levels in captive and free-ranging macaques. We also conducted a food reduction experiment, with daily monitoring of body weight and UCP levels. UCP levels showed significant positive correlations with BMI and skinfold fatness in both captive and free-ranging animals and with plasma C-peptide levels in captive ones. In the feeding experiment, UCP levels were positively correlated with changes in body mass and were significantly lower during food reduction than during re-feeding and the pre-experimental control condition. We conclude that UCPs may be used as reliable biomarkers of body condition and nutritional status in studies of free-ranging catarrhines. Our results open exciting opportunities for energetic studies on free-ranging primates and possibly also other mammals.

Topics: Animals; Biomarkers; Body Mass Index; Body Weight; C-Peptide; Diet; Feeding Behavior; Female; Housing, Animal; Macaca; Male; Nutritional Status; Skinfold Thickness; Species Specificity

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

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

In preparation for islet transplantation, diabetes was induced using streptozotocin (STZ) in non-human primates ranging from juveniles to adults with diverse body types: we studied the process with respect to the diabetic state and emergence of adverse events (AEs) and their severity, and identified risk factors for clinical and laboratory AEs. Pharmaceutical-grade STZ was given based on body surface area (BSA) (1050-1250 mg/m(2), equivalent to 80-108 mg/kg) or on body weight (BW) (100 mg/kg) to 54 cynomolgus and 24 rhesus macaques. AEs were related to risk factors, i.e. obesity parameters, BW and BSA, age and STZ dose in mg/m(2). Clinical AEs during the first days after infusion prompted euthanasia of three animals. Except for those three animals, diabetes was successfully induced as shown by circulating C-peptide levels, the intravenous glucose tolerance test and/or arginine stimulation test. C-peptide after infusion weakly correlated (P = 0.048) with STZ dose in mg/m(2). Grade ≥3 nephrotoxicity or hepatotoxicity (serum markers >3× baseline or >5 × baseline, respectively) occurred in about 10% of cases and were generally mild and reversible. Grade ≥2 clinical AEs occurred in seven of 78 animals, reversed in four cases and significantly correlated with obesity parameters. Taking girth-to-height ratio (GHtR) as an indicator of obesity, with threshold value 0.92-0.95, the positive predictive value of obesity for AEs was 92% and the specificity 94%. We conclude that diabetes is successfully induced in non-obese animals using a 100 mg/kg pharmaceutical grade STZ dose. Obesity is a significant risk factor, and animals with a higher than normal GHtR should preferably receive a lower dose. The incidence of relevant clinical or laboratory AEs is low. Careful monitoring and supportive medical intervention can result in recovery of AEs.

Topics: Animals; Body Surface Area; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glucose Tolerance Test; Macaca fascicularis; Macaca mulatta; Male; Obesity; Risk Factors; Streptozocin

The effects of long-term dietary supplementation of fish oil (n-3 PUFA-rich) in adult male pigs on body condition as well as insulin sensitivity and secretion were examined. Fifteen Duroc boars aged 204.5 (sd 9.4) d (body weight 145.8 (sd 16.8) kg) received daily 2.5 kg basal diet with a supplement of: (1) 62 g hydrogenated animal fat (n 5); (2) 60 g menhaden oil containing 10.8 g DHA and 9.0 g EPA (n 6); (3) 60 g tuna oil containing 19.8 g DHA and 3.9 g EPA (n 4). Rations were balanced to be isoenergetic. After 7 months of treatments, oral glucose and meal tolerance tests were conducted after insertion of a catheter into the jugular vein. Dietary supplementation with n-3 PUFA altered the blood plasma profile: DHA and EPA increased whereas arachidonic acid decreased (P < 0.01). Plasma glucose, insulin and C-peptide responses to oral glucose and the test meal were not affected by treatments (P>0.34). For all animals, total body fat estimated from body weight and back fat thickness was correlated with both beta-cell function (by homeostasis model assessment (HOMA); r+0.63) and insulin sensitivity (index of whole-body insulin sensitivity and by HOMA; r - 0.63 and r+0.66, respectively). In conclusion, long-term supplementation with dietary n-3 PUFA did not affect insulin metabolism in healthy adult male pigs. The relationship between body fat and insulin sensitivity, well documented in human subjects, suggests that the adult male pig could be a promising animal model for studies on insulin metabolism.

Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; C-Peptide; Dietary Fats; Dietary Supplements; Eating; Fatty Acids; Fatty Acids, Nonesterified; Fish Oils; Glucose Tolerance Test; Insulin; Insulin Secretion; Male; Swine; Weight Gain

The glucose-lowering effect of fat and protein is attenuated or absent in diabetic patients, which suggests that the same may occur in insulin-resistant subjects without diabetes.. The objective was to determine whether the postprandial metabolic responses elicited by fat and protein were influenced by the insulin sensitivity of the subjects and whether fat and protein modulate glucose responses through different mechanisms.. Healthy nondiabetic subjects aged 18-45 y took 50 g oral glucose with 0-30-g doses of canola oil and whey protein on 11 separate mornings after fasting overnight. The subjects were classified into 3 fasting serum insulin (FSI) groups: FSI < 40 pmol/L (n = 9), 40 < or = FSI < 70 pmol/L (n = 8), and FSI > or = 70 pmol/L (n = 8). The relative glycemic response was expressed as the incremental area under the curve (AUC) after each test meal divided by the mean AUC of the glucose control in each subject.. Protein significantly decreased glucose (P < 0.0001) and hepatic insulin extraction (P <0.0001) and increased insulin (P < 0.0001) and glucagon-like peptide 1 (P = 0.004); however, protein had no significant effect on C-peptide (P = 0.69) or on the insulin secretion rate (P = 0.13). No significant FSI x fat (P = 0.19) or FSI x protein (P = 0.08) interaction effects on glucose AUC were observed. In addition, the changes in relative glycemic response per gram of fat (r = -0.05, P = 0.82) or protein (r = -0.08, P = 0.70) were not related to FSI.. The hypoglycemic effect of fat and protein was not blunted by insulin resistance. Protein increased insulin but had no effect on C-peptide or the insulin secretion rate, which suggests decreased hepatic insulin extraction or increased C-peptide clearance.

Topics: Adult; Blood Glucose; Blood Pressure; Body Height; Body Mass Index; Body Weight; C-Peptide; Dietary Fats; Dietary Proteins; Ethnicity; Fasting; Fatty Acids, Monounsaturated; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Liver; Male; Middle Aged; Milk Proteins; Racial Groups; Rapeseed Oil; Reference Values; Waist Circumference; Whey Proteins; Young Adult

The metabolic syndrome (MS) has become an epidemiological problem in Western countries. We developed a diet-induced obese rat model that mimics all the symptoms of MS in humans, but whose insulin resistance, hyperphagia and hyperleptinemia are caused by nutrition rather than genetic modifications.. Spontaneously hypertensive rats (SHR) were allowed for 12 weeks to choose between a cafeteria diet (CD, 20.3 kJ/g) and standard rat chow (11.7 kJ/g). Controls received rat chow.. Body weight (BW) exceeded control levels when SHR were fed with CD. The increase in BW was attributed to enhanced energy intake. The abundance of abdominal fat as well as the plasma levels of leptin and triglycerides increased concomitant with glucose, insulin and C-peptide. This prediabetic condition was further confirmed by a markedly increased insulin response following glucose challenge and by impaired glucose utilization after insulin tolerance tests.. Increases in food intake and BW despite hyperleptinemia indicate leptin resistance following CD feeding. CD-fed SHR feature leptin and insulin resistance, hypertension and obesity, thus mimicking the situation of MS patients. As such, our model is more suitable than the genetically modified rat models used to study human MS.

Topics: Abdominal Fat; Animals; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diet; Disease Models, Animal; Energy Intake; Heart Rate; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Triglycerides

Ghrelin and GH secretagogues, including GH-releasing peptide (GHRP)-6, stimulate food intake and adiposity. Because insulin modulates the hypothalamic response to GH secretagogues and acts synergistically with ghrelin on lipogenesis in vitro, we analyzed whether insulin plays a role in the metabolic effects of GHRP-6 in vivo. Streptozotocin-induced diabetic rats received saline, GHRP-6, insulin, or insulin plus GHRP-6 once daily for 8 wk. Rats receiving saline suffered hyperglycemia, hyperphagia, polydipsia, and weight loss. Insulin, but not GHRP-6, improved these parameters (P < 0.001 for all), as well as the diabetes-induced increase in hypothalamic mRNA levels of neuropeptide Y and agouti-related peptide and decrease in proopiomelanocortin. Cocaine amphetamine-related transcript mRNA levels were also reduced in diabetic rats, with GHRP-6 inducing a further decrease (P < 0.03) and insulin an increase. Diabetic rats receiving insulin plus GHRP-6 gained more weight and had increased epididymal fat mass and serum leptin levels compared with all other groups (P < 0.001). In epididymal adipose tissue, diabetic rats injected with saline had smaller adipocytes (P < 0.001), decreased fatty acid synthase (FAS; P < 0.001), and glucose transporter-4 (P < 0.001) and increased hormone sensitive lipase (P < 0.001) and proliferator-activated receptor-gamma mRNA levels (P < 0.01). Insulin normalized these parameters to control values. GHRP-6 treatment increased FAS and glucose transporter-4 gene expression and potentiated insulin's effect on epididymal fat mass, adipocyte size (P < 0.001), FAS (P < 0.001), and glucose transporter-4 (P < 0.05). In conclusion, GHRP-6 and insulin exert an additive effect on weight gain and visceral fat mass accrual in diabetic rats, indicating that some of GHRP-6's metabolic effects depend on the insulin/glucose status.

Topics: Adipocytes; Agouti-Related Protein; Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Epididymis; Fats; Fatty Acid Synthases; Gene Expression; Ghrelin; Glucose Transporter Type 4; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Neuropeptide Y; Oligopeptides; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Weight Gain

The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect.. The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 + or - 3 yr (mean + or - sd); body mass index 23 + or - 2 kg/m(2); glycosylated hemoglobin 5.4 + or - 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity.. The 12-d intervention period resulted in significant increases in body weight [79 + or - 5 vs. 80 + or - 6 kg (mean + or - sd), P = 0.03] and fasting plasma glucose (5.1 + or - 0.1 vs. 5.6 + or - 0.2 mm, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 + or - 1.7 vs. 9.2 + or - 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 + or - 1.1 vs. 7.8 + or - 2.5 mm, P < 0.0001) and area under curve (AUC) (152 + or - 45 vs. 384 + or - 53 mm.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin,OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 + or - 5 vs. 43 + or - 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation.. Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes.

Topics: Adult; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Diet; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Motor Activity; Prednisolone

The aim of this study is to investigate the effect of body size on insulin-mediated, whole-body glucose uptake (M-value) in morbidly obese (MO) subjects, who have large amounts of fat mass. Furthermore, we aimed at verifying which surrogate insulin-sensitivity index can better substitute the euglycemic clamp values and whether the insulin secretion/insulin resistance index is meaningful also in MO subjects.. The study design is cross-sectional, case-control study of insulin sensitivity--assessed by different methods--and insulin secretion.. One-hundred and sixty-eight subjects ca. 39 years old, with a body mass index (BMI) between 17 and 64 kg m⁻², underwent euglycemic hyperinsulinemic clamp and oral glucose tolerance test (OGTT) with surrogate measures of insulin sensitivity together with body composition by ³H₂O dilution. Insulin secretion rate (ISR) was measured at fast and after OGTT by C-peptide deconvolution.. The population was divided into quartiles of BMI. In the fourth quartile, the best insulin-sensitivity variable between M/I/kg(FFM) and M/I/kg(bw) was the latter, as shown by area under the receiver-operator characteristic (ROC) curve (0.85 vs 0.89). The best index to identify insulin-resistant individuals (lowest distribution quartile: M/I/kg(bw)≤ 29.3 μmol min⁻¹ kg⁻¹ nmol l⁻¹) were Matsuda index and oral glucose insulin sensitivity (OGIS), whereas fasting insulin concentration, QUICKI, and HOMA failed (ROC analysis). M-value declined exponentially as the BMI increased, whereas ISR linearly increased. The insulin secretion/insulin resistance index well applied to MO.. In MO subjects, in which the fat mass is highly represented, fat-free mass cannot be considered the only determinant of insulin sensitivity, thus M-value should be normalized by total body weight. The best surrogates of insulin sensitivity measured by euglycemic clamp are Matsuda index and OGIS. BMI directly affects both insulin sensitivity and ISR and the insulin secretion/insulin resistance index is a valid model to correlate ISR with insulin sensitivity also in MO.

Topics: Adult; Area Under Curve; Blood Glucose; Body Mass Index; Body Size; Body Weight; C-Peptide; Case-Control Studies; Cross-Sectional Studies; Fasting; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Obesity, Morbid

Peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha agonists individually reduce intra-organ triglyceride content and improve insulin sensitivity. However, the precise effects of combined PPAR-gamma and PPAR-alpha therapy on intra-organ triglyceride content and insulin sensitivity in subjects with Type 2 diabetes have not yet been determined.. Diet-controlled Type 2 subjects (n = 9) were studied before and after 16 weeks of combined PPAR-gamma [pioglitazone (PIO), 45 mg daily] and PPAR-alpha [bezafibrate (BEZA), modified release 400 mg daily] agonist therapy. Glucose metabolism and endogenous glucose production were measured following a standard liquid test meal. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy.. Combined PIO and BEZA therapy reduced mean fasting (7.5 +/- 0.5 vs. 6.5 +/- 0.2 mmol/l, P = 0.04) and peak postprandial plasma glucose (15.3 +/- 1.1 vs. 11.7 +/- 0.6 mmol/l, P = 0.007). No significant change in hepatic or muscle triglyceride content was observed. Postprandial suppression of endogenous glucose production remained similar on both study days. Both subcutaneous and visceral fat content increased following therapy.. Combined PIO and BEZA therapy in Type 2 diabetes does not decrease intrahepatic triglyceride content or postprandial endogenous glucose production. This study demonstrates an unexpected adverse interaction of PPAR-alpha with PPAR-gamma agonist therapy.

Topics: Abdominal Muscles; Adult; Aged; Bezafibrate; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Liver; Middle Aged; Pioglitazone; PPAR alpha; PPAR gamma; Thiazolidinediones; Triglycerides

Embryonic stem cell therapy has been proposed as a therapeutic strategy to restore β-cell mass and function in T1DM. Recently, a group from Novocell (now ViaCyte) reported successful development of glucose-responsive islet-like structures after implantation of pancreatic endoderm (PE) derived from human embryonic stem cells (hESC) into immune-deficient mice. Our objective was to determine whether implantation of hESC-derived pancreatic endoderm from Novocell into athymic nude rats results in development of viable glucose-responsive pancreatic endocrine tissue. Athymic nude rats were implanted with PE derived from hESC either via implantation into the epididymal fat pads or by subcutaneous implantation into TheraCyte encapsulation devices for 20 wk. Blood glucose, weight, and human insulin/C-peptide secretion were monitored by weekly blood draws. Graft β-cell function was assessed by a glucose tolerance test, and graft morphology was assessed by immunohistochemistry and immunofluorescence. At 20 wk postimplantation, epididymal fat-implanted PE progressed to develop islet-like structures in 50% of implants, with a mean β-cell fractional area of 0.8 ± 0.3%. Human C-peptide and insulin were detectable, but at very low levels (C-peptide = 50 ± 26 pmol/l and insulin = 15 ± 7 pmol/l); however, there was no increase in human C-peptide/insulin levels after glucose challenge. There was no development of viable pancreatic tissue or meaningful secretory function when human PE was implanted in the TheraCyte encapsulation devices. These data confirm that islet-like structures develop from hESC differentiated to PE by the protocol developed by NovoCell. However, the extent of endocrine cell formation and secretory function is not yet sufficient to be clinically relevant.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Embryonic Stem Cells; Endoderm; Fluorescent Antibody Technique, Direct; Glucose Clamp Technique; Humans; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Longitudinal Studies; Male; Rats; Rats, Nude; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms

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

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

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

Insulin dependent diabetes mellitus (IDDM) results from irreversible loss of beta cells (beta-cells) of the pancreas. A Streptozotocin (STZ)-induced diabetes in animal model mimics, in some aspects, recent onset IDDM. This study was conducted to investigate the effect of nicotinamide on experimentally-induced IDDM. Thirty Spraque Dawley rats were divided into 3 groups; a control group, a diabetic group which received an intraperitoneal (i.p.) injection of 55 mg/kg STZ and a nicotinamide group (1g/kg/day) which were dosed orally for 3 days followed by (i.p.) STZ (55 mg/kg) with the nicotinamide treatment continuing for an additional 14 days. Rats receiving STZ became diabetic after 2 weeks. This diabetic group showed hyperglycemia, and a very low level of C-peptide. Furthermore, pancreatic islets exhibited increased nitric oxide (NO) production together with an increased apoptotic index (as detected by TUNEL and electron microscopy). Nicotinamide treatment prevented STZ-induced diabetes, it also antagonized an increase in NO, and inhibited beta-cell apoptosis. Fasting blood glucose, serum insulin and serum C-peptide were all within the normal range in the nicotinamide group. The nicotinamide protection of beta-cells may be facilitated via inhibition of apoptosis and nitric oxide generation. It is suggested that nicotinamide might be considered an effective agent for the prevention and treatment of IDDM in prediabetic, and early stages, of IDDM.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Niacinamide; Nitrites; Rats; Rats, Sprague-Dawley

Caloric sweetened beverages have been suggested to be a major dietary contributor to weight gain, particularly among adolescents. Dietary recommendations are for moderating intakes of added sugars; however, the question remains whether certain types of sugars should be limited. The objective of this study was to determine the effect of drinking different caloric sweetened beverages on the development of adiposity, metabolic, and endocrine disorders. Young (age 28 days) female Sprague-Dawley rats (n = 8-9 rats/group) were randomly assigned to drink either deionized distilled water (ddH2O) or ddH2O sweetened with 13% (w/v) glucose, sucrose, fructose or high fructose corn syrup 55 (HFCS-55) for 8 weeks. Rats drinking caloric sweetened solutions failed to completely compensate for liquid calories ingested by reducing their consumption of solid food. This resulted in greater total energy intake compared to the ddH2O control; however, there was no significant difference in total energy intake between rats drinking sucrose, fructose or HFCS-55. Of the different caloric sweeteners, only rats drinking HFCS-55 had greater (P < 0.05) final body weights and fat mass compared to the rats drinking ddH2O or glucose solution. This may have occurred because drinking HFCS-55 solution promoted a faster body weight gain. Adiposity induced by caloric sweetened water was not accompanied by metabolic disorders indicated by the absence of dyslipidemia and no differences in fasting serum glucose, insulin or C-peptide among the treatment groups. However, rats drinking HFCS-55 showed lengthened estrous cycles due to prolonged estrus. Based on this study, the type of caloric sweetener added to beverages should be considered when making dietary recommendation for reducing excess body weight and related health risk.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Dyslipidemias; Energy Intake; Fat Body; Female; Insulin; Male; Rats; Rats, Sprague-Dawley; Reproduction; Sweetening Agents

Evaluation of engrafted islets mass is important for clinical care of patients after islet transplantation. Recently, we developed the secretory unit of islet transplant objects (SUITO) index, which reflected engrafted islet mass. In this study, we evaluated the SUITO index for the prediction of clinical outcome after single islet transplantation. Single islet transplantations were performed into six type 1 diabetic patients. Isolated islets were quantitatively assessed at the time of transplantation. The SUITO index was calculated as follows: fasting C-peptide (ng/dl)/[fasting blood glucose (mg/dl) - 63] x 1500. Islet yield/recipient's body weight and SUITO index were evaluated, along with HbA(1C), relative insulin dose (insulin dose posttransplant/pretransplant), and M-values. HbA(1C) improved in all cases, irrespective of the SUITO index score or islet yield/body weight. The average SUITO index from postoperative days 3 to 30 (R(2) = 0.728, p < 0.04), but not islet yield/body weight (R(2) = 0.259, p = 0.303), correlated with relative insulin dose. The daily SUITO index strongly correlated with the daily relative insulin dose (R(2) = 0.558, p < 0.0001) and weakly correlated with the daily M-values (R(2) = 0.207, p < 0.02). A SUITO index score of less than 10 was associated with increasing insulin dose even after islet transplantation. The SUITO index seems to be a better predictor of success of islet transplantations than islet yield/body weight. SUITO index is recommended to assess clinical outcome of islet transplantation.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Cell Separation; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Tissue Donors; Treatment Outcome

The study objective was to determine if Ramadan fasting was safe in patients with type 2 diabetes mellitus (T2D), based upon a determination of the effect of fasting on a broad range of physiological and clinical parameters, including markers of glycemic control and blood pressure. The study was carried out in Ramadan 1422 (December 2001-January 2002) at the Diabetology Services, Hopital Ibn Sina, Rabat, Morocco. One hundred and twenty T2D Moroccan patients (62 women, 58 men), aged 48-60 yrs with well-controlled diabetes through diet and/or oral hypoglycemic drugs (OHD), received dietary instructions and readjustment of the timing of the dose of OHD (gliclazide modified release) according to the fasting/eating periods. Anthropometric indices and physiological parameters (blood pressure, lipid, hematological, and serum electrolyte profiles, as well as markers of glycemic control, nutrition, renal and hepatic function) were measured on the day before Ramadan and then on the 15(th) and 29(th) day of fasting and thereafter 15 days later. Statistical analysis was done by standard methods. Ramadan fasting had no major effect on energy intake, body weight, body mass index, blood pressure, and liver enzymes. Fasting and post-prandial glucose levels decreased, while insulin levels increased. Diabetes was well controlled, as indicated by HbA1c, fructosamine, C-peptide, HOMA-IR, and IGF-1 values. There were fluctuations in some lipid and hematological parameters, creatinine, urea, uric acid, total protein, bilirubin, and electrolytes; however, all values stayed within the proper physiological range. In conclusion, diabetes was well-controlled in patients with dietary/medical management, without serious complications. With a regimen adjustment of OHD, diet control, and physical activity, most patients with T2D whose diabetes was well-controlled before Ramadan can safely observe Ramadan fasting.

Topics: Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Female; Fructosamine; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Islam; Liver Function Tests; Male; Middle Aged; Morocco; Patient Education as Topic; Religion and Medicine; Risk Factors; Treatment Outcome; Triglycerides

In recent years methodological improvements have allowed for more precise estimates of nutrient intake in wild primates. However, estimates of energetic condition have remained relatively imprecise due to the difficulties of estimating digestive efficiency and energy expenditure in these animals. In the absence of a reliable intake-expenditure calculation, a method is needed that directly links changes in energetic condition, such as body mass, to physiological changes that can be detected via markers in body excretions such as urine or feces. One promising marker is C-peptide, a metabolic byproduct of insulin synthesis. Here we present the results of a food restriction experiment carried out in a group of captive bonobos (Pan paniscus). We measured changes in food availability and body mass and determined urinary C-peptide levels with the help of a time-resolved fluoroimmunoassay routinely used for measuring C-peptide in human blood. Urinary C-peptide levels decreased during a period of food restriction and increased again when food availability was continuously increased. During this refeeding phase an increase in body mass was significantly correlated with an increase in urinary C-peptide levels. Our results suggest that urinary C-peptide levels are an accurate indicator of individual energy balance. In conclusion, measuring C-peptide in urine is a promising method to quantify the energetic condition of wild apes.

Topics: Animals; Animals, Zoo; Body Weight; C-Peptide; Caloric Restriction; Circadian Rhythm; Diet; Eating; Energy Metabolism; Female; Freezing; Male; Monitoring, Physiologic; Pan paniscus; Protein Stability; Temperature

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

The aim of present study was to identify the visceral adipose tissue genes differentially expressed in a well-characterized rat model of high-fat diet (HFD)-induced obesity. Male Sprague-Dawley rats were fed either the HFD (17 g lard + 3 g corn oil/100 g) or the normal diet (5 g corn oil/100 g) for 9 weeks. The HFD rats weighed 55% more and accumulated 85% to 133% greater visceral fats than did the normal-diet rats (P < .05). Animals given the HFD for 9 weeks acquired dyslipidemia, fatty liver, insulin resistance, and hyperleptinemia along with the overexpression of several obesity-related genes, such as leptin, tumor necrosis factor alpha, resistin, peroxisome proliferator-activated receptor gamma2, CCAAT/enhancer-binding protein alpha, and sterol regulatory element-binding protein-1c, in the epididymal adipose tissue. The differential gene expression profile obtained from the cDNA microarray analysis followed by the real-time polymerase chain reaction confirmation led to a recruitment of several uncharacterized adipose tissue genes responding to the HFD. We report herein, for the first time, that a series of genes which might be implicated in the insulin-stimulated glucose transporter 4 translocation, such as protein phosphatase 2 (formerly 2A), cell division cycle 42-interacting protein 4, syntaxin 6, linker of T-cell receptor pathways 10, as well as the genes which might be involved in cancer development, such as heat shock 10-kd protein 1, and ras-related C3 botulinum toxin substrate 1, were differentially expressed in the epididymal adipose tissue of rats rendered obese by an HFD.

Topics: Animals; Body Weight; C-Peptide; Dietary Fats; Epididymis; Gene Expression Profiling; Gene Expression Regulation; Glucose; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipids; Liver; Male; Obesity; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley

Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the "Edmonton protocol." To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial.. Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up.. Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test.. These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Etanercept; Exenatide; Follow-Up Studies; Graft Survival; Humans; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Middle Aged; Peptides; Receptors, Tumor Necrosis Factor; Treatment Failure; Venoms

Taurine had the hypoglycemic effect during experimental insulin-dependent diabetes mellitus and decreased the concentrations of glucose and fructosamine, and increased the contents of insulin, C-peptide, and glycogen in the liver. Studying the dynamics of structural changes in pancreatic tissue confirmed a positive effect of taurine on beta-cell function. The protective effect of taurine manifested in the absence of morphological signs for alloxan-induced diabetes: decrease in the number and size of pancreatic islets, change in their distribution, reduction of beta-cell count, and accumulation of homogeneous deposits in islets.

Topics: Animals; Body Weight; C-Peptide; Cell Count; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diuresis; Drinking; Fructosamine; Glucose; Glycogen; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liver; Male; Pancreas; Rats; Taurine

Low body weight type2 diabetes mellitus (T2DM) is a distinct entity in T2DM having different clinical presentation, morbidity and mortality patterns as well as biochemical profile when compared with classical T2 DM. This study was aimed at comparing three subtypes of T2 DM-overweight (BMI>25), normal weight (BMI>18.5 but <25) and low body weight or lean type2 DM (BM1<18.5). Seventy-five cases of T2 DM (25-lean, 25-normal weight and 25-overweight) were selected. The present study revealed that normal C-peptide level with basal hyperglycaemia is an important characteristic of lean T2 DM. Lower prevalence of hypercholesterolaemia and higher level of triglycerides were found in low body weight T2 DM.Lower prevalence of macrovascular and higher prevalence of microvascular complications are also noted.

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; India; Male; Middle Aged; Triglycerides

The protective effect of Pycnogenol against cardiovascular diseases was clearly demonstrated. Nevertheless, little is known about its antithrombotic effect, especially in diabetes associated with enhanced thromboxane synthesis leading to severe vascular complications. Therefore, the main purpose of our study was to evaluate the effect of long-term Pycnogenol intake on synthesis of prothrombotic thromboxane A(2) (TXA(2)) in animal model of insulin-dependent diabetes. The levels of main plasma TXA(2) metabolite, thromboxane B(2) (TXB(2)), were assessed by enzyme-linked immunosorbent assay. Diabetes was induced in Wistar male rats by single injection of streptozotocin, resulting after 8 weeks in significant body weight reduction, increased plasma glucose concentrations, and decreased plasma C-peptide levels, compared to non-diabetic animals. There was no significant reduction of plasma glucose concentrations after Pycnogenol ingestion. It was found, however, that daily administration of either Pycnogenol (5mg/kg b.wt.) or acetylsalicylic acid (ASA, 10mg/kg b.wt.) significantly reduced plasma TXB(2) concentrations, and this inhibitory effect was higher in the latter case. Nonetheless, simultaneous administration of Pycnogenol and ASA did not improve effectiveness of ASA-mediated decrease in TXB(2) generation. The results of the present study suggest that Pycnogenol might have a beneficial antithrombotic effect when administered alone or as a supplementation of standard antiplatelet therapy in diabetic patients.

Topics: Animals; Aspirin; Blood Glucose; Body Weight; C-Peptide; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Flavonoids; Male; Plant Extracts; Rats; Rats, Wistar; Thromboxane B2; Thromboxanes

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

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

Streptozotocin (STZ) has been widely used to induce diabetes in rodents and nonhuman primates, but it has been found difficult to achieve a completely diabetic state in pigs in the absence of detrimental side effects. As a result, pancreatectomy has been advocated in this species. We have investigated the effects of 2 dosages of STZ to safely induce diabetes in pigs.. Three pigs received Zanosar STZ at 150 mg/kg (group 1). Four pigs received Zanosar STZ at 200 mg/kg (group 2). The levels of glucose, insulin, and C-peptide when (a) fasting, (b) 30 minutes after eating, and (c) during intravenous glucose tolerance tests (IVGTTs) were measured in all pigs for 4 weeks after STZ injection. To confirm how long the diabetic state can be maintained after induction with STZ, levels were measured for 20 weeks in group 2.. One to 4 weeks after STZ administration, in group 1 (150 mg/kg) pigs, insulin and C-peptide levels were detected up to 7 microIU/mL and 0.4 ng/mL, respectively, both when fasting and after a meal test or IVGTT, indicating that the pigs had failed to become fully diabetic. In group 2 (200 mg/kg) pigs, insulin and C-peptide levels were less than the 2 microIU/mL and 0.25 ng/mL respective detection levels and did not increase after a meal test or IVGTT. Group 2 remained completely diabetic for the entire 20-week period of follow-up, without STZ-related hepatic or renal dysfunction.. High-dose (200 mg/kg) Zanosar STZ induces diabetes safely and completely in pigs without side effects. Pancreatectomy can, therefore, be avoided.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Pancreas; Streptozocin; Swine

Insulin glargine is a long-acting insulin analogue increasingly used instead of neutral protamine Hagedorn (NPH) insulin in young subjects with type 1 diabetes.. We evaluated the clinical course of diabetes in children and adolescents who were switched from NPH to insulin glargine.. Between August 2003 and November 2004, a total of 76 subjects were switched to glargine in our clinic, treating 340 children with type 1 diabetes. All the subjects had been receiving insulin NPH, and their serum C-peptide levels had been non-detectable for at least 1 yr. Data were collected retrospectively, and 12-18 months after the change, experiences with glargine were inquired using a questionnaire. Seven subjects (9.2%) discontinued glargine before 12 months, and seven refused to participate.. Data for 62 subjects were analyzed. At the switch (0 months), their mean age was 12.7 yr (range 5.1-17.5), mean duration of diabetes was 6.7 yr (range 1.8-14.3), and mean hemoglobin A1c was (HbA1c) 9.2%. Twelve months later (+12 months), the mean HbA1c remained similar (9.2%), the proportion of long-acting insulin was smaller (47.7 vs. 58.1%; p < 0.001), and the daily insulin dose was lower (0.97 vs. 1.05 IU/kg; p < 0.001). The number of injections was lower at +12 months (17.7% with more than five injections vs. 64.5%; p < 0.001). No differences were seen in weight for height or the number of severe hypoglycemias. Most subjects who continued with glargine for > or =12 months considered glargine better than NPH.. A switch to insulin glargine retains a similar glycemic control and does not change the number of severe hypoglycemias.

Topics: Adolescent; Age of Onset; Biomarkers; Blood Glucose; Body Height; Body Weight; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Reference Values; Retrospective Studies

The impact of strategies for prevention of type 2 diabetes in isolated impaired fasting glycaemia (i-IFG) vs isolated impaired glucose tolerance (i-IGT) may differ depending on the underlying pathophysiology. We examined insulin secretion during OGTTs and IVGTTs, hepatic and peripheral insulin action, and glucagon and incretin hormone secretion in individuals with i-IFG (n = 18), i-IGT (n = 28) and normal glucose tolerance (NGT, n = 20).. Glucose tolerance status was confirmed by a repeated OGTT, during which circulating insulin, glucagon, glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels were measured. A euglycaemic-hyperinsulinaemic clamp with [3-3H]glucose preceded by an IVGTT was performed.. Absolute first-phase insulin secretion during IVGTT was decreased in i-IFG (p = 0.026), but not in i-IGT (p = 0.892) compared with NGT. Hepatic insulin sensitivity was normal in i-IFG and i-IGT individuals (p > or = 0.179). Individuals with i-IGT had peripheral insulin resistance (p = 0.003 vs NGT), and consequently the disposition index (DI; insulin secretion x insulin sensitivity) during IVGTT (DI(IVGTT))) was reduced in both i-IFG and i-IGT (p < 0.005 vs NGT). In contrast, the DI during OGTT (DI(OGTT)) was decreased only in i-IGT (p < 0.001), but not in i-IFG (p = 0.143) compared with NGT. Decreased levels of GIP in i-IGT (p = 0.045 vs NGT) vs increased levels of GLP-1 in i-IFG (p = 0.013 vs NGT) during the OGTT may partially explain these discrepancies. Basal and post-load glucagon levels were significantly increased in both i-IFG and i-IGT individuals (p < or = 0.001 vs NGT).. We propose that differentiated preventive initiatives in prediabetic individuals should be tested, targeting the specific underlying metabolic defects.

Topics: Blood Glucose; Body Composition; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Secreting Cells; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin-Secreting Cells; Myocardial Ischemia; Prediabetic State

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

There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.

Topics: Animals; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Progression; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Glycated Hemoglobin; Glycine; Hypoglycemic Agents; Insulin; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Oxazoles; Pancreas; PPAR alpha; PPAR gamma; Triglycerides

Korean type 2 diabetics differ from Western diabetics in showing non-obese but centrally obese anthropometry and relatively more insulin secretory defects than insulin resistance. We assessed insulin secretion based on fasting serum C-peptide level and insulin resistance using the short insulin tolerance test (Kitt; rate constant for plasma glucose disappearance) in 1601 type 2 diabetic Korean patients (831 men and 770 women). Insulin secretory defects were catergorized as severe (C-peptide<1.10 ng/ml), moderate (C-peptide 1.10-1.69 ng/ml), and mild to non-secretory defect (C-peptide> or=1.70 ng/ml). Groups with a Kitt value of less than 2.5%/min were considered insulin-resistant, while those with a Kitt value > or =2.5%/min were considered insulin-sensitive. Overall, 42.5% of patients had a BMI>or =25.0 kg/m(2), and 70.2% had a BMI> or =23.0 kg/m(2); 45.2% (41.7% of men and 58.3% of women) were abdominally obese (waist> or =90 cm in men and 80 cm in women); mean fasting serum C-peptide level was 1.93+/-0.90 ng/ml, and the mean Kitt value was 2.03+/-0.96%/min. Accordingly, 13, 33, and 54% of patients showed a severe, moderate, and mild to non-secretory defect, respectively; 70.6% were insulin-resistant; and 29.4% were insulin-sensitive. Obese type 2 diabetes is recently increasing in Korea, indicating a shift from insulin secretory defects to insulin resistance.

Topics: Adult; Aged; Anthropometry; Blood Glucose; Body Mass Index; Body Size; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Insulin Resistance; Korea; Male; Middle Aged

The worldwide trend towards obesity in childhood is also observed in the Netherlands and one of the consequences may be type 2 diabetes. In this study, we assessed the number of children with type 2 diabetes, diagnosed by paediatricians, in the Netherlands.. In 2003 and 2004 the Dutch Paediatric Surveillance Unit, a nationwide paediatric register, was used to assess new cases of diabetes mellitus. Data on socio-demographic and clinical characteristics were collected by means of a questionnaire. A second questionnaire was sent to the reporting paediatrician if the diagnosis was inconclusive or if the diagnosis was type 1 diabetes in combination with overweight or obesity, according to international criteria.. During the 24 months of registration, the paediatricians reported 1142 new cases of diabetes, 943 of which were eligible for analysis. Initially, 14 patients (1.5%) were reported with type 2 diabetes. Only seven of these patients were classified as type 2 diabetes according to the ADA criteria, as information on C-peptides or antibodies was often missing. Based on clinical characteristics, the other seven patients were very likely to have type 2 diabetes. After the second questionnaire, six more patients met the ADA criteria and two were very likely to have type 2 diabetes. Most of the patients were female (95%), 14% were of Turkish and 18% of Moroccan origin.. This study shows a discrepancy between the number of patients with type 2 diabetes diagnosed by paediatricians in daily practice and diagnosed according to the ADA criteria. Moreover, a considerable amount of reported patients were misclassified. Finally, 2.4% patients were classified as (very likely) type 2 diabetes. The development of programmes and protocols for prevention, diagnosis and classification applicable in daily practice is warranted.

Topics: Adolescent; Body Mass Index; Body Weight; C-Peptide; Child; Child, Preschool; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Infant; Infant, Newborn; Male; Morocco; Netherlands; Obesity; Population Surveillance; Sex Factors; Surveys and Questionnaires; Turkey

Recent data suggest that circulating retinol-binding protein (RBP) might be involved in the pathogenesis of insulin resistance. Moreover, protein C inhibitor (PCI), which specifically binds retinoic acid, was found to be increased in myocardial infarction survivors who are also insulin resistant.. The objective of this study was to investigate the association of insulin resistance with RBP factors and PCI active antigen.. This was a clinical study.. Nondiabetic humans with high (IS; n = 20, 14 females, six males, aged 47.2 +/- 1.9 yr, body mass index 26 +/- 1 kg/m(2)) and low (IR; n = 20, 14 females, six males, aged 45.5 +/- 1.7 yr, body mass index 28 +/- 1 kg/m(2)) insulin-stimulated glucose-disposal (M) participated in this study.. M was measured by 2-h hyperinsulinemic (40 mU.min(-1).m(-2))-isoglycemic clamp tests. Measurements of RBP were performed using a nephelometric method and validated using quantitative Western blotting.. M (80-120 min) was higher in IS (10.9 +/- 0.6 mg.min(-1).kg(-1)) than IR (4.0 +/- 0.2; P < 10(-12)). Fasting plasma RBP concentrations were comparable between IS and IR measured by both nephelometry (IS: 4.4 +/- 0.3; IR: 4.6 +/- 0.3 mg/dl, P = 0.6) and quantitative Western blot (IS 7.9 +/- 0.5, IR 8.3 +/- 0.6 mg/dl; P = 0.6). Fasting plasma PCI active antigen was similar in both groups. Plasma RBP and PCI were not significantly related to M. RBP was positively correlated with uric acid (r = 0.488, P = 0.003), triglycerides (r = 0.592, P < 0.001), prealbumin (r = 0.63, P < 0.0001), and vitamin A (r = 0.75, P < 10(-6)).. Our data demonstrate that healthy, insulin-resistant humans do not show altered plasma retinol binding factors, such as RBP and PCI. Both do not significantly correlate with insulin sensitivity. Thus, our findings do not support the hypothesis of insulin sensitivity modulation by proteins involved in retinol transport.

Topics: Aging; Blood Glucose; Blotting, Western; Body Mass Index; Body Weight; C-Peptide; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Female; Gas Chromatography-Mass Spectrometry; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Protein C Inhibitor; Retinol-Binding Proteins, Plasma; Sex Characteristics; Vitamin A

This study examines whether anti-diabetic effects of genistein and daidzein are mediated by hepatic glucose and lipid regulating enzyme activities in type 2 diabetic animals. Male C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice and age-matched non-diabetic littermates (db/+) were used in this study. The db/db mice were divided into control, genistein (0.02%, w/w) and daidzein (0.02%, w/w) groups. The blood glucose and HbA(1c) levels were significantly lower in the genistein and daidzein groups than in the control group, while glucose tolerance only was significantly improved in the genistein-supplemented group. The plasma insulin and C-peptide levels did not differ significantly between groups, yet the glucagon level was lower in the genistein and daidzein groups compared to that in the control db/db or db/+ group. The genistein and daidzein supplements increased the insulin/glucagon ratio in the type 2 diabetic animals. While the hepatic glucokinase activity was significantly lower in the db/db control group, the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly higher in the control group compared to the db/+ group. Interestingly, these hepatic glucose metabolizing enzyme activities were reversed by the genistein and daidzein supplementation in db/db mice compared to the control group. The hepatic fatty acid synthase, beta-oxidation and carnitine palmitoyltransferase activities were all significantly lower in the genistein and daidzein groups than in the control group. The genistein and daidzein supplements also improved the plasma total cholesterol, triglyceride, HDL-cholesterol/total cholesterol, free fatty acid and hepatic triglyceride concentrations in the db/db mice. These results suggest that genistein and daidzein exert anti-diabetic effect in type 2 diabetic conditions by enhancing the glucose and lipid metabolism.

Topics: Animals; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet; Eating; Genistein; Glucagon; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Isoflavones; Leptin; Lipid Metabolism; Liver; Liver Glycogen; Mice; Mice, Inbred C57BL; Phytoestrogens; Receptors, Cell Surface; Receptors, Leptin

This study first examined whether urinary C-peptide (UCP), stored at -20 degrees C, remains stable over the long term, and second, whether the dietary glycemic index (GI) and the glycemic load (GL: GI x g carbohydrates) are related to the 24-h UCP excretion of healthy children. Participants in the Dortmund Nutrition and Anthropometric Longitudinally Designed Study with 24-h urine collections and a simultaneously completed weighed dietary record were included. From these, 3 comparable groups of 7- to 8-y-old children (n = 40 each) from 1990, 1996, and 2002 were randomly selected (total n = 120). C-peptide was measured with a 1-site ELISA. A GI value was assigned to all recorded foods containing carbohydrates (CHO). Statistical equivalence tests corroborated that UCP excretion in the 3 sampling periods was equivalent when corrected for body weight and protein intake (P < 0.05). UCP excretion was associated with the GL after adjustment for body weight, protein, and fiber intake [mean UCP (95% CI) in GL tertiles 1-3: 6.19 (5.37, 7.14) vs. 7.82 (6.77, 9.02) vs. 7.76 (6.71, 8.97) nmol/d, P for difference 0.04]. GI was not significantly related to UCP excretion [adjusted means (95% CI): 7.27 (6.28, 8.41) vs. 6.51 (5.64, 7.51) vs. 7.94 (6.86, 9.18), P for difference 0.2]. In conclusion, UCP retrospectively measured with a 1-site ELISA remained stable for up to 12 y (from 1990 until 2002). The observed positive relation of UCP with GL appears to result largely from its association with the amount of CHO, whereas dietary GI may be relevant only at higher intake levels.

Topics: Body Weight; C-Peptide; Child; Cross-Sectional Studies; Diet Records; Dietary Carbohydrates; Glycemic Index; Humans; Insulin; Insulin Secretion; Longitudinal Studies; Specimen Handling

p8 protein expression is known to be upregulated in the exocrine pancreas during acute pancreatitis. Own previous work revealed glucose-dependent p8 expression also in endocrine pancreatic beta-cells. Here we demonstrate that glucose-induced INS-1 beta-cell expansion is preceded by p8 protein expression. Moreover, isopropylthiogalactoside (IPTG)-induced p8 overexpression in INS-1 beta-cells (p8-INS-1) enhances cell proliferation and expansion in the presence of glucose only. Although beta-cell-related gene expression (PDX-1, proinsulin I, GLUT2, glucokinase, amylin) and function (insulin content and secretion) are slightly reduced during p8 overexpression, removal of IPTG reverses beta-cell function within 24 h to normal levels. In addition, insulin secretion of p8-INS-1 beta-cells in response to 0-25 mM glucose is not altered by preceding p8-induced beta-cell expansion. Adenovirally transduced p8 overexpression in primary human pancreatic islets increases proliferation, expansion, and cumulative insulin secretion in vitro. Transplantation of mock-transduced control islets under the kidney capsule of immunosuppressed streptozotocin-diabetic mice reduces blood glucose and increases human C-peptide serum concentrations to stable levels after 3 days. In contrast, transplantation of equal numbers of p8-transduced islets results in a continuous decrease of blood glucose and increase of human C-peptide beyond 3 days, indicating p8-induced expansion of transplanted human beta-cells in vivo. This is underlined by a doubling of insulin content in kidneys containing p8-transduced islet grafts explanted on day 9. These results establish p8 as a novel molecular mediator of glucose-induced pancreatic beta-cell expansion in vitro and in vivo and support the notion of existing beta-cell replication in the adult organism.

Topics: Adenoviridae; Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Blotting, Western; Body Weight; C-Peptide; Cell Count; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Experimental; Glucose; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Isopropyl Thiogalactoside; Kidney; Mice; Mice, Inbred C57BL; Neoplasm Proteins; Organisms, Genetically Modified; Pancreas; Transplantation, Heterologous

1. Diabetes mellitus is a serious metabolic disorder with micro- and macrovascular complications that results in significant morbidity and mortality. 2. The aim of the present study was to evaluate the hypoglycaemic efficacy of commonly used traditional Indian plants, such as Murraya koenigii, Mentha piperitae, Ocimum sanctum and Aegle marmelos, in streptozotocin (STZ)-induced experimental rats. 3. Oral administration of the ethanolic extract of these plants resulted in a significant decrease in the levels of blood glucose, glycosylated haemoglobin and urea, with a concomitant increase in glycogen, haemoglobin and protein, in diabetic rats. Treatment with these plant extracts also resulted in an increase in insulin and C-peptide levels and glucose tolerance. 4. The decreased activities of carbohydrate-metabolising enzymes, such as hexokinase, glucose-6-phosphate dehydrogenase and glycogen synthase, in diabetic rats were significantly elevated towards near normal in rats treated with extracts of M. koenigii, O. sanctum and A. marmelos; the increased activities of lactate dehydrogenase, fructose-1,6-bisphosphatase, glucose-6-phosphatase and glycogen phosphorylase in STZ diabetic rats were significantly reduced following treatment with the plant extracts. 5. Elevated specific binding of [(125)I]-labelled insulin to the receptor found in diabetic rats was markedly decreased in extract-treated groups. However, treatment of diabetic rats with M. piperitae did not result in any significant modification in all parameters. 6. Phytochemical screening conducted by us revealed the presence of biologically active ingredients in the ethanolic extracts of M. koenigii, O. sanctum and A. marmelos, which may readily account for the observed hypoglycaemic activity.

Topics: Animals; Blood Glucose; Blood Urea Nitrogen; Body Weight; C-Peptide; Carbohydrates; Creatinine; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen Phosphorylase; Glycogen Synthase; Hemoglobins; Hypoglycemic Agents; India; Insulin; Liver Glycogen; Male; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar

The current study investigated whether Du-zhong (Eucommia ulmoides Oliv.) leaves could improve the hyperglycemia in streptozotocin (STZ)-induced diabetic rats. Male Sprague-Dawley rats were divided into a non-diabetic group (NDM), diabetic group (DM), diabetic group supplemented with powdered Du-zhong leaves (DM-PDZ) and diabetic group supplemented with a water extract of the powdered Du-zhong leaves (DM-WDZ). Diabetes was induced by injecting STZ (70 mg/kg B.W., i.p.). The powdered Du-zhong leaves or its powdered water extract was add to a standard diet based on 1% dried Du-zhong leaves (1 g PDZ/100 g diet and 0.187 g WDZ/100 g diet, respectively) for 3 weeks. Body weight was significantly higher in both types of Du-zhong leaves supplemented groups than in the DM group. The blood glucose levels were significantly lower in the DM-PDZ and DM-WDZ groups than in the DM group (20.05+/-0.88 and 18.96+/-1.23 mmol/l versus 24.42+/-1.07 mmol/l, P<0.05), whereas the plasma insulin and C-peptide levels were significantly higher in the PDZ and WDZ supplemented groups than in the DM group (7.45+/-0.27 and 7.62+/-0.69 microl U/ml versus 3.75+/-0.27 microl U/ml for the plasma insulin, and 224.52+/-14.6 and 239.76+/-15.52 pmol/l versus 166.5+/-10.4 pmol/l for the plasma C-peptide, respectively, P<0.05). The supplementation of PDZ and WDZ also resulted in lower plasma urea nitrogen levels compared to the DM group. Du-zhong leaves supplement seemed to be helpful to preserve the normal histological appearance of pancreatic islets as well as to preserve insulin-positive beta-cells but it did not reverse the effect of STZ to a great extent. Accordingly, the reduction in plasma glucose by the powdered Du-zhong leaves and its water extract is quite small but significant, nevertheless, this was occurred with simultaneous the increase in plasma insulin and C-peptide. They improved hyperglycemia and seemingly enhance the function of pancreatic beta-cells in STZ-induced diabetic rats.

Topics: Animals; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Eucommiaceae; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Phytotherapy; Plant Leaves; Rats; Rats, Sprague-Dawley; Urea

Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis.. Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation.. After approximately 12 weeks of olanzapine therapy, the median increase in body weight was 4.7 kg, a significant increase of 7.3% from first observation. Body fat, measured by dual-energy x-ray absorptiometry, increased significantly, with a propensity for central fat deposition. Lean body mass and bone mineral content did not change. Resting energy expenditure, measured by indirect calorimetry, did not change. Respiratory quotient significantly increased 0.12 with olanzapine and was greatest in those who gained >5% of their initial weight. Fasting insulin, C-peptide, and triglyceride levels significantly increased, but there were no changes in glucose levels; total, high density lipoprotein, or low density lipoprotein cholesterol levels; or leptin levels.. Olanzapine appears to have induced an increase in central body fat deposition, insulin, and triglyceride levels, suggesting the possible development of insulin resistance. The decrease in fat oxidation may be secondary or predispose patients to olanzapine-induced weight gain.

Topics: Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; C-Peptide; Energy Metabolism; Female; Humans; Insulin; Male; Obesity; Olanzapine; Oxidation-Reduction; Psychotic Disorders; Respiratory Physiological Phenomena; Schizophrenia; Triglycerides

Insulin resistance and hyperinsulinemia are often considered intrinsic features of the polycystic ovary syndrome (PCOS). Nevertheless, conflicting results of insulin sensitivity and secretion have been obtained in the subgroup of normal-weight women with PCOS. Differences in body composition, ethnicity, and diet composition and a family history of metabolic diseases may act as confounding variables in women with PCOS. In the present study, insulin sensitivity and secretion were estimated by an iv glucose tolerance test (IVGTT), analyzed by minimal models, in 20 normal-weight healthy women with PCOS and no family history of type 2 diabetes mellitus and in 20 normally ovulating women, matched for age and body mass index. Insulin sensitivity [mean (95% confidence intervals); PCOS 4.0 (2.8-5.1) vs. controls 4.5 (3.5-5.4) 10(-4) min(-1)/microU.ml], and insulin secretion, expressed as the acute insulin response to glucose [PCOS 3.7 (3.3-4.2) vs. controls 3.7 (3.4-4.0) microU/ml] were similar in the two groups. The women with PCOS showed an increased proportion of total body fat (PCOS 29% vs. controls 27.2%; P < 0.01). They also showed decreased glucose effectiveness, i.e. the proportion of glucose uptake independent from insulin activity [PCOS 2.6 (2.1-3.0) vs. controls 3.8 (3.0-4.6) mg x 100 min(-1); P = 0.01]. The levels of insulin sensitivity and of glucose effectiveness did not correlate in either group. Whether the isolated finding of decreased glucose effectiveness could reflect an early stage in the development of the metabolic aberrations often associated with the syndrome remains to be clarified.

Topics: Adult; Blood Glucose; Body Size; Body Weight; C-Peptide; Diet; Energy Intake; Female; Glucose Tolerance Test; Hormones; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Polycystic Ovary Syndrome; Reference Values; Surveys and Questionnaires

To identify factors associated with insulin requirement in Type 2 diabetic patients, and to examine the significance of a normal plasma triglyceride level.. One hundred and three poorly controlled (HbA1c = 9.4 +/- 1.9%) Type 2 diabetic patients initially not treated with insulin were followed up for 5 years. Insulin was administered if HbA1c > 8% despite maximal oral anti-diabetic treatment and bodyweight control. Variables were compared between insulin requiring and non-insulin-treated patients using unpaired t-tests. The outcomes of initially normotriglyceridaemic (< 1.7 mmol/l) and hypertriglyceridaemic patients were compared using unpaired t-tests, and a survival analysis (Cox proportional hazards model).. Sixty-three patients were transferred to insulin. They were 5 years older (P = 0.004), with a 3-year longer duration of their diabetes (P = 0.03), a 1.2% higher HbA1c (P = 0.002), and 50% lower triglyceride levels (P = 0.02) than the others. The survival analysis showed that a long duration of diabetes, a high HbA1c, and a normal triglyceride level were associated with the need for insulin; the effect of normotriglyceridaemia was significant in the most poorly controlled (HbA1c > 9.5%) patients (relative risk: 2.35, 95% confidence interval: 1.16-5.52, P = 0.016). The 46 normotriglyceridaemic patients were leaner (P = 0.0004) and had lower C-peptide levels (P = 0.0008) than the others. Despite similar diabetes duration and HBA1c, more were transferred to insulin (normotriglyceridaemic: 71%, hypertriglyceridaemic: 52%, P = 0.03).. A normal triglyceride level is associated with a need for insulin in poorly controlled Type 2 diabetes.

Topics: Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Survival Analysis; Time Factors; Treatment Outcome; Triglycerides

Preferential visceral adipose tissue (VAT) accumulation has been clearly associated with insulin resistance. In contrast, the impact of visceral obesity on beta cell function is controversial.. In 62 non-diabetic women and men (age 24-69 years, BMI 21-39 kg/m2), we measured VAT and subcutaneous adipose tissue (SAT) fat mass by magnetic resonance imaging. We also measured insulin secretion and beta cell function by C-peptide deconvolution and physiological modelling of data from a frequently sampled, 75-g, 3-h OGTT, respectively.. VAT (range 0.1-3.1 kg) was strongly related to sex, age and BMI; SAT was related to sex and BMI. Controlling for sex, age, BMI and SAT by multivariate analysis, excess VAT was associated with a clinical phenotype comprising higher plasma glucose levels, BP, heart rate and serum transaminases. The corresponding metabolic phenotype consisted of insulin resistance (partial r=-0.38) and hyperinsulinaemia (partial r=0.29). The latter, however, was appropriate for the degree of insulin resistance regardless of obesity and abdominal fat distribution. Moreover, none of the model-derived parameters describing beta cell function (glucose sensitivity, rate sensitivity and potentiation) was independently associated with excess VAT.. In non-diabetic Caucasian adults of either sex, preferential visceral fat deposition in itself is part of an insulin-resistant phenotype. The insulin secretory response to a physiological challenge is increased to fully compensate for the insulin resistance, but the dynamics of beta cell function (glucose sensitivity, rate sensitivity and potentiation) are largely preserved.

Topics: Adipose Tissue; Adult; Anthropometry; Area Under Curve; Body Weight; C-Peptide; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Lipids; Magnetic Resonance Imaging; Male; Models, Biological; Pancreatic Function Tests; Phenotype

Connecting peptide (C-peptide) is secreted along with insulin in equimolar amounts into portal circulation in response to beta cell stimulation. The biological function of C-peptide had been mostly limited to establishing the secondary and tertiary structure of proinsulin. Recent studies have suggested that C-peptide can impact several functions, such as autonomic and sensory nerve function, insulin secretion, and microvascular blood flow. In this study we examined the effects of C-peptide in the presence or absence of insulin on cardiovascular and sympathetic nerve activity in both normal and streptozotocin (STZ)-induced diabetic Wistar rats. Animals were made diabetic by a single intravenous injection of STZ (50 mg/kg) and maintained for 6 weeks. The diabetic animals had higher plasma glucose, lower plasma insulin, and C-peptide, compared with the normal animals. To characterize cardiovascular and autonomic nervous responses, the animals were anesthetized with urethane/alpha-chloralose and instrumented for the recording of mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (LSNA). A bolus administration of C-peptide alone did not alter MAP, HR, or LSNA in normal or diabetic animals. The bolus administration of insulin alone increased HR and LSNA in normal and diabetic animals. However, the administration of insulin plus C-peptide attenuated the increase in HR in normals and the increase in LSNA in diabetic rats. We concluded that the C-peptides play a role in modulating the insulin-stimulated sympathetic nerve response.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Drug Interactions; Heart Rate; Insulin; Lumbosacral Region; Male; Rats; Rats, Wistar; Sympathetic Nervous System

Studies of C-peptide cellular effects show that not only the full-length native peptide but also specific C-terminal fragments are biologically active in in vitro systems. In the present study, the effect of five C-peptide fragments and the native peptide on whole-body glucose turnover was studied in streptozotocin diabetic rats using the insulin clamp technique. Insulin was infused intravenously at 18 pmol kg(-1) min(-1) for 90 min and blood glucose concentration was clamped at 8 and 4 mM in diabetic and non-diabetic animals. A steady state was reached during the last 30 min of the study period. Rat C-peptide II and fragments comprising residues 27-31 and 28-31 were effective in augmenting glucose turnover in diabetic rats (+100% to 150%), while no significant effects were seen for segments 1-26, 11-19 and 11-15. The metabolic clearance rate for glucose during infusion of C-peptide or fragments 27-31 and 28-31 in diabetic rats was similar to that seen in non-diabetic animals. We conclude that C-terminal tetra- and pentapeptides, but not fragments from the middle segment of C-peptide, are as effective as the full-length peptide in stimulating whole-body glucose turnover in diabetic rats.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Glucose Clamp Technique; Infusions, Intravenous; Insulin; Male; Metabolic Clearance Rate; Peptide Fragments; Rats; Rats, Wistar

The incidence of type 2 diabetes mellitus (DM2) in children has increased worldwide and is commonly associated with overweight. Forty-four children with DM2 were studied by clinical histories, anthropometric measurements, and biochemical analysis. Homeostasis model assessment (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were determined to evaluate insulin resistance. Only five patients presented normal body mass index (BMI); the remainder were overweight, and 76% had acanthosis nigricans. Laboratory results yielded hyperglycemia, elevated glycosylated hemoglobin, insulin and C-peptide. Elevated HOMA-IR and decreased QUICKI values suggest insulin resistance. No significant difference was found between sexes, although overweight in girls had more influence over blood pressure and lipid levels (p <0.05). Time from diagnosis and HOMA-IR yielded relevant values (p = 0.010). Laboratory results, QUICKI, and HOMA-IR values suggested that these patients present DM2 and decreased insulin sensitivity. We recommend prevention of overweight and sedentary life-style.

Topics: Acanthosis Nigricans; Adolescent; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 2; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Lipids; Male; Mexico; Sex Factors

We tested whether chronic overstimulation by levels of hyperglycaemia commonly found in Type 2 diabetes can irreversibly desensitise beta cells and, if so, whether desensitisation relates to the reduction of insulin content and/or the number of beta cells.. We transplanted islets from Wistar-Furth rats under the kidney capsule to neonatally streptozotocinised recipients. Recipients received daily vehicle, diazoxide (100 mg/kg) or the selective activator of beta cell type K(+)-ATP channels 6-chloro -3-(1-methylcyclopropyl) amino-4 H-thienol [3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414) (3 mg/kg) intragastrically for at least 9 weeks. Endpoint measurements were made exactly 7 days after cessation of treatment.. Blood glucose did not differ between groups (mean of total: 13.2+/-1.4 mmol/l). C-peptide levels were significantly depressed in drug- versus vehicle-treated rats 3 to 4 hours after the last gastric tubing event, but not at endpoint. Insulin responses to 27 mmol/l glucose from perifused grafts were not significant after vehicle (median increment 18 x 10(-3) microU.islet(-1).min(-1)) but were significant per se and versus vehicle in the diazoxide and NN414 groups (median 107 and 83 x 10(-3) respectively). Rising second-phase secretion was seen only in the drug-treated groups. Stimulation by 25 mmol/l KCl, together with 0.5 mmol/l 3-isobutyl-1-methylxanthine and 3.3 mmol/l glucose, was enhanced in the drug-treated groups (p<0.05 versus vehicle). Graft insulin content did not differ between groups, nor did percentage of beta cells (between 67 and 68% of endocrine cells).. Chronic overstimulation by moderate hyperglycaemia damages signalling events including those required for glucose-induced insulin secretion. This signal transduction defect occurs in the absence of any effect on islet macro-morphometry or insulin stores.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Insulin; Insulin Secretion; Ion Channel Gating; Islets of Langerhans Transplantation; Male; Potassium Channels; Rats; Rats, Inbred WF; Signal Transduction; Transplantation, Isogeneic

Oxidative stress and neurovascular dysfunction have emerged as contributing factors to the development of experimental diabetic neuropathy (EDN) in streptozotocin-diabetic rodents. Additionally, depletion of C-peptide has been implicated in the pathogenesis of EDN, but the mechanisms of these effects have not been fully characterized. The aims of this study were therefore to explore the effects of diabetes on neurovascular dysfunction and indexes of nerve oxidative stress in type 1 bio-breeding Worcester (BB/Wor) rats and type 2 BB Zucker-derived (ZDR)/Wor rats and to determine the effects of C-peptide replacement in the former. Motor and sensory nerve conduction velocities (NCVs), hindlimb thermal thresholds, endoneurial blood flow, and indicators of oxidative stress were evaluated in nondiabetic control rats, BB/Wor rats, BB/Wor rats with rat II C-peptide replacement (75 nmol C-peptide.kg body wt(-1).day(-1)) for 2 mo, and diabetes duration-matched BBZDR/Wor rats. Endoneurial perfusion was decreased and oxidative stress increased in type 1 BB/Wor rats. C-peptide prevented NCV and neurovascular deficits and attenuated thermal hyperalgesia. Inhibition of nitric oxide (NO) synthase, but not cyclooxygenase, reversed the C-peptide-mediated effects on NCV and nerve blood flow. Indexes of oxidative stress were unaffected by C-peptide. In type 2 BBZDR/Wor rats, neurovascular deficits and increased oxidative stress were unaccompanied by sensory NCV slowing or hyperalgesia. Therefore, nerve oxidative stress is increased and endoneurial perfusion decreased in type 1 BB/Wor and type 2 BBZDR/Wor rats. NO and neurovascular mechanisms, but not oxidative stress, appear to contribute to the effects of C-peptide in type 1 EDN. Sensory nerve deficits are not an inevitable consequence of increased oxidative stress and decreased nerve perfusion in a type 2 diabetic rodent model.

Topics: Animals; Body Weight; C-Peptide; Diabetic Nephropathies; Enzyme Inhibitors; Hindlimb; Hot Temperature; Hyperalgesia; Insulin; Lipid Peroxidation; Male; Motor Neurons; Nerve Tissue; Neural Conduction; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Oxidative Stress; Oxidoreductases; Rats; Rats, Inbred BB; Rats, Zucker; Reaction Time; Regional Blood Flow

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P <.001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P <.001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P =.055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.

Topics: Administration, Oral; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Liver; Middle Aged; Peptide Fragments; Protein Precursors; Regression Analysis; Time Factors

In GH-deficient humans, GH and IGF-I treatment cause opposite effects on serum insulin concentrations and insulin sensitivity. This finding contrasts with the somatomedin hypothesis that IGF-I mediates GH action, as postulated for skeletal growth, and raises the question whether GH-induced IGF-I acts on the endocrine pancreas in the same way as administered IGF-I.. To compare the effects of the two hormones on the endocrine pancreas of hypophysectomized rats.. Animals were infused for 2 days, via miniosmotic pumps, with IGF-I (300 microg/day), GH (200 mU/day) or vehicle. We measured (i) glucose, IGF-I, insulin, C-peptide and glucagon in serum and (ii) IGF-I, insulin and glucagon mRNAs and peptides in the pancreas by radioimmunoassay, immunohistochemistry and northern analysis.. Both GH and IGF-I treatment increased serum and pancreatic IGF-I but, unlike GH, IGF-I treatment strongly reduced serum insulin and C-peptide (and, to a lesser extent, serum glucagon). Nevertheless, the animals did not become hyperglycaemic. GH, but not IGF-I, increased pancreatic insulin and glucagon content, as also indicated by immunohistochemistry, and increased IGF-I mRNA. Neither GH nor IGF-I caused significant changes in insulin and glucagon mRNA.. The decrease in serum insulin and C-peptide by IGF-I treatment without significant changes in insulin gene expression and pancreatic insulin content suggests inhibition of insulin secretion. Within this setting, the absence of hyperglycaemia points to enhanced insulin sensitivity, although an insulin-like action of infused IGF-I may have partially compensated for the decreased insulin concentrations. GH-induced circulating or pancreatic IGF-I, or both, does not mimic the pancreatic effects of infused IGF-I in the absence of GH, suggesting that GH may counteract the action of GH-induced IGF-I on the endocrine pancreas.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Fluorescent Antibody Technique; Glucagon; Growth Hormone; Hypophysectomy; Insulin; Insulin-Like Growth Factor I; Islets of Langerhans; Male; Organ Size; Pituitary Diseases; Rats; Rats, Wistar; RNA, Messenger

Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.

Topics: Animals; Anorexia; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cell Line, Tumor; Eating; Female; Fibrosarcoma; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Interleukin-1; Leptin; Liver; Mice; Mice, Inbred C57BL; Monosaccharide Transport Proteins; Neoplasm Transplantation; Protein Serine-Threonine Kinases; RNA, Messenger

The Trp64Arg polymorphism of beta(3)-adrenergic receptor (ADRB3) has been reported to be associated with insulin resistance and gestational diabetes mellitus (GDM). The objective of this study is to investigate whether the ADRB3 Arg variant confers susceptibility to GDM in a Taiwanese population. A total of 299 pregnant women (mean +/- SD, 31.1 +/- 4.2 years) was recruited. Two-hour, 75-g oral glucose tolerance tests (OGTT) were conducted at 24 to 31 weeks gestation (28.3 +/- 1.6 weeks). Forty-one GDM subjects and 258 controls with normal glucose tolerance (NGT) level were genotyped for the ADRB3 Trp64Arg polymorphism. The genotype distribution and allele frequency of ADRB3 did not significantly differ between GDM and NGT subjects (9.8% v 14.5%). Body weight gain during pregnancy was not different between ADRB3 genotypes. However, the GDM subjects with the Arg64 variant had higher fasting (P =.04) and postload 120 minutes (P =.03) insulin levels as compared with the GDM subjects with the Trp64Trp allele. In all subjects, the women with the Arg64 allele (n = 76) had significantly higher level of insulin secretion (the ratio of Deltainsulin(60)/Deltaglucose(60)) during OGTT than those without (n = 223) (P =.03) despite similar plasma levels of glucose and insulin in both genotypes. Our results indicated that the ADRB3 Trp64Arg variant is not related to the development of GDM and has no effect on obesity during pregnancy in a Taiwanese population. However, ADRB3 polymorphism might be a possible determinant of insulin resistance.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes, Gestational; DNA; Female; Gene Frequency; Genotype; Glucose Tolerance Test; Humans; Insulin; Polymorphism, Genetic; Pregnancy; Receptors, Adrenergic, beta-3; Taiwan

Several epidemiological and animal studies have shown that the offsprings of diabetic mothers have higher incidences of glucose intolerance, obesity, insulin resistance, and hypertension in later life. It is well known that glucocorticoid metabolism plays a crucial role on several adult disease originated from fetal environment. The aim of this study was to investigate the relation between diabetic pregnancy and glucocorticoid metabolism of both mother and fetus, focusing on the 11 beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. A model of diabetic pregnancy was made by intravenous injection of streptozotocin (35 mg/kg body weight) to Sprague-Dawley rats, and blood and tissue samples were collected on day 20 of pregnancy. In the diabetic group, expression of 11 beta-hydroxysteroid dehydrogenase type 2 in placentas and fetal kidneys was decreased remarkably. Corticosterone levels of diabetic mothers were lower than those of control rats. Despite the differences in maternal corticosterone levels, fetal levels of corticosterone did not differ between the groups. Our results lend support to the concept that diabetic pregnancy imprints glucocorticoid regulation in these fetuses, which may contribute to their increased incidence of higher blood pressure as adults.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Animals; Blood Glucose; Blotting, Northern; Body Weight; C-Peptide; Corticosterone; Diabetes Mellitus, Experimental; DNA, Complementary; Female; Fetus; Gene Expression Regulation; Kidney; Litter Size; Placenta; Pregnancy; Rats

It is well known that sometimes it is difficult to distinguish between type 1 and 2 diabetes mellitus using clinical criteria, in subjects with disease onset relatively early in adult life. The measurement of C peptide level and of immunological markers may represent important additional tools for establishing the correct diagnosis. The aim of the study is to assess the trend of basal C peptide in patients with clinical diagnosis of type 2 diabetes and to relate it to the type of treatment, the body weight and the positivity for pancreatic autoantibodies.. we studied a group of 268 patients with type 2 diabetes, aged between 30 and 50 years, with a diabetes duration of less than 5 years. In all patients, we measured basal C peptide, islet cell autoantibodies and antibodies against glutamic acid decarboxylase, computed the body mass index and recorded the current antidiabetic treatment.. Based on basal C peptide value, diabetic subjects fell under 3 categories: a) low C peptide (<0.58 ng/ml): 7.5%, b) normal C peptide (0.58-2.70 ng/ml): 57.8%, and c) high C peptide (>2.70 ng/ml): 34.7%. Patients with low C peptide were treated more often with insulin, while those in high C peptide group received more often biguanides. A direct correlation between C peptide and body weight was established. Mean C peptide was lower in patients positive for at least one pancreatic autoantibody, compared to those who were negative for antibodies. Low basal C peptide can be considered criterion for transferring the patients, initially diagnosed as type 2 diabetes, in the type 1 diabetes group.

Topics: Adult; Autoantibodies; Biguanides; Biomarkers; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Pancreas; Predictive Value of Tests; Treatment Outcome

Circadian rhythms in glucose metabolism are well documented. Most studies, however, evaluated such variations under conditions of continuous glucose supply, either via food intake or glucose infusion. Here we assessed in 30 subjects circadian variations in concentrations of plasma glucose, serum insulin, and C-peptide during a 72-hour fasting period to evaluate rhythms independent from glucose supply. Furthermore we assessed differences in these parameters between normal-weight (n = 20) and overweight (n = 10) subjects. Blood was sampled every 4 hours. During fasting, plasma glucose, serum insulin, and C-peptide levels gradually decreased (all P < .001). While there was no circadian variation in plasma glucose levels after the first day of fasting, serum levels of insulin were constantly higher in the morning (8.00 h) than at night (0.00 h) (P < .001), although the extent of this morning-associated rise in insulin levels decreased with the time spent fasting (P = .001). Also, morning C-peptide concentrations were higher compared to the preceding night (P < .001). The C-peptide/insulin ratio (CIR) decreased during prolonged fasting (P = .030), suggesting a decrease in hepatic insulin clearance. Moreover, CIR was significantly lower in the morning than at the night of day 1 and day 2 of fasting (P = .010 and P = .004, respectively). Compared to normal-weight subjects, overweight subjects had higher plasma glucose, as well as serum insulin and C-peptide levels (all P < .03). Data indicate preserved circadian rhythms in insulin concentrations in the presence of substantially decreased glucose levels in normal-weight and overweight subjects. This finding suggests a central nervous system contribution to the regulation of insulin secretion independent of plasma glucose levels.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Circadian Rhythm; Fasting; Female; Humans; Insulin; Male; Middle Aged; Obesity; Sex Factors; Time Factors

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

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

We report two black adolescent subjects who presented with diabetic ketoacidosis, but who lacked autoimmune markers and demonstrated clinical and biochemical characteristics more typical of Type 2 diabetes, including obesity, acanthosis nigricans, positive family history for Type 2 diabetes, and Type 2 diabetic dyslipidaemia. Subsequent to acute presentation, insulin was discontinued in both subjects and excellent glycaemic control was achieved with metformin therapy alone. Four months following acute presentation, both had adequate C-peptide responses to intravenous glucagon. Type 2 diabetes can present as diabetic ketoacidosis in obese adolescent subjects.

Topics: Acanthosis Nigricans; Adolescent; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metformin; Obesity

Androgens are suggested to interact with leptin production and with insulin sensitivity in both polycystic ovary syndrome (PCOS) and obesity. The aim of the study was to follow these interactions along with two forms of antiandrogen treatment. Twenty women with PCOS were treated with ethinylestradiol and high dose of cyproteroneacetate (EE-CA) and 8 with the gonadotrophin-releasing hormone (GnRH) analogue goserelin for 6 months. The patients were divided into a low and a high body weight group and compared with a group of overweight women without PCOS. Both treatments resulted in a significant reduction of free testosterone but the concentration of leptin remained unchanged. EECA treatment resulted in deterioration and GnRH in improvement of insulin sensitivity. Serum leptin correlated only with body weight and body fat. It is concluded that leptin levels do not adequately reflect changes in insulin sensitivity or androgen levels after short-term antiandrogen or antigonadotropin treatment.

Topics: Adipose Tissue; Adult; Androgen Antagonists; Apolipoproteins A; Apolipoproteins B; Blood Glucose; Body Composition; Body Constitution; Body Mass Index; Body Weight; C-Peptide; Cyproterone Acetate; Dehydroepiandrosterone Sulfate; Ethinyl Estradiol; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Insulin; Insulin Resistance; Leptin; Lipoprotein(a); Obesity; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone; Triglycerides

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. beta-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the beta-cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Obesity; Peptide Fragments; Protein Precursors; Random Allocation

Little research has explored associations of drinking patterns with glycemic control, especially among women. Our objective was to determine the relationship of patterns of alcohol consumption-including average daily consumption, weekly frequency of consumption, drinking with meals, and beverage type-with biologic markers of insulin resistance in young women.. This study was cross-sectional in design. The subjects consisted of a stratified random subpopulation of 459 U.S. normal-weight and overweight female nurses, 33-50 years of age, drawn from the Nurses' Health Study II and sampled for distinct drinking patterns. Women provided blood samples and detailed information on dietary and lifestyle factors between 1995 and 1999. The main outcome measures were fasting insulin, C-peptide, and HbA(1c).. Adjusting for age, smoking, physical activity, television watching, BMI, and several dietary factors, average alcohol intake was inversely associated with HbA(1c) (units in percentage of HbA(1c)): 0 g/day (reference = 5.36%), 0.1 to <5.0 g/day (-0.04%), 5.0 to <15.0 g/day (-0.09%), 15.0 to <25.0 g/day (-0.10%), and > or =25.0 g/day (-0.17%) (P value, test for trend <0.001). We found an inverse association of alcohol intake and insulin, but only for women with a BMI > or =25 kg/m(2). Specifically, insulin levels were lowest for episodic drinkers consuming > or =2 drinks per day on 0-3 days per week. Consumption with meals and type of alcoholic beverage did not further influence these results.. Moderate alcohol consumption of 1-2 drinks per day on a few to several days of the week may have a beneficial glycemic effect, particularly among overweight women.

Topics: Adult; Alcohol Drinking; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cross-Sectional Studies; Diet; Female; Humans; Middle Aged; Multivariate Analysis; Obesity; Regression Analysis; Temperance

The effects of tibolone on body weight, body composition, and fasting carbohydrate measures in surgically postmenopausal cynomolgus monkeys were compared to those of conjugated equine estrogens (CEE) with and without medroxyprogesterone acetate (MPA). Monkeys were fed a moderately atherogenic diet with either no hormones (control n = 29), CEE (0.042 mg/kg, n = 27), CEE + MPA (0.167 mg/kg, n = 29), low-dose tibolone (LoTib, 0.05 mg/kg, n = 30), or high-dose tibolone (HiTib, 0.20 mg/kg, n = 31) daily for 2 years. Body weight (BW) was measured throughout the study, and dual-energy x-ray absorptiometry (DEXA) scans of the abdominal region (lumbar vertebrae 1 through 5) were performed at the end of the trial to assess abdominal body composition. Fasting carbohydrate measures (glucose, insulin, C-peptide, and fructosamine) were determined at baseline and after 2 years of treatment. Compared to controls, BW significantly increased and abdominal soft tissue mass was greater (analysis of variance [ANOVA], P <.001, P = 0.003, respectively) in all but the CEE-treated group (P =.78, P =.94, respectively). HiTib-treated monkeys had greater abdominal lean mass compared to controls (P =.008), while there was no significant treatment effect on abdominal fat mass (analysis of covariance [ANCOVA], P =.29). Fasting insulin concentrations and fasting insulin/glucose ratios were greater in CEE + MPA- (P =.002, P =.03, respectively) and HiTib-treated monkeys (P =.03, P =.02, respectively) compared to controls. There was a strong trend for a treatment effect on fasting blood glucose concentration (ANCOVA, P =.06) with CEE + MPA-treated animals having the greatest values, despite no difference in fructosamine concentration (ANCOVA, P =.57). Using these fasting measures, the homeostasis model assessment (HOMA-IR) revealed significant insulin resistance with CEE + MPA treatment compared to controls (P =.008), while the quantitative insulin sensitivity check index (QUICKI) showed significantly impaired insulin sensitivity in all hormone replacement therapy (HRT) groups (all P values <.03), except CEE (P =.12). In conclusion, HRT with CEE + MPA or tibolone results in greater BW, abdominal soft tissue, and insulin resistance (CEE + MPA and HiTib) compared to control-treated monkeys.

Topics: Animals; Arteriosclerosis; Blood Glucose; Body Composition; Body Weight; C-Peptide; Carbohydrates; Dietary Fats; Energy Intake; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Fasting; Female; Fructosamine; Insulin; Insulin Resistance; Macaca fascicularis; Medroxyprogesterone Acetate; Norpregnenes; Ovariectomy; Postmenopause

Topics: Adult; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Follow-Up Studies; Glycated Hemoglobin; Humans; Pancreas Transplantation; Time Factors; Tissue Donors; Treatment Outcome

Hypertension often coexists with hyperlipidemia, insulin resistance, and glucose intolerance, a comorbidity known as metabolic syndrome X. Different antihypertensives have mixed effects on these associated abnormalities. We compared three antihypertensives in the spontaneously hypertensive obese rat model of syndrome X. Moxonidine (4 mg/kg), an imidazoline and alpha2-adrenergic agonist, alpha-methyldopa (200 mg/kg), an alpha2-adrenergic agonist, or the vasodilator hydralazine (10 mg/kg) was given orally for 15 d. All three agents lowered blood pressure equally. Moxonidine significantly reduced fasting plasma insulin, glucagon, cholesterol, triglycerides, and free fatty acids (FFA) compared with untreated controls. In contrast, syndrome X markers were not affected by alpha-methyldopa treatment, and hydralazine reduced only glucagon and FFA. Relative to untreated controls, moxonidine improved glucose tolerance as shown by reduced glucose area under the curve (AUC) (13.6 +/- 2.4 versus 42.5 +/- 9.9 g x min/dl). Insulin AUC was increased (7.4 +/- 0.9 versus 3.9 +/- 1.8 microg x min/ml) as was the plasma C-peptide response to the glucose load. In contrast, alpha-methyldopa and hydralazine worsened glucose tolerance (68 +/- 26 and 110 +/- 21 g x min/ml, respectively) and significantly reduced insulin AUC (2.5 +/- 0.8 and -2.3 +/- 1.0 microg x min/ml, respectively) compared with controls. Moxonidine reduced but alpha-methyldopa and hydralazine elevated glucagon levels after the glucose load. Contrary to the "hemodynamic hypothesis" for the metabolic actions of antihypertensives, which predicts roughly equal benefits, only moxonidine had a positive impact on comorbidities. This unique action suggests a role for direct stimulation of imidazoline receptors.

Topics: Adrenergic alpha-Agonists; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Cholesterol; Eating; Fatty Acids, Nonesterified; Glucagon; Glucose Tolerance Test; Homeostasis; Imidazoline Receptors; Insulin; Lipid Metabolism; Male; Metabolism; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Receptors, Drug; Sympathetic Nervous System; Triglycerides; Vascular Resistance

Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes.. One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study.. Serum AHSG was determined by radial immunodiffusion.. We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns.. AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development.

Topics: alpha-2-HS-Glycoprotein; Blood Glucose; Blood Proteins; Body Height; Body Weight; C-Peptide; Cephalometry; Diabetes, Gestational; Female; Gestational Age; Humans; Infant, Newborn; Insulin Resistance; Leptin; Pregnancy; Tumor Necrosis Factor-alpha

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% (n = 7) or >30% (n = 7) and 14 young, nonobese men with body fat <25% (n = 7) or >25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized (1)H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.

Topics: Adult; Anthropometry; Antigens, CD; Body Weight; C-Peptide; Energy Metabolism; Fasting; Female; Glucose; Homeostasis; Humans; Hydrocortisone; Insulin; Leptin; Lipid Metabolism; Lipids; Male; Muscle, Skeletal; Oxidation-Reduction; Postprandial Period; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Reference Values

The aim of the present study was to assess a suitable expression of the urinary concentration of a protein/ peptide hormone such as insulin-like growth factor-I (IGF-I), measured in the urine of healthy individuals when the specimen collection is executed randomly. One hundred and twenty male subjects were divided by age into four groups, namely healthy sedentary young (SYA) and older (SOA) adults, older (OC) and young (YC) children. In a single urine specimen, randomly collected during the morning from each individual, total urinary IGF-I was measured by immunoradiometric method, and urinary creatinine (uCr) and total proteins (utPr) were measured by capillary electrophoresis and spectrophotometric methods, respectively. The urinary IGF-I concentrations were not significantly different in all groups investigated and they were (mean +/- SD): 82.7 +/- 82.8 ng/l, 103.5 +/- 83.3 ng/l, 80.4 +/- 64.4 ng/l in OC, SYA and SOA, respectively; only in the YC group there was a tendency to higher values (125.2 +/- 93.2 ng/l) compared with the other groups. utPr ranged from 26 to 40 mg/l and did not demonstrate significant differences between groups. The urinary IGF-I correlated with uCr and utPr, and statistical significance was observed in all measurements. The measurement of urinary IGF-I in random urine and its ratio to utPr is an innovative, useful way of investigation of urinary protein/peptide hormones.

Topics: Adolescent; Adult; Aging; Body Height; Body Weight; C-Peptide; Child; Creatinine; Electrophoresis, Polyacrylamide Gel; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Proline; Radioimmunoassay; Random Allocation; Reference Values; Regression Analysis; Sampling Studies; Spectrophotometry

In addition to stimulating insulin secretion, glucagon-like peptide and its long-acting analog exendin 4 have been reported to increase beta-cell mass by both differentiation/neogenesis of precursor cells and enhanced replication of existing beta-cells. Here, we investigated the effect of exendin 4 in the growth and differentiation of beta-cells from undifferentiated precursors in islet-like cell clusters (ICCs) derived from human fetal pancreases. Our results show that the addition of exendin 4 to the culture media stimulates PDX 1 expression in ICCs as shown by immunofluorescence staining. The up-regulation of PDX 1 was not accompanied by changes in insulin expression because we did not find a significant difference in the number of insulin-positive cells in the exendin 4-treated ICCs, compared with controls. We also tested the effects of exendin 4 in the glucose-induced insulin secretion of human ICCs transplanted under the kidney capsule of athymic rats. In the exendin 4-treated rats (given ip during 10 d) 8 wk after the beginning of the treatment, insulin was released in response to glucose as detected by the measurement of circulating human C-peptide. In control (saline-treated) rats, the basal levels of human C-peptide did not change significantly after glucose stimulation. Thus, exendin 4 induces functional maturation of fetal beta-cells in response to glucose. In these rats, serial sections of the kidney-bearing grafts were examined histologically for insulin containing cells. We found a significant increase in beta-cell number, compared with the control rats. Overall, these results show that in vivo exendin 4 causes growth and differentiation of human fetal beta-cells from undifferentiated precursor cells. It also accelerates the functional maturation of fetal beta-cells as evidenced by their glucose-stimulated insulin secretion.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cell Division; Cells, Cultured; Culture Media; Exenatide; Gene Expression Regulation; Gestational Age; Homeodomain Proteins; Humans; Immunohistochemistry; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Peptides; Rats; Rats, Nude; Trans-Activators; Transplantation, Heterologous; Venoms

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Eating; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Models, Biological

Patients with type 2 diabetes (DM) demonstrate inadequate insulin release, elevated gluconeogenesis, and diminished nonoxidative glucose disposal. Similar metabolic changes occur during systemic injury caused by infection, trauma, or cancer. Described here are metabolic changes occurring in 16 DM and 11 lung cancer patients (CA) and 13 normal volunteers (NV). After a 10-h overnight fast, all subjects had fasting hormone and substrate concentrations determined, along with rates of glucose production, leucine appearance (LA), and leucine oxidation (LO). Fasting insulin (data not shown) and C-peptide concentrations were elevated in DM and CA compared with weight-matched NV (0.72 +/- 0.09 and 0.64 +/- 0.08 vs. 0.51 +/- 0.03 mg/l, P < 0.05). C-reactive protein concentration was elevated in CA compared with DM and NV (23.3 +/- 6.0 vs. 4.2 +/- 1.4 and 2.1 +/- 0.5 mg/l, P < 0.01). All counterregulatory hormones were normal except for serum cortisol (11.4 +/- 1.0 and 12.1 +/- 1.0 vs. 8.9 +/- 0.7 microg/dl, DM and CA vs. NL, respectively, P < 0.05). Glucose production was increased in DM and CA compared with NV (4.22 +/- 0.6 and 3.53 +/- 0.3 vs. 2.76 +/- 0.2 mg x kg lean body wt(-1) x min(-1), P < 0.01). LO and LA were increased in DM and CA compared with NV (LO: 27.3 +/- 1.5 and 19.7 +/- 1.5 vs. 12.5 +/- 1.1 mmol x kg lean body wt(-1) x min(-1), P < 0.05; LA: 91.9 +/- 6.6 and 90.7 +/- 7.0 vs. 79.1 +/- 6.0 mmol. kg lean body wt(-1) x min(-1), P < 0.01). DM share similar metabolic derangements with CA. The increase in LA may be secondary to an increased glucose production where amino acids are mobilized to provide the liver with adequate substrate to make glucose. The increase in glucose production may also be part of the injury response, or it may represent a form of insulin resistance that exists in both the DM and (non-DM) CA patients.

Topics: Acute-Phase Reaction; Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glucagon; Gluconeogenesis; Humans; Hydrocortisone; Insulin; Interleukin-6; Leucine; Lung Neoplasms; Middle Aged; Triiodothyronine; Tumor Necrosis Factor-alpha

To test the hypothesis that elevated midpregnancy serum insulin (IRI) and C-peptide (CP) concentrations are associated with later development of pregnancy-induced hypertension (PIH), independent of prepregnancy obesity and midpregnancy blood pressure.. In this prospective study, a cohort of normotensive women, ages > or = years performed a 50-g glucose challenge test at 24-30 weeks' gestational age. Blood samples were collected after an overnight fast and 1 h after glucose ingestion. Serum IRI and CP concentrations were measured in each sample. Maternal height, blood pressure and proteinuria were measured at the time of glucose challenge testing and after 36 weeks' gestational age.. Of 320 subjects enrolled 44 women (13.8%) had subsequent PIH. Crude odds ratios (ORs) for devevelopment of PIH associated with each 1 U rise in log fasting IRI, log lasting CP. and glucosed-induced increase in CP (expressed as log [postprandial CP/fasting CP]) were 2.0 (95% CI 1.3-3.3), 1.8 (CI 1.2-2.7), and 2.3 (CI 1.1-4.9) respectively. After controlling for prepregnancy BMI, gestational age, and midpregnancy mean arterial pressure, adjusted ORs corresponding to log fastig IRI and CP for the development of PIH were 1.3 (95% CI 0.7-2.3) and 1.7 (CI 1.1-2.7) respectively, and, afterq adjustment for fasting CP, the adjusted OR of the glucose-induced rise in log CP was 3.7 (CI 1.5-9.3).. Mid-pregnancy tasting and postoral glucose CP levels are associated with subsequent development of PIH, independent of maternal obesity and midpregnancy baseline blood pressure. These findings many reflect an amplified beta3-cell response to glycemic stimulus, similar to that found in states of insulin resistance, that appears to be independently associated with PIH.

Topics: Adult; Biomarkers; Blood Pressure; Body Height; Body Mass Index; Body Weight; C-Peptide; Cohort Studies; Ethnicity; Female; Humans; Hypertension; Insulin; Postprandial Period; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies; Racial Groups; Rhode Island

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

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

To determine prevalence estimates in order to monitor diabetes, particularly type 2 diabetes, in American Indian youth.. To explore the feasibility of developing a case definition using information from primary care records, all youth aged <20 years with an outpatient visit or hospitalization for diabetes were identified from the Billings Area Indian Health Service database in Montana and Wyoming from 1997 to 1999, and the medical records were reviewed. Classification for probable type 1 diabetes was based on age < or =5 years, weight per age < or =15th percentile at diagnosis, or positive results of islet cell antibody test. Classification for probable type 2 diabetes was based on weight per age > or =85th percentile or presence of acanthosis nigricans at diagnosis, elevated C-peptide or insulin, family history for type 2 diabetes, or use of oral hypoglycemic agents with or without insulin or absence of current treatment 1 year after diagnosis.. A total of 52 case subjects with diabetes were identified, 3 of whom had diabetes secondary to other conditions. Of the remaining 49 case subjects, 25 (51%) were categorized as having probable type 2 diabetes, 14 (29%) as having probable type 1 diabetes, and 10 (20%) could not be categorized because of missing or negative information. Prevalence estimates for diabetes of all types, type 1 diabetes, and type 2 diabetes were 2.3, 0.6, and 1.1, respectively, per 1,000 youth aged <20 years.. Our definitions may be useful for surveillance in primary care settings until further studies develop feasible case definitions for monitoring trends in diabetes among youth.

Topics: Acanthosis Nigricans; Adolescent; Adult; Autoantibodies; Body Weight; C-Peptide; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Guidelines as Topic; Humans; Indians, North American; Inpatients; Insulin; Islets of Langerhans; Medical Records; Montana; Outpatients; Retrospective Studies; Wyoming

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

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

Cyclo (His-Pro) (CHP) is a gut-brain peptide whose plasma levels in humans are increased after glucose ingestion and preferentially altered by oral glucose ingestion compared to intravenous administration in rats, suggesting a role in the enteroinsular response to nutrient ingestion. We were interested in examining levels of CHP in women of differing weights and comparing these levels to various parameters of insulin secretion. Plasma from 26 fasting, nondiabetic women ranging from 21 to 70 years of age and weighing 43 to 114 kg was assayed for CHP. Insulin and C-peptide levels were measured in 17 of the 26. Fasting CHP levels were elevated in obese compared to nonobese women (2075+/-144 vs. 905+/-187 pg/ml; p < 0.001) and were related by regression analysis to weight (r = 0.668, p < 0.001) and body mass index (r = 0.636, p = 0.001). The fasting C peptide/insulin molar ratio, which may be used as an estimate of hepatic insulin clearance (HIC), was inversely related to CHP levels (r = -0.568, p = 0.017). We conclude CHP levels are increased in obese women and inversely related to their C-peptide/insulin molar ratio. The elevation of CHP in those with a decrease in this estimate of HIC (obese) is interesting as the greater insulin response seen in normal persons after oral glucose compared to intravenous glucose has been postulated to be due to a decrease in HIC by some gut factor. The presence of such a factor in excess in the obese might explain part of their hyperinsulinemia.

Topics: Adult; Aged; Body Constitution; Body Mass Index; Body Weight; C-Peptide; Female; Humans; Insulin; Liver; Middle Aged; Obesity; Peptides, Cyclic; Piperazines; Regression Analysis

The pig is useful as a model for human physiology and pathophysiology and could be an important supplement to the many available rodent models of diabetes mellitus. Due to their small size, Göttingen minipigs are especially suitable for long-term studies. The aim of the study reported here was to establish reference values for a range of glucose and lipid homeostasis parameters of interest that could be used to identify possible diabetes-prone male Göttingen minipig individuals, families, or age groups. Plasma samples from nonfed animals were analyzed for glucose, leptin, fructosamine, insulin, C-peptide, triglyceride, free fatty acids, and total cholesterol values. Breeding family had significant effects only on plasma triglyceride concentrations (P < 0.001). Plasma concentrations of glucose (P = 0.012), fructosamine (P < 0.001) and triglycerides (P < 0.001) increased significantly with age, whereas total cholesterol concentration decreased significantly (P = 0.001) with age. Age did not influence other parameters. In conclusion, glycemia and insulinemia increased with age and body weight, possibly indicating a small deterioration in insulin sensitivity with age. It is, therefore, hypothesized that older, compared to younger animals may be more useful in the development of a model of type-2 diabetes mellitus. Furthermore, on the basis of decrease in cholesterol concentration with age, animals fed ad libitum with possibly a high calorie diet might be even more useful in the development of a type-2 diabetes mellitus model.

Topics: Aging; Animals; Blood Glucose; Body Weight; Breeding; C-Peptide; Diabetes Mellitus, Type 2; Disease Models, Animal; Fructosamine; Homeostasis; Humans; Insulin; Lipids; Male; Reference Values; Swine; Swine, Miniature; Triglycerides

We examined the determinants of glycaemic control in a consecutive cohort of 562 newly-referred Chinese type 2 diabetic patients (57% women) during a 12-month period. All patients underwent a structured assessment with documentation of clinical and biochemical characteristics. Pancreatic beta-cell function was assessed by fasting plasma C-peptide concentration. Insulin deficiency was defined as fasting plasma C-peptide <0.2 pmol/ml. Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA) based on a product of fasting plasma glucose and insulin concentrations. Treatment was considered appropriate when insulin-deficient patients were treated with insulin and non-insulin-deficient patients were treated with oral agents or diet. Mean (+/-SD) age was 54.3+/-13.8 years (range 17-87 years) and disease duration was 5.0+/-5.9 years. At the time of referral, 70.5% (n=396) were on drug therapy (9% on insulin and 62.8% on oral agents), 20.6% (n=116) were on diet and 9% (n=50) had not received any form of treatment. The mean HbA(lc) was 8.4+/-2.3%. The geometric mean (x// antilog SD) of IR was 4.62x//2.51 (range 0. 63-162.7) and correlated only with waist : hip ratio (WHR, p=0.008). The geometric mean of plasma C peptide was 0.47x//2.89 nmol/l and correlated with BMI (p<0.001). Glycated haemoglobin was correlated positively with age (p=0.013), disease duration (p<0.001), IR (p<0. 001) and negatively with BMI (p<0.001). Glycated haemoglobin was lower in patients who had seen a dietitian (7.9% vs. 8.7%, p<0.001) or diabetes nurse (7.8% vs. 8.7%, p<0.001) or who performed self blood glucose monitoring (7.9% vs. 8.6%, p=0.001) and higher among smokers (8.9% vs. 8.2%, p=0.003). Compared to insulin-deficient patients (n=118), non-insulin-deficient patients (n=413) had features resembling that of the Metabolic Syndrome with increased WHR (p=0.005), blood pressure (p<0.001), BMI (p=0.001) and were older (p=0.04). Amongst the insulin-deficient patients, 27% were treated with oral agents or diet. Patients receiving appropriate therapy (n=362) had a lower HbA(lc) than those treated inappropriately (n=173) (8.2% vs. 8.7%, p=0.02). On multivariate analysis, short disease duration (p<0.001), low IR (p<0.001), high BMI (p=0.001), diabetes education (p<0.001), lack of smoking (p=0. 014) and choice of appropriate treatment (p=0.009) were the independent determinants of good glycaemic control.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Blood Glucose Self-Monitoring; Blood Pressure; Body Weight; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Male; Middle Aged; Multivariate Analysis; Patient Education as Topic

The hormone leptin is considered to contribute to body weight regulation through modulation of feeding behavior and energy expenditure. The aim of the present study was 1) to assess the day-to-day within-subject variation (biovariability) of serum leptin concentrations in healthy subjects and 2) to investigate whether this variation is associated with food intake, exercise, anthropometric measurements or various metabolic covariates (insulin, C-peptide and glucagon, glucose, lactate, 3-hydroxybutyrate (3-OHB), triglycerides, non-esterified-fatty acids and glycerol). Serum leptin levels were taken daily on 12 consecutive days after an overnight fast in 12 healthy subjects with a mean (SD) age of 22.7 (1.5) yr. and a BMI of 22.8 (1.6) kg/m2. Food intake, exercise, anthropometric measurements and various metabolic covariates were also determined during this period. The overall mean of serum leptin concentration was 33.3 pmol/L with a within-subject SD range of 27-41 pmol/L and a between-subject SD range of 18-61 pmol/L. The within-subject variance of serum leptin as a proportion of total variance was 9.5%. Within-subject variation of serum leptin concentrations is small in relation to between-subject variation in healthy, normal weight subjects. This has implications for the power of interventional or prospective studies. In men, 6.7% of the variation in serum leptin concentration was associated with body weight measured on the same day (p= 0.037). In women, however, 66% of the variation was negatively associated with 3-OHB measured on both the same and the previous day (p=0.0003 and 0.002), and positively associated with triglyceride concentration measured on the previous day (p=0.0017) and insulin measured on the same day (p=0.0002). Within-subject associations in women could be due to phasic changes in unmeasured variables, possibly related to the menstrual cycle or might suggest that energy balance may exert a delayed influence on serum leptin levels, with plasma 3-OHB and triglycerides acting as markers for the state of the fat stores that regulate leptin secretion. The differences between the genders remain unexplained, however.

Topics: 3-Hydroxybutyric Acid; Adult; Alcohol Drinking; Blood Glucose; Body Constitution; Body Weight; C-Peptide; Diet; Exercise; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glycerol; Humans; Insulin; Leptin; Male; Reference Values; Regression Analysis; Reproducibility of Results; Sex Characteristics; Time Factors; Triglycerides

To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later.. We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis.. The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children.. Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.

Topics: Adolescent; Adult; Age of Onset; Alleles; Autoantibodies; Blood Glucose; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Finland; Glutamate Decarboxylase; Glycated Hemoglobin; Histocompatibility Antigens Class II; HLA-DQ Antigens; HLA-DQ beta-Chains; Hospitals, University; Humans; Islets of Langerhans; Male

When models are used to measure or predict physiological variables and parameters in a given individual, the experiments needed are often complex and costly. A valuable solution for improving their cost effectiveness is represented by population models. A widely used population model in insulin secretion studies is the one proposed by Van Cauter et al. (Diabetes 41:368-377, 1992), which determines the parameters of the two compartment model of C-peptide kinetics in a given individual from the knowledge of his/her age, sex, body surface area, and health condition (i.e., normal, obese, diabetic). This population model was identified from the data of a large training set (more than 200 subjects) via a deterministic approach. This approach, while sound in terms of providing a point estimate of C-peptide kinetic parameters in a given individual, does not provide a measure of their precision. In this paper, by employing the same training set of Van Cauter et al., we show that the identification of the population model into a Bayesian framework (by using Markov chain Monte Carlo) allows, at the individual level, the estimation of point values of the C-peptide kinetic parameters together with their precision. A successful application of the methodology is illustrated in the estimation of C-peptide kinetic parameters of seven subjects (not belonging to the training set used for the identification of the population model) for which reference values were available thanks to an independent identification experiment.

Topics: Adult; Bayes Theorem; Bias; Body Height; Body Surface Area; Body Weight; C-Peptide; Case-Control Studies; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Female; Humans; Linear Models; Male; Markov Chains; Monte Carlo Method; Obesity; Predictive Value of Tests; Tissue Distribution

To compare serum leptin levels in type 1 diabetic and obese children.. We studied serum leptin levels in 35 type 1 diabetic, 32 obese, and 35 healthy children. Seven of 35 were new-onset diabetics with ketoacidosis. C-peptide (CPE) levels were used for estimating insulin secretion.. Serum leptin levels were lower in diabetics than in controls (p<0.001). Obese children had higher leptin and CPE levels than diabetics and controls. In new-onset diabetics, 1 month insulin treatment did not cause any change in leptin levels (p>0.05). Leptin was correlated positively with body mass index and CPE (p<0.001) and inversely with glucose (p = 0.001) and HbA1c (p<0.05) in the combined group. HbA1c and gender were the independent predictors of leptin in diabetic children (p<0.01).. Low serum leptin levels in type 1 diabetic children may be due to chronic insulin deficiency related with their metabolic control. Leptin and insulin may have complementary roles in maintaining a stable body weight.

Topics: Adolescent; Body Mass Index; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Matched-Pair Analysis; Obesity; Statistics as Topic

To determine the relationships between serum leptin levels and maternal weights in late pregnancy and cord blood leptin levels to birth-weights, C-peptide, insulin and insulin like growth factor (IGF-II).. Fifty normal pregnant women at 37-38 weeks and their newborns were studied, and 29 non-pregnant women were set as control. Venous blood was taken from women and from the cord at delivery. Blood leptin and cord blood C-peptide, insulin, and IGF-II were measured by radio-immunoassay.. The average leptin level in maternal sera was (13.62 +/- 3.68) micrograms/L, significantly higher than that in the control (6.60 +/- 3.04) micrograms/L and that in cord blood (8.05 +/- 4.61) micrograms/L. Maternal leptin levels were significantly correlated with maternal weights and body mass index (BMI. r = 0.33, 0.35, P < 0.05), but not with infant birth-weights (r = 0.10, P > 0.05). Cord blood leptin levels were significantly correlated with birth-weights and BMI (r = 0.54, 0.49, P < 0.001) but have no correlation with maternal leptin levels (r = 0.19, P > 0.05). Significant difference of the cord leptin levels was not seen between the males and females. The cord blood C-peptide was (0.86 +/- 0.35) microgram/L, insulin (8.49 +/- 4.76) mU/L and IGF-II (0.218 +/- 0.076) microgram/T. Cord leptin levels were correlated with C-peptide levels (r = 0.37, P < 0.05), but not with insulin and IGF-II levels (r = 0.19, -0.14, P > 0.05).. Maternal leptin levels in late pregnancy were significantly higher than those in normal non-pregnant women and positively correlated with maternal weights and BMI. Cord blood leptin levels were positively correlated with birth-weights and BMI of the newborns. The leptin levels of cord blood were correlated with those of C-peptide but not insulin and IGF-II.

Topics: Adult; Birth Weight; Body Weight; C-Peptide; Female; Fetal Blood; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor II; Leptin; Pregnancy

The present study examines the effect of subcutaneous pancreatic tissue grafts (SPTG) on endocrine and metabolic functions in streptozotocin (STZ)-induced diabetic rats using radioimmunoassay and biochemical techniques. SPTG survived even after 15 weeks of transplantation and significantly improved the weight of STZ-diabetic rats over a 15-week period. Although blood glucose-, cholesterol-, and glycosylated-haemoglobin (GHb) levels were not significantly lower in STZ-diabetic rats treated with SPTG, the values of these biochemical parameters were lower than those in untreated diabetic rats. Plasma and pancreatic immunoreactive C-peptide (IRCP) levels did not improve after SPTG (IRCP expressed as mean +/- standard deviation were 0.22 +/- 0.07, 0.072 +/- 0.02 and 0.08 +/- 0.03 pg ml-1 in the plasma non-diabetic diabetic and treated rats respectively, while IRCP levels in the pancreas of the non-diabetic, diabetic and treated rats were 433.8 +/- 0.1, 22.9 +/- 0.01 and 10.4 +/- 0.01 pg mg tissue-1 respectively). SPTG, however, improved plasma immunoreactive insulin (IRI) levels in both plasma and pancreas. IRI values in plasma were 54.7 +/- 13.6, 18.0 +/- 5.0 and 22.1 +/- 4.3 microUI ml-1 in non-diabetic, diabetic and treated rats respectively and were 277.3 +/- 37.1, 14.7 +/- 1.8 and 30.3 +/- 15.9 microIU micrograms tissue-1 in the pancreas of non-diabetic, diabetic and treated rats respectively. There was improvement in immunoreactive glucagon (IRG) levels after SPTG. IRG values in the plasma of non-diabetic, diabetic and treated rats were 147.0 +/- 10.7, 408.0 +/- 76.5 and 247.7 +/- 3 pg ml-1 respectively whereas, IRG measured in the pancreas was 1642.25 +/- 424.23, 1899.0 +/- 290.4 and 1714.1 +/- 301.98 pg micrograms tissue-1 in non-diabetic, diabetic and treated rats, respectively. The pancreas:plasma ratio of pancreatic hormones was deranged in untreated diabetes but improved after SPTG. In conclusion, SPTG significantly improved the weight gain, pancreatic insulin content, plasma IRG and pancreas: plasma ratio of IRCP, IRI and IRG. It also reduced blood glucose-, cholesterol-, and glycosylated-hemoglobin levels in STZ-diabetic rats.

Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Experimental; Endocrine System; Female; Glucagon; Glycated Hemoglobin; Insulin; Male; Pancreas Transplantation; Rats; Rats, Wistar; Skin; Transplantation, Heterologous

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

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

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

The aim of this study was to compare, in 19-month-old male Fischer 344 rats, the influence of brief (20 days) and prolonged (approximately 15 months) calorie restriction (CR; consuming approximately 60% of ad libitum, AL, intake) on circulating levels of glucose, insulin, C-peptide, and free fatty acids (FFA); age-matched AL rats were also studied. In the prolonged CR group, there was an approximately 85% decline in fat pad masses (epididymal and retroperitoneal) compared to AL and brief CR rats (these latter groups did not differ significantly). Compared to AL levels, glucose was 15% lower with prolonged CR (p < 0.05) while the brief CR values tended to be lower (10%) than AL; the CR groups did not differ significantly. Plasma FFA levels were significantly (p < 0.05) greater (85-106%) in the brief CR group compared to each of the other groups. Plasma insulin concentrations for the CR groups were lower (p < 0.05; approximately 50-60%) than AL levels. Plasma concentrations of C-peptide (an indicator of insulin secretion) were also lower for each CR group vs AL levels, and a high correlation was found between plasma insulin and C-peptide concentrations (r2 = 0.90; p < 0.001). The C-peptide/insulin ratios for the CR groups were similar, and the value of each CR group exceeded that for the AL rats. These results demonstrate that: the CR-induced reduction in plasma insulin is attributable in large part to reduced insulin secretion; these decreases in insulin secretion and concentration are essentially undiminished when brief CR is initiated rather late in life, and the reductions are independent of substantial reductions in body fat.

Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; C-Peptide; Energy Intake; Fatty Acids, Nonesterified; Food Deprivation; Insulin; Insulin Secretion; Male; Rats; Rats, Inbred F344; Time Factors

We examined the importance of ethnicity in terms of beta-cell secretion and hepatic insulin extraction (HIE) and insulin clearance (IC) to peripheral insulin levels before and after stimulation in three populations of West African ancestry, namely African-Americans, Ghanaian immigrants, and native Ghanaians living in diverse environments, and white Americans. Following 10 to 12 hours of overnight fasting, each subject ingested a 75-g oral glucose load. Blood samples for determination of serum glucose, insulin, and C-peptide were obtained at baseline and after the oral glucose load at 30-minute intervals for 240 minutes. Basal HIE and IC were calculated as the molar ratios of C-peptide and insulin concentrations at basal steady state, and postprandial values as molar ratios of the incremental integrated C-peptide and insulin areas. Clinical characteristics of the patients were not significantly different among the four groups. During the fasting and postprandial state, serum glucose levels were not significantly different among the four groups. Surprisingly, the mean fasting insulin concentration was significantly greater in native Ghanaians (21.19 +/- 0.93 microU/mL, P < .05) than in African-Americans (11.90 +/- 1.02,microU/ML), Ghanaian immigrants (8.14 +/- 0.96 microU/mL), and white Americans (7.03 +/- 0.78 microU/mL). Following the oral glucose load, the mean serum peak and incremental integrated areas of insulin were significantly (P < .05) greater in native Ghanaians, African-Americans, and Ghanaian immigrants compared with white Americans. In contrast, there were no significant differences in postprandial serum insulin responses among the three groups of West African ancestry, irrespective of country of origin or residence. Despite the higher insulin concentrations in blacks of West African ancestry compared with whites, the corresponding basal and postprandial serum C-peptide levels were not significantly different among the four groups. Mean basal and postprandial HIE and IC were significantly (P < .05 to .01) reduced (25% to 52%) in the three populations of West African ancestry compared with the white Americans, but these values were not significantly different among the West African descendants. When comparing metabolic responses in obese (body mass index [BMI] > 27 kg/m2) and non-obese (BMI < 27 kg/m2) native Ghanaians, we found no significant differences in fasting insulin, C-peptide, and basal HIE or IC. Also, there were no significant relat

Topics: Adult; Aging; Black People; Body Height; Body Mass Index; Body Weight; C-Peptide; Female; Ghana; Glucose; Humans; Insulin; Liver; Male; Obesity; United States; White People

Osteopenia has been described as a complication of insulin-dependent diabetes mellitus (IDDM). We measured bone modeling indexes during the first year of IDDM. At each time point the values obtained from diabetic children have been compared with those of control subjects. We selected 27 prepubertal children with IDDM (6.35 +/- 2.16 years). We also enrolled 30 healthy prepubertal children of comparable age (5.85 +/- 3.05 years). Height, height standard deviation scores, glycated haemoglobin (HbA1C), basal c-peptide concentrations, insulin dose, serum concentrations of procollagen type I C-terminal propeptide (PICP), and collagen type I C-terminal telopeptide (ICTP) were measured at onset of IDDM and at 3, 6 and 12 months. ICTP was in the normal range at onset of IDDM and decreased during the follow-up to reach a significant difference compared to controls after 3, 6 and 12 months of insulin treatment (P < 0.04). PICP concentrations increased significantly at 3 months (P = 0.05) compared to onset. At 3 and 12 months PICP values were significantly higher than those of control children (P = 0.04). Correlations were found between PICP concentrations and HbA1C and c-peptide at onset of diabetes (r = -0.45 and r = 0.47, respectively). Bone formation at onset of IDDM is not impaired; the introduction of insulin therapy, together with the achievement of a good metabolic control, determines an increase of bone matrix formation coupled with a decrease of bone resorption, that determines a positive balance of bone modeling.

Topics: Adolescent; Biomarkers; Body Height; Body Weight; Bone Development; Bone Diseases, Metabolic; C-Peptide; Child; Cohort Studies; Collagen; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Insulin; Male; Peptide Fragments; Procollagen; Reference Values; Regression Analysis; Time Factors

The significance of gestational diabetes mellitus (GDM) results from its short-term detrimental effects on the fetus and its long-term prediction of NIDDM in the mother. We compared several variables associated with insulin resistance between GDM and non-GDM pregnant women to show the similarities between GDM and NIDDM (and thus insulin resistance).. On the basis of a 3-h oral glucose tolerance test (OGTT), 52 GDM patients and 127 non-GDM patients were recruited from pregnant, non-diabetic women who had a nonfasting 1-h-50-g glucose screening test > or = 7.2 mmol/l (130 mg/dl) performed between 16 and 33 weeks of gestation (a total of 518 of 3,041 women drawn from six community health care prenatal clinics were screened positive). During the OGTT, several potential markers of insulin resistance were measured at fasting and 2-h time points, in addition to the standard glucose measurements. The relationship of these variables with the diagnosis of GDM was studied.. GDM patients, compared with non-GDM patients, had 1) higher prepregnancy weight (P = 0.011), prepregnancy BMI (P = 0.006), C-peptide at fasting (P = 0.002) and at 2 h (P < 0.001), insulin at fasting (P = 0.001) and at 2 h (P < 0.001), triglycerides at fasting (P = 0.005) and at 2 h (P = 0.003), free fatty acids at fasting (P = 0.017), beta-hydroxybutyrate at fasting (P = 0.007); and 2) lower HDL cholesterol at fasting (P = 0.029). These variables were all predictive of GDM (P < 0.036) individually. Using stepwise logistic regression with all of these variables available, fasting (P = 0.019) and 2-h (P < 0.001) insulin levels, fasting free fatty acids (P = 0.031), and fasting beta-hydroxybutyrate (P = 0.036) were statistically significant as jointly predictive of GDM. Comparisons between GDM patients and non-GDM patients matched by BMI confirmed that the metabolic abnormalities persisted when difference in BMI was taken into account. Concomitant blood pressure measurements in women with GDM did not differ significantly from those without GDM.. Our results show that many of the known metabolic components of the syndrome of insulin resistance (syndrome X) are predictive of GDM. These results are in keeping with the argument that GDM is one phase of the syndrome of insulin resistance. We suggest that GDM be looked upon as a component of the syndrome of insulin resistance that provides an excellent model for the study and prevention of NIDDM in a relatively young age-group.

Topics: Adolescent; Adult; Analysis of Variance; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Diabetes, Gestational; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Lipids; Lipoproteins; Odds Ratio; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Reference Values

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 examine the impact of gestational diabetes mellitus(GDM) on perinatal outcome in a setting where influences of maternal age and obesity would be minimal.. A case-control study was done to compare the outcome of pregnancy in 65 women with GDM and 153 women with normal carbohydrate metabolism matched for age, height, and prepregnancy weight.. The frequencies of preeclampsia and primary cesarean sections were higher and delivery was earlier in pregnancies complicated by GDM. Birth weight, symmetry index, and chest circumference were greater, and macrosomia and need for phototherapy were more common in offspring of mothers with GDM. Cord-serum C-peptide and insulin concentrations were higher in the infants of mothers with GDM and were strongly correlated with birth weight and symmetry index. However, maternal age, prepregnancy weight, and prepregnancy BMI were not correlated with birth weight. Postprandial glucose levels during the first 2 weeks after diagnosis of GDM had associations with the infants' birth weight, symmetry index, and cord insulin concentration in the diet-treated patients with GDM.. Antepartum maternal glucose metabolism was significantly associated with fetal hyperinsulinemia and excessive fetal growth in relatively nonobese Korean women. These findings support a direct role for metabolic factors in the adverse outcomes in pregnancies complicated by GDM.

Topics: Adult; Birth Weight; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Case-Control Studies; Cesarean Section; Diabetes, Gestational; Female; Fetal Blood; Fetal Macrosomia; Gestational Age; Humans; Infant, Newborn; Jaundice, Neonatal; Korea; Maternal Age; Morbidity; Obesity; Parity; Phototherapy; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Regression Analysis

We evaluated the influence of family history of hypertension on insulin sensitivity in lean and obese hypertensive subjects (H): 40 lean [body mass index (BMI) < or = 25 kg m-2] H with normotensive parents (F-), 50 lean H with one or two parents hypertensive (F+), 30 obese HF- (BMI > or = 30 kg m-2) and 35 obese HF+. The four groups were comparable in terms of age, sex and ambulatory blood pressure values. We evaluated glucose, insulin and C-peptide before and 30, 60, 90 and 120 min after an oral glucose load, insulin sensitivity index (ISI, fasting glucose/insulin ratio), fasting insulin/C-peptide ratio (I/Cp). Glucose, fasting and during test, and I/Cp were similar among the four groups; insulin and C-peptide, fasting and stimulated, were significantly higher and ISI lower in obese H than in lean H; at similar BMI, insulin and C-peptide were significantly higher in F+ than in F-. Insulin directly correlated with night-time blood pressure only in lean HF-. The correlation between insulin and BMI was significantly closer in F-than in F+. In conclusion, family history of hypertension appears to play a relevant role in insulin sensitivity in hypertensive subjects also in the presence of obesity.

Topics: Adult; Aging; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Female; Humans; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Regression Analysis; Sex Characteristics

The majority (> 80%) of patients with non insulin dependent diabetes mellitus (NIDDM) present in Europe and America are obese. In developing countries like India, most NIDDM (> 60%) are non-obese and many are actually lean with a body mass index (BMI) of < 18.5 and are referred to as 'lean NIDDM'. This paper compares the clinical profile of a cohort of 347 lean NIDDM, with a group of 6274 NIDDM of ideal body weight (IBW) and 3252 obese NIDDM attending a diabetes centre at Madras in South India. The lean NIDDM who constituted 3.5% of all NIDDM patients seen at our centre, had more severe diabetes and an increased prevalence of retinopathy (both background and proliferative), nephropathy and neuropathy. Although a larger percentage of the lean NIDDM patients were treated with insulin, 47% of the males and 53% of the females were still on oral hypoglycaemic agents even after a mean duration of diabetes of 9.2 +/- 8.1 years. Studies of GAD antibodies, islet cell antibodies (ICA) and fasting and stimulated C-peptide estimations done in a small subgroup of the lean NIDDM showed that they were distinct from IDDM patients. More studies are needed on metabolic, hormonal and immunological profile of lean NIDDM seen in developing countries like India.

Topics: Adult; Autoantibodies; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Cohort Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Diastole; Dose-Response Relationship, Drug; Fasting; Female; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; India; Insulin; Islets of Langerhans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Obesity; Postprandial Period; Smoking; Systole; Triglycerides

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results mu

Topics: Adult; Birth Weight; Body Weight; C-Peptide; Denmark; Female; Gene Frequency; Glucose; Heterozygote; Homozygote; Humans; Insulin; Insulin Resistance; Male; Obesity; Point Mutation; Polymorphism, Genetic; Receptors, Adrenergic, beta

The purpose of this work was to investigate the relationship of gonadotropin levels to body weight and insulin levels in woman with polycystic ovary syndrome (PCOS). Specifically, we wished to test the hypothesis that circulating luteinizing hormone (LH) and insulin levels are different in obese and normal weight patients with PCOS. The basal plasma levels of gonadotropins, estrogens, androgens and sex hormone-binding globulin, the gonadotropin responses to gonadotropin releasing hormone (GnRH) and the insulin and C-peptide responses to a 3-hour oral glucose tolerance test (OGTT) were measured in 19 obese and 19 normal weight patients with PCOS and 7 obese and 8 normal weight ovulatory controls. Data of the patients were evaluated according to body weight (obese vs normal weight) and basal LH (high vs normal). There was no significant difference in basal LH and androgen levels and in the insulin response to oral glucose between obese and normal weight patients with PCOS. Compared to the weight matched controls, both obese and non obese patients showed significantly higher LH responses to GnRH and C-peptide responses to OGTT. When the high LH patients (no = 18) were compared those with normal LH (no = 20), the high LH subjects exhibited significantly higher androstenedione levels. Both obese (no = 10) and normal weight (no = 8) patients with high LH showed significantly greater C-peptide responses to OGTT than obese (no = 9) and non obese (no = 11) patients with normal LH. However, as compared with the weight matched controls, both the high LH and normal LH patients had significantly greater C-peptide responses to OGTT. We conclude that obese and non obese patients with PCOS do not seem to differ in the prevalence of elevated LH levels or in the LH secretory pattern. Insulin resistance, expressed by an enhanced pancreatic sensitivity to oral glucose, is present in both the high LH and the normal LH subjects, even though the PCOS patients with elevated LH tend to be more insulin resistant and hyperandrogenic than the normal LH patients.

Topics: Adult; Androgens; Body Mass Index; Body Weight; C-Peptide; Female; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Insulin; Luteinizing Hormone; Obesity; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin

To investigate the metabolic effects of dietary fructose and sucrose in type II diabetic patients.. Sixteen well-controlled type II diabetic subjects were fed three isocaloric diets for 28 days each. The three diets provided 50-55, 15, and 30-35% of total energy from carbohydrate, protein, and fat, respectively. In one diet, 20% of total calories were derived from fructose; in another, 19% of total calories were derived from sucrose; and in the control diet, only 5% of daily calories were derived from sugars, all other carbohydrates being supplied as polysaccharides.. No significant differences were observed between either the fructose or the sucrose diet and the control polysaccharide diet in any of the measures of glycemic control, serum lipid levels, or insulin and C-peptide secretion.. Our data suggest that in the short and middle terms, high fructose and sucrose diets do not adversely affect glycemia, lipemia, or insulin and C-peptide secretion in well-controlled type II diabetic subjects.

Topics: Adult; Aged; Blood Glucose; Blood Proteins; Body Weight; C-Peptide; Chlorpropamide; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Sucrose; Energy Intake; Female; Fructose; Glyburide; Glycated Serum Proteins; Glycoproteins; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Postprandial Period; Triglycerides

Topics: Adult; Age of Onset; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Insulin; Male; Obesity

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

We examined the effects of a magnesium-supplemented (Mg-S) diet in the male obese Zucker diabetic fatty rat, a model of non-insulin-dependent diabetes mellitus (NIDDM). Obese rats were maintained on either a control (0.20% Mg) or magnesium-supplemented (Mg-S; 1% Mg) diet for 6 wk beginning at 6 wk of age. The rats maintained on the Mg-S diet had markedly lower fasting and fed-state blood glucose concentrations and an improved glucose disposal. By 12 wk of age, all of the eight animals on the control diet became diabetic, whereas diabetes developed in only one of eight animals on the Mg-S diet. Insulin and C-peptide concentrations, in addition to pancreatic GLUT-2 and insulin mRNA expression, were higher in the male obese Mg-S rats than in their control-fed counterparts. A subgroup of rats on the control diet with established diabetes was switched to a Mg-S diet for an additional 4 wk. The Mg-S diet did not reverse diabetes once already established. These data indicate that an increased dietary Mg intake in male obese rats prevents deterioration of glucose tolerance, thus delaying the development of spontaneous NIDDM.

Topics: Aging; Animals; Blood Glucose; Body Weight; C-Peptide; Cations; Cholesterol; Diabetes Mellitus, Type 2; Diet; Fasting; Glucose Tolerance Test; Glucose Transporter Type 2; Insulin; Magnesium; Male; Monosaccharide Transport Proteins; Rats; Rats, Zucker; RNA, Messenger; Triglycerides

The purpose of this study was to investigate whether young insulin-dependent diabetic patients still develop peripheral nerve dysfunction when using modern multiple insulin injection therapy and to elucidate if this correlated with various disease parameters. Seventy-five patients, 7 to 20 years old with a duration of diabetes of more than 3 years, and 128 age-matched healthy control subjects underwent bilateral studies of median, peroneal, and sural nerves. Presence of diabetes lowered motor conduction velocity (p < 0.0001), sensory conduction velocity (p < 0.0001) and sensory nerve action potential (p < 0.05) in all examined nerves. The mean change in conduction velocity induced by diabetes was -4.8 m/s in the peroneal nerve, -3.3 m/s in the median motor nerve, -2.6 m/s in the sural nerve and -2.4 m/s in the median sensory nerve. Fifty-seven percent of the patients had abnormal conduction (values outside 95% predictive interval) which was seen most often in the motor nerves, especially in the peroneal nerve (41%) followed by the median nerve (24%). In multiple regression analysis, long-term poor metabolic control and increased body length correlated with nerve dysfunction identified in most examined parameters. Three patients had signs or symptoms suggestive of neuropathy. It is concluded that despite modern multiple insulin injection therapy, with reasonably good metabolic control, nerve dysfunction is still common in children and adolescents with insulin-dependent diabetes mellitus. Risk factors are increased height and long-term poor metabolic control.

Topics: Adolescent; Adult; Age of Onset; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Child; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Functional Laterality; Glycated Hemoglobin; Humans; Male; Median Nerve; Motor Neurons; Neural Conduction; Neurons, Afferent; Patient Dropouts; Peroneal Nerve; Regression Analysis; Sural Nerve

In overweight women with polycystic ovary syndrome (PCOS), increased insulin resistance has been observed. Since abdominal obesity is associated with impaired fibrinolytic capacity and elevated levels of plasminogen activator inhibitor (PAI-1) and since PAI-1 seems to be related to insulin resistance, we investigated the possible effects of dietary intervention on lipids, fibrinolysis, coagulation, and insulin sensitivity in obese PCOS women. Nine women aged 22 to 39 years (median weight, 97 kg) ate a protein-rich very-low-calorie diet (VLCD) (Nutrilett, Nycomed Pharma, Oslo, Norway; 421 kcal/d) for 4 weeks (part 1). After significant reductions of body fat (13%, P < .01), two of nine women achieved regular menstruation and became pregnant. Six of the remaining women continued on a conventional low-calorie diet (1,000 to 1,500 kcal/d) for the next 20 weeks (part 2), during which time they were generally able to preserve the body fat loss obtained in part 1 of the study. During part 1, significant reductions of total serum cholesterol (29%, P = .001) and fasting triglyceride ([TG] 31%, P < .05) levels were observed, as well as significant reductions of fasting glucose (6%, P < .05) and insulin (20%, P < .05). Insulin sensitivity (glucose disposal rate [GDR]) was increased by 93% (P < .05). After finishing part 2, insulin sensitivity was still significantly increased (86%, P < .05) and PAI-1 activity was significantly reduced (54%, P < .05). Moreover, overall fibrinolytic activity was significantly improved (serum D-dimer concentration increased by 75%, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diet, Reducing; Factor VII; Female; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Insulin; Insulin Resistance; Lipids; Obesity; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone; Time Factors; Tissue Plasminogen Activator

To study the relationships between blood pressure, insulin secretion and insulin resistance in obese female subjects.. Evaluation of insulin-secretion and resistance respectively by blood C-peptide determination and glucose clamp technique in nonhypertensive and hypertensive obese female subjects.. Outpatient clinic of University Hospital.. 12 female obese subjects, six of whom were nonhypertensive, and six hypertensive; and nine nonobese nonhypertensive subjects as control.. Baseline and during OGTT blood C-peptide as insulin secretion index; M, MCR and M/I ratio evaluated by euglycemic hyperinsulinemic clamp as expression of insulin resistance.. No difference is shown in C-peptide levels, between the two groups of obese subjects; the M, MCR and M/I values are significantly lower in hypertensive obese vs nonhypertensive obese subjects and controls (P < 0.001). Considering all the subjects, the same parameters are significantly inversely correlated with mean blood pressure values (P < 0.001).. In the groups of considered obese subjects, homogeneous for age, sex, body weight excess, fat distribution and glucose tolerance, blood pressure values are directly related to insulin resistance but not to insulin secretion.

Topics: Adult; Blood Glucose; Blood Pressure; Body Constitution; Body Weight; C-Peptide; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Middle Aged; Obesity

We have previously demonstrated that glucose-tolerant American blacks manifest significantly higher insulin concentrations and a lower insulin sensitivity than native African blacks who reside in their respective countries. It is, however, unknown whether the serum glucose, beta-cell function and insulin sensitivity are different in native Africans and African-Americans who reside in the same environments. We have studied 68 healthy American blacks and age- and weight-matched 30 African blacks recently immigrated from Ghana residing in Franklin County, Ohio, USA. Each subject underwent a standard oral glucose tolerance test to determine glucose tolerance status. Insulin sensitivity index (Si) and glucose effectiveness (Sg) were measured by the insulin-modified, frequently-sampled intravenous glucose tolerance test. The body composition variables were measured by the bioelectrical impedance analyser and body fat distribution pattern by the waist-hip ratio. The clinical characteristics were identical in the African-American and the African blacks; the mean fasting serum glucose, insulin and C-peptide levels were not different. Following the oral and intravenous glucose administration, the mean peak and incremental areas of serum glucose, insulin and C-peptide were not different in the two groups. The mean Si (3.1 +/- 0.7 vs 2.4 +/- 0.3 x 10(-4).(min/microU.1-1)-1 and Sg (2.5 +/- 0.3 vs 2.7 +/- 0.2 x 10(-2).min-1) were not significantly different in the American and African blacks, respectively. In summary, the metabolic parameters measured in the American blacks and recent African immigrants were identical.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adult; Analysis of Variance; Black or African American; Black People; Blood Glucose; Body Height; Body Mass Index; Body Weight; C-Peptide; Female; Ghana; Glucose Tolerance Test; Humans; Insulin; Male; Ohio; Reference Values; Regression Analysis; Reproducibility of Results; Sensitivity and Specificity; Sex Characteristics

1. Both increased and decreased sensitivity to insulin has been proposed to precede the development of obesity. Therefore, insulin sensitivity was measured during a 2 h hyperinsulinaemia (100 m-units min-1 m-2) euglycaemic (4.5 mmol/l) glucose clamp combined with indirect calorimetry in nine weight-stable post-obese women and in nine matched control women preceded by 12 h fasting after 48 h on a standardized diet. 2. Both glucose disposal rate (post-obese women, 9.5 +/- 2.2 mg min-1 kg-1, control women, 11.2 +/- 1.4 mg min-1 kg-1, not significant) and glucose oxidation (3.6 +/- 0.5 mg min-1 kg-1 versus 4.0 +/- 0.7 mg min-1 kg-1, not significant) were similar in the two groups during the last 30 min of the clamp. Lipid oxidation also decreased similarly during the clamp in the post-obese women (from 30.4 +/- 12 to 2.0 +/- 7 J min-1 kg-1) and in the control women (from 33.6 +/- 11 to 5.4 +/- 8 J min-1 kg-1, not significant). Basal plasma concentrations of free fatty acids were similar, but at the end of the clamp free fatty acids were lower in the post-obese women than in the control women (139 +/- 19 and 276 +/- 48 mumol/l, P = 0.02). 3. We conclude that the insulin sensitivity of glucose metabolism is unaltered in the post-obese state. The study, however, points to an increased antilipolytic insulin action in post-obese subjects, which may favour fat storage and lower lipid oxidation rate postprandially.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Energy Metabolism; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Obesity; Oxidation-Reduction

The development of hyperinsulinemia and insulin resistance, both common in adults with established obesity, was studied in 16 children, weighing 169 +/- 8% ideal body weight who were 12.7 +/- 0.4 years of age with obesity duration of 0.5-8.5 years and continuous weight gain in excess of normal, and compared with 11 age-matched normal children. Early in the evolution of obesity, insulin and C-peptide responses to a normal meal were increased by 76 and 80%. The first insulin peak was higher (613 +/- 53 pmol/ml) than normal (413 +/- 59 pmol/ml, P < 0.02) and occurred only 50 +/- 7 min after onset of lunch versus 33 +/- 11 min in normal children (P < 0.0005). Obese patients had a total of 3.0 +/- 0.2 large insulin peaks within the 6-h period after the lunch versus only 1.5 +/- 0.2 peaks in normal children (P < 0.0005). In contrast, fasting plasma insulin and C-peptide levels remained normal during the initial years of obesity, then increased progressively with duration (r = 0.73, P < 0.001) and degree (r = 0.59, P < 0.02) of obesity. Insulin sensitivity evaluated as the rate of glucose uptake during a three-step hyperinsulinemic euglycemic clamp was comparable in the obese (20 +/- 1.5 mmol.m-2.min-1) and the normal (21.7 +/- 1.5 mmol.m-2.min-1) children. Initially higher than normal in obese children, the maximal rate of glucose uptake decreased with both obesity duration (r = -0.67, P < 0.005) and children's age (r = -0.66, P < 0.005), indicating the progressive development of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Analysis of Variance; Blood Glucose; Body Weight; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Eating; Female; Glucose Clamp Technique; Humans; Insulin; Insulin Secretion; Male; Obesity; Prediabetic State; Reference Values; Time Factors

This study was performed to investigate whether different patterns of body fat distribution may have distinct effects on the clinical, hormonal, and metabolic features of women with clinical hyperandrogenism such as polycystic ovary syndrome (PCOS). Ninety-seven consecutive women with PCOS were included in the study after assessment of gynecological and obesity history and careful clinical examination. Women were divided into three tertile groups based on the waist to hip ratio (WHR). Those with peripheral body fat distribution (P-BFD) had a WHR of less than 0.80, those with intermediate body fat distribution (I-BFD) had a WHR of 0.81 to 0.90, and those with abdominal body fat distribution (A-BFD) had a WHR exceeding 0.90. Baseline blood and urine samples were obtained for several hormone and lipid determinations, and the response of glucose, insulin, and C-peptide to a glucose oral challenge (75 g) was investigated. In the PCOS group, WHR values were higher than those used to define P-BFD and A-BFD in the normal female population. As WHR values increased, a significantly greater prevalence of obesity and acanthosis nigricans and a lower prevalence of acne was present. No significant differences were present in any of the other clinical features between the three groups. Ovarian morphology and volumes were similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adolescent; Adult; Anthropometry; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Peptide; Feeding Behavior; Female; Humans; Insulin; Lipids; Ovary; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Ultrasonography

The hypothesis that spontaneous obesity in rhesus monkeys is associated with abnormalities in energy expenditure was tested. Obese (n=7) and non-obese (n=5) monkeys were described in terms of body size and composition, food intake, and physical activity. Additionally, the relationships among fasting and stimulated insulin levels in serum, C-peptide levels in serum and urine, and urinary catecholamines were examined. Obese animals had primarily abdominal deposition of excess body fat, as indicated by markedly elevated abdominal circumferences and skin-fold thicknesses. Food intake did not differ between groups. Physical activity was much lower in the obese group. Obese monkeys had markedly higher serum insulin and C-peptide levels in the fasted state and in response to an intravenous glucose challenge. Urinary excretion of C-peptide and catecholamines was measured during successive 2-day periods of ad libitum feeding, food deprivation, and refeeding in order to examine potential differences between groups in sympathoadrenal activity and their relationship to insulin secretion. C-peptide excretion was greater for obese and decreased for both groups during food deprivation. Urinary dopamine (DA), norepinephrine (NE), and epinephrine (E) levels were significantly greater for obese animals in all conditions. DA excretion was lowest during deprivation and E excretion was lowest during refeeding, whereas NE excretion was relatively unaffected by feeding condition. The overall patterns of C-peptide and catecholamine excretion were qualitatively similar for both groups, and there were no reliable differences between obese and non-obese in their responses to the feeding manipulation. The results suggest that hyperinsulinemia associated with obesity in rhesus monkeys is linked to increased catecholamine secretion and a resistance to catecholaminergic action.

Topics: Adrenal Glands; Animals; Body Weight; C-Peptide; Catecholamines; Chromatography, High Pressure Liquid; Dopamine; Eating; Epinephrine; Feeding Behavior; Female; Glucose Tolerance Test; Insulin; Lipid Metabolism; Macaca mulatta; Male; Motor Activity; Norepinephrine; Obesity; Physical Conditioning, Animal; Time Factors

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

Although it is known that circulating levels of the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) fluctuate in response to changes in nutritional status, there is little information regarding either relative contributions from different dietary components or regulation by insulin in nondiabetic subjects. To define dietary contributions to IGF regulation, the authors examined the effects of fasting and hypocaloric diets of differing nutritional composition on serum IGF-1 and a IGFBP-1 in 16 healthy, obese adult women. Subjects received an isocaloric diet for 6 days, followed by 14 days of calorie restriction (fasting or a hypocaloric diet enriched in either protein, fat, or carbohydrate), and by 4 days refeeding. All diets produced 6-8% weight loss over 14 days with little difference between groups. The "protein-sparing" diet sustained nitrogen balance (+1.2 g/d, versus -4.5 g/d for the other three groups; p < 0.05). Serum IGF-1 levels decreased during calorie restriction with fasting or with diets high in fat or carbohydrates (CHO; combined mean 40 +/- 7%) but showed little change with the high protein regimen (3 +/- 16%; p < 0.05 compared to the other diets). In contrast, IGFBP-1 increased during calorie restriction in all four groups but significantly less with the high CHO diet (43 +/- 17% above baseline) than with the other diets (168 +/- 31%; p < 0.05). Levels of IGF-1 were correlated with nitrogen balance (r = 0.51; p < 0.05) but levels of IGFBP-1 were not. Although IGFBP-1 levels inversely correlated with measures of insulin secretion, IGF-1 levels did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Body Weight; C-Peptide; Carrier Proteins; Diet; Fasting; Female; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Nitrogen; Obesity; Prealbumin; Transferrin

Secondary failure and the requirement is common in patients with non-insulin dependent diabetes mellitus. The combination of sulfonylureas with NPH insulin at bedtime has been proposed to avoid high doses of insulin. We treated 18 patients (2 men, age range 47-76 yr) non respondent to diet and glibenclamide, combining NPH insulin in an average dose of 0.3 +/- 0.03 U/kg BW at bedtime for 6 months. Fasting serum glucose improved from 256 +/- 11 to 132 +/- 6 mg/dl and HbA1C from 13.6 +/- 0.4 to 9.9 +/- 0.2%. Four patients achieved a good control (defined as a HbA1C < 9), 9 a fair control (HbA1C 9.1-10) and 5 persisted with a bad control (HbA1C > 10). Well controlled patients were younger, had a shorter duration of diabetes and had a non significantly higher body mass index. Fasting serum insulin and C peptide levels achieved after glucagon injection were not predictors of the metabolic response to combined therapy. Tolerance to treatment was good, without changes in blood pressure or serum lipids and with a low incidence of hypoglycemia. There was a mean increase of 3.6 kg in body weight. After 6 months of therapy, maximum achieved C peptide values after glucagon increased from 3.3 +/- 0.3 to 4.5 +/- 0.4 ng/ml. It is concluded that combined glibenclamide and NPH insulin at bedtime is useful to treat secondary failure in non-insulin dependent diabetic patients, but their response in variable and non dependent on their beta insular secretion.

Topics: Aged; Analysis of Variance; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Humans; Insulin; Male; Middle Aged; Time Factors; Treatment Failure

Forty-six newborn babies (11 macrosomic, 11 small-for-dates and 24 of normal weight) have been prospectively studied. The levels of C-peptide in the umbilical blood were determined and the results were statistically analyzed for relationships to several perinatal variables of the mother, newborn and placenta. A positive correlation between C-peptide levels and neonatal weight, newborn ponderal index and maternal weight-gain during gestation were observed. Some other variables strongly related to neonatal infant weight (maternal weight, net placental weight and placental volume) were independent of C-peptide levels.

Topics: Body Weight; C-Peptide; Female; Fetal Macrosomia; Gestational Age; Humans; Infant, Low Birth Weight; Infant, Newborn; Organ Size; Placenta; Predictive Value of Tests; Pregnancy; Prospective Studies; Sensitivity and Specificity

To test whether nonhypertensive subjects with a two-generation positive family history of hypertension (PFH) are characterized by disturbed glucose metabolism, 16 men (38 +/- 6 years old) with PFH and 25 subjects matched for age and with negative family histories of hypertension (NFH) were recruited. Blood pressure; serum lipids; erythrocyte transmembrane sodium transport; and the glucose, plasma insulin, and C-peptide responses to an oral glucose tolerance test were investigated. Subjects with PFH had higher blood pressure, body weight, body mass index (BMI), waist/hip ratio (WHR), and abdominal sagittal diameter than subjects with NFH. Baseline blood glucose, plasma insulin, serum lipids, and transmembrane sodium transport did not differ between the two groups. Blood glucose levels at 90 and 120 minutes after oral glucose were significantly higher in subjects with PFH than in controls. Blood glucose adjusted for BMI and WHR at 90 minutes was significantly related to a PFH. Plasma insulin level at 90 minutes during the glucose load was significantly higher in subjects with PFH. In multivariate analysis, WHR was significantly related to baseline blood pressure, insulin, and cholesterol, whereas BMI was significantly associated with the insulin response to the oral glucose tolerance test. Transmembrane sodium transport was significantly related to blood pressure only. In conclusion, subjects with PFH are characterized by increased body weight and BMI, increased visceral fat accumulation, and an altered blood glucose response to an oral glucose load. It was also shown that WHR was related to blood pressure and that BMI was more related to cholesterol and response to glucose loading than a PFH was.

Topics: Adult; Biological Transport; Blood Glucose; Body Constitution; Body Mass Index; Body Weight; C-Peptide; Erythrocyte Membrane; Glucose; Glucose Tolerance Test; Hip; Humans; Hypertension; Insulin; Lipids; Male; Middle Aged; Multivariate Analysis; Sodium

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

Of 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached less than or equal to 6.0 mmol.l-1 after 10 weeks of dietary regulation, 15, who had had a weight reduction of -2.8 kg by dietary control, did achieve a fasting blood glucose less than or equal to 6.0 mmol.l-1 after addition of less than or equal to 20 mg glipizide daily. They had a sustained (greater than or equal to 2 years) increase in meal-induced insulin secretion (32% increase in postprandial C-peptide AUC), and a sustained reduction in postprandial hyperglycaemia (34% reduction in AUC). Ten of the patients took a mean daily dose less than 5 mg (4.8 mg) and had a sustained increase in insulin secretion rate (increased C-peptide slope). The 15 patients had no elevation of basal insulin secretion and no impairment of weight reduction. The remaining 8 subjects, who showed little or no weight reduction on dietary control, had little or no reduction in fasting blood glucose despite long-term treatment with 20 mg glipizide daily, a less sustained increase in meal-induced insulin secretion, a smaller reduction of postprandial hyperglycaemia, and an increase in body weight. On diagnosis the 8 subjects did not differ from the other 15 subjects in age, body weight, blood glucose, HbA1c, C-peptide or insulin, nor in their glucose and insulin responses to a test dose of glipizide; the main reason for the apparent drug failure appeared to be deficient compliance with dietary regulation rather than a primary inability to respond to sulphonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Energy Intake; Glipizide; Humans; Insulin; Insulin Secretion; Linear Models; Time Factors

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

Black Americans (blacks) have a higher prevalence and earlier onset of type 2 diabetes than white Americans (whites). To examine metabolic differences in both races, we measured the basal glucose turnover rates (D-]3-3H]glucose technique) and plasma glucose, insulin, and C-peptide levels before and after an oral glucose load in 24 glucose-tolerant black and 14 white female relatives of patients with type 2 diabetes. Eight black and 8 white female subjects with no family history of diabetes served as controls. Mean fasting and postglucose plasma glucose levels were not significantly different between the black and white relatives and the control subgroups. Mean fasting plasma insulin and C-peptide levels were slightly greater but not significantly different between the relatives. After oral glucose ingestion, mean incremental integrated plasma insulin areas were significantly (P less than 0.02) greater in the black than the white relatives (70 +/- 14 vs. 29 +/- 6 nM.min). In addition, incremental integrated C-peptide areas were greater in the black than the white relatives (303 +/- 55 vs. 115 +/- 33; P less than 0.005). Similarly, we found significantly greater integrated incremental insulin (61 +/- 11 vs. 22 +/- 3 nM.min; P less than 0.02) and C-peptide (248 +/- 58 vs. 47 +/- 16; P less than 0.005) areas in the black than the white controls, respectively. The estimated basal and postglucose hepatic insulin extraction values, expressed as molar ratios of C-peptide and insulin, were not significantly different between the relatives. While basal hepatic insulin extraction was significantly (P less than 0.05) lower in the black controls, the postprandial insulin clearance was not different between the black and white controls. Mean basal hepatic glucose production was greater (P less than 0.02) in the black than the white relatives (2.49 +/- 0.13 vs. 2.02 +/- 0.12 mg/kg.min). Similarly, the black controls had greater hepatic glucose production than the white controls (2.36 +/- 0.15 vs. 1.81 +/- 0.08 mg/kg.min; P less than 0.001). We conclude that basal and poststimulation glucose homeostatic regulation appear to be different in black and white females, regardless of family history of type 2 diabetes.

Topics: Adult; Aging; Black People; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Liver; White People

The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.

Topics: Adult; beta-Endorphin; Blood Glucose; Body Weight; C-Peptide; Female; Glucagon; Glucose Tolerance Test; Humans; Infusions, Intravenous; Insulin; Kinetics; Male; Obesity; Reference Values

Gestational diabetes mellitus (GDM) is a strong predictor of glucose intolerance later in life. Former GDM (n = 145) and control (n = 41) subjects were studied 3-4 yr after the index pregnancy. They were subjected to a 75-g oral glucose tolerance test (OGTT) with measurements of insulin, C-peptide, and proinsulin in the basal state and every 30 min for 180 min. In the former GDM group, 5 subjects (3.4%) had developed non-insulin-dependent diabetes mellitus (NIDDM), and 32 (22%) had developed impaired glucose tolerance (IGT; by World Health Organization criteria). In the control group, 2 (4%) had IGT. In the GDM group, IGT or NIDDM was significantly associated with obesity (body mass index [BMI] greater than or equal to 25 kg/m2) and earlier diagnosis of GDM during pregnancy (P less than 0.001). Nonobese (BMI less than 25 kg/m2) GDM subjects with normal glucose tolerance at follow-up had significantly higher mean glucose (P less than 0.01), insulin (P less than 0.05), and proinsulin (P less than 0.001) values during the OGTT than control subjects, whereas there was no significant difference in C-peptide values. A comparison between control subjects with normal OGTT and BMI less than 25 kg/m2 (n = 39) and GDM subjects (n = 39) selected to have a comparable area under the glucose curve, BMI, and age demonstrated no group differences in glucose, C-peptide, or insulin levels, whereas the proinsulin levels were significantly higher (P less than 0.001) during the glucose load. The molar ratio between proinsulin and insulin was also significantly higher among the former GDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Birth Weight; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Infant, Newborn; Insulin; Pregnancy; Proinsulin

Hypopituitarism is associated with reduced lean body mass and increased body fat, while in acromegaly the converse is true. Fasting plasma glucose is increased in acromegaly but fasting plasma insulin and C-peptide are increased in both groups. There is a positive association between fat mass and fasting serum insulin in hypopituitarism, suggesting insulin resistance. Hypoglycaemia unresponsiveness, rather than insulin sensitivity, is the feature of growth hormone deficiency. Basal metabolic rate (expressed per kg body weight) is increased in acromegaly and decreased in hypopituitarism but when expressed 'per kg lean body mass', is increased in both groups. There is a close correlation between fat mass and fasting free fatty acid and glycerol levels in obese but not normal weight patients with hypopituitarism; slim patients appear to metabolise and oxidise their fat stores more effectively than those who remain obese. Thus indirect evidence suggests that growth hormone has an important role in maintaining normal body composition and energy stores.

Topics: Acromegaly; Adipose Tissue; Adult; Basal Metabolism; Blood Glucose; Body Composition; Body Weight; C-Peptide; Female; Humans; Hypopituitarism; Insulin; Insulin-Like Growth Factor I; Male

To assess the total insulin secretion in children in different nutritional states we have analysed the 24 h urinary C-peptide excretion in 32 obese children (16 boys and 16 girls) 8-15 years of age as well as in 7 girls with anorexia nervosa 11-16 years of age. Obese children had a median urinary C-peptide excretion rate of 0.27 nmol/kg/24 h, which was not different from that of a group of normal-weight children. In the group of anorectic girls, on the other hand, the median value 0.47 nmol/kg/24 h was significantly (p less than 0.05) higher than for normal-weight girls of the same age (median = 0.26 nmol/kg/24 h). These results indicate that in obese children insulin secretion, measured as the 24 h urinary C-peptide excretion per kg body weight, is the same as in normal-weight children. Total insulin secretion is consequently increased. In anorexia nervosa, on the other hand, the higher C-peptide excretion per kg body weight compared with normal-weight children, indicates that insulin secretion is increased in relation to body weight.

Topics: Adolescent; Anorexia Nervosa; Body Weight; C-Peptide; Child; Circadian Rhythm; Female; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Obesity

Over the last four years, we have done a prospective study of insulin requiring diabetes (IRD). We offered 59 patients insulin therapy during 10 to 14 days by means of continuous subcutaneous insulin injection with the help of a pump in order to maintain the patient under oral hypoglycemic agents (OHA). We divided our population into two characteristic groups and isolated parameters that were predictive of post-insulin therapy evolution by means of C peptide assays. In one group, in 50% of cases, endogenous insulin production appeared impaired and could not be restored by insulin therapy. The patients in this group suffered a renewed drug failure within 3 months. In the other group, 50% of cases, endogenous insulin production was preserved and the CP/blood glucose level ratio improved. On insulin treatment interruption, we observed a significantly improved fasting blood glucose level and we observed decreased insulin needs. The patients, who were probably insulin resistant, suffered only late failures or went into remission, often for longer than one year. The data bring us to the logical conclusion of IRD heterogeneity. Only some of these patients can benefit from temporary insulin therapy and the remission attempt should be limited to them.

Topics: Biomarkers; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Infusion Systems; Male; Middle Aged; Obesity; Prognosis; Prospective Studies; Treatment Outcome

The responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin (0.5 mg/h) were studied in 10 formerly obese subjects who had lost 35 kg by dieting (body mass index less than 25) and compared with those of 10 normal-weight control (body mass index less than 25) and 10 obese (body mass index greater than 30) subjects. The fasting plasma concentrations of beta-endorphin were significantly higher in both the obese and the post-obese group than in the control group. In both obese and post-obese subjects, the infusion of beta-endorphin caused significant increases in peripheral plasma glucose, insulin, C-peptide and glucagon concentrations. In the control group, matched for age, sex and weight with the formerly obese group, there was no appreciable change in plasma insulin and C-peptide concentrations during the infusion of beta-endorphin, but the rise in plasma glucose was more sustained. Thus, 1. the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; and 2. formerly obese, normal-weight subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin infusion. The alteration of the opioid system in human obesity may play some role in the predisposition to weight gain.

Topics: Adult; beta-Endorphin; Blood Glucose; Body Weight; C-Peptide; Female; Glucagon; Humans; Insulin; Kinetics; Male; Obesity

Coronary heart disease has been described to be increased with both glucose intolerance and cigarette smoking. All three of these have also been reported to be associated with central adiposity (disproportionate deposition of fat on the trunk compared to the extremities). The purpose of this analysis was to determine the relationship of cigarette smoking to glucose intolerance and coronary heart disease, the relationship of cigarette smoking to risk factors such as adiposity, body fat distribution, and plasma lipoprotein and insulin levels, the relationship of cigarette smoking to these risk factors independent of disease status, and whether these risk factors could account for any of the relationship between cigarette smoking and disease status.. The study design was cross-sectional. The study sample contained 219 middle-aged and elderly Japanese-American men: 77 with normal and 74 with impaired glucose tolerance and 68 with type II diabetes. There were 54 men with coronary heart disease. A detailed smoking history was obtained. Glucose tolerance status was established by medical history and a 75-g oral glucose tolerance test. Coronary heart disease was determined by medical history and a resting electrocardiogram. Adiposity and fat distribution measurements were body mass index (kg/m2), skinfold thicknesses, body circumferences, and cross-sectional fat areas by computed tomography. Levels of insulin, C-peptide, cholesterol (total, low-density lipoprotein [LDL], high-density lipoprotein [HDL], HDL2, HDL3, very-low-density lipoprotein [VLDL]), and triglyceride (total, VLDL) were measured in fasting blood specimens.. A central pattern of body fat was associated with both non-insulin-dependent diabetes mellitus and coronary heart disease. Smoking history was related to both adiposity and body fat distribution, and was strongly related to coronary heart disease but not to diabetes. Past smokers who had smoked up to a month ago were the heaviest while present smokers who were currently smoking or had smoked within the past month were the leanest. However, although present smokers had reduced amounts of fat, this was attributable to those present smokers without heart disease. Present smokers with heart disease were not as lean and had increased amounts of intra-abdominal fat. Past smokers had the greatest amount of central fat and this was attributable to those with heart disease. By two-way (smoking history and coronary heart disease status) analysis of covariance, smoking history was significantly related only to subcutaneous fat disposition on the chest and abdomen independent of coronary heart disease, while coronary heart disease status was strongly related to plasma levels of insulin C-peptide, VLDL, HDL, HDL2, and HDL3 cholesterol, and total and VLDL triglyceride, independent of smoking history. Further analysis showed that none of the body fat variables could account for the risk of coronary heart disease associated with smoking history. Higher fasting plasma C-peptide levels in past smokers accounted statistically for part of the risk of coronary heart disease associated with cigarette smoking. However, this effect was not mediated by any of the body fat measurements.. Disproportionately increased intra-abdominal fat is related to coronary heart disease but not to smoking history. Smoking history is related to coronary heart disease but not to diabetes. Weight gain is associated with smoking cessation and appears to be concentrated in the central subcutaneous regions, especially for those who have coronary heart disease. Weight gain associated with cessation of smoking appears to be unrelated to atherogenic changes in lipids, lipoproteins, or insulin. Other pathogenic processes must be considered in the association between smoking and coronary heart disease.

Topics: Adipose Tissue; Adrenergic beta-Antagonists; Analysis of Variance; Body Mass Index; Body Weight; C-Peptide; Cholesterol, HDL; Cholesterol, VLDL; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Insulin; Japan; Male; Middle Aged; Regression Analysis; Skinfold Thickness; Smoking; United States

Using computed tomography on 19 obese female subjects, we determined abdominal adipose tissue, both subcutaneous and visceral adipose tissue, before and after 2 weeks of a very low caloric diet (VLCD). The following parameters were also determined before and after 15-20 days of VLCD: plasma glucose and insulin levels, oral glucose tolerance test, basal pancreatic insulin secretion estimated by fasting C peptide (Cp), and fasting insulin hepatic clearance calculated by Cp/insulin molar ratio. After VLCD the body weight and body mass index significantly declined (p less than 0.01); whereas abdominal adipose tissue and visceral abdominal tissue (VAT) significantly decreased (p less than 0.01), modifications of subcutaneous abdominal tissue (SAT) were not significant. Fasting insulin levels and plasma glucose response to oral glucose load significantly decreased (p less than 0.05). Insulin response remained unchanged. Cp immunoreactive insulin (IRI) significantly increased (p less than 0.01). A significant positive correlation was found between delta VAT and delta Cp/IRI before and after VLCD (p less than 0.01). Our data seem to suggest that the weight loss induced by VLCD fundamentally involves a decrease in VAT. The reduction in visceral fat could be associated with an increase in hepatic insulin clearance.

Topics: Abdomen; Adipose Tissue; Adolescent; Adult; Blood Glucose; Body Weight; C-Peptide; Diet, Reducing; Female; Humans; Insulin; Liver; Middle Aged

In 26 type 2 diabetic patients with failure to diet and sulphonylureas (fasting blood glucose levels greater than 8.0 mmol/l) the effects of insulin therapy on blood glucose control, islet B-cell function and plasma lipids were studied. Age was 58 +/- 11 (SD) yr, median duration of diabetes 6.5, range 1-24 yr, and body mass index 24.5, range 18.9-36.3 kg/m2. Six patients were obese. Therapy comprised twice daily injections of intermediate-acting insulin with additional fast-acting insulin when necessary. After six months, insulin dose was 39 +/- 10 U in the non-obese patients. Their fasting (14.0 +/- 2.7 mmol/l) and post-prandial blood glucose (17.9 +/- 4.5 mmol/l) and glycosylated haemoglobin (HbA1, 13.0 +/- 2.0%) declined to 7.7 +/- 1.6 mmol/l, 10.6 +/- 2.6 mmol/l and 9.5 +/- 1.0%, respectively (p less than 0.001). Median body weight increased by 3.7 kg (p less than 0.001). The changes in body weight correlated well with the changes in fasting blood glucose (r = -0.75, p less than 0.01) and HbA1 (r = -0.73, p less than 0.01). Fasting plasma insulin increased (p less than 0.01), whereas fasting plasma C-peptide and C-peptide release after glucagon did not change. Free fatty acids, LDL-cholesterol, total and VLDL-triglycerides showed a significant (p less than 0.05) decrease during insulin treatment. In the six obese patients insulin dose after six months was 44 +/- 18 U. Fasting blood glucose fell from 11.3 +/- 2.2 to 8.8 +/- 2.7 mmol/l (p less than 0.01), and HbA1 decreased from 10.7 +/- 1.1% to 9.8 +/- 1.3% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Administration Schedule; Eating; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipoproteins; Male; Middle Aged; Obesity; Sulfonylurea Compounds; Triglycerides

Autoantibodies against insulin, C-peptide, and glucagon were determined by radio-binding assay in 63 new-onset Type 1 (insulin-dependent) diabetic patients as well as in 70 controls. Plasma peptide binding was determined by means of 125I-labeled peptides and charcoal-dextran separation technique. Binding values exceeding the mean plus three standard deviations of the controls were considered as antibody-positive. Sixteen patients (25%) were positive for IAA, as 6 (10%) were positive for CAA and 2 (3%) for GAA. Of all control subjects, none were positive for either IAA or CAA, whereas 2 (2%) had GAA. The mean 125I-glucagon binding in the patients' group was, however, slightly enhanced and could be suppressed to normal values by excess unlabeled glucagon. The presence of IAA and/or CAA was significantly associated with more severe symptoms at diabetes manifestation. These results indicate that in new-onset Type 1 diabetics autoimmunity arises against all the insular peptides tested but is predominantly directed against those antigens secreted from the beta cells. Nevertheless, extremely low-binding GAA seem to be common in these patients. The determination of IAA/CAA might be useful in detecting a possible heterogeneity of Type 1 diabetes with regard to its clinical mode of manifestation.

Topics: Age Factors; Autoantibodies; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Humans; Insulin; Islets of Langerhans; Male; Sex Factors

Based on an analysis of data obtained in a group of 145 men and women with type 2 diabetes perssiting for 10.1 +/- 6.6 years who were hospitalized on account of unsatisfactory compensation of diabetes, the authors provided evidence that the fasting blood sugar level is associated with a reduced response of C peptide to an alimentary stimulus, while the excessive weight of the patients has a bearing on the elevated concentration of C peptide on fasting and causes their insulin resistance. The body weight has a bearing on the level of risk factors, i.e. HDL cholesterol, uric acid and in women also triacylglycerols. The elevated blood sugar level influences in a mirror image manner the sodium and potassium level. The relations between the blood sugar level and glomerular filtration draw attention to the interference with the water economy even at blood sugar levels which are still tolerated. The trend of rising potassium levels must be foreseen in case of a poor compensation even in case of insulin treatment of diabetes. The risk of elevated potassium should be taken into account also with regard to indications of antihypertensive treatment. The authors also draw attention to the need of acloser compensation of type 2 diabetes. Early adjustment of the energy metabolism in diabetics deserves priority. When insulin treatment is needed, the all-day requirement should be met by 2-3 doses.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Electrolytes; Female; Humans; Lipids; Male; Middle Aged; Time Factors; Urea

A representative group of middle-aged (45- to 64-yr-old) patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 133; 70 men, 63 women) were examined at the time of diagnosis and 5 yr afterward for metabolic control and insulin response to oral glucose; 144 nondiabetic control subjects (62 men, 82 women) were similarly examined twice between 5-yr intervals. At the 5-yr examination, 56 of the diabetic patients (36 men, 20 women) were on diet therapy only, 60 (27 men, 33 women) received oral antidiabetic drugs, and 5 were treated with insulin. The metabolic control of diabetic patients was poor at the time of diagnosis and 5-yr examination. Fasting plasma insulin levels were higher in diabetic patients than in control subjects both at baseline (23 +/- 2 vs. 14 +/- 1 mU/L, P less than 0.01, for men; 26 +/- 2 vs. 15 +/- 1 mU/L, NS, for women) and 5-yr examination (19 +/- 1 vs. 16 +/- 2 mU/L, NS, for men; 29 +/- 5 vs. 15 +/- 1 mU/L, P less than 0.05, for women). The frequency of insulin deficiency in diabetic patients based on a postglucagon (1 mg i.v.) C-peptide level less than 0.60 nM was 3.3% at the 5-yr examination, indicating that true insulin deficiency was uncommon during the first years after diagnosis of diabetes in middle-aged subjects.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Follow-Up Studies; Humans; Insulin; Male; Middle Aged; Reference Values; Sex Factors; Skinfold Thickness

Computed tomography (CT) was used to study the association between adipose tissue localization and glucose tolerance in a sample of 52 premenopausal obese women aged 35.7 +/- 5.5 yr (mean +/- SD) and with a body fat of 45.9 +/- 5.5%. Body-fat mass and the body mass index (BMI) were significantly correlated with plasma glucose, insulin, and connecting peptide (C-peptide) areas after glucose (75 g) ingestion (.40 less than or equal to r less than or equal to .51, P less than .01). Trunk-fat accumulation and the size of fat cells in the abdomen displayed highly significant correlations with postglucose insulin levels. The C-peptide area was also positively correlated with abdominal fat cell size (r = .76, P less than .01) and was more closely associated with the sum of trunk skin folds (r = .59, P less than .001) than with the extremity skin folds (r = .29, P less than .05). Subcutaneous and deep-abdominal-fat areas measured by CT displayed comparable associations with the plasma insulin area (r = .44 and .49, respectively; P less than .001) but marked differences in the associations with glucose tolerance. Indeed, subcutaneous abdominal fat was not significantly correlated with the glucose area, whereas deep abdominal fat showed a significant correlation (r = .57, P less than .001) with the glucose area. Midthigh fat deposition measured by CT was not, however, correlated with plasma glucose, insulin, or C-peptide areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abdomen; Adipose Tissue; Adult; Blood Glucose; Body Weight; C-Peptide; Female; Glucose Tolerance Test; Humans; Insulin; Obesity; Radiography

The effect of sex on longitudinal changes in serum C-peptide immunoreactivity (CPR) response to the oral glucose tolerance test (OGTT) was examined up to 48 mo in 30 islet cell antibody-positive (ICA+), non-insulin-dependent diabetes mellitus (NIDDM) subjects (15 men, 15 women) who were matched for age, duration of diabetes, and mode of treatment. The subjects were recruited from 2858 NIDDM patients screened for ICA between 1980 and 1984. In male NIDDM subjects, CPR levels to OGTT decreased insidiously, and 8 of 15 men developed the insulin-dependent state with abolished CPR. Only 2 female NIDDM subjects progressed to the insulin-dependent state (P less than .05, women vs. men). Thus, CPR in female subjects tended to decrease less than in male subjects. There were no significant differences between the two groups in human leukocyte antigens (HLA) or titer of ICA during the follow-up period. These results suggest that maleness is a major risk factor for slowly progressive beta-cell dysfunction in adult-onset insulin-dependent diabetes mellitus (IDDM).

Topics: Adult; Autoantibodies; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; HLA Antigens; Humans; Islets of Langerhans; Longitudinal Studies; Male; Risk Factors; Sex Factors

Obesity and fat topography are risk factors for hyperinsulinemia, insulin resistance, and diabetes mellitus. The relative contribution of obesity and body fat distribution indices to fasting and oral glucose-stimulated C peptide, insulin, and glucose concentrations were determined in 33 healthy premenopausal women. Obesity level was assessed by hydrostatic weighing and fat topography by computerized tomography-derived intraabdominal fat area, waist to hip ratio, subscapular skinfold thickness and the ratio of subscapular to triceps skinfold thickness. Both fat mass and regional fat distribution indices were associated closely with changes in insulin secretion. Fat topography indices were more closely correlated (p less than 0.001) to insulin response than were fat mass indices (p less than 0.01). The subscapular skinfold thickness had the greatest integrity for reflecting fat mass and fat distribution as they relate to the metabolic profile. The subscapular skinfold thickness may help identify individuals at risk for noninsulin dependent diabetes mellitus.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; Body Weight; C-Peptide; Female; Glucose; Homeostasis; Humans; Insulin; Male; Menopause; Obesity; Scapula; Skinfold Thickness; Tomography, X-Ray Computed

Studies of zinc status in insulin-dependent diabetes mellitus (IDDM) have shown contradictory results. Zinc is essential for many enzymes involved in the human metabolism and may play a role in the biosynthesis and storage of insulin in the B-cell. We therefore prospectively followed 26 patients (14 males and 12 females) with newly diagnosed IDDM in order to determine the plasma zinc variation at the time of diagnosis and after 1, 3, 6, 12 and 24 months. Seventy-two healthy persons (36 males and 36 females) served as controls. Only minor differences in plasma zinc were demonstrated during the first 2 years of IDDM. A sex difference was found in healthy controls but only after 24 months in the diabetics. Quantitative changes of the B-cell function, development of insulin antibodies, age, body weight and serum albumin did not correlate with the course of plasma zinc.

Topics: Adolescent; Adult; Age Factors; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin Antibodies; Islets of Langerhans; Male; Middle Aged; Prospective Studies; Serum Albumin; Sex Factors; Zinc

Topics: Adult; Blood Pressure; Body Weight; C-Peptide; Diet, Reducing; Energy Intake; Female; Humans; Hypertension; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity

To compare high fibre diet, basal insulin supplements and a regimen of insulin four times daily in non-insulin dependent (type II) diabetic patients who were poorly controlled with sulphonylureas.. Run in period lasting 2-3 months during which self monitoring of glucose concentration was taught, followed by six months on a high fibre diet, followed by six months' treatment with insulin in those patients who did not respond to the high fibre diet.. Teaching hospital diabetic clinics.. 33 patients who had had diabetes for at least two years and had haemoglobin A1 concentrations over 10% despite receiving nearly maximum doses of oral hypoglycaemic agents. No absolute indications for treatment with insulin.. During the high fibre diet daily fibre intake was increased by a mean of 16 g (95% confidence interval 12 to 20 g.) Twenty five patients were then started on once daily insulin. After three months 14 patients were started on four injections of insulin daily.. Control of diabetes (haemoglobin A1 concentration less than or equal to 10% and fasting plasma glucose concentration less than or equal to 6 mmol/l) or completion of six months on insulin treatment.. No change in weight, diet, or concentrations of fasting glucose or haemoglobin A1 occurred during run in period. During high fibre diet there were no changes in haemoglobin A1 concentrations, but mean fasting glucose concentrations rose by 1.7 mmol/l (95% confidence interval 0.9 to 2.5, p less than 0.01). With once daily insulin mean concentrations of fasting plasma glucose fell from 12.6 to 7.6 mmol/l (p less than 0.001) and haemoglobin A1 from 14.6% to 11.2% (p less than 0.001). With insulin four times daily concentrations of haemoglobin A1 fell from 11.5% to 9.6% (p less than 0.02). Lipid concentrations were unchanged by high fibre diet. In patients receiving insulin the mean cholesterol concentrations fell from 7.1 to 6.4 mmol/l (p less than 0.0001), high density lipoprotein concentrations rose from 1.1 to 1.29 mmol/l (p less than 0.01), and triglyceride concentrations fell from 2.67 to 1.86 mmol/l (p less than 0.05). Patients taking insulin gained weight and those taking it four times daily gained an average of 4.2 kg.. High fibre diets worsen control of diabetes in patients who are poorly controlled with oral hypoglycaemic agents. Maximum improvements in control of diabetes were achieved by taking insulin four times daily.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Dietary Fiber; Glycated Hemoglobin; Humans; Injections; Insulin; Lipids; Time Factors

It seems rational to consider that residual insulin secretion is one of the factors which determine the short-term course of inaugural type I diabetes. But what about the mid-term course? We evaluated prospectively the insulin reserve (fasting and post-prandial C peptide) in 52 patients throughout the subsequent development of the disease. The patients (36 men, 16 women, mean age 35 years), who presented with ketonuria and weight loss, received a 10-day course of intensive insulin therapy, after which a remission of insulin dependence was observed in 40 of them (77 per cent). These 40 patients differed from those who had no such remission in that they were heavier and had a better initial insulin secretion. There was no significant difference between the two groups with regards to immunogenetic markers (presence of anti-islet antibodies 28/35 vs 8/12, DR3 and/or DR4 tissue group 27/37 vs 8/10). Following intensive insulin therapy, the C peptide value was consistently increased. At 6, 12 and 18 months the insulin secretion in patients of the remission group remained stable and always higher than that of patients who did not have a remission and whose insulin secretion collapsed at 18 months. Another characteristic of the remission group was that C peptide secretion could be stimulated by meals throughout the follow-up period (post-prandial C peptide at 18 months: 0.63 nmol/l). It is concluded that residual insulin secretion is one of the most effective predictive factors of remission when type I diabetes is first diagnosed and remains stable for the first 18 months of the disease in patients who show a remission.

Topics: Adolescent; Adult; Aged; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Insulin Infusion Systems; Male; Middle Aged; Remission, Spontaneous; Time Factors

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

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

To improve criteria for entry into future trials of immunosuppression, we enrolled 40 children with recent-onset Type I insulin-dependent diabetes in a pilot trial of cyclosporine. Twenty-seven patients were able to discontinue insulin therapy 48 +/- 5 days after the start of immunosuppression. At four months, their fasting and postprandial blood glucose concentrations averaged 110 and 160 mg per deciliter (6.1 and 8.9 mmol per liter) with a mean hemoglobin A1c level of 6.15 percent. Seventy-five percent of these patients with early remission still did not need insulin at 12 months, and their glycemic control was similar to that at 4 months. The major differences between the 27 patients with remission and the 13 without remission were the duration of symptoms before diagnosis (26.8 vs. 48.0 days, P less than 0.01), the degree of weight loss (3.2 vs. 10 percent of body weight, P less than 0.001), the initial hemoglobin A1c level (10.7 vs. 13.2 percent, P less than 0.001), and the frequency of ketoacidosis (11 vs. 61.5 percent, P less than 0.001). The lesser degree of weight loss was the strongest independent predictor of remission. The response of C-peptide to intravenous glucagon (0.50 vs. 0.17 pmol per milliliter, P less than 0.05) was also an independent predictor. No differences were observed between the two groups of patients in age, sex, HLA phenotype, autoantibodies to insulin or islet-cell antigens, or doses or trough levels of cyclosporine. Only minimal manifestations of toxicity were detected over the period of observation. We conclude that early treatment with cyclosporine in children with recent-onset Type I diabetes can induce remission from insulin dependence, with half the patients not requiring insulin after a full year.

Topics: Adolescent; Age Factors; Blood Glucose; Body Weight; C-Peptide; Child; Cyclosporins; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Insulin; Male; Pilot Projects; Remission Induction; Sex Factors; Time Factors

To determine whether non-insulin-dependent diabetes mellitus (NIDDM) is characterized by day-long hypoinsulinemia, we measured 24-h serum profiles for glucose, insulin, and C-peptide by use of a constant-rate blood-withdrawal technique in diabetic and control subjects fed isocaloric meals. When only lean subjects were considered, diabetic subjects (relative body weight 0.99 +/- 0.3) and control subjects (relative body weight 0.95 +/- 0.03) had similar 24-h integrated serum insulin concentrations (13.4 +/- 2.5 vs. 16.1 +/- 2.0 microU/ml, P NS) due to the offsetting effects of increased basal levels and decreased postprandial responses in NIDDM. In contrast, both basal and meal-stimulated insulin levels were decreased in obese NIDDM subjects (relative body weight 1.39 +/- 0.07) compared with obese control subjects (relative body weight 1.60 +/- 0.08), resulting in a 61% reduction in the 24-h integrated insulin value (18.7 +/- 1.5 vs. 48.4 +/- 13.7 microU/ml). Thus, the capacity to increase 24-h integrated serum insulin as a function of relative body weight was impaired in NIDDM subjects (r = 0.27, P NS) compared with control subjects (r = .70, P less than .01). In contrast, 24-h integrated C-peptide was decreased (P less than .01) in both lean (0.92 +/- 0.13 pM/ml) and obese (1.52 +/- 0.19 pM/ml) NIDDM patients compared with the respective control groups (1.50 +/- 0.13 and 3.03 +/- 0.44 pM/ml). The molar ratio of 24-h integrated C-peptide to insulin was diminished in lean but not obese NIDDM compared with control subjects. A 3-wk period of intensive insulin therapy led to normalization of the mean 24-h integrated insulin (but not integrated serum C-peptide) value in NIDDM compared with a control group that had an identical mean relative body weight. The 24-h urinary C-peptide measured on the same day as the serum profile was correlated (P less than .01) with both the 24-h integrated serum insulin (r = .69) and C-peptide (r = .67) concentrations in control subjects but not in NIDDM subjects (r = .20 and .04, respectively, P NS). Additionally, the urinary clearance of C-peptide was increased in NIDDM (38.1 +/- 7.8 vs. 20.4 +/- 1.7 ml/min in control subjects, P less than .05) and varied with treatment status (26.0 +/- 4.6 ml/min after insulin therapy).(ABSTRACT TRUNCATED AT 400 WORDS)

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

We assessed the effects of weight loss on pancreatic secretion and hepatic extraction of insulin in 11 obese subjects with noninsulin-dependent diabetes mellitus. Weight loss of 15.4 +/- 2.0 kg (mean +/- SE) resulted in decreased fasting insulin [20.2 +/- 2.5 to 9.8 +/- 2.5 microU/mL (145 +/- 18 to 70 +/- 18 pmol/L); P less than 0.02] and C-peptide (850 +/- 80 to 630 +/- 110 pmol/L; P less than 0.05) levels. The plasma glucose response to oral glucose and iv glucagon was improved with unchanged peripheral insulin levels. When plasma glucose levels were matched to those before weight loss, peripheral serum insulin and plasma C-peptide responses to iv glucagon were increased and similar to those in obese nondiabetic subjects studied at euglycemia. The total insulin response (area under the curve) to iv glucagon was reduced 30% (P less than 0.005), while the total C-peptide response area did not change after weight loss. At matched hyperglycemia, the total response area was enhanced 72% for insulin (P less than 0.002) and 64% for C-peptide (P less than 0.001). Incremental (above basal) response areas after weight loss did not change for insulin, but increased 66% for C-peptide (P less than 0.05). The incremental areas were augmented nearly 2-fold (196%) for insulin (P less than 0.01) and 1.7-fold (173%) for C-peptide (P less than 0.01) when assessed at matched hyperglycemia. Both basal (7.3 +/- 0.5 to 14.1 +/- 1.8; P less than 0.01) and total stimulated (6.1 +/- 0.4 to 8.8 +/- 1.4; P less than 0.05) C-peptide to insulin molar ratios increased after weight loss. We conclude that after weight loss in noninsulin-dependent diabetes mellitus, 1) insulin secretion is decreased in the basal state but increased after stimulation; 2) changes in insulin secretion are reflected by peripheral levels of C-peptide but not insulin, due in part to enhanced hepatic insulin extraction; and 3) at matched levels of hyperglycemia insulin secretion is markedly increased and similar to that in obese nondiabetic subjects studied at euglycemia.

Topics: Basal Metabolism; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Fasting; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Liver; Male; Middle Aged; Obesity; Pancreas

Topics: Adult; Amniotic Fluid; Body Weight; C-Peptide; Female; Fetus; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; Infant Mortality; Insulin; Pregnancy; Pregnancy in Diabetics

We evaluated the safety and efficacy of a highly supplemented controlled low-energy (1764 kJ [420 kcal]) diet in the treatment of non-insulin-dependent diabetes and obesity. Six obese, diabetic women ranging from 143% to 297% of ideal body weight were studied in a metabolic ward for 48 days. The subjects ingested a weight-maintenance diet during an eight-day control period followed by 40 days of an experimental diet containing 1764 kJ (420 kcal) of a mixture of protein (43% of energy intake), carbohydrates (51%), and fat (6%), supplemented with minerals, trace elements, and vitamins. The subjects were monitored for balances of nitrogen and minerals, as well as for the appearance of cardiac arrhythmias by 24-hour electrocardiographic recordings. Weight loss was rapid and sustained and averaged 10.1% +/- 0.8% over 40 days. Fasting plasma glucose levels declined from 16.2 +/- 1.9 mmol/L (293 +/- 36 mg/dL) to 6.9 +/- 0.8 mmol/L (126 +/- 16 mg/dL) by day 35. Similarly, hemoglobin A1c levels fell from 0.11 +/- 0.009 (11.2% +/- 0.9%) to 0.8 +/- 0.001 (8.2% +/- 1.1%). Urinary C-peptide levels declined from 62.2 +/- 15.6 nmol/48 h to 20.0 +/- 5.9 nmol/48 h by days 39 to 40 and paralleled the decline in plasma glucose values, the majority of which occurred in the first seven days. Concentrations of serum cholesterol and triglycerides decreased. Balances for nitrogen, potassium, and magnesium were negative at -1.7 g/24 h, -2.2 mEq/24 h, and -2.9 mg/dL, respectively. Blood pressure decreased without orthostasis. Resting metabolic rate fell a mean of 18% but remained within normal limits. Triiodothyronine levels also declined. Twenty-four-hour ambulatory electrocardiographic readings disclosed no significant bradyarrhythmia or tachyarrhythmia for any patient. These studies, based on a limited number of subjects, demonstrate that a highly supplemented controlled low-energy diet is a safe and efficacious treatment for diabetes and obesity, leading to significant decreases in weight, blood pressure, and levels of plasma glucose and plasma lipids. Such diets may be the optimal initial treatment of moderate to markedly obese patients with non-insulin-dependent diabetes.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet, Reducing; Electrocardiography; Electrolytes; Energy Metabolism; Female; Hospitalization; Humans; Middle Aged; Monitoring, Physiologic; Obesity; Physical Exertion

The presence and physiologic importance of cephalic phase insulin release in humans remains controversial. The aim of these studies was to determine whether cephalic phase insulin release could be demonstrated in normal weight subjects and whether it would be associated with changes in blood glucose, free fatty acid, and pancreatic polypeptide levels. The studies were followed by a hyperglycemic clamp to determine whether cephalic responses would alter overall glucose disposal or glucose-stimulated insulin secretion. In all, 17 subjects were studied on two occasions with and without (control study) presentation of food stimuli. Tease-feeding alone (n = 6), or the administration of a sweet taste alone (aspartame, n = 5) failed to stimulate cephalic responses. However, the presentation of the combined stimuli (tease meals plus sweet taste, n = 7) resulted in a significant fall (P less than .005) in blood glucose levels and a variable rise in serum insulin (% insulin rise 38 +/- 15%, P less than .05) and C-peptide levels (7 +/- 6%, NS) within five minutes of the food presentation when compared with control studies, with no change seen in free fatty acid or pancreatic polypeptide levels. The blood glucose fall correlated strongly (r = .90, P less than .01) with a score of the subjective response to the food and taste.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Fatty Acids, Nonesterified; Female; Food; Humans; Insulin; Insulin Secretion; Male; Sensation; Smell; Taste; Visual Perception

To define those patients most likely to benefit from the hypolipidemic effect of low-glycemic-index (GI) traditional starchy foods, 30 hyperlipidemic patients were studied for 3 mo. During the middle month, low-GI foods were substituted for those with a higher GI with minimal change in dietary macronutrient and fiber content. Only in the group (24 patients) with raised triglyceride levels (types IIb, III, and IV) were significant lipid reductions seen: total cholesterol 8.8 +/- 1.5% (p less than 0.001), LDL cholesterol 9.1 +/- 2.4% (p less than 0.001), and serum triglyceride 19.3 +/- 3.2% (p less than 0.001) with no change in HDL cholesterol. The percentage reduction in serum triglyceride related to the initial triglyceride levels (r = 0.56, p less than 0.01). The small weight loss (0.4 kg) on the low-GI diet did not relate to the lipid changes. Low-GI diets may be of use in the management of lipid abnormalities associated with hypertriglyceridemia.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Dietary Carbohydrates; Female; Fructosamine; Hexosamines; Humans; Hyperlipidemias; Insulin; Lipids; Male; Middle Aged; Triglycerides

In a 3 yr epidemiological cohort study of 273 diabetics treated with oral hypoglycaemic agents (OHA) and 60 diet-treated diabetics the predictive value of fasting plasma C-peptide levels was assessed with the attempt to discriminate between insulin dependence and non-insulin dependence. Serum insulin, blood glucose, haemoglobin AI, bicarbonate, urine for ketone bodies, height and weight were measured too. All but 8 OHA-treated patients (97%) had fasting C-peptide greater than 0.40 pmol/ml at both investigations. Six had C-peptide in the interval 0.21-0.40 pmol/ml at both investigations and 2 a C-peptide less than or equal to 0.20 pmol/ml all of which became insulin dependent during the 3 yr period. The highest fasting C-peptide concentrations were found in overweight diabetics with a blood glucose level greater than 8.5 mmol/l. Overweight diabetics had significantly elevated fasting insulin compared to the normal weights but when the IRI concentrations were corrected by the body mass index hyperinsulinaemia was positively correlated with high levels of blood glucose and haemoglobin AI, i.e. poor glycaemic control and not with overweight. The results suggest that determination of fasting plasma C-peptide can be an additional clinical help in discriminating between insulin dependence and non-dependence.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diet, Diabetic; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged

Circulating levels of insulin and C-peptide in response to oral glucose administration (75 g) were measured in 25 PCOS patients (13 were obese and 12 non-obese) without acanthosis nigricans and in 12 non-obese normal cycling women of similar age. Fasting levels of insulin and C-peptide as well as the sums of their levels in response to glucose were significantly greater in PCO patients than in controls despite similar glucose responses. Obese PCO patients had greater basal levels, maximum increments and sums of insulin and C-peptide levels than non-obese PCO patients and controls. PCO patients with increased basal total testosterone levels had significantly greater mean fasting insulin levels (p less than 0.005) than those with normal testosterone levels but their responses to glucose were not significantly different. Hyperprolactinaemic PCO patients had neither basal level nor sums of insulin and C-peptide levels in response to glucose greater than normoprolactinaemic PCO patients. In all PCO patients BMI correlated significantly with insulin (p less than 0.05) and C-peptide levels (p less than 0.001). Total serum testosterone levels correlated significantly with fasting levels and the sum of C-peptide levels in response to glucose. The correlations of total serum testosterone levels with fasting and the sum of insulin levels in response to glucose were also positive but not significant. These results clearly indicate that in PCOS there is a significant degree of hyperinsulinaemia which is mainly related to obesity.

Topics: Body Weight; C-Peptide; Female; Humans; Insulin; Islets of Langerhans; Polycystic Ovary Syndrome; Prolactin; Testosterone

24-h urinary C-peptide excretion was studied in 19 healthy normal weight women with normal glucose tolerance, and related to weight gain and skinfold thickness at 12, 20, 30, 36 weeks of gestation and 6-8 weeks post partum. The urinary C-peptide values (total nmoles or nmoles per kg body weight) showed a significant and progressive increase with gestation. The average C-peptide value was already at 12 weeks of gestation 4 times higher than under non-pregnant conditions. The urinary C-peptide excretion was neither related to maternal weight, weight gain or skinfold thickness at any of the observation periods during pregnancy, nor to the plasma C-peptide response to an oral glucose load at 32 weeks of gestation. A significant correlation was found between urinary C-peptide excretion and body weight determined post partum (r = 0.54, p less than 0.05). The increment in urinary C-peptide excretions at 12 weeks of gestation was unrelated to body mass, suggesting that insulin resistance is present already at this early stage of normal gestation.

Topics: Blood Glucose; Body Weight; C-Peptide; Creatinine; Female; Humans; Islets of Langerhans; Pregnancy

Anthropometric, clinical and biochemical findings were compared in 30 rural (group A), 18 urban insulin-requiring (group B) and 45 urban oral-agent-responsive (group C) newly diagnosed diabetics. Mean ages at onset were 28.3 +/- 12.0, 25.6 +/- 14.5 and 42.1 +/- 10.5 years respectively. The differences between A and C and between B and C were significant. Group A were poor and malnourished, with body mass index (BMI) 15.9 +/- 1.9 and 17.2 +/- 3.7 kg/m2 for males and females respectively, presented with a long history of classical diabetes without ketoacidosis and required insulin in modest doses. 3 of 10 cases had excess stool fat but none of 13 unselected cases had pancreatic calcification. Group C were better nourished, with BMI 22.6 +/- 2.8 and 22.4 +/- 4.5 kg/m2, and responded to oral agents. Group B, with BMI 17.2 +/- 2.6 and 18.6 +/- 3.1 kg/m2, required insulin for control but had C-peptide levels above 0.02 nmol/1 in 10 of 15 cases. Anthropometric indices for males, but not for females, were significantly lower in group A than in group B or C. There were significant differences in levels of glucose between A and B and A and C, free fatty acids between A and C and B and C, insulin between A and B and A and C and C-peptide between A and C and B and C. Of the 3 groups the rural type most closely resembled the tropical variants.

Topics: Adolescent; Adult; Blood Glucose; Body Height; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Ethiopia; Fatty Acids, Nonesterified; Female; Humans; Insulin; Male; Middle Aged; Nutritional Status; Skinfold Thickness

The importance of androgenic activity in mediating the effects of obesity and body fat topography on splanchnic insulin metabolism and peripheral insulin sensitivity was studied in 19 nonhirsute premenopausal women with a wide range of ideal body weight [percent ideal body weight (% IBW), 78-202%] and body fat distribution pattern [waist to hip girth ratio (WHR), 0.67-0.91]. Turnover kinetics of peripheral plasma C-peptide and insulin were measured, and estimates of pancreatic insulin production (PIP) and the hepatic extraction fraction (HEF) were calculated. The peripheral insulin sensitivity index (M/I) was determined during an euglycemic insulin clamp study. Androgenic activity was assessed by estimating the plasma level of sex hormone-binding globulin (SHBG) and percentage of free testosterone (% FT). After iv glucose stimulation, PIP ranged from 40-254 mU/min X m2 and correlated highly with % IBW (r = 0.78; P less than 0.01). Insulin HEF ranged from 5-69% of the pancreatic production and was inversely proportional to WHR (r = -0.60; P less than 0.01). Increasing WHR also correlated with the diminution in M/I (r = -0.47; P less than 0.05), which, in turn, correlated with the decline in the HEF of insulin (r = 0.60; P less than 0.01). Since PIP, HEF, and M/I correlated with SHBG and % FT, and since the degree of androgenic activity correlated with % IBW and WHR, partial regression analysis was performed. After adjusting for the effects of SHBG and % FT, the relationship between % IBW and PIP remained unaltered, whereas the correlation between WHR and HEF or M/I and their relationship to each other were either markedly reduced or became insignificant. Thus, in premenopausal women, the increase in pancreatic insulin production with increasing weight is independent of the degree of androgenic activity. On the other hand, the decline in hepatic insulin extraction and diminution in peripheral insulin sensitivity with upper body fat localization are in part mediated by increased androgenic activity. This association may account for the pronounced hyperinsulinemia and insulin resistance characteristic of this form of obesity.

Topics: Adipose Tissue; Adolescent; Adult; Age Factors; Androgens; Blood Glucose; Body Weight; C-Peptide; Female; Humans; Insulin; Liver; Menopause; Metabolic Clearance Rate; Obesity; Splanchnic Circulation

To determine the effects of different hypocaloric diets on insulin secretion, 24-h urine C-peptide was measured in 11 obese subjects on a weight-maintaining baseline diet, and the results were compared with values obtained during 14-day periods of diets containing 400 kcal/day of only protein (n = 6) or glucose (n = 5), followed by 14 days of fasting and 14 days of refeeding on 800-1000 kcal/day. A significant positive correlation between total caloric intake and urine C-peptide excretion was found once the C-peptide excretion reached steady state after several days on each diet. Multiple regression analysis showed no contribution of body weight to urine C-peptide during the different diets. In contrast, a significant correlation was found between body weight and urine C-peptide in the fasting state. A marked and identical decrease of approximately 75% in urine C-peptide occurred over the first 5-7 days of the two 400-kcal diets, followed by a further decrease during fasting to 5% of baseline values. Refeeding was associated with a progressive increase. Plasma insulin and C-peptide followed the same trends as found for urine C-peptide, although the magnitude of change was much smaller. C-peptide clearance was not assessed because of the variation in plasma levels on eating meals. However, the same responses were found when C-peptide excretion was factored for creatinine excretion. Thus, the major determinant of urine C-peptide excretion appears to be food intake, and adaptations take 5-7 days to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Body Weight; C-Peptide; Energy Intake; Energy Metabolism; Fasting; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity

In massively obese patients hyperinsulinemia and insulin insensitivity usually improve with weight loss. To clarify the mechanism of these reversible abnormalities eight nondiabetic massively obese patients were studied before and at intervals (3 months and 1 yr) after weight loss following gastroplasty. Insulin dynamics were studied during the hyperglycemic clamp (change in glucose, 7 mmol L-1 for 2 h) by measuring the area under the insulin and C-peptide response curves, representing, respectively, systemic insulin response and insulin production. Compared to lean age-matched normal subjects the massively obese patients had the expected fasting hyperinsulinemia and an exaggerated insulin response (P less than 0.05). Within 3 months and after an approximately 20% weight loss, they had a marked reduction in the systemic insulin response but no change in the C-peptide response. Therefore, the reduction in insulin response was due to enhanced hepatic insulin clearance rather than reduced insulin production. Thus, the liver serves a gate-keeping role in regulating the systemic insulin response to a glucose challenge. With additional weight loss of 14% and then weight maintenance, insulin clearance was further increased, and a reduction in insulin production became evident, since the C-peptide response was reduced. Exogenous insulin clearance was measured using the euglycemic clamp technique before and after weight loss. Insulin clearance was initially lower in the massively obese patients compared to that in the normal subjects (P less than 0.05) and increased toward normal with weight loss (P less than 0.05). Similarly, insulin sensitivity, as measured by the ratio of glucose metabolised per U endogenous insulin, normalized with weight loss and weight maintenance. Thus, after significant weight loss followed by weight maintenance at a reduced, but not ideal, level, insulin clearance, production, and sensitivity all reverted to normal. These findings suggest that adipose mass per se may not be exclusively responsible for altered insulin and glucose dynamics in obesity and that additional factors associated with obesity, such as nutrient load, adipose distribution, fat cell size, or fatty acid flux, play a contributing role.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Fasting; Female; Glucagon; Humans; Insulin; Male; Metabolic Clearance Rate; Middle Aged; Obesity, Morbid

Twenty-five human subjects, whose body mass indices (BMI) ranged from 18.0 to 34.1 kg/m2, underwent euglycemic clamps at both low (1.5 mU/kg/min) and high (10 mU/kg/min) insulin infusion rates. Mean C-peptide concentrations were less than or equal to 0.5 ng/mL at the end of each two-hour period. The metabolic clearance rates (MCR) of insulin (mL/kg/min) were significantly (P less than .001) inversely correlated with BMI at both the low (r = -.65) and high (r = -.71) insulin infusion rates. The negative inverse correlations with BMI remained significant at both the low (r = -.42, P less than .05) and high (r = -.61, P less than .005) insulin infusion rates if the MCR were expressed as mL/m2/min. There were no significantly correlations (r less than .21) between the MCR at either rates of insulin infusion and age or tracer insulin binding to monocytes. Decreased MCR of insulin may contribute to the hyperinsulinemia seen in obese subjects.

Topics: Adult; Aged; Body Weight; C-Peptide; Female; Humans; Insulin; Insulin Infusion Systems; Male; Metabolic Clearance Rate; Middle Aged

To determine whether the severity of insulin resistance in obesity, as assessed by the traditional hyperinsulinemic glucose clamp, reflects the severity of resistance present during changing insulin concentrations, such as occur after meal ingestion, 9 moderately obese and 12 lean subjects were studied on 2 occasions: once during a primed continuous insulin infusion and once during a variable 8-step insulin infusion. Identical amounts of insulin were given on each occasion, and euglycemia was maintained by a glucose infusion. Stimulation of isotopically determined glucose utilization above the basal value was lower in the obese than in the lean subjects during the variable [2.4 +/- 0.5 (+/- SEM) vs. 5.4 +/- 0.7 g/m2; P = 0.004] and the constant (2.9 +/- 0.7 vs 4.2 +/- 0.9 g/m2; P = 0.32) insulin infusions; however, the differences were only significant with the variable insulin infusion. The variable insulin infusion also was associated with lower rates of activation of glucose utilization (slope, 0-90 min, 0.27 +/- 0.05 vs. 0.55 +/- 0.09 mg/m2 X min 2; P = 0.01) in obese compared to lean subjects. In contrast, rates of activation during the low constant infusion (0.24 +/- 0.05 vs. 0.29 +/- 0.06 mg/m2 X min 2; P = 0.51) did not differ in the lean and obese subjects. Despite identical amounts of insulin, stimulation of glucose utilization was greater (P less than 0.03) during the variable than during the constant insulin infusion in the lean subjects. In contrast, stimulation during the variable and constant insulin infusions was equal in the obese subjects. These observations indicate that insulin resistance in obesity is due to a defect in the rate as well as absolute response achieved and suggest that under conditions of daily living the contribution of insulin resistance to impaired carbohydrate tolerance is greater than that previously estimated by a constant insulin infusion.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Glucagon; Glucose; Humans; Insulin; Insulin Resistance; Kinetics; Middle Aged; Obesity

Sixteen newly diagnosed non insulin dependent diabetic patients were treated for 3 months with an individual energy restricted diet. The effect on weight, hyperglycaemia and insulin response to oral glucose was measured in all subjects, and in 7, peripheral insulin resistance was estimated using a hyperinsulinaemic glucose clamp at two insulin infusion rates (40 and 400 mU m-2 X min-1). After diet, fasting plasma glucose fell from 12.0 +/- 0.7 mmol/l (mean +/- SEM) to 7.4 +/- 0.5 mmol/l (P less than 0.001) and weight fell from 92.9 +/- 4.2 kg to 85.0 +/- 3.1 kg (P less than 0.001). The plasma insulin response to oral glucose was unchanged after diet therapy. Insulin induced glucose disposal (M) was also unaffected by diet at insulin infusion rates of 40 mU m-2 X min-1 (12.5 +/- 1.5 mumol X kg-1 X min-1 vs 15.7 +/- 1.6 mumol X kg-1 X min-1) and 400 mU m-2 X min-1 (49.5 +/- 2.7 mumol X kg-1 X min-1 vs 55.1 +/- 2.5 mumol X kg-1 X min-1). These results show that 3 months reduction of energy consumption with weight loss in newly diagnosed non insulin dependent diabetics improves B-cell responsiveness to glucose but has no effect on liver glucose output or on peripheral insulin action.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet, Reducing; Energy Intake; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Prospective Studies

We compared sensitivity, specificity and accuracy of selected clinical characteristics (age at diagnosis, initiation of permanent insulin therapy from diagnosis and degree of obesity) in the discrimination between diabetics with low or high fasting or post-glucagon C-peptide level in a population of 171 middle-aged insulin-treated diabetics (81 men, 90 women) living in East Finland. Individual clinical criteria were poor discriminators alone but their combinations gave high specificity for the low and high fasting and post-glucagon C-peptide classes. The specificity and the accuracy of combined criteria seemed to be somewhat higher among male than among female insulin-treated diabetics. The association between clinical characteristics and fasting or postglucagon C-peptide classes seemed to be similar.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon; Humans; Male; Middle Aged; Sex Factors

The use of glucose (G)--C-peptide (C)--body mass indexes (BMI) as clinical determinants of likely response to oral sulphonylurea agents in type 2 diabetic patients have been suggested by some investigators. The relationships between these clinical parameters are usually expressed as scores (C/G, G/BMI and C/BMI scores). Based on this approach, we have determined the significance of these clinical scores using isotopically-derived basal glucose fluxes (D[3-3H]glucose technique) in 26 subjects (10 type 2 diabetics and 16 nondiabetics) with a broad range (72-346 mg/dl) of fasting serum glucose (FSG) and BMI (19-39 kg/m2). The basal hepatic glucose output (HGO) correlated positively with FSG, BMI and G/BMI score and negatively with C/G score in the diabetic patients. We found no significant relationships between basal HGO and most of these parameters except FSG and G/BMI in the normal subjects. The basal metabolic clearance rate of glucose (MCR) significantly correlated, but inversely, with FSG and G/BMI score, but not with the C/G score or BMI in the diabetic patients. In the normal subjects, MCR significantly, but negatively, correlated with the BMI, but not with FSG, C/G or G/BMI scores. Neither basal HGO nor MCR correlated with fasting serum C-peptide, duration of diabetes or daily insulin dose. As a group, the basal HGO correlated positively with FSG, BMI and G/BMI scores but negatively with C/G Score. However, the basal MCR correlated negatively with FSG, BMI and G/BMI scores but positively with C/G score. In summary, the present cross-sectional study provides additional information on the determinants of fasting serum glucose levels in type 2 diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liver; Male; Metabolic Clearance Rate; Middle Aged; Reference Values

We evaluated the clinical characteristics and relationships between values of serum glucose, C-peptide, and body mass index (BMI) in 40 type II diabetic patients. Patients were divided into three groups according to the drug therapy: group A (n=16), oral sulfonylurea agent; group B (n=16), insulin alone; and group C (n=8), combined insulin and oral agent. The relationships between the various factors were expressed as ratios (C-peptide/BMI, glucose/BMI, and C-peptide/glucose scores). Using glycosylated hemoglobin (HbA1) value of less than 10.5% to denote response to therapy, each group was subdivided into responders and nonresponders. Comparing the data in group A, mean (+/-SEM) fasting serum glucose levels were significantly lower in responders vs nonresponders. The mean HbA1 levels were 8.59+/-0.54% vs 1 2.34+/-0.34%, respectively. The C-peptide/BMI scores were 7.4+/-1.0 vs 8.14+/-1.2; C-peptide/glucose scores, 1.73+/-0.27 vs 0.81+/-0.12; and glucose/BMI scores, 493+/-54 vs 1,082+/-168, respectively. The responders and nonresponders in group B had values similar to those of group A. Group C patients had data A and B. The responders in each group were characterized by serum glucose levels less than 200 mg/dL, C-peptide/glucose score greater than 1, and glucose/BMI score less than 700. T he 200 mg/dL, C-peptide/glucose score less than 1, and glucose/BMI score greater than 700. These simple calculated scores validate the importance of glucose/C-peptide/BMI interrelationships in ambulatory diabetic patients.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged

We studied effects of isocaloric diets of varied composition (each diet offered for 5 to 7 days) on urine C-peptide and creatinine excretion in eight healthy subjects. C-peptide excretion was higher on the high carbohydrate (60% CHO, 20% PRO) and high protein (45% CHO, 30% PRO) diets than on the low carbohydrate (30% CHO, 20% PRO) and low protein diets (45% CHO, 10% PRO). C-peptide excretion correlated with total kilocalories ingested (r = 0.594, p less than 0.001), and also with CHO (r = 0.469, p = 0.003) and PRO intake (r = 0.453, p = 0.004). Multiple regression analysis is given by the formula: Urine C-peptide (nmol/24 h) = 17.3 + 0.01 (kcal/24 h) + 0.021 (gm CHO/24 h) + 0.049 (gm PRO/24 h) Creatinine excretion was related to body weight (r = 0.959, p less than 0.001) and also to total PRO intake (r = 0.569, p less than 0.001) and meat intake (r = 0.367, p less than 0.05). We conclude that diet composition, especially protein intake, is an important stimulus to sustained insulin production as measured by C-peptide in healthy subjects. Diet composition has a significant impact on creatinine excretion. Urine creatinine cannot be assumed to reflect only lean body weight when it is used as a measure of the adequacy of timed urine collections.

Topics: Adult; Analysis of Variance; Blood Urea Nitrogen; Body Weight; C-Peptide; Creatinine; Dietary Carbohydrates; Dietary Proteins; Energy Intake; Female; Humans; Insulin; Male; Meat; Sex Factors

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

Plasma insulin and C-peptide levels in the fasting state and after a 2-h 75 g oral glucose tolerance test (OGTT) in a large number of healthy subjects are reported. 247 volunteers (134 males, 113 females), aged 13-69 years, who had a negative history of diabetes, no history of significant disease, normal physical examination, normal body weight, normal glucose tolerance, normal blood tests, and who were taking no drugs were studied. Results, mean +/- SEM (range): fasting glucose concentration = 4.64 +/- 0.03 mmol/l (3.10 - 6.10), 1-h glucose concentration = 5.23 +/- 0.10 mmol/l (2.20 - 9.90), 2-h glucose concentration = 4.11 +/- 0.06 mmol/l (2.00 - 6.80); fasting insulin level = 0.088 +/- 0.002 nmol/l (0.03 - 0.28), 1-h insulin level = 0.45 +/- 0.01 nmol/l (0.06 - 1.63), 2-h insulin level = 0.24 +/- 0.01 nmol/l (0.05 - 1.12); fasting C-peptide concentration = 0.60 +/- 0.01 nmol/l (0.14 - 1.34), 1-h C-peptide concentration = 2.17 +/- 0.05 (0.63 - 8.56), 2-h C-peptide concentration = 1.77 +/- 0.04 nmol/(0.35 - 5.74). Fasting insulin and fasting C-peptide concentrations correlated to post-glucose insulin and C-peptide concentrations, respectively. At each sampling-point insulin concentration correlated to C-peptide concentration. After glucose ingestion, both insulin and C-peptide plasma levels correlated significantly with the corresponding glucose levels. During fasting, C-peptide but no insulin level correlated to glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aging; Blood Glucose; Body Weight; C-Peptide; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Regression Analysis; Sex Factors

Insulin secretion, work capacity and plasma lipids were evaluated in 52 middle-aged men with impaired glucose tolerance (IGT), and the values were compared with those of 23 normoglycemic subjects with family histories of Type 2 diabetes and of 22 non-hereditary normoglycemic controls. All subjects were non-obese males of comparable age. Estimated maximal oxygen uptake was significantly lower (p less than 0.01) and triglyceride concentrations significantly higher (p less than 0.01) in IGT individuals than in subjects of the non-hereditary normoglycemic group, while no significant differences were noted in comparison with the hereditary group. IGT individuals showed an impaired insulin response to glucose with significantly lower absolute values of insulin and C-peptide during the early phase of the oral glucose tolerance test (OGTT) than in non-hereditary normoglycemic subjects, but not significantly lower than in the hereditary group. Similarly, at most time points of the OGTT the ratios of insulin and C-peptide to glucose were significantly lower in the IGT group than in the non-hereditary group, while these differences were less pronounced in comparison with the hereditary group. These findings suggest some similarities of metabolic disturbances in lean normoglycemics with positive family histories of Type 2 diabetes and in lean IGT individuals. Family history of diabetes (both first degree and second degree only) was significantly more prevalent among IGT individuals than among normals.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Lipids; Male; Middle Aged; Oxygen Consumption; Physical Fitness; Triglycerides

The relationship between changes in gastric inhibitory polypeptide (GIP), C-peptide and insulin responses to meals was studied in 8 normal subjects after 2 weeks of Acarbose treatment. Acarbose caused a significant reduction of GIP and insulin responses (P less than 0.05). The decrease in insulin response could not be explained by changes in the glycaemic stimulus of insulin secretion, as Acarbose did not significantly change the plasma glucose response to meals during the study. The reduced insulin response was seen without a concomitant reduction in the C-peptide response to the meals, thus resulting in a decreased insulin/C-peptide ratio after Acarbose treatment (P less than 0.05). The changes in GIP response after Acarbose correlated positively with the change in insulin/C-peptide ratio (r = 0.69; P less than 0.05). Our data thus challenge the concept that Acarbose therapy affects the secretion of insulin. The positive relationship between changes in GIP response and changes in the insulin/C-peptide ratio rather suggests that GIP affects the metabolism of insulin or C-peptide.

Topics: Acarbose; Adult; Blood Glucose; Body Weight; C-Peptide; Double-Blind Method; Female; Food; Gastric Inhibitory Polypeptide; Glucagon; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Random Allocation; Trisaccharides

In order to see if subcutaneous insulin treatment of type II diabetes might produce lasting physiologic changes, ten patients received one month's insulin treatment under strict dietary supervision. When compared to the pretreatment period, 48 hours after discontinuing insulin treatment fasting plasma glucose had fallen (P = 0.005), fasting serum insulin had risen (P = 0.005), and fasting hepatic glucose production measured by 3H-3-glucose turnover had fallen (P = 0.008). The metabolic clearance rate of glucose measured with the glucose clamp rose significantly after treatment at insulin infusion rates of 40 mU m-2 min-1 (P = 0.015) and 400 mU m-2 min-1 (P = 0.012). The serum insulin and C-peptide responses to oral glucose improved after the treatment in association with the improvement in glucose tolerance, but the plasma glucose response was unchanged. Six other type II diabetic patients who received only dietary supervision did not show significant changes in these variables. Six weeks after discontinuing insulin, the patients' fasting hepatic glucose production was still reduced compared to pretreatment (P = 0.028) and insulin action was still improved at both the lower (P = 0.028) and the higher (P = 0.028) insulin infusion rates, but the fasting plasma glucose and insulin and C-peptide responses to oral glucose had returned to pretreatment values. The improvement in glucose tolerance and beta-cell function induced by insulin treatment seems to be of more limited duration than the improvements in basal hepatic glucose production and in insulin action.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucose; Humans; Insulin; Male; Metabolic Clearance Rate; Middle Aged

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

We have examined gravida with gestational diabetes mellitus (GDM), as defined by the National Diabetes Data Group (Diabetes 1979; 28:1039), for phenotypic and genotypic heterogeneity. Fasting plasma glucose (FPG) at diagnosis was used for further stratification of GDM according to putative metabolic severity into class A1 (FPG less than 105 mg/dl [N = 129]), class A2 (FPG 105-129 mg/dl [N = 47]), and class B1 (FPG greater than or equal to 130 mg/dl [N = 23]). All GDM classes tended to be older and heavier than consecutive gravida with documented normal glucose tolerance (controls, N = 148). Subdivision into "lean" and "obese" indicated that plasma immunoreactive insulin (IRI) was greater after overnight fast in the obese of all groups except B1. However, absolute increases in IRI above fasting levels in response to glucose during OGTT were significantly enhanced by obesity only in class A2 gravida. Adjustment for the effects of age and weight by covariate analysis indicated that the IRI response to glycemic stimulation is usually attenuated in all forms of GDM. Mean values for increases in IRI above fasting values during the first 15 min and IRI increments relative to the increases in plasma glucose throughout the 180-min OGTT were below control values in all GDM groups and progressively so, i.e., A1 less than A2 less than B1. The absolute insulinopenia was not invariable; a small number of gravida from all GDM groups displayed well-preserved IRI responses to oral glucose. Genotypic evaluation of the GDM population disclosed an increased occurrence of "markers" known to be associated with type I diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Autoantibodies; Birth Weight; Blood Glucose; Body Weight; C-Peptide; Fasting; Female; Fetal Blood; Glucose Tolerance Test; Histocompatibility Antigens Class II; HLA-DR3 Antigen; HLA-DR4 Antigen; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Maternal Age; Pregnancy; Pregnancy in Diabetics

Twenty women with abnormal glucose tolerance, detected from a routine program of antenatal screening for gestational diabetes mellitus (GDM) at 28 wk, were admitted for 24-h metabolic profiles. They were then alternately allocated to either insulin and dietary restriction or dietary restriction alone and then retested 4 wk later while on therapy. Ten normal controls were assessed twice at similar gestations to the study group. Before treatment, the 20 gestational diabetic subjects had higher mean concentrations of plasma glucose and 3-hydroxybutyrate than the controls for most of the profile, but mean insulin values were similar. Insulin therapy was associated with a reduction in mean glucose concentrations so that the profile was similar to the controls, while in the diet-alone group the reduction was less. The 3-hydroxybutyrate concentrations rose between profiles in the normal group and also rose in those treated by diet alone, but still remained within the upper range of normal even at night. Insulin therapy resulted in a similar 3-hydroxybutyrate profile to the controls. The C-peptide response to breakfast was reduced in both groups to levels below that of the controls. Neonatal outcome indices were similar in the two treatment groups, despite the differences in maternal metabolites, but because of the size of this study, conclusions about the neonate must be tentative.

Topics: 3-Hydroxybutyric Acid; Adult; Birth Weight; Blood Glucose; Body Weight; C-Peptide; Circadian Rhythm; Female; Gestational Age; Humans; Hydroxybutyrates; Insulin; Pregnancy; Pregnancy in Diabetics

Serum lipids and lipoproteins were measured in 170 insulin-treated diabetics (90 females, 80 males) and in 124 nondiabetic control subjects (59 females, 65 males) aged 45 to 64 years. Plasma C-peptide response to intravenous (IV) glucagon was measured in order to classify the patients according to their capacity of endogenous insulin secretion. In both sexes, HDL and HDL2 cholesterol were higher in diabetics with no C-peptide response than in controls, whereas diabetics with high C-peptide response (postglucagon C-peptide level greater than 0.60 nmol/L) showed lower levels of HDL and HDL2 than nondiabetic controls. When adjustment for age, alcohol consumption, physical activity, body mass index, and insulin dose was made by analysis of covariance, the highly significant difference in HDL and HDL2 cholesterol level between diabetics with no C-peptide response and diabetics with high C-peptide response still remained in both sexes. This study gives support to the hypothesis that elevated HDL and HDL2 cholesterol levels in insulin-treated diabetics are not explained by effects of treatment with exogenous insulin, but rather are associated with the type of diabetes characterized by deficient endogenous insulin secretion.

Topics: Body Weight; C-Peptide; Cholesterol, HDL; Diabetes Mellitus; Female; Glucagon; Humans; Insulin; Insulin Secretion; Lipoproteins; Lipoproteins, HDL; Lipoproteins, HDL2; Lipoproteins, HDL3; Male; Middle Aged; Triglycerides

The predictive value of the intravenous glucagon test in assessing the requirement of insulin therapy in diabetes mellitus was evaluated in 105 adult diabetics. Basal and stimulated C-peptide concentrations and increments of C-peptide concentration were examined separately among newly and previously diagnosed diabetics. The poststimulatory C-peptide concentration of 0.6 nmol/l (Novo, antibody M 1230) proved to be the most reliable basis for the choice of therapy. Adequate therapy could have been assessed in 70 cases (67%) without glucagon stimulation. To derive maximal information of plasma C-peptide concentrations, a biphasic scheme of the use for C-peptide determinations and glucagon stimulation is presented. Basal and stimulated C-peptide levels of insulin-requiring diabetics correlated negatively with the duration of diabetes but they did not correlate with the relative body weights. Basal and stimulated C-peptide levels of non-insulin-requiring diabetics did not correlate with the duration of diabetes, but they correlated positively with the relative body weights.

Topics: Adolescent; Adult; Aged; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Middle Aged

Pancreatic B-cell function was studied as part of a health control examination by measuring fasting plasma C-peptide concentration in 433 44-55 year-old males with normal glucose tolerance. Fasting C-peptide levels were correlated with relative body weight (r = 0.48) and fasting blood glucose concentrations (r = 0.43), yielding a multiple correlation coefficient of 0.56, and the multiple regression equation: FCP (nmol/l) = -0.89 + 0.61 X RBW + 0.16 X FBG (mmol/l). (FCP = fasting plasma C-peptide, RBW = relative body weight, FBG = fasting blood glucose). In 26 subjects with impaired glucose tolerance, fasting plasma C-peptide levels were even more strongly correlated with relative body weight (r = 0.63) and fasting blood glucose concentrations (r = 0.47). Subjects older than 52 years had a significantly higher fasting C-peptide level than younger subjects (p less than 0.01). In the 26 subjects with impaired glucose tolerance, fasting plasma C-peptide levels were not significantly different from those in the 433 men with normal glucose tolerance. However, when compared to a group with normal glucose tolerance matched for relative body weight, the subjects with impaired glucose tolerance had an elevated fasting blood glucose level (p less than 0.01) without difference in C-peptide level, suggesting a reduced insulin sensitivity. It is concluded that, in order to evaluate B-cell secretory function by determining fasting plasma C-peptide concentration, the relative body weight and simultaneous blood glucose concentration should be taken into consideration.

Topics: Adult; Age Factors; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glucose Tolerance Test; Humans; Islets of Langerhans; Male; Middle Aged; Reference Values

Glyburide, a second-generation sulfonylurea compound, was combined with insulin to evaluate its therapeutic effectiveness in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM), poorly controlled by insulin alone. Patients were studied before and three months after the addition of glyburide to their insulin program. Fasting plasma glucose concentration fell an average of 57 mg/dL, associated with an approximately 25% reduction in postprandial glucose response. Therapeutic responses varied widely from patient to patient; the greatest improvement in diabetic control was seen in heavier patients, who had retained the ability to secrete insulin in response to meals and who were not excessively insulin resistant. The glyburide-induced fall in plasma glucose concentration was associated with improvements in both insulin secretion and insulin action, but only the enhanced insulin action correlated with the reduction in fasting and postprandial glucose levels. Thus, diabetic control was significantly improved by glyburide. Combined insulin-sulfonylurea therapy may be useful in the treatment of NIDDM that cannot be easily controlled with either agent alone.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Energy Intake; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Liver; Male; Metabolic Clearance Rate; Middle Aged

Urine C-peptide per 24 h urine (UCPR) was assayed and correlated with the degree of insulin dependence in 324 diabetic patients. The UCPR and UCPR/weight were 74.7 +/- 26.3 micrograms/day and 1.27 +/- 0.36 micrograms/day, kg in healthy subjects, and these values were similar in diet- and sulfonylurea-treated patients. Insulin-dependent diabetics (IDDM) with history of ketosis or ketoacidosis and/or unstable plasma glucose, and patients refractory to sulfonylureas had lower UCPR values (8.5 +/- 6.6 and 22.3 +/- 14.6 micrograms/day) than the other insulin-treated patients (45.4 +/- 30.7 micrograms/day). In more than 90% of diet- and sulfonylurea-treated patients, UCPR exceeded 30 micrograms/day and UCPR/wt. exceeded 0.6 micrograms/day, kg. UCPR was less than 20 micrograms/day and UCPR/wt. less than 0.4 microgram/day,kg in more than 90% of IDDM patients, and less than 40 micrograms/day and 0.8 microgram/day,kg respectively in 80% of sulfonylurea-refractory patients. IDDM patients with more than 20 U/day of insulin doses had lower UCPR values. Longer duration of diabetes was associated with lower UCPR in IDDM patients. The results indicate that UCPR more than 30 micrograms/day or UCPR/wt. more than 0.6 micrograms/day,kg suggest non-insulin dependence, and UCPR less than 20 micrograms/day or UCPR/wt. less than 0.4 micrograms/day,kg suggest insulin dependence. Assay of UCPR provides a simple, non-invasive test for evaluating the degree of insulin dependence in diabetic patients.

Topics: Adolescent; Adult; Aged; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Humans; Insulin; Middle Aged; Sulfonylurea Compounds

The daily excretion of C-peptide in the urine was measured in 105 healthy infants and children from birth to 14 years of age. For technical reasons no studies were performed from 1-3 years of age. The excretion of C-peptide showed a close positive correlation with age and weight. The relationship with weight was already apparent in the 1st days of life. The C-peptide/weight and the C-peptide/creatinine ratios were constant throughout most of childhood with the exception of the age range of 1 month-1 year when the C-peptide/creatinine was significantly higher. In obese children the C-peptide/weight and C-peptide/creatinine ratios were similar to those found in children with normal weight. In growth hormone deficiency these ratios were low and increased during the 1st week of growth hormone therapy. It is concluded that urinary C-peptide is a reliable indicator of integrated insulin production and gives new information about insulin secretion in various conditions.

Topics: Adolescent; Aging; Body Constitution; Body Height; Body Weight; C-Peptide; Child; Child, Preschool; Growth Hormone; Humans; Infant; Infant, Newborn

The effect of a 6-wk training period on the oxidation of a 100-g glucose load given orally during exercise was investigated in six healthy male volunteers. The subjects were submitted before and 24 h after the training program to a 105-min exercise bout (performed at about 40% of the pretraining VO2max) followed by a 90-min resting period. Naturally labeled [13C]glucose was given 15 min after the beginning of exercise. Exogenous glucose oxidation was derived from 13CO2 measurements in expired air, and total glucose and lipid oxidation were evaluated by indirect calorimetry. Training (60-min bicycling 5 days a week at 30-40% VO2max) resulted in a 29% increase in VO2max. During the 15 min of exercise that preceded glucose ingestion, the rate of total carbohydrate oxidation was slightly decreased after training, whereas the rate of lipid oxidation was slightly increased. Training did not affect the response of blood glucose, plasma insulin, or plasma free fatty acids to the glucose ingested during exercise; in contrast, the circulating levels of epinephrine, glycerol, and lactate were significantly reduced after training. Substrate utilization measurements revealed similar oxidation rates of carbohydrates (106.9 +/- 2.7 before vs. 100.2 +/- 4.7 g/3 h after training) and of lipids. However, detailed analysis revealed a significant 17% increase in exogenous glucose oxidation, thus indicating a significant sparing of endogenous carbohydrates. In conclusion, physical training induces a modest but significant increase in the oxidation of an oral load of glucose given during subsequent exercise of moderate intensity, a phenomenon reinforcing the sparing of endogenous carbohydrate stores.

Topics: Administration, Oral; Adult; Blood Glucose; Body Weight; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glucose; Glycerol; Humans; Insulin; Lactates; Lactic Acid; Male; Norepinephrine; Physical Exertion; Physical Fitness; Potassium

This study was designed to evaluate the influence of age, duration of diabetes, relative body weight and glycaemic control on beta-cell function and insulin sensitivity in 250 patients with onset of nonketotic diabetes between the age of 35 and 70 years (Type 2 diabetes). Beta-cell function was assessed by measuring serum C-peptide concentrations after 1 mg of glucagon iv. It was not influenced by age, age at onset of diabetes nor by the duration of the disease. This suggests that progressive deterioration of beta-cell function with time is not a consistent finding in Type 2 diabetes. Insulin sensitivity, measured as the glucose disappearance rate, KITT, in response to iv-insulin, was not significantly influenced by age or age at onset, but decreased consistently with the duration of the disease (P less than 0.001). Beta-cell function was not correlated to fasting blood glucose and HbA1 concentrations. In contrast, there was a strong inverse relationship between glycaemic control and insulin sensitivity (P less than 0.001) indicating that decreased insulin sensitivity contributes to poor glycaemic control in these patients. Attempts to improve glycaemic control in patients with Type 2 diabetes should therefore include means to improve insulin sensitivity.

Topics: Adult; Age Factors; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glycated Hemoglobin; Humans; Insulin; Islets of Langerhans; Male; Middle Aged

Oral and iv glucose tolerance, insulin response to iv and oral glucose load as well as insulin sensitivity were evaluated in 58 'low insulin responders'. They were selected from a group of 226 healthy subjects with normal fasting blood glucose and normal iv glucose tolerance test on the basis of a low insulin response during a standardized glucose infusion test (GIT). The insulin response to GIT was analysed by parameter identification in a mathematical model (parameter KI). Insulin sensitivity was also measured by computer analysis of GIT (parameter KG) and, in a limited group of subjects, by a somatostatin infusion test. Thirty-three low insulin responders had normal OGTT, whereas 5 demonstrated borderline-1, 16 borderline-2, and 4 decreased OGTT. The first group of subjects demonstrated normal or enhanced insulin sensitivity. Borderline and decreased OGTT, in most instances, was accompanied by decreased insulin sensitivity, implying that a subgroup of low insulin responders exhibited signs of both impaired insulin response to glucose and insulin resistance. Since these defects characterize manifest type-2 diabetes, these subjects possibly may run a high risk to develop this type of diabetes. On the other hand, low insulin response in combination with increased insulin sensitivity may reflect adaptation of the secretory capacity of B-cells to the need of insulin.

Topics: Adult; Age Factors; Blood Glucose; Body Weight; C-Peptide; Computers; Female; Glucagon; Glucose Tolerance Test; Growth Hormone; Humans; Insulin; Insulin Secretion; Male; Somatostatin

Insulin secretion was investigated in 65 insulin-dependent diabetic patients by determining C peptide levels before and after stimulation with either an 800 calories test meal or an injection of glucagon or arginine i.v. Most patients had very low basal C peptide levels and response to all stimulation tests was poor as compared to controls. In normal subjects, response to glucagon or arginine stimulation appeared to be slightly stronger than response to test meal stimulation. There was apparently no correlation between diabetes control, as assessed by haemoglobin A1c values, and C peptide levels before and after stimulation. On the other hand, C peptide levels were inversely proportional to the duration of diabetes. Finally, C peptide levels after test meal stimulation were found to correlate with the doses of insulin administered.

Topics: Adult; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Female; Homeostasis; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Peptides; Time Factors

C-Peptide is secreted from the beta-cell in equimolar quantities with insulin. Since a fraction of C-peptide is excreted in the urine, measurement of C-peptide in timed urine collections is a simple indirect measure of integrated insulin production. Normal subjects were studied to determine the effects of diet and oral prednisone on urinary C-peptide excretion. In subjects on a defined diet, there is a positive correlation of urinary C-peptide with body weight. When insulin production is increased after oral prednisone, there is also a positive correlation with body mass index and percent ideal body weight. Prednisone increases plasma glucose, immunoreactive insulin, and serum and urinary C-peptide levels beginning 8-12 h after oral administration. This effect of prednisone is most marked in the postprandial state. Diets high in carbohydrate and protein result in significantly more insulin production, as measured by urinary C-peptide, than isocaloric diets with low protein or carbohydrate composition.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diet; Dietary Carbohydrates; Dietary Proteins; Female; Humans; Insulin; Male; Middle Aged; Peptides; Prednisone

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.

Topics: Adolescent; Adult; Antibodies; Blood Glucose; Body Surface Area; Body Weight; C-Peptide; Diabetes Mellitus; Epinephrine; Glucagon; Humans; Hypoglycemia; Insulin; Islets of Langerhans

The fact that hyperinsulinemia occurs in simple obesity and mild glucose intolerance has been well established. Altered hepatic insulin extraction may influence the levels of circulating hormone. The simultaneous measurement of insulin and C-peptide concentrations in peripheral blood enables an in vivo estimation of hepatic insulin removal. To evaluate hepatic insulin extraction, insulin and C-peptide responses to oral glucose were studied in 176 obese and nonobese subjects with normal, impaired, or diabetic glucose tolerance. Insulin levels as well as insulin incremental areas in glucose intolerant subjects were significantly higher than in weight-matched controls. The levels of C-peptide as well as C-peptide incremental areas were only slightly enhanced in subjects with impaired glucose tolerance, whereas they were reduced in subjects with diabetic tolerance. The molar ratios of C-peptide to insulin, both in the fasting state and after ingestion of glucose, as well as the relationship between the incremental areas of the two peptides were used as measures of hepatic insulin extraction. They were significantly reduced in glucose intolerant subjects and, to a lesser extent, in nondiabetic obese subjects. These results indicate that peripheral hyperinsulinemia in subjects with simple obesity or impaired glucose tolerance is a result of both pancreatic hypersecretion and diminished hepatic insulin extraction. In subjects with a more severe degree of glucose intolerance, decreased hepatic insulin removal is the primary cause of hyperinsulinemia.

Topics: Adolescent; Adult; Body Weight; C-Peptide; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Insulin; Liver; Male; Middle Aged; Obesity

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

Fasting insulin secretion was assessed by measuring fasting serum C-peptide levels in 529 women and 399 men aged 18-90 years, to study the relationship between insulin secretion, insulin resistance and risk factors for coronary heart disease. Subjects with low serum high density lipoprotein (HDL) cholesterol levels showed higher mean serum insulin and C-peptide levels than subjects with normal HDL cholesterol levels. In male subjects these differences were significant for both serum insulin and serum C-peptide results (P less than 0.005). In female subjects serum insulin results differed significantly (P less than 0.0005) but for the difference in mean serum C-peptide levels P was equal to 0.012. Fasting serum C-peptide correlated negatively with serum HDL cholesterol. However, serum C-peptide also correlated with serum triglyceride and serum triglyceride correlated negatively with serum HDL cholesterol. Each correlation was statistically significant (P less than 0.001). Multiple regression analysis suggested that the apparent association of C-peptide with HDL cholesterol was a consequence of the interrelated association between C-peptide, triglyceride and HDL cholesterol. The analysis was consistent with the hypothesis that obesity and increased insulin resistance were associated with increased insulin secretion and in turn with high serum triglyceride levels and consequentially low levels of serum HDL cholesterol. The data were compatible with the suggestion that insulin resistance rather than fasting insulin concentration per se could be a risk factor for coronary heart disease.

Topics: Adolescent; Adult; Aged; Body Weight; C-Peptide; Cholesterol; Cholesterol, HDL; Coronary Disease; Fasting; Female; Humans; Insulin; Insulin Resistance; Lipoproteins, HDL; Male; Middle Aged; Risk; Triglycerides

In our study the glycosylated haemoglobin was positively correlated with the mean bloodglucose concentration and the levels of serum triglycerides and proved to be a valuable parameter, which completes the hitherto existing possibilities of diabetes control. The difference of the levels of serum triglycerides and C-peptide between non-insulin-dependent and insulin-dependent diabetics, with the same quality of the levels of HbA 1 and mean bloodglucose, give us a help to decide, which therapeutic way would be the best in the introduction respectively correction of the treatment of the elderly diabetic patients.

Topics: Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Hemoglobin A; Humans; Male; Middle Aged; Triglycerides

Blood glucose, serum insulin, C-peptide, free fatty acids and growth hormone were evaluated in 45 patients with histologically established hepatic steatosis after an oral glucose load (100 g). Glucose tolerance was impaired in 59 per cent of the patients. Significantly increased levels were found for blood glucose (fasting and after 60 and 120 min), insulin (after 60, 120 and 180 min), C-peptide (fasting and after 60, 120 and 180 min), and free fatty acids (fasting and after 60 and 120 min). Human growth hormone levels were not altered. After glucose administration the C-peptide/insulin ratio was significantly reduced in hepatic steatosis compared to controls. In patients with hepatic steatosis there were no differences between subjects with normal body weight or overweight nor between stadium I and stadium II ('alcoholic hepatic steatosis') concerning glucose, insulin, C-peptide, HGH and FFA levels in blood. We conclude, that hepatic steatosis is associated with relative insulin resistance to which elevated FFA may contribute. In addition, the decreased C-peptide/insulin ratios suggest an impaired hepatic insulin degradation as it was already described for more serious liver diseases.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Fatty Acids, Nonesterified; Fatty Liver; Fatty Liver, Alcoholic; Female; Glucose Tolerance Test; Growth Hormone; Humans; Insulin; Male

In an attempt to determine the mechanism of decreased glucose tolerance in lean type 2 diabetics, glucose turnover in such subjects and controls was studied under basal conditions and during hyperglycemia induced by intravenous administration of glucose. The diabetics had decreased intravenous glucose tolerance and a fasting plasma glucose of 6-8 mM (108-144 mg/dl). Glucose was infused for 2 hr at 2 mg/kg per min in the controls (n = 16) and diabetics (n = 9). Furthermore, 11 healthy subjects were infused also with glucose at 4 mg/kg per min to match the glycemia of the diabetics. Glucose production, utilization, and metabolic clearance were assessed by the primed constant tracer infusion technique. In the basal state, diabetics showed normal plasma insulin, C peptide, and glucagon concentrations. Their increased basal plasma glucose levels were associated with normal rates of glucose production and utilization, but the metabolic glucose clearance was 21% lower than in the controls (P < 0.001), indicating decreased sensitivity to insulin. During infusion of glucose at 2 mg/kg per min, the hyperglycemia attained in the diabetics (170 mg/dl) was higher than that in controls (115 mg/dl) but comparable to that of the controls exposed to the higher glucose load. With the lower glucose load, metabolic clearance rate decreased more markedly in diabetics, again suggesting insulin resistance. This was further substantiated by the fact that, at the same insulin levels, glucose utilization did not increase more in the diabetics than in the controls, although the glycemia reached was considerably higher in the diabetics. With the lower glucose load, glucose production was suppressed to the same degree in the controls and diabetics, although the attained glycemia was much more marked in the latter. Because both insulin and hyperglycemia can suppress glucose production, some defect in the regulation of glucose production of the diabetics is also indicated. The insulin and C peptide levels were much higher in the controls than in the diabetics at the same levels of glycemia, demonstrating the inadequacy of insulin response to glycemia of the diabetics. Glucagon concentration was equally suppressed in all groups. In conclusion, impaired glucose tolerance of mild type 2 diabetics resulted both from inadequate insulin response and from decreased sensitivity to insulin. The insulin resistance could mainly be ascribed to inadequate glucose uptake, but a defect in glucose-ind

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged

Twenty-four hour integrated concentrations of growth hormone (IC-GH) were significantly lower in young, obese subjects than in young subjects who were lean. Significant inverse correlations were found between IC-GH and body mass index (BMI) as well as the IC-GH and the 24 hr integrated concentrations of insulin (IC-I) and C-peptide (IC-C) in obese subjects below 30 yr of age. Since IC-GH decreases with age, the effect of obesity on IC-GH could not be demonstrated in the older subjects; a weak inverse correlation (p less than 0.05) between IC-GH and IC-C was found. Prolactin was significantly lower in the older subjects but did not correlate with IC-GH and was similar in lean and obese. Lipid deposition in adipose cells is promoted by high concentrations of insulin as well as low concentrations of growth hormone. We found a significant correlation between the IC-I/IC-GH ratio and BMI of both the young and older subjects. Correlations between these two factors do not necessarily imply a cause and effect relationship. It is plausible, however, that the elevated IC-I/IC-GH of the obese may facilitate their lipid storage and counter their efforts at weight reduction.

Topics: Adolescent; Adult; Age Factors; Body Weight; C-Peptide; Female; Growth Hormone; Humans; Insulin; Male; Middle Aged; Obesity; Peptides; Prolactin

We studied the changes of glandular kallikrein activity in plasma of nine normal female volunteers, aged 22.2 +/- 1.20 years (mean +/- SEM), following 75 g glucose ingestion along with those of immunoreactive insulin, C-peptide immunoreactivity, free fatty acid and blood glucose using our recently developed assay system for plasma glandular kallikrein activity. Glandular kallikrein activities decreased initially from mean baseline level and then returned to baseline level with the lapse of time after glucose load. Furthermore, in hyperinsulinemic group, mean glandular kallikrein activities at 120 min after glucose load revealed to be significantly higher than those of normoinsulinemic group. The findings suggest that active glandular kallikrein is consumed and utilized during glucose uptake at the peripheral tissues, and hyperinsulinemia brings about prolonged activation of kallikrein-kinin system.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Kallikreins; Time Factors

Insulin secretion and insulin resistance were examined in seven obese type II diabetics before and after control of plasma glucose levels without weight loss. Control was achieved by regular insulin injection (60-205 U/day in four doses). After 10 days of therapy, plasma insulin and C-peptide responses to oral glucose were significantly improved. Insulin-induced glucose rates, estimated by the glucose clamp technique, averaged 1.08 +/- 0.30 mg/kg. min (mean +/- SEM; n = 7) before treatment and were unchanged (1.08 +/- 0.25) after treatment. These indicate that short term control of plasma glucose improved insulin secretion but not insulin sensitivity. The impaired insulin secretion and insulin sensitivity in type II diabetics appears to be, in part, secondary to metabolic abnormalities associated with hyperglycemia.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity

Melatonin, free and total cortisol, insulin, C-peptide and glucose-dependent insulin-releasing peptide (GIP) were measured in the plasma of twelve normal volunteers (eight women and four men), at hourly intervals for 24 h following a meal and subsequent fasting. One volunteer was excluded from calculations due to a possible effect of stress on melatonin secretion. Melatonin and cortisol showed the normal 24-h variation with peak values at 0200-0500 h, and 0900 h respectively. Following post-prandial stimulation, gut hormones remained basal throughout the sampling period. No significant relationship was found between 24-h melatonin secretion and basal, or stimulated gut hormone secretion. Melatonin secretion did relate significantly to body weight, suggesting that data concerning pineal effects in endocrine physiology and pathology, and affective disease, should be reviewed in the light of these observations.

Topics: Adult; Body Weight; C-Peptide; Fasting; Female; Gastric Inhibitory Polypeptide; Humans; Hydrocortisone; Insulin; Male; Melatonin; Pineal Gland

Topics: Adult; Body Weight; C-Peptide; Cholesterol; Glucose Tolerance Test; Humans; Insulin; Lipids; Lipoproteins, HDL; Physical Exertion; Skinfold Thickness; Triglycerides

Hypersecretion of immunoreactive gastric inhibitory polypeptide (IRGIP) has been reported previously in patients with diabetes mellitus (DM) and obesity. To ascertain the relative contribution of glucose intolerance and obesity to the abnormalities of IRGIP secretion, 114 subjects were studied during a standard oral glucose (75 g) tolerance test; responses of glucose, insulin, C-peptide, IRGIP, and glucagon were evaluated. The subjects were divided into six subgroups according to body weight and the degree of glucose intolerance. In normal weight subjects, the IRGIP response to oral glucose was significantly higher in the patients with impaired glucose tolerance (IGT) and DM than in the healthy control subjects (P less than 0.05). In the obese subjects, no significant differences in mean IRGIP responses could be detected among control, IGT, and DM subjects. In spite of similar IRGIP responses, the obese IGT patients did release more insulin than the obese control subjects, suggesting that incretin factors other than GIP may be operative in this condition. When obese and nonobese patients were compared, the obese subjects with normal glucose tolerance released a greater amount of IRGIP and insulin than the normal weight controls, whereas no significant difference between obese and nonobese could be found within the IGT and DM groups. We conclude that in the absence of obesity, glucose intolerance may induce IRGIP hypersecretion. On the other hand, obesity is associated with IRGIP hypersecretion, and glucose intolerance has no further effect, indicating a different pathogenetic mechanism for the IRGIP abnormalities. In both the obese and nonobese diabetic groups, IRGIP hypersecretion was associated with a failure of plasma glucagon levels to fall after oral glucose; this effect might be related to the glucagonotropic action of this peptide.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Obesity

Ninety obese "diabetic" patients, including 55 treated with insulin injection, were characterized by measurement of levels of insulin or connecting peptide of proinsulin (C peptide) induced during oral glucose tolerance testing. After reduction of body weight to ideal values, patients whose peak serum insulin levels were initially 64 microunits/mL or greater had reductions of blood glucose values from 227 +/- 24 to 122 +/- 10 mg/dL (fasting) and from 400 +/- 49 to 160 +/- 11 mg/dL (two hours postprandial); at C-peptide peaks of 6.0 ng/mL or greater, these blood glucose values fell from 244 +/- 30 to 118 +/- 12 mg/mL and from 400 +/- 51 to 160 +/- 16 mg/dL, respectively. Patients with peak values of less than 60 microunits/ml for insulin or less than 6.0 ng/mL for C peptide did not normalize the blood glucose concentration after weight loss. This critical level of insulin secretory reserve separating these groups was similar to that previously reported for avoidance of diabetic retinopathy and neuropathy. These results suggest that levels of insulin or C peptide induced during glucose tolerance testing distinguish between two types of hyperglycemic obesity-insulin-dependent diabetes mellitus and insulin-resistant obesity. Blood glucose levels alone did not identify these groups. Among consecutive hyperglycemic obese patients, 36% achieved normoglycemia by weight loss alone, including 33% of those previously treated with insulin injection.

Topics: Adult; Body Weight; C-Peptide; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Peptides

Amniotic fluid (AF) volumes were determined by sodium p-aminohippurate (PAH) dilution in a consecutive series of 24 diabetic women at 34-35 weeks gestation. AF and maternal venous blood samples were analysed for C-peptide immunoreactivity (CPR). When the patients were subgrouped according to the presence (n = 17) or absence (n = 8) of neonatal morbidity, AF volumes (1340 +/- 236 ml vs 807 4/- 130 ml; mean +/- SEM), AF concentrations of CPR (1.38 +/- 0.54 nmol/l vs 0.61 +/- 0.14 nmol/l) and maternal blood glucose levels (5.3 +/- 0.2 nmol/l vs 4.8 +/- 0.3 nmol/l) during the last trimester of pregnancy were not different. The total content of CPR was significantly (P less than 0.05) greater in pregnancies with neonatal complications (1.25 +/- 0.31 nmol/ compared with that in pregnancies without neonatal complications (0.54 +/- 0.18 nmol). AF volumes were significantly (P less than 0.02) larger in pregnancies where feeding problems occurred (1546 +/- 307 ml, n = 9) compared with that in pregnancies without such problems (957 +/- 188 ml, n = 16). These findings indicate an impact of fetal hyperinsulinism on the functional maturation of the fetus. When the patients were subgrouped according to the presence or absence of detectable maternal plasma CPR, i.e. greater than 0.05 nmol/l, and to insulin dependent and gestational diabetes no differences of AF volumes, AF concentrations of CPR or total AF contents of CPR were found.

Topics: Amniotic Fluid; Birth Weight; Blood Glucose; Body Weight; C-Peptide; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Peptides; Pregnancy; Pregnancy in Diabetics

A new modification of pancreas transplant technique, the vascularized segmental intraperitoneal graft without duct ligation, has provided reversal of insulin-dependent (type I) diabetes mellitus for as long as 2 years of comfortable life. Although the risks associated with immunosuppression remain high (two of the 12 patients have died of early postoperative infection), selected data are presented from six cases to show the following striking hormonal and metabolic results after transplantation and withdrawal of insulin: restoration of normal beta cell function as shown by 24-hour urine C-peptide excretion and acutely responsive serum insulin, restoration of normal suppressibility of plasma glucagon, elimination of ketosis and negative nitrogen balance, normal fasting plasma glucose and glycosylated hemoglobin, and normal or near-normal glucose tolerance. These results provide a standard for current explorations of new ways of treating insulin-dependent diabetes.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Glucagon; Hormones; Humans; Hydroxybutyrates; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Urea

Infants with transient neonatal diabetes mellitus are small for gestational age and fail to thrive postnatally unless insulin is administered. We have measured the concentrations of insulin-related growth factors in an infant girl with this condition to learn if deficiencies in one or more of these factors could be responsible for the impaired growth. Cord blood serum radioimmunoassayable insulin and somatomedin C/insulin-like growth factor I (SMC/IGF-I) were low, but insulin-like growth factor II (IGF-II) measured by a specific radioreceptor assay was normal. Insulin therapy begun on the fourth day of life resulted in a prompt increase in weight and a delayed rise in SMC/IFG-I. No significant changes in IGF-II were observed. After 2.5 months, insulin treatment was discontinued. At that time, endogenous insulin secretion was documented by increased urinary C-peptide. Normal growth and SMC/IFG-I levels persisted. We conclude that growth failure in this condition may be related not only to a lack of insulin but also to SMC/IGF-I deficiency. A deficiency in IGF-II is not involved.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Small for Gestational Age; Insulin; Insulin Secretion; Insulin-Like Growth Factor I; Peptides; Somatomedins

In a previous study we determined the glucose disappearance rate (kt) in 129 newborn large-for-dates infants (LFD) born to mothers without known diabetes. Twenty-six infants (i.e. 20.6%) had elevated kt values similar to those in offspring of diabetic mothers. A follow-up study of 123 of these mothers was performed 7 years after delivery and included determination of early insulin and C-peptide response to intravenous glucose, plasma concentrations of 3-hydroxybutyrate, cholesterol, triglycerides, lipoproteins and HLA-typing. Two subjects had developed diabetes and altogether 14% had a kt below 1.0. Measures of the early insulin and C-peptide response to glucose were equally well correlated to maternal kt values (r = 0.40, P less than 0.001). Measures of the early insulin and C-peptide responses were significantly correlated (r = 0.64, P less than 0.001). The frequency distribution of HLA antigens were not different from normal and there was no association between HLA-B8 or B15 and impaired insulin response or glucose tolerance. Multiple regression and discriminate analysis of clinical and biochemical variables could not accurately identify women with high or low kt values. Multiple regression analysis using infant kt value as the dependent variable disclosed only a weak, but significant, inverse association to maternal insulin response to glucose at follow-up.

Topics: Adult; Birth Weight; Blood Glucose; Body Weight; C-Peptide; Female; Follow-Up Studies; Glucose Tolerance Test; HLA Antigens; Humans; Infant, Newborn; Insulin; Lipids; Peptides; Pregnancy

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

Nine of ten non-obese non-ketotic diabetics attending Port Moresby General Hospital had detectable C-peptide in plasma. All had received insulin for at least two months at the time of study. It is concluded that many non-obese non-ketotic young diabetics in Papua New Guinea retain pancreatic insulin secretion and so resemble the maturity onset diabetics of "Western" countries.

Topics: Adolescent; Adult; Body Weight; C-Peptide; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Insulin; Insulin Secretion; Male; New Guinea

Diabetes is an endocrine deficiency disease, a logical treatment of which is hormone replacement therapy. Many patients who are thought to be controlled by diet alone continue to have high plasma-glucose levels. As the rise in the basal plasma glucose concentration is the predominant glucose abnormality of diabetes, treatment should be aimed primarily at producing basal normoglycaemia. 18 mild, maturity onset diabetics have been treated with a basal insulin supplement provided by single daily injections of insulin zinc suspension (crystalline) 'Ultralente'. Overnight basal normoglycaemia has been obtained with markedly reduced plasma-glucose levels during the day. Plama-triglyceride levels have become normal in most patients. The required insulin dose need not be determined empirically, but can be calculated from the basal plasma-glucose level and the degree of obesity. There is minimum risk of hypoglycaemia, and rigid dietary restriction is unnecessary. As mild diabetics are prone to complications, treatment with basal insulin supplements may be beneficial when diet alone fails to produce basal normoglycaemia.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Circadian Rhythm; Diabetes Mellitus; Diet, Diabetic; Follow-Up Studies; Humans; Injections, Subcutaneous; Insulin, Long-Acting; Middle Aged; Obesity; Triglycerides

The effect of somatostatin on plasma C-peptide immunoreactivity was studied in seven normal men following an intravenous 25 g glucose load. No elevation in plasma insulin was observed and similarly no rise in plasma C-peptide immunoreactivity occurred, indicating that somatostatin inhibits glucose-induced C-peptide release as well as insulin release.

Topics: Blood Glucose; Body Weight; C-Peptide; Glucose; Humans; Insulin; Male; Middle Aged; Peptides; Radioimmunoassay; Somatostatin