Plasma Adiponectin Levels in High Risk African‐Americans with Normal Glucose Tolerance,Impaired Glucose Tolerance,and Type 2 Diabetes**

Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African‐American patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C‐peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment‐insulin resistance index (HOMA‐IR) and HOMA‐β cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA‐IR < 2.68 and insulin resistance as HOMA‐IR > 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA‐IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2‐fold greater (11.09 ± 4.98 vs. 6.42 ± 3.3811 μg/mL) in insulin‐sensitive (HOMA‐IR, 1.74 ± 0.65) than in insulin‐resistant (HOMA‐IR, 5.12 ± 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin‐resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA‐IR (r = ?0.502, p = 0.046) and with HOMA‐β cell function (r = ?0.498, p = 0.042) but not with the percentage body fat (r = ?0.368, p = 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin‐resistant, non‐diabetic first degree relatives of African‐American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African‐American relatives before development of IGT and type 2 diabetes.     

Type II diabetes of early onset: a distinct clinical and genetic syndrome?

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.     

Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes

AIMS/HYPOTHESIS: Since insulin secretion in response to exogenous gastric inhibitory polypeptide (GIP) is diminished not only in patients with type 2 diabetes, but also in their normal glucose-tolerant first-degree relatives, it was the aim to investigate the integrity of the entero-insular axis in such subjects. METHODS: Sixteen first-degree relatives of patients with type 2 diabetes (4 male, 12 female, age 50+/-12 years, BMI 26.1+/-3.8 kg/m(2)) and 10 matched healthy controls (negative family history, 6 male, 4 female, 45+/-13 years, 26.1+/-4.2 kg/m(2)) were examined with an oral glucose load (75 g) and an "isoglycaemic" intravenous glucose infusion. Blood was drawn over 240 min for plasma glucose (glucose oxidase), insulin, C-peptide, GIP and glucagon-like peptide 1 (GLP-1; specific immunoassays). RESULTS: The pattern of glucose concentrations could precisely be copied by the intravenous glucose infusion (p=0.99). Insulin secretion was stimulated significantly more by oral as compared to intravenous glucose in both groups (p<0.0001). The percent contribution of the incretin effect was similar in both groups (C-peptide: 61.9+/-5.4 vs. 64.4+/-5.8%; p=0.77; insulin: 74.2+/-3.3 vs. 75.8+/-4.9; p=0.97; in first-degree relatives and controls, respectively). The individual responses of GIP and GLP-1 secretion were significantly correlated with each other (p=0.0003). The individual secretion of both GIP and GLP-1 was identified as a strong predictor of the integrated incremental insulin secretory responses as well as of the incretin effect. CONCLUSION/INTERPRETATION: Despite a lower insulin secretory response to exogenous GIP, incretin effects are similar in first-degree relatives of patients with type 2 diabetes and control subjects. This may be the result of a B cell secretory defect that affects stimulation by oral and intravenous glucose to a similar degree. Nevertheless, endogenous secretion of GIP and GLP-1 is a major determinant of insulin secretion after oral glucose.     

Family history of diabetes mellitus determines insulin sensitivity and beta cell function in polycystic ovary syndrome

Objective: To examine the impact of family history of diabetes mellitus 2 (DM 2) on insulin sensitivity and secretion in lean women with polycystic ovary syndrome (PCOS). Thirteen healthy women (C), 14 PCOS without family history of DM 2 (FH-) and 8 PCOS with family history of DM 2 (FH+) were examined using euglycemic hyperinsulinemic clamp and an arginine secretion test (insulin and glucagon at fasting glycemia (AIR(FG) and AGR(FG)) and at hyperglycemia (AIR(14) and AGR(14)). FH+ women were more insulin resistant than FH- with lower insulin sensitivity index corrected per lean body mass (p 0.05). They had significantly higher triglycerides (p 0.05) and lower HDL-cholesterol (p 0.05) than C or FH- women. Concerning insulin secretion, AIR(FG) was increased in FH+ women comparing FH- women (p 0.05). Disposition indices derived from AIR(FG) or AIR(14) and insulin sensitivity index did not differ between FH+ or FH-. Thus, women with PCOS with the concomitant family history of DM 2 have lower insulin sensitivity than healthy control women. Insulin resistance observed in these women with PCOS is compensated by increased insulin secretion.     

Association between Family History Risk Categories and Prevalence of Diabetes in Chinese Population

AimTo investigate the association between different family history risk categories and prevalence of diabetes in the Chinese population.MethodsThe family history of diabetes was obtained from each subject, and an oral glucose tolerance test was performed for measuring the fasting and postload glucose and insulin levels based on a national representative cross-sectional survey of 46,239 individuals (age ≥ 20 years) in the 2007–2008 China National Diabetes and Metabolism Disorders Study. The family history risk categories of diabetes were high, moderate, and average (FH2 and FH1: at least two generations and one generation of first-degree relatives with diabetes, respectively; FH0: no first-degree relatives with diabetes).ResultsThe age- and gender-adjusted prevalence rates of diabetes were 32.7% (95% confidence interval (CI): 26.4–39.7%) in FH2, 20.1% (95% CI: 18.2–22.1%) in FH1, and 8.4% (95% CI: 7.9–8.9%) in FH0 (P < 0.0001). The calculated homeostatic model assessment-estimated insulin resistance (HOMA-IR), Matsuda insulin sensitivity index (ISI), and insulinogenic index (ΔI30/ΔG30) values showed significant trending changes among the three risk categories, with the most negative effects in FH2. Multivariate logistic regression analysis showed that the odds ratios of having diabetes were 6.16 (95% CI: 4.46–8.50) and 2.86 (95% CI: 2.41–3.39) times higher in FH2 and FH1, respectively, than in FH0 after adjustment for classical risk factors for diabetes.ConclusionsFamily history risk categories of diabetes have a significant, independent, and graded association with the prevalence of this disease in the Chinese population.     

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

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

Impact of exercise training on insulin sensitivity, physical fitness, and muscle oxidative capacity in first-degree relatives of type 2 diabetic patients

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

Leptin levels in type 2 diabetes: associations with measures of insulin resistance and insulin secretion.

Interactions between leptin and insulin have been shown previously, in vitro and in vivo. In this study, we evaluate the associations of leptin levels with insulin secretion and insulin sensitivity in type 2 diabetes. Fasting leptin levels, HbA 1c, glucose, insulin, C-peptide, intact and des-31,32-proinsulin were measured in 100 non-insulin-treated type 2 diabetic patients. Glucose, insulin and C-peptide were measured 2 hours after an oral glucose load. Insulin resistance and beta-cell function were calculated using HOMA. Leptin levels were found to be associated with all measures of beta-cell secretion: with fasting and 2 hours insulin and C-peptide, with intact and des-31,32-proinsulin concentrations, and with beta-cell secretion estimated with HOMA. This association was independent of age and body fat in women, but in men, associations with insulin and C-peptide weakened after controlling for fat mass, whereas those with intact and des-31,32-proinsulin disappeared. Fasting insulin and C-peptide levels were also significant in multiple regression analyses, besides gender and fat mass. Insulin resistance, as assessed by HOMA, was strongly correlated with leptin, also after correction for age and fat mass in both genders. We conclude that, besides fat mass and gender - the main determinants for leptin levels in type 2 diabetic subjects as in healthy subjects - insulin secretion and the degree of insulin resistance also seem to contribute significantly to leptin levels.     

Effect of cyproheptadine administration on insulin secretion in acromegalic, diabetic and normal subjects.

The effect of cyproheptadine (Cypro) and Placebo administration on insulin secretion and glucose utilization following i.v. glucose (IVGTT) was evaluated in 8 normal, 7 diabetic and 8 acromegalic subjects. Five of the diabetic subjects had overt diabetes and two of the diabetic subjects had "chemical" diabetes (oral GTT). One of the acromegalic subjects had overt diabetes, while one had borderline glucose tolerance and six had normal glucose tolerance (oral GTT). Cypro increased insulin secretion in the acromegalic but not in the diabetic or normal subjects. Methysergide (Methyl) increased insulin secretion in acromegalic and diabetic subjects but not in normal subjects. Methy and Cypro both increased insulin secretion in the same acromegalic subjects. None of the three groups of subjects had a modification in insulin secretion following Placebo administration. Neither Placebo, Cypro or Methy altered the glucose utilization rate contant (KG). There was no change in insulin half life or tissue sensitivity to insulin from Cypro (normal and acromegalic subjects) or Methy (normal subjects) administration. Despite their increase in insulin secretion in response to serotonin antagonists, acromegalic subjects have normal urinary 5-hydroxyindoleacetic acid excretion and normal serum serotonin concentrations. Their response cannot therefore be attributed to a generalized overproduction of serotonin.     

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty‐one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA‐IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([ΔI5/ΔG5]/HOMA‐IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol², P < 0.001). One month following BPD, in both groups BW was reduced (by ～11%), but all subjects were still severely obese; HOMA‐IR and leptin decreased significanlty, while high‐molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non‐diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.     

Improved indices of insulin resistance and insulin secretion for use in genetic and population studies of type 2 diabetes mellitus.

Homeostasis model assessment (HOMA) provides indices of insulin secretion (beta) and insulin resistance (R) derived from fasting plasma glucose (FPG) and fasting plasma insulin (FPI) levels. However, these indices could not account for a significant heritability of fasting plasma glucose (FPG) (h2 = 0.75, P<0.01) in a group of 214 female twins. This result is consistent with a misclassification between effects due to insulin secretion and resistance in the HOMA indices. We report here evidence of such misclassification in the HOMA indices and describe a minor modification to the model which corrects it. Direct measures of insulin resistance (euglycaemic clamp) and secretion (i.v. glucose bolus) were obtained in 43 non-diabetic subjects. Heritability was estimated by statistical modelling of genetic and environmental influences in data from 214 non-diabetic female subjects. Modified HOMA (HOMA') indices were obtained from beta' = (Ln(FPI) - c)/FPG and R' = (Ln(FPI) - c)*FPG where c is a constant derived from regression analysis of Ln(FPI) vs FPG. Indices from both models correlated with the direct measures similarly (r = 0.63 (R), 0.49 (R'), 0.45 (beta), 0.39 (beta'), all P< 0.01). Directly measured insulin resistance and secretion were not significantly correlated (r = 0.13, P = 0.21). However, unmodified HOMA-beta and R were strongly related (r = 0.78, P<0.0001 vs. 0.13) demonstrating substantial misclassification. The relationship between beta' and R' (r = 0.13) was not different from that between the two direct measures and significant heritability of beta' (h2 = 0.68, P<0.01) and R' (h2 = 0.59, P<0.05) was evident in the twin data. The proposed modification to HOMA significantly reduces misclassification and reveals separate components of insulin resistance and insulin secretion in the heritability of FPG.     

Impaired non-esterified fatty acid suppression is associated with endothelial dysfunction in insulin resistant subjects.

In a recent study, we found a significant association between insulin resistance (IR) and disturbed flow-associated (endothelial-dependent) vasodilation in first-degree relatives of subjects with type 2 diabetes. However, the mechanisms linking insulin resistance and endothelial dysfunction (ED) have not been fully elucidated. Experimental data have pointed out that non-esterified fatty acids (NEFA) have a modulating effect on NO-synthase activity, and therefore on endothelial function. The aim of our study was to evaluate whether insulin resistance associated impaired NEFA suppression is present in subjects with ED. We examined 53 first-degree relatives (FDR) of patients with type 2 diabetes (32f, 21 m, mean age 35 years). Endothelial function was measured as flow-associated vasodilation (FAD%) of the brachial artery. Insulin sensitivity was evaluated with a standard hyperinsulinemic glucose clamp (insulin infusion rate of 1 mU/kg/min). While under fasting conditions, NEFA did not differ between groups with high or low FAD (0.415+/-0.033 vs. 0.394 +/- 0.040 mmol/l; p = n. s.), reduced FAD% was significantly associated with higher non-esterified fatty acids concentrations during steady state of the glucose clamp (0.072+/-0.022 vs. 0.039+/-0.016mmol/l; p=0.04). This association was independent of insulin levels under fasting conditions and during the glucose clamp. In conclusion, our results reveal a significant association between endothelial dysfunction and impaired non-esterified fatty acid suppression in insulin resistant subjects. As insulin resistance of lipolysis is a feature of the insulin resistance syndrome, these results suggest that elevated NEFA concentrations could play a role linking endothelial dysfunction and insulin resistance in vivo.     

Insulin and C-peptide secretion and kinetics in humans: direct and model-based measurements during OGTT

To directly evaluate prehepatic secretion of pancreatic hormones during a 3-h oral glucose tolerance test (OGTT), we measured insulin and C-peptide in six healthy control, six obese, and six type 2 diabetic subjects in the femoral artery and hepatic vein by means of the hepatic catheterization technique. Hypersecretion in obesity was confirmed (309 +/- 66 nmol in obese vs. 117 +/- 22 in control and 79 +/- 13 in diabetic subjects, P 0.3, r(2) = 0.93), whereas estimation of hepatic insulin extraction and insulin clearance needs further investigation for improvement.     

Insulin Sensitivity,Body Fat Distribution,and Family Diabetes History: The IRAS Family Study

Objectives : Markers of insulin resistance are often apparent in nondiabetic relatives of subjects with type 2 diabetes. Whether diabetes family history (FH) also predicts visceral fat accumulation and, if so, whether the increased insulin resistance in relatives of diabetic subjects occurs independently of visceral fat accumulation are not known. Research Methods and Procedures : To examine this issue, we studied the relationship of diabetes FH with insulin sensitivity and fat measures, measured by minimal model analysis and computed tomography, respectively, in families participating in the Insulin Resistance Atherosclerosis (IRAS) Family Study. FH scores were based on the diabetes status of the participants’ parents and older siblings. Results : FH scores were significantly correlated with reduced insulin sensitivity (p < 0.05) and increased subcutaneous (p < 0.05) and visceral (p < 0.05, San Antonio only) fat in families from San Antonio and Los Angeles but not in the leaner Hispanic families from San Luis Valley. There was no evidence for a stronger association of FH score with visceral fat accumulation than with subcutaneous fat or insulin resistance. Discussion : The absence of an association between FH score and insulin resistance/fat accumulation in San Luis Valley is consistent with the idea that the expression of transmitted diabetes genes may be suppressed in leaner, more physically active populations.     

Distribution of vasoactive intestinal polypeptide, neuropeptide-Y and substance P and their effects on insulin secretion from the in vitro pancreas of normal and diabetic rats

This study examined the pattern of distribution of vasoactive intestinal polypeptide (VIP), neuropeptide-Y (NPY) and substance P (SP) in the pancreas of diabetic rat to determine whether there are changes in the number and pattern of distribution of these neuropeptides after the onset of diabetes. Moreover, the effect of VIP, NPY and SP on insulin secretion from the pancreas of normal and diabetic rats was also examined. Diabetes mellitus (DM) was induced by a single dose of streptozotocin (STZ) given intraperitoneally (i.p.) (60 mg kg body weight(-1)). Four weeks after the induction of DM, diabetic (n = 6) and normal (n = 6) rats were anesthetized with chloral hydrate and their pancreases removed and processed for immunohistochemistry and insulin secretion. The number of insulin-positive cells in the islets of Langerhans was reduced while that of VIP and NPY increased significantly after the onset of diabetes. The pattern of distribution of VIP, NPY and SP in the nerves innervating the pancreas was similar in both normal and diabetic rats. VIP-evoked large and significant (P < 0.02) increases in insulin secretion from the pancreas of normal and diabetic rats. NPY also induced a marked (P < 0.005) increase in insulin release from pancreatic tissue fragments of normal rat. Stimulation of pancreatic tissue fragments of diabetic rat with NPY resulted in a slight but not significant increase in insulin release. SP induced a large and significant (P < 0.005) increase in insulin secretion from the pancreas of normal rat but inhibited insulin secretion significantly (P < 0.03) from isolated pancreas of diabetic rat. In summary, VIP and NPY can stimulate insulin secretion from the pancreas after the onset of diabetes. The stimulatory effect of SP on insulin secretion is reversed to inhibitory in diabetic rats.     

Effect of glycine on insulin secretion and action in healthy first-degree relatives of type 2 diabetes mellitus patients.

The aim of this study was to identify the effect of glycine on insulin secretion and action in healthy first-degree relatives of Type 2 diabetes mellitus patients. A randomized, double-blind, placebo-controlled clinical trial was performed in 12 healthy, non-obese volunteers who were first-degree relatives of Type 2 diabetes mellitus patients. Six volunteers received a morning dose of glycine 5 g orally and the other six received placebo. At baseline without drugs and after pharmacological intervention, a metabolic profile and, to assess insulin secretion and action, a hyperglycemic-hyperinsulinemic clamp study were performed. There were no significant differences in baseline metabolic profile, insulin secretion or action between groups. Changes from baseline of early (p < 0.05), late (p < 0.05), and total insulin (p < 0.02) responses were higher in the glycine group than in controls. There were no significant differences in the changes from baseline of insulin action between groups. In conclusion, a morning dose of glycine 5 g orally increased early, late and total insulin responses without changes in insulin action in healthy first-degree relatives of Type 2 diabetes mellitus patients.     

Characterization of beta-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests

To investigate early secretory defects in prediabetes, we evaluated beta-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. beta-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 +/- 6 vs. 87 +/- 6 pmol x min(-1) x m(-2), P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, rho = -0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5 x M1.23), compensation for insulin resistance was impaired in FDR (10.8 +/- 1.0 vs. 13.4 +/- 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 +/- 0.08 vs. 1.62 +/- 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters (P < 0.05 or less). beta-Cell function parameters were also related to mean 24-h glucose levels (r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, beta-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a beta-cell defect in the amplifying pathway of insulin secretion.     

Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP

Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance (n=14) had as many L cells (15+/-1), expressed per 1,000 gut epithelial cells, as K cells (13+/-1), with some containing both hormones (L/K cells, 5+/-1). In type 2 diabetes, the number of L and L/K cells was increased (26+/-2; P<0.001 and 9+/-1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype.     

Association of low birth weight with beta cell function in the adult first degree relatives of non-insulin dependent diabetic subjects.

OBJECTIVE--To examine the relation between birth weight and beta cell function in the first degree relatives of non-insulin dependent diabetic subjects. DESIGN--Cross sectional study of 101 adults of known birth weight from 47 families which had at least one member with non-insulin dependent diabetes. SUBJECTS--101 white adults aged mean 43 (SD 7) years. SETTING--Oxfordshire, England. MAIN OUTCOME MEASURES--Glucose tolerance was measured by continuous infusion glucose tolerance test. beta cell function and insulin sensitivity were calculated from the fasting plasma glucose and insulin concentrations with homeostasis model assessment. beta cell function was standardised to allow for the confounding effects of age and obesity. RESULTS--Twenty seven subjects had non-insulin dependent diabetes, 32 had impaired glucose tolerance, and 42 were normoglycaemic. Birth weight correlated with the beta cell function of the complete cohort (rs = 0.29, p = 0.005), the non-insulin dependent diabetic subjects (rs = 0.50, p = 0.023), and the non-diabetic subjects (rs = 0.29, p = 0.013). The non-insulin dependent diabetic (n = 27) and the non-diabetic (n = 74) subjects had similar mean (inter-quartile range) centile birth weight 50% (19%-91%), and 53% (30%-75%) respectively. Non-insulin dependent diabetic subjects had significantly lower beta function than the non-diabetic subjects: 69% (48%-83%) v 97% (86%-120%), p < 0.001. CONCLUSIONS--The cause of the association between low birth weight and reduced beta cell function in adult life is uncertain. Impaired beta cell function in non-insulin dependent diabetic subjects was not accounted for by low birth weight, and genetic or environmental factors are likely to be necessary for development of diabetes.     

Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training

Recent findings have indicated that creatine supplementation may affect glucose metabolism. This study aimed to examine the effects of creatine supplementation, combined with aerobic training, on glucose tolerance in sedentary healthy male. Subjects (n = 22) were randomly divided in two groups and were allocated to receive treatment with either creatine (CT) ( approximately 10 g . day over three months) or placebo (PT) (dextrose). Administration of treatments was double blind. Both groups underwent moderate aerobic training. An oral glucose tolerance test (OGTT) was performed and both fasting plasma insulin and the homeostasis model assessment (HOMA) index were assessed at the start, and after four, eight and twelve weeks. CT demonstrated significant decrease in OGTT area under the curve compared to PT (P = 0.034). There were no differences between groups or over time in fasting insulin or HOMA. The results suggest that creatine supplementation, combined with aerobic training, can improve glucose tolerance but does not affect insulin sensitivity, and may warrant further investigation with diabetic subjects.