Absence of an acute insulin response predicts onset of type 2 diabetes in a Caucasian population with impaired glucose tolerance

Context: In persons with impaired glucose tolerance (IGT), both impaired insulin secretion and insulin resistance contribute to the conversion to type 2 diabetes mellitus (T2DM). However, few studies have used criterion standard measures to asses the predictive value of impaired insulin secretion and insulin resistance for the conversion to T2DM in a Caucasian IGT population. Objectives: The objective of the study was to determine the predictive value of measures of insulin secretion and insulin resistance derived from a hyperglycemic clamp, including the disposition index, for the development of T2DM in a Caucasian IGT population. Design, Setting, and Participants: The population-based Hoorn IGT study consisted of 101 Dutch IGT subjects (aged < 75 yr), with mean 2-h plasma glucose values, of two separate oral glucose tolerance tests, between 8.6 and 11.1 mmol/liter. A hyperglycemic clamp at baseline was performed to assess first-phase and second-phase insulin secretion and insulin sensitivity. During follow-up, conversion to T2DM was assessed by means of 6-monthly fasting glucose levels and yearly oral glucose tolerance tests. Results: The cumulative incidence of T2DM was 34.7%. Hazard ratio for T2DM development adjusted for age, sex, and body mass index was 5.74 [95% confidence interval (CI) 2.60-12.67] for absence of first insulin peak, 1.58 (95% CI 0.60-4.17) for lowest vs. highest tertile of insulin sensitivity, and 1.78 (95% CI 0.65-4.88) for lowest vs. highest tertile of the disposition index. Conclusions: In these Caucasian persons with IGT, the absence of the first insulin peak was the strongest predictor of T2DM. Copyright © 2008 by The Endocrine Society

Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents

BACKGROUND: Insulin resistance is the best predictor for the development of type 2 diabetes. Recent studies have shown that young, lean, insulin-resistant (IR) offspring of parents with type 2 diabetes have reduced basal rates of muscle mitochondrial phosphorylation activity associated with increased intramyocellular lipid (IMCL) content, which in turn blocks insulin signaling and insulin action in muscle. In order to further characterize mitochondrial activity in these individuals, we examined insulin-stimulated rates of adenosine triphosphate (ATP) synthesis and phosphate transport in skeletal muscle in a similar cohort of participants. METHODS AND FINDINGS: Rates of insulin-stimulated muscle mitochondrial ATP synthase flux and insulin-stimulated increases in concentrations of intramyocellular inorganic phosphate (P(i)) were assessed by (31)P magnetic resonance spectroscopy (MRS) in healthy, lean, IR offspring of parents with type 2 diabetes and healthy, lean control participants with normal insulin sensitivity. IMCL content in the soleus muscle of all participants was assessed by (1)H MRS. During a hyperinsulinemic-euglycemic clamp, rates of insulin-stimulated glucose uptake were decreased by approximately 50% in the IR offspring compared to the control participants (p = 0.007 versus controls) and were associated with an approximately 2-fold increase in IMCL content (p < 0.006 versus controls). In the control participants rates of ATP synthesis increased by approximately 90% during the hyperinsulinemic-euglycemic clamp. In contrast, insulin-stimulated rates of muscle mitochondrial ATP synthesis increased by only 5% in the IR offspring (p = 0.001 versus controls) and was associated with a severe reduction of insulin-stimulated increases in the intramyocellular P(i) concentrations (IR offspring: 4.7% ± 1.9% versus controls: 19.3% ± 5.7%; p = 0.03). Insulin-induced increases in intramyocellular P(i) concentrations correlated well with insulin-stimulated increases in rates of ATP synthesis (r = 0.67; p = 0.008). CONCLUSIONS: These data demonstrate that insulin-stimulated rates of mitochondrial ATP synthesis are reduced in IR offspring of parents with type 2 diabetes. Furthermore, these IR offspring also have impaired insulin-stimulated phosphate transport in muscle, which may contribute to their defects in insulin-stimulated rates of mitochondrial ATP synthesis

Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Background/Aims: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-gamma transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. Methods: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. Results: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm(2) to 475/mm(2) in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3 alpha and PPAR coactivator-1 alpha (PGC-1 alpha) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. Conclusion: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis. Copyright (C) 2012 S. Karger AG, Base

Hyperinsulinemia is associated with menstrual irregularity and altered serum androgens in Pima Indian women

To determine whether hyperinsulinemia is associated with menstrual irregularity or hyperandrogenemia among Pima Indians, a population with a high prevalence of hyperinsulinemia, we retrospectively studied 20 hyperinsulinemic (higher insulin [HI]) and 20 relatively nonhyperinsulinemic (lower insulin [LI]) nondiabetic Pima women 18 to 45 years of age. Reproductive histories were obtained by review of medical records. Stored serum samples were used for measurement of total testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) levels. Fifty percent (nine of 18) of HI women had irregular menses, as compared with none of the LI women (0 of 19, P = .0004). HI women were significantly more obese than LI women. Serum testosterone and androstenedione levels were similar in HI and LI women (median testosterone, 1.13 v 1.13 nmol/L, P = .55; median androstenedione, 3.79 v 3.26 nmol/L, P = .90). Serum DHEAS was lower in HI than in LI women (median, 2.85 v 4.55 [mu]mol/L, P v 0.76, nmol/L, P = .04). Androstenedione and DHEAS levels were not different between these women. In conclusion, the association of obesity, hyperinsulinemia, irregular menstruation, and high testosterone concentration described in the polycystic ovarian syndrome (PCO) also occurs in Pima Indian women. Moreover, low concentrations of DHEAS are associated with hyperinsulinemia in these women.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31484/1/0000406.pd

Ethnicity Modifies the Relationships of Insulin Resistance, Inflammation, and Adiponectin With Obesity in a Multiethnic Asian Population

10.2337/dc10-2097Diabetes Care3451120-1126DICA