Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes.

OBJECTIVE: Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness. RESEARCH DESIGN AND METHODS: In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced VO(2max), measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n = 424) and measured by a euglycemic-hyperinsulinemic clamp (n = 185). Subjects included in the study were young (34 +/- 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n = 183), a second-degree relative with T2DM (n = 94), or no family history of T2DM (control subjects, n = 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). RESULTS: BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P = 0.76). The appropriateness of beta-cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 +/- 4 units) versus control subjects (104 +/- 6 units, P = 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results. CONCLUSIONS: In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced VO(2max) precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature.

Acute effect of glimepiride on insulin-stimulated glucose metabolism in glucose-tolerant insulin-resistant offspring of patients with type 2 diabetes.

OBJECTIVE: This study addressed whether acute infusion of glimepiride influences glucose metabolism independent of its effect on insulin secretion. RESEARCH DESIGN AND METHODS: Ten healthy, glucose-tolerant but insulin-resistant probands were subjected to a placebo-controlled, double-blind, cross-over study. Each individual received infusions of either 0.15 mol/l saline or glimepiride in randomized order on two separate occasions. A three-step hyperinsulinemic (0.5, 1.0, and 1.5 mU. kg(-1). min(-1))-euglycemic glucose clamp was performed on both occasions to determine insulin sensitivity. Glimepiride-induced insulin secretion was inhibited by octreotide. Endogenous glucose production and glucose elimination were measured with the "hot" glucose infusion method using U-[(13)C]glucose as tracer. Glucose oxidation was determined from indirect calorimetry. Lipolysis was evaluated by measurements of nonesterified fatty acid (NEFA) and glycerol concentration and measurement of glycerol production. RESULTS: Plasma glucose and insulin concentrations were not significantly different between glimepiride or saline infusions. There was a significant increase in the rate of glucose infusion necessary to maintain euglycemia during infusion of glimepiride during the low- (12.2 +/- 1.1 vs. 16.1 +/- 1.7 micro mol. kg(-1). min(-1)) and intermediate-dose insulin infusion (24.4 +/- 1.7 vs. 30.0 +/- 2.8 micro mol. kg(-1). min(-1)). This was explained by an increased rate of glucose elimination and to a lesser degree by a decrease in glucose production. Glucose oxidation rate was not different. NEFA and glycerol concentration and glycerol production were equally suppressed. CONCLUSIONS: Glimepiride improves peripheral glucose uptake and decreases endogenous glucose production independent of its insulin secretagogue action. The effects shown in this acute study are, however, too small to be considered therapeutically beneficial for the individual patient.