Declining β-Cell Function Relative to Insulin Sensitivity With Increasing Fasting Glucose Levels in the Nondiabetic Range in Children

OBJECTIVE In adults, higher fasting plasma glucose (FPG) levels, even within the normoglycemic range, are associated with increased diabetes risk. This investigation tested the hypothesis that beta-cell function relative to insulin sensitivity decreases with increasing FPG in youth. RESEARCH DESIGN AND METHODS A total of 223 youth with FPG <126 mg/dl underwent evaluation of first- and second-phase insulin secretion during a 2-h hyperglycemic (approximately 225 mg/dl) clamp, insulin sensitivity during a 3-h hyperinsulinemic-euglycemic clamp, body composition, and abdominal adiposity with dual-energy X-ray absorptiometry and computed tomographic scan. beta-Cell function relative to insulin sensitivity was calculated as the product of first-phase insulin and insulin sensitivity, i.e., glucose disposition index (GDI). The subjects were divided into three FPG categories: 90-<100, and >or=100-<126 mg/dl. RESULTS GDI decreased significantly across the three categories as FPG increased (1,086 +/- 192 vs. 814 +/- 67 and 454 +/- 57 mg/kg/min, P = 0.002). This decline remained significant after adjustment for race, sex, BMI, and percent body fat or visceral fat. Within each FPG category, GDI declined with increasing BMI percentiles. CONCLUSIONS The impairment in beta-cell function relative to insulin sensitivity is apparent even within the nondiabetic FPG range in children. At the current cutoff of 100 mg/dl for impaired fasting glucose (IFG), there is an approximately 49% decline in the GDI independent of obesity and race. This observation may reflect a heightened risk of beta-cell dysfunction and progression to diabetes in these children. Considering the near doubling of IFG prevalence among youth between National Health and Nutrition Examination Survey 1999-2000 and 2005-2006, our findings have important public health implications.