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: <or=90, >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.