Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range

OBJECTIVE - To assess the contribution of decreased glucose clearance to the rise in fasting plasma glucose (FPG) in the nondiabetic range. RESEARCH DESIGN AND METHODS - A total of 120 subjects with normal glucose tolerance received an oral glucose tolerance test and euglycemic insulin clamp with 3-[³H]glucose. The basal and insulin-stimulated rates of glucose appearance, glucose disappearance, and glucose clearance and the basal hepatic insulin resistance index were calculated. Simple Pearson's correlation was used to assess the relationship between variables. RESULTS - The increase in FPG (range 75-125 mg/dl) correlated (r = 0.32, P < 0.0001) with the increase in BMI (20-50 kg/m²). The fasting plasma insulin (FPI) concentration also increased progressively with the increase in BMI (r = 0.62, P < 0.0001). However, despite increasing FPI, the basal glucose clearance rate declined and correlated with the increase in BMI (r = -0.56, P < 0.0001). Basal hepatic glucose production (HGP) decreased with increasing BMI (r = -0.51, P < 0.0001) and correlated inversely with the increase in FPI (r = -0.32, P < 0.0001). The hepatic insulin resistance (basal HGP x FPI) increased with rising BMI (r = 0.52, P < 0.0001). During the insulin clamp, glucose disposal declined with increasing BMI (r = -0.64, P < 0.0001) and correlated with the basal glucose clearance (r = 0.39, P < 0.0001). CONCLUSIONS - These results demonstrate that in nondiabetic subjects, rising FPG is associated with a decrease (not an increase) in basal hepatic glucose production and is explained by a reduction in glucose clearance.