Metabolic fate of plasma glucose during hyperglycemia in impaired glucose tolerance: evidence for further early defects in the pathogenesis of type 2 diabetes

摘要

We examined the intracellular metabolic fate of plasma glucose during a hyperglycemic clamp in impaired glucose-tolerant (IGT; n = 21) and normal glucose-tolerant subjects (n = 10) using a combination of [3-3H]glucose infusion with measurement of [3H]water formation and indirect calorimetry. IGT was associated with <35% reduced first-phase insulin responses, normal second-phase insulin response, and 2530% reduced insulin sensitivity, resulting in <35% reduced plasma glucose disposal. This was coupled with <55% reduced storage of plasma glucose (P < 0.01) and <1520% reduced glycolysis of plasma glucose (P < 0.03), accounting for <75 and 25% of the reduction in glucose disposal, respectively. Decreased glucose oxidation accounted for virtually all the decrease in glycolysis. Therefore, nonoxidative glycolysis of plasma glucose in IGT was similar to that in NGT (P > 0.9) and accounted for an increased proportion of systemic glucose disposal (P < 0.05). We conclude that, in IGT, decreased disposal of plasma glucose involves mainly decreased glycogen synthesis and to a lesser extent decreased glycolysis, which is accounted for by decreased glucose oxidation. An increased proportion of plasma glucose hence undergoes nonoxidative glycolysis, representing a novel early abnormality in the pathogenesis of T2DM.