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

Department of Endocrinology, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona Submitted 11 June 2008 ; accepted in final form 4 January 2009 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- 3 H]glucose infusion with measurement of [ 3 H]water formation and indirect calorimetry. IGT was associated with 35% reduced first-phase insulin responses, normal second-phase insulin response, and 25–30% reduced insulin sensitivity, resulting in 35% reduced plasma glucose disposal. This was coupled with 55% reduced storage of plasma glucose ( P < 0.01) and 15–20% 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. glucose oxidation; glycogen synthesis; glycolysis Address for reprint requests and other correspondence: C. Meyer, Carl T. Hayden VA Medical Center, 650 East Indian School Road, Phoenix, AZ 85012 (e-mail: christian.meyer{at}va.gov )