MECHANISM OF IMPAIRED INSULIN-STIMULATED MUSCLE GLUCOSE-METABOLISM INSUBJECTS WITH INSULIN-DEPENDENT DIABETES-MELLITUS

To determine the mechanism of impaired insulin-stimulated muscle glyco gen metabolism in patients with poorly controlled insulin-dependent di abetes mellitus (IDDM), we used C-13-NMR spectroscopy to monitor the p eak intensity of the C1 resonance of the glucosyl units in muscle glyc ogen during a 6-h hyperglycemic-hyperinsulinemic clamp using [1-C-13]g lucose-enriched infusate followed by nonenriched glucose. Under simila r steady state (t=3-6 h) plasma glucose (similar to 9.0 mM) and insuli n concentrations (similar to 400 pM), nonoxidative glucose metabolism was significantly less in the IDDM subjects compared with age-weight-m atched control subjects (37+/-6 vs. 73+/-11 mu mol/kg of body wt per m inute, P <0.05), which could be attributed to an similar to 45% reduct ion in the net rate of muscle glycogen synthesis in the IDDM subjects compared with the control subjects (108+/-16 vs. 195+/-6 mu mol/liter of muscle per minute, P <0.001). Muscle glycogen turnover in the IDDM subjects was significantly less than that of the controls (16+/-4 vs, 33+/-5%, P <0.05), indicating that a marked reduction in flux through glycogen synthase was responsible for the reduced rate of net glycogen synthesis in the IDDM subjects. P-31-NMR spectroscopy was used to det ermine the intramuscular concentration of glucose-6-phosphate (G-6-P) under the same hyperglycemic-hyperinsulinemic conditions. Basal Ga-P c oncentration was similar between the two groups (similar to 0.10 mmol/ kg of muscle) but the increment in G-6-P concentration in response to the glucose-insulin infusion was similar to 50% Less in the IDDM subje cts compared with the control subjects (0.07+/-0.02 vs. 0.13+/-0.02 mm ol/kg of muscle, P <0.05). When nonoxidative glucose metabolic rates i n the control subjects were matched to the IDDM subjects, the incremen t in the G-6-P concentration (0.06+/-0.02 mmol/kg of muscle) was no di fferent than that in the IDDM subjects. Together, these data indicate that defective glucose transport/phosphorylation is the major factor r esponsible for the lower rate of muscle glycogen synthesis in the poor ly controlled insulin-dependent diabetic subjects.