Mechanism of impaired insulin-stimulated muscle glucose metabolism in subjects with insulin-dependent diabetes mellitus

Abstract

To determine the mechanism of impaired insulin-stimulated muscle glycogen metabolism in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM), we used 13C-NMR spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units in muscle glycogen during a 6-h hyperglycemic-hyperinsulinemic clamp using [1-13C]glucose-enriched infusate followed by nonenriched glucose. Under similar steady state (t = 3- 6 h) plasma glucose (~ 9.0 mM) and insulin concentrations (~ 400 pM), nonoxidative glucose metabolism was significantly less in the IDDM subjects compared with age-weight-matched control subjects (37 ±6 vs. 73 ± 11 μmol/kg of body wt per minute, P < 0.05), which could be attributed to an ~ 45% reduction in the net rate of muscle glycogen synthesis in the IDDM subjects compared with the control subjects (108±16 vs. 195±6 μmol/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. 31P-NMR spectroscopy was used to determine the intramuscular concentration of glucose-6-phosphate (G-6-P) under the same hyperglycemic-hyperinsulinemic conditions. Basal G-6-P concentration was similar between the two groups (~ 0.10 mmol/kg of muscle) but the increment in G-6-P concentration in response to the glucose-insulin infusion was ~ 50% less in the IDDM subjects compared with the control subjects (0.07±0.02 vs. 0.13±0.02 mmol/kg of muscle, P < 0.05). When nonoxidative glucose metabolic rates in the control subjects were matched to the IDDM subjects, the increment in the G-6-P concentration (0.06±0.02 mmol/kg of muscle) was no different than that in the IDDM subjects. Together, these data indicate that defective glucose transport/phosphorylation is the major factor responsible for the lower rate of muscle glycogen synthesis in the poorly controlled insulin-dependent diabetic subjects.