IMPAIRED ACTIVATION OF GLYCOGEN-SYNTHASE IN PEOPLE AT INCREASED RISK FOR DEVELOPING NIDDM

To study whether impaired activation of muscle glycogen synthase represents an early defect in the pathogenesis of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM), we quantitated rates of nonoxidative glucose metabolism and measured activities of glycogen synthase and phosphorylase and concentrations of free glucose and glucose-6-phosphate in muscle biopsies, obtained before and after a euglycemic insulin clamp, in 16 NIDDM patients, 18 first-degree relatives of NIDDM patients, and 16 nondiabetic control subjects. Insulin-stimulated glucose storage (20.1 +/- 1.5 and 11.6 +/- 1.7 vs. 27.9 +/- 1.7-mu-mol . kg-1 lean body mass [LBM] . min-1, P < 0.01-0.001 [3.6 +/- 0.3 and 2.1 +/- 0.3 vs. 5.0 +/- 0.3 mg . kg-1 LBM . min-1] and glycogen synthase activity, measured at 0.1 mM glucose-6-phosphate concentration (11.3 +/- 1.3 and 11.6 +/- 1.3 vs. 18.3 +/- 2.0 nmol . min-1 . mg-1 protein, P < 0.01), were impaired in relatives and diabetic subjects compared with control subjects. Glycogen synthase activity correlated with the rate of glucose storage (r = 0.53, P < 0.001). Glycogen phosphorylase fractional activity did not differ among the groups. Apart from increased intramuscular basal glucose concentrations in NIDDM patients, no consistent differences were observed in free glucose and glucose-6-phosphate concentrations between the groups. We conclude that impaired activation of muscle glycogen synthase by insulin is observed in patients with a genetic risk of developing NIDDM and may represent an early defect in the pathogenesis of NIDDM.