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 mumol.kg-1 lean body mass [LBM].min-1, P less than 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 less than 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 less than 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.