Insulin-mediated glycogen synthase activity in muscle of spontaneously insulin-resistant and diabetic rhesus monkeys.

Altered insulin action on glycogen synthase activity has been well recognized in non-insulin-dependent diabetes, and some prior evidence has suggested this alteration may be one of the earliest disturbances preceding the development of diabetes. The present study, using the spontaneously insulin-resistant and diabetic rhesus monkey, examined insulin's effect on glycogen synthase at the earliest point of identification of developing diabetes. The normal monkeys (n = 11) had a greater insulin-mediated change in glycogen synthase-independent activity compared with the hyperinsulinemic (n = 8) (P < 0.05) and diabetic (n = 8) (P < 0.01) monkeys. Compared with normal monkeys, the diabetic monkeys had lower basal and insulin-stimulated total glycogen synthase activity (P < 0.05). Monkeys with normal beta-cell responsiveness to intravenous glucose had greater insulin-mediated change in glycogen synthase fractional velocity compared with those with exaggerated (P < 0.01) or absent beta-cell responses to glucose (P < 0.05). We conclude that an alteration in insulin action on glycogen synthase is present as early as beta-cell hyperresponsiveness, one of the earliest detected abnormalities in the progression toward diabetes.