RELATIONSHIP OF SKELETAL-MUSCLE GLUCOSE-6-PHOSPHATE TO GLUCOSE DISPOSAL RATE AND GLYCOGEN-SYNTHASE ACTIVITY IN INSULIN-RESISTANT AND NON-INSULIN-DEPENDENT DIABETIC RHESUS-MONKEYS

Reduced insulin action on skeletal muscle glycogen synthase activity and reduced whole-body insulin-mediated glucose disposal rates in insulin-resistant subjects may be associated with an alteration in muscle glucose transport (or phosphorylation) or with a defect distal to glucose 6-phosphate. To examine this issue we determined the glucose 6-phosphate concentration and glycogen synthase activity in muscle samples obtained under basal and euglycaemic hyperinsulinaemic clamp conditions in 27 rhesus monkeys (Macaca mulatta). They ranged from metabolically normal (n = 11) to insulin-resistant (n = 8) to overtly diabetic (non-insulin-dependent) (n = 8). The glucose 6-phosphate measured under insulin-stimulated conditions was inversely correlated to insulin-stimulated glycogen synthase independent activity (r = -0.54, p < 0.005), the change in glycogen synthase independent activity (insulin-stimulated minus basal) (r = -0.58, p < 0.002) and to whole-body insulin-mediated glucose disposal rate (r = -0.60, p < 0.002). The insulin-resistant and diabetic monkeys had significantly higher insulin-stimulated glucose 6-phosphate concentrations (0.57+/-0.11 and 0.62+/-0.11 nmol/mg dry weight, respectively) compared to the normal monkeys (0.29+/-0.05 nmol/mg dry weight) (p's < 0.05). We conclude that under euglycaemic/hyperinsulinaemic conditions, a defect distal to glucose 6-phosphate is a major contributor to reduced whole-body insulin-mediated glucose disposal rates and to reduced insulin action on glycogen synthase in insulin-resistant and diabetic monkeys.