The regulation of liver and skeletal muscle glycogen synthase by plasma insulin and glucose has not been investigated in vivo at physiological blood glucose concentrations. We have,therefore, used the glucose clamp technique to investigate the effects of these variables independently in rats. Short-term streptozocin-(0.15 g/kg) diabetic animals were used in addition to normal rats to avoid endogenous insulin secretion during hyperglycemic clamps. In normal and diabetic animals, 3 h of hyperinsulinemia without change in blood glucose concentrations caused only a small increase in liver glycogen synthase activity (+ 34%), whereas hyperglycemic clamps at 6.0 and 10.0 mmol/L resulted in marked increases (+ 268 and +394% of basal, P < 0.001). Liver glycogen concentrations at the end of the clamps reflected these changes. In skeletalmuscle, glycogen synthase was increased by +58% by the euglycemic hyperinsulinemic clamp and was not increased significantly further by hyperglycemia. Similarly, muscle glycogen concentration increased with the 4.0-mmol/L clamp but during the hyperglycemic clamps was only raised more indirect proportion to blood glucose concentrations. The results confirm that blood glucose concentration is the major short-term regulator of glycogen synthase activity in the liver but that insulin is of prime importance in skeletal muscle.

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