Mechanism of Control of Hepatic Glycogenesis by Insulin

Insulin produces an increase in the conversion of the D form (glucose-6-P dependent) of liver glycogen synthase to the I form (glucose-6-P independent) when injected intravenously into fed alloxan diabetic rats. Insulin activates glycogen synthase previously inactivated by glucagon in isolated perfused livers from normal rats, while increasing 14Cglucose incorporation into glycogen and decreasing glucagon-stimulated glucose production. This change in synthase activity is associated with a decrease in synthase (protein) kinase activity and tissue adenosine 3′,5′-monophosphate levels when insulin is used to antagonize the effects of glucagon. Finally, insulin alone has a direct effect on the activation of glycogen synthase (D to I shift) in perfused livers from normal rats if insulin infusion is begun after an initial 30-min perfusion period. This effect is maximal between 6 and 15 min and is no longer present after 30 min. Associated changes include an increase in 14C-glucose incorporation into glycogen at 10 min and a decrease in synthase kinase activity at 6 and 15 min. This decrease in kinase activity is not associated with a decrease in apparent hepatic concentrations of adenosine 3′,5′-monophosphate.