A dual role for insulin in the regulation of cardiac glycogen synthase.

The effects of insulin on enzymes involved in regulation of glycogen synthesis were investigated in the perfused rat heart. In hearts from normal fed rats, perfusion with insulin (10m8 M) for 5, 10, and 15 min resulted in a 100% increase in the activity of the I (glucose 6-phosphate-independent) form of glycogen synthase. Glycogen synthase activity was completely unresponsive to insulin when hearts from fed alloxandiabetic rats were perfused under exactly the same conditions. The effect of insulin to activate glycogen synthase in hearts from normal rats was apparent using either glucose (5 mM) or palmitate (0.5 mm) as substrate, showing synthase activation to be independent of glucose transport. While the acute effect of insulin was associated with a 50% increase in total glycogen after 15 and 30 min in normal hearts, neither insulin nor diabetes produced any apparent changes in the activities of protein kinase or glycogen phosphorylase or tissue concentrations of adenosine 3’:5’-monophosphate (cyclic AMP). The impairment of synthase activation in diabetic hearts was coincident with a 60 to 70% decrease in total synthase phosphatase activity. The acute effect of insulin to activate synthase in perfused diabetic hearts could be restored by treatment of diabetic rats, in duo, with 4 units of insulin 1 to 6 h prior to heart perfusion. This restoration of the synthase activation was accompanied by restoration of total synthase phosphatase activity. Restoration of both synthase activation and total phosphatase activity by treatment, in duo, of diabetic rats with insulin could be blocked by simultaneous treatment with 10 mg of cycloheximide. Although perfusion of hearts with insulin was not found to alter synthase phosphatase activity, these data suggest that the regulation of synthase phosphatase activity may be involved in insulin-mediated glycogen synthase activation. Further, these data demonstrate a dual role for insulin in regulation of cardiac glycogen synthase. One effect involves protein synthesis and maintenance of the enzymatic machinery responsible for acute regulation of glycogen synthase activity. The other effect is a rapid effector activation of glycogen synthase through an as yet undetermined mechanism.