Effects of a Novel Glycogen Synthase Kinase-3 Inhibitor on Insulin-Stimulated Glucose Metabolism in Zucker Diabetic Fatty (fa/fa) Rats

Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen syn-thase kinase (GSK)-3 represents a potential new ther-apeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 2% (P < 0.001) and 26 4 % (P < 0.05) reduction in the area under the glucose and insulin concentration curves, respectively, during the OGTT. This improve-ment in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen syn