- Alpha lipoic acid (lipoate [LA]), a cofactor of α-ketodehydrogenase, exhibits unique antioxidant properties. Recent studies suggest a direct effect of LA on glucose metabolism in both human and experimental diabetes. This study examines the possbility that LA positively affects glucose homeostasis in streptozotocin (STZ)-induced diabetic rats by altering skeletal muscle glucose utilization. Blood glucose concentration in STZ-diabetic rats following 10 days of intraperitoneal (IP) injection of LA 30 mg/kg was reduced compared with that in vehicle-treated diabetic rats [495 ± 131 v 641 ± 125 mg/dL in fed state, P = .003, and 189 ± 48 v 341 ± 36 mg/dL after 12-hour fast, P = .001). No effect of LA on plasma insulin was observed. gastroenemius muscle crude membrane GLUT4 protein was elevated both in control and in diabetic rats treated with LA by 1.5- and 2.8-fold, respectively, without significant changes in GLUT4 mRNA levels. Gastroenemius lactic acid was increased in diabetic rats (19.9 ± 5.5 v 10.4 ± 2.8 μmol/g muscle, P < .05 v nondiabetic rats), and was normal in LA-treated diabetic rats (9.1 ± 5.0 μmol/g muscle). Insulin-stimulated 2-deoxyglucose (2 DG) uptake into isolated soleus muscle was reduced in treatment prevented this reduction, resulting in insulin-stimulated glucose uptake comparable to that of nondiabetic animals. These results suggest that daily LA treatment may reduce blood glucose concentrations in STZ-diabetic rats by enhancing muscle GLUT4 protein content and by increasing muscle glucose utilization.