THE ANTIOXIDANT ALPHA-LIPOIC ACID ENHANCES INSULIN-STIMULATED GLUCOSE-METABOLISM IN INSULIN-RESISTANT RAT SKELETAL-MUSCLE

Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM . The obese Zucker (fa/fa) rat-an animal model of muscle insulin resis tance-was used to test whether acute (100 mg/kg body wt for 1 h) and c hronic (5-100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant alpha-lipoic acid (ALA) could improve gluco se metabolism in insulin-resistant skeletal muscle, Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and, glucose oxidation were determined in the isolated epit rochlearis muscles in the absence or presence of insulin (13.3 nmol/l) . Severe insulin resistance of 2-DG uptake, glycogen synthesis, and gl ucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30 mg . kg(-1) . day(-1), a maximally effecti ve dose) with ALA significantly (P < 0.05) improved insulin-mediated 2 -DG uptake in epitrochlearis muscles from the obese rats by 62 and 64% , respectively. Chronic ALA treatment increased both insulin-stimulate d glucose oxidation (33%) and glycogen synthesis (38%) and was associa ted with a significantly greater (21%) in vivo muscle glycogen concent ration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15-17%) plasma levels of in sulin and free fatty acids. No significant effects on glucose transpor ter (GLUT4) protein level or on the activities of hexokinase and citra te synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhance s the capacity of the insulin-stimulatable glucose transport system an d of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle.