DIFFERENTIAL-EFFECTS OF LIPOIC ACID STEREOISOMERS ON GLUCOSE-METABOLISM IN INSULIN-RESISTANT SKELETAL-MUSCLE

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhance s insulin-stimulated glucose metabolism in insulin-resistant humans an d animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of a n animal model of insulin resistance, hyperinsulinemia, and dyslipidem ia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperiton eally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2 -deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidatio n were determined in the epitrochlearis muscles in the absence or pres ence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediat ed 2-DG uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced pl asma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle -treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was inc reased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA admini stration resulted in only a 29% improvement. Chronic R-(+)-ALA treatme nt elicited a 26% increase in insulin-stimulated glycogen synthesis an d a 33% enhancement of insulin-stimulated glucose oxidation. No signif icant increase in these parameters was observed after S-(-)-ALA treatm ent. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non oxidative and oxidative glucose metabolism in insulin-resistant rat sk eletal muscle, with the R-(+) enantiomer being much more effective tha n the S-(-) enantiomer.