Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle

Am J Physiol. 1997 Jul;273(1 Pt 1):E185-91. doi: 10.1152/ajpendo.1997.273.1.E185.

Abstract

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally 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 oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma 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 increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. 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 skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Biological Transport / drug effects
  • Blood Glucose / metabolism
  • Deoxyglucose / metabolism
  • Fatty Acids, Nonesterified / blood
  • Female
  • Glucose / metabolism*
  • Glycogen / biosynthesis*
  • Humans
  • Insulin / blood
  • Insulin / pharmacology*
  • Insulin Resistance*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / physiopathology*
  • Rats
  • Rats, Zucker
  • Reference Values
  • Stereoisomerism
  • Thioctic Acid / pharmacology*

Substances

  • Antioxidants
  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • Thioctic Acid
  • Glycogen
  • Deoxyglucose
  • Glucose