title: Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle.
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.
authors.affiliation: Department of Physiology, University of Arizona, Tucson 85721-0093, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Streeper
authors.forename: E J
authors.initials: EJ
authors.lastname: Henriksen
authors.forename: S
authors.initials: S
authors.lastname: Jacob
authors.forename: J Y
authors.initials: JY
authors.lastname: Hokama
authors.forename: D L
authors.initials: DL
authors.lastname: Fogt
authors.forename: H J
authors.initials: HJ
authors.lastname: Tritschler
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D013237:Stereoisomerism; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008063:Thioctic Acid; D006003:Glycogen; D003847:Deoxyglucose; D005947:Glucose