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Protection Against Oxidative Stress—Induced Insulin Resistance in Rat L6 Muscle Cells by Micromolar Concentrations of -Lipoic Acid

From the Diabetes Research Laboratory (B.A.M., W.S., A.L.G., I.D.G.), Mount Zion Hospital, San Francisco, California; the Department of Pharmacology (J.C.L.), University of Virginia, Charlottesville, Virginia; and the Medical Research Institute (J.L.E.), San Bruno, California.

Address correspondence and reprint requests to Dr. Betty A. Maddux, Diabetes Research Laboratory, Mount Zion Hospital, University of California at San Francisco, 2200 Post St., San Francisco, CA 94143-1616. E-mail: bmaddux{at}itsa.ucsf.edu .

In diabetic patients, -lipoic acid (LA) improves skeletal muscle glucose transport, resulting in increased glucose disposal; however, the molecular mechanism of action of LA is presently unknown. We studied the effects of LA on basal and insulin-stimulated glucose transport in cultured rat L6 muscle cells that overexpress GLUT4. When 2-deoxy-D-glucose uptake was measured in these cells, they were more sensitive and responsive to insulin than wild-type L6 cells. LA, at concentrations 1 mmol/l, had only small effects on glucose transport in cells not exposed to oxidative stress. When cells were exposed to glucose oxidase and glucose to generate H₂O₂ and cause oxidative stress, there was a marked decrease in insulin-stimulated glucose transport. Pretreatment with LA over the concentration range of 10-1,000 µmol/l protected the insulin effect from inhibition by H₂O₂. Both the R and S isomers of LA were equally effective. In addition, oxidative stress caused a significant decrease (50%) in reduced glutathione concentration, along with the rapid activation of the stress-sensitive p38 mitogen-activated protein kinase. Pretreatment with LA prevented both of these events, coincident with protecting insulin action. These studies indicate that in muscle, the major site of insulin-stimulated glucose disposal, one important effect of LA on the insulin-signaling cascade is to protect cells from oxidative stress-induced insulin resistance.

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