Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of alpha-lipoic acid

In diabetic patients, alpha -lipoic acid (LA) improves skeletal muscle gluc ose transport, resulting in increased glucose disposal; however, the molecu lar 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 meas ured in these cells, they were more sensitive and responsible to insulin th an wild-type L6 cells. LA, at concentrations less than or equal to1 mmol/l, had only small effects on glucose transport in cells not exposed to oxidat ive stress. When cells were exposed to glucose oxidase and glucose to gener ate 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 pmol/l protected the insulin effect from inhibition by H2 O2. Both the R and S isomers of LA were equally effective. In addition, oxi dative stress caused a significant decrease (similar to 50%) in reduced glu tathione concentration, along with the rapid activation of the stress-sensi tive p38 mitogen-activated protein kinase. Pretreatment with LA prevented b oth of these events, coincident with protecting insulin action. These studi es indicate that in muscle, the major site of insulin-stimulated glucose di sposal, one important effect of LA on the insulin-signaling cascade is to p rotect cells from oxidative stress-induced insulin resistance.