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

被引:311
作者
Maddux, BA
See, W
Lawrence, JC
Goldfine, AL
Goldfine, ID
Evans, JL
机构
[1] Univ Calif San Francisco, Mt Zion Hosp, Diabet Res Lab, San Francisco, CA 94143 USA
[2] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA
[3] Med Res Inst, San Bruno, CA USA
关键词
D O I
10.2337/diabetes.50.2.404
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In diabetic patients, alpha -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 responsible to insulin than 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 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 pmol/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 (similar to 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.
引用
收藏
页码:404 / 410
页数:7
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