The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake viaboth GLUT4 translocation and GLUT4 activation - Potential role of p38 mitogen-activated protein kinase in GLUT4 activation

The cofactor of mitochondrial dehydrogenase complexes and potent antioxidan t alpha -lipoic acid has been shown to lower blood glucose in diabetic anim als. alpha -lipoic acid enhances glucose uptake and GLUT1 and GLUT4 translo cation in 3T3-L1 adipocytes and L6 myotubes, mimicking insulin action. In b oth cell types, insulin-stimulated glucose uptake is reduced by inhibitors of p38 mitogen-activated protein kinase (MAPK). Here we explore the effect of alpha -lipoic acid on p38 MAPK, phosphatidylinositol (PI) 3-kinase, and Akt1 in L6 myotubes. alpha -lipoic acid (2.5 mmol/l) increased PI 3-kinase activity (31-fold) and Akt1 (4.9-fold). Both activities were inhibited by 1 00 nmol/l wortmannin. alpha -Lipoic acid also stimulated p38 MAPK phosphory lation by twofold within 10 min. The phosphorylation persisted for at least 30 min. Like insulin, alpha -lipoic acid increased the kinase activity of the alpha (2.8-fold) and beta (2.1-fold) isoforms of p38 MAPK, measured by an in vitro kinase assay. Treating cells with 10 mu mol/l of the p38 MAPK i nhibitors SB202190 or SB203580 reduced the alpha -lipoic acid-induced stimu lation of glucose uptake by 66 and 55%, respectively. In contrast, SB202474 , a structural analog that does not inhibit, p38 MAPK, was without effect o n glucose uptake. In contrast to 2-deoxyglucose uptake, translocation of GL UT4myc to the cell surface by either alpha -lipoic acid or insulin was unaf fected by 20 mu mol/l of SB202190 or SB203580. The results suggest that inh ibition of 2-deoxyglucose uptake in response to alpha -lipoic acid by inhib itors of p38 MAPK is independent of an effect on GLUT4 translocation. Inste ad, it is likely that regulation of transporter activity is sensitive to th ese inhibitors.