The Antihyperglycemic Drug α-Lipoic Acid Stimulates Glucose Uptake via Both GLUT4 Translocation and GLUT4 Activation

Abstract

The cofactor of mitochondrial dehydrogenase complexes and potent antioxidant α-lipoic acid has been shown to lower blood glucose in diabetic animals. α-Lipoic acid enhances glucose uptake and GLUT1 and GLUT4 translocation in 3T3-L1 adipocytes and L6 myotubes, mimicking insulin action. In both cell types, insulin-stimulated glucose uptake is reduced by inhibitors of p38 mitogen-activated protein kinase (MAPK). Here we explore the effect of α-lipoic acid on p38 MAPK, phosphatidylinositol (PI) 3-kinase, and Akt1 in L6 myotubes. α-Lipoic acid (2.5 mmol/l) increased PI 3-kinase activity (31-fold) and Akt1 (4.9-fold). Both activities were inhibited by 100 nmol/l wortmannin. α-Lipoic acid also stimulated p38 MAPK phosphorylation by twofold within 10 min. The phosphorylation persisted for at least 30 min. Like insulin, α-lipoic acid increased the kinase activity of the α (2.8-fold) and β (2.1-fold) isoforms of p38 MAPK, measured by an in vitro kinase assay. Treating cells with 10 μmol/l of the p38 MAPK inhibitors SB202190 or SB203580 reduced the α-lipoic acid–induced stimulation of glucose uptake by 66 and 55%, respectively. In contrast, SB202474, a structural analog that does not inhibit p38 MAPK, was without effect on glucose uptake. In contrast to 2-deoxyglucose uptake, translocation of GLUT4myc to the cell surface by either α-lipoic acid or insulin was unaffected by 20 μmol/l of SB202190 or SB203580. The results suggest that inhibition of 2-deoxyglucose uptake in response to α-lipoic acid by inhibitors of p38 MAPK is independent of an effect on GLUT4 translocation. Instead, it is likely that regulation of transporter activity is sensitive to these inhibitors.