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Diabetes 50:1464-1471, 2001
© 2001 by the American Diabetes Association, Inc.

The Antihyperglycemic Drug {alpha}-Lipoic Acid Stimulates Glucose Uptake via Both GLUT4 Translocation and GLUT4 Activation

Potential Role of p38 Mitogen-Activated Protein Kinase in GLUT4 Activation

Daniel Konrad1,2, Romel Somwar1,3, Gary Sweeney1, Karen Yaworsky1, Michiko Hayashi1, Toolsie Ramlal1, and Amira Klip1,3

1 Programme in Cell Biology, the Hospital for Sick Children
2 Institute of Medical Science and the
3 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada

The cofactor of mitochondrial dehydrogenase complexes and potent antioxidant {alpha}-lipoic acid has been shown to lower blood glucose in diabetic animals. {alpha}-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 {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 100 nmol/l wortmannin. {alpha}-Lipoic acid also stimulated p38 MAPK phosphorylation 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 ß (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 {alpha}-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 {alpha}-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 {alpha}-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.


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