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

• Published in: Diabetes (New York, N.Y.) Vol. 50; no. 6; pp. 1464 - 1471
• Main Authors: Konrad, Daniel, Somwar, Romel, Sweeney, Gary, Yaworsky, Karen, Hayashi, Michiko, Ramlal, Toolsie, Klip, Amira
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01.06.2001
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.50.6.1464

The Antihyperglycemic Drug α-Lipoic Acid Stimulates Glucose Uptake via Both GLUT4 Translocation and GLUT4 Activation Potential Role of p38 Mitogen-Activated Protein Kinase in GLUT4 Activation Daniel Konrad 1 2 , Romel Somwar 1 3 , Gary Sweeney 1 , Karen Yaworsky 1 , Michiko Hayashi 1 , Toolsie Ramlal 1 and Amira Klip 1 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 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. Footnotes Address correspondence and reprint requests to Amira Klip, Programme in Cell Biology, Hospital for Sick Children, 555 University Ave.,Toronto, Ontario, M5G 1X8, Canada. E-mail: amira{at}sickkids.on.ca . Received for publication 13 October 2000 and accepted in revised form 13 March 2001. ANOVA, analysis of variance; ATF, activating transcription factor; DTT, dithiothreitol; IRS-1, insulin receptor substrate-1; MAPK, mitogen-activated protein kinase; MEM, minimum essential medium; PI, phosphatidylinositol.