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.
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 beta (2.1-fold) isoforms of p38 MAPK, measured by an in vitro kinase assay. Treating cells with 10 micromol/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 micromol/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.
Konrad
D
D
Programme in Cell Biology, the Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada.
Somwar
R
R
Sweeney
G
G
Yaworsky
K
K
Hayashi
M
M
Ramlal
T
T
Klip
A
A
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D029681:Arabidopsis Proteins; D001692:Biological Transport / Q000187:drug effects; D003847:Deoxyglucose / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010940:Plant Proteins / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology*; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D029681:Arabidopsis Proteins; D003847:Deoxyglucose; D004791:Enzyme Inhibitors; D005947:Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007093:Imidazoles; D020928:Mitogen-Activated Protein Kinases; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins; D015221:Potassium Channels; D011725:Pyridines; D008063:Thioctic Acid; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C495693:Slc2a4 protein, mouse; C074500:AKT1 protein, Arabidopsis; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole