caa a22 4500 475771990 CHVBK 20180406123620.0 cr unu---uuuuu 170329e20000301xx s 000 0 eng 10.1007/s001250050047 doi (NATIONALLICENCE)springer-10.1007/s001250050047 Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by α -lipoic acid in 3T3-L1 adipocytes [Elektronische Daten] [K. Yaworsky, R. Somwar, T. Ramlal, H. J. Tritschler, A. Klip] Aims/hypothesis. A natural cofactor of mitochondrial dehydrogenase complexes and a potent antioxidant, α-lipoic acid improves glucose metabolism in people with Type II (non-insulin-dependent) diabetes mellitus and in animal models of diabetes. In this study we investigated the cellular mechanism of action of α-lipoic acid in 3T3-L1 adipocytes.¶Methods. We treated 3T3-L1 adipocytes with 2.5 mmol/l R (+) α-lipoic acid for 2 to 60 min, followed by assays of: 2-deoxyglucose uptake; glucose transporter 1 and 4 (GLUT1 and GLUT4) subcellular localization; tyrosine phosphorylation of the insulin receptor or of the insulin receptor substrate-1 in cell lysates; association of phosphatidylinositol 3-kinase activity with immunoprecipitates of proteins containing phosphotyrosine or of insulin receptor substrate-1 using a in vitro kinase assay; association of the p85 subunit of phosphatidylinositol 3-kinase with phosphotyrosine proteins or with insulin receptor substrate-1; and in vitro activity of immunoprecipitated Akt1. The effect of R (+) α-lipoic acid was also compared with that of S(-) α-lipoic acid.¶Results. Short-term treatment of 3T3-L1 adipocytes with R (+) α-lipoic acid rapidly stimulated glucose uptake in a wortmannin-sensitive manner, induced a redistribution of GLUT1 and GLUT4 to the plasma membrane, caused tyrosine phosphorylation of insulin receptor substrate-1 and of the insulin receptor, increased the antiphosphotyrosine-associated and insulin receptor substrate-1 associated phosphatidylinositol 3-kinase activity and stimulated Akt activity.¶Conclusion/interpretation. These results indicate that R (+) α-lipoic acid directly activates lipid, tyrosine and serine/threonine kinases in target cells, which could lead to the stimulation of glucose uptake induced by this natural cofactor. These properties are unique among all agents currently used to lower glycaemia in animals and humans with diabetes. [Diabetologia (2000) 43: 294-303] Springer-Verlag Berlin Heidelberg, 2000 Keywordsα-Lipoic acid, glucose transport, phosphatidylinositol 3-kinase, Akt, subcellular fractionation, 3T3-L1 adipocytes, insulin receptor nationallicence Yaworsky K. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut Somwar R. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut Ramlal T. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut Tritschler H. J. ASTA-Medica, Frankfurt, Germany, DE aut Klip A. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut https://doi.org/10.1007/s001250050047 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250050047 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yaworsky K. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut NATIONALLICENCE 700 1- Somwar R. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut NATIONALLICENCE 700 1- Ramlal T. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut NATIONALLICENCE 700 1- Tritschler H. J. ASTA-Medica, Frankfurt, Germany, DE aut NATIONALLICENCE 700 1- Klip A. Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, CA aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer