Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes.

Abstract:

AIMS/HYPOTHESIS:A natural cofactor of mitochondrial dehydrogenase complexes and a potent antioxidant, alpha-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 alpha-lipoic acid in 3T3-L1 adipocytes. METHODS:We treated 3T3-L1 adipocytes with 2.5 mmol/l R (+) alpha-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 (+) alpha-lipoic acid was also compared with that of S(-) alpha-lipoic acid. RESULTS:Short-term treatment of 3T3-L1 adipocytes with R (+) alpha-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 (+) alpha-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.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Yaworsky K,Somwar R,Ramlal T,Tritschler HJ,Klip A

doi

10.1007/s001250050047

subject

Has Abstract

pub_date

2000-03-01 00:00:00

pages

294-303

issue

3

eissn

0012-186X

issn

1432-0428

journal_volume

43

pub_type

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