Ethanol impairs insulin's actions through phosphatidylinositol 3-kinase.
Insulin plays an important role in cell metabolism and proliferation. In the present study, we examined the effect of ethanol on insulin actions such as glucose uptake, DNA synthesis, and c-Jun gene expression. Acute treatment with ethanol (200 mM) for 60 minutes inhibited insulin-stimulated 2-deoxyglucose uptake by 50% in 3T3-L1 adipocytes. Insulin-induced DNA synthesis and c-Jun protein expression were also reduced by ethanol treatment in Rat-1 fibroblasts overexpressing normal human insulin receptor. Ethanol has no effect on tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. However, association of the insulin receptor and IRS-1 with the Src homology 2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) was reduced by ethanol. Pretreatment with the antidiabetic drug troglitazone, an insulin-sensitizer, reversed ethanol's inhibition. These results suggest that ethanol specifically inhibits the association of the insulin receptor and IRS-1 with the p85 subunit of PI3-kinase, which is required for increased glucose uptake, DNA synthesis, and c-Jun expression by insulin.
Yi
Sun-ju
SJ
Department of Nanotechnology, Pusan National University, Busan, Korea.
Jhun
Byung H
BH
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D004247:DNA / Q000096:biosynthesis; D000431:Ethanol / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*
C526292:IRS1 protein, human; D007328:Insulin; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D000431:Ethanol; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D005947:Glucose