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Mol Endocrinol. 2015 Aug;29(8):1184-94. doi: 10.1210/ME.2015-1090. Epub 2015 Jul 6.

New Insight Into Metformin Action: Regulation of ChREBP and FOXO1 Activities in Endothelial Cells.

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Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.


Metformin has been considered a potential adjunctive therapy in treating poorly controlled type 1 diabetes with obesity and insulin resistance, owing to its potent effects on improving insulin sensitivity. However, the underlying mechanism of metformin's vascular protective effects remains obscure. Thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox state induced by high-glucose concentration, decreases thioredoxin reductase activity and mediates apoptosis induced by oxidative stress. Here we report that high glucose-induced endothelial dysfunction is associated with induction of TXNIP expression in primary human aortic endothelial cells exposed to high-glucose conditions, whereas the metformin treatment suppresses high-glucose-induced TXNIP expression at mRNA and protein levels. We further show that metformin decreases the high-glucose-stimulated nuclear entry rate of two transcription factors, carbohydrate response element-binding protein (ChREBP) and forkhead box O1 (FOXO1), as well as their recruitment on the TXNIP promoter. An AMP-activated protein kinase inhibitor partially compromised these metformin effects. Our data suggest that endothelial dysfunction resulting from high-glucose concentrations is associated with TXNIP expression. Metformin down-regulates high-glucose-induced TXNIP transcription by inactivating ChREBP and FOXO1 in endothelial cells, partially through AMP-activated protein kinase activation.

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