Journal article

Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity

Rebecca J Ford, Morgan D Fullerton, Stephen L Pinkosky, Emily A Day, John W Scott, Jonathan S Oakhill, Adam L Bujak, Brennan K Smith, Justin D Crane, Regje M Bluemer, Katarina Marcinko, Bruce E Kemp, Hertzel C Gerstein, Gregory R Steinberg

Biochemical Journal | PORTLAND PRESS LTD | Published : 2015

Abstract

Metformin is the mainstay therapy for type 2 diabetes (T2D) and many patients also take salicylate-based drugs [i.e., aspirin (ASA)] for cardioprotection. Metformin and salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) and salicylate interacting directly at the AMPK β1 drug-binding site. AMPK activation by both drugs results in phosphorylation of ACC (acetyl-CoA carboxylase; P-ACC) and inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme controlling fatty acid synthesis (lipogenesis). We find doses of metformin and salicylate used clinically synergistically activ..

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University of Melbourne Researchers

Grants

Awarded by Canadian Diabetes Association


Awarded by Canadian Institute for Health Research (CIHR)


Awarded by Canadian Foundation for Innovation


Awarded by Australian Research Council


Awarded by National Health and Medical Research Council


Funding Acknowledgements

This study was supported by the Canadian Diabetes Association [grant number OG-1-09-2698-65 (to G.R.S.)]; the Canadian Institute for Health Research (CIHR) [grant numbers MOP-11480 (to G.R.S.), and BPF-112934 (to M.D.F.)]; the Canadian Foundation for Innovation [grant number 2008M00051 (to G.R.S.)]; the Canadian Liver Foundation Undergraduate Scholarship; the Australian Research Council [grant number DP130104548 (to B.E.K.)]; the National Health and Medical Research Council [grant number APP1085460 (to B.E.K. and G.R.S.) and grant number APP1049197 (to J.S.O. and J.W.S.)]; the Victorian Government's Operational Infrastructure Support Program; and Sanofi.