Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity.
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 activate AMPK in vitro and in vivo, resulting in reduced liver lipogenesis, lower liver lipid levels and improved insulin sensitivity in mice. Synergism occurs in cell-free assays and is specific for the AMPK β1 subunit. These effects are also observed in primary human hepatocytes and patients with dysglycaemia exhibit additional improvements in a marker of insulin resistance (proinsulin) when treated with ASA and metformin compared with either drug alone. These data indicate that metformin-salicylate combination therapy may be efficacious for the treatment of non-alcoholic fatty liver disease (NAFLD) and T2D.
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Rebecca J
RJ
Ford
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Morgan D
MD
Fullerton
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Stephen L
SL
Pinkosky
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Emily A
EA
Day
†St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
John W
JW
Scott
†St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
Jonathan S
JS
Oakhill
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Adam L
AL
Bujak
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Brennan K
BK
Smith
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Justin D
JD
Crane
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Regje M
RM
Blümer
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Katarina
K
Marcinko
†St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
Bruce E
BE
Kemp
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Hertzel C
HC
Gerstein
*Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8N 3Z5.
Gregory R
GR
Steinberg
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL
D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; C554549:Prkab1 protein, mouse; D055372:AMP-Activated Protein Kinases; D001241:Aspirin