title: The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels.
abstract: Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose reuptake by sodium/glucose cotransporter (SGLT) 2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMPK, an effect also seen with phloretin (the aglycone breakdown product of phlorizin), but not to any significant extent with dapagliflozin, empagliflozin, or phlorizin. AMPK activation occurred at canagliflozin concentrations measured in human plasma in clinical trials and was caused by inhibition of Complex I of the respiratory chain, leading to increases in cellular AMP or ADP. Although canagliflozin also inhibited cellular glucose uptake independently of SGLT2, this did not account for AMPK activation. Canagliflozin also inhibited lipid synthesis, an effect that was absent in AMPK knockout cells and that required phosphorylation of acetyl-CoA carboxylase (ACC) 1 and/or ACC2 at the AMPK sites. Oral administration of canagliflozin activated AMPK in mouse liver, although not in muscle, adipose tissue, or spleen. Because phosphorylation of ACC by AMPK is known to lower liver lipid content, these data suggest a potential additional benefit of canagliflozin therapy compared with other SGLT2 inhibitors.
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hawley
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Brennan K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Gowans
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, U.K.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mancini
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Pitt
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Day
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, U.K.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Salt
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada d.g.hardie@dundee.ac.uk gsteinberg@mcmaster.ca.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, U.K. d.g.hardie@dundee.ac.uk gsteinberg@mcmaster.ca.
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D000068896:Canagliflozin / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism*; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose