The Na+ glucose co-transporter inhibitor canagliflozin activates AMP-activated protein kinase by inhibiting mitochondrial function and increasing cellular AMP levels

Hawley, S. A., Ford, R. J., Smith, B. K., Gowans, G. J., Mancini, S., Pitt, R. D., Day, E. A., Salt, I. P. , Steinberg, G. R. and Hardie, D. G. (2016) The Na+ glucose co-transporter inhibitor canagliflozin activates AMP-activated protein kinase by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes, 65(9), pp. 2784-2794. (doi:10.2337/db16-0058) (PMID:27381369) (PMCID:PMC5689380)

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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 re-uptake by SGLT2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMP-activated protein kinase (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 ACC1 and/or ACC2 at the AMPK sites. Oral administration of canagliflozin activated AMPK in mouse liver, although not in muscle, adipose tissue or spleen. As phosphorylation of acetyl-CoA carboxylase by AMPK is known to lower liver lipid content, these data suggest a potential additional benefit of canagliflozin therapy compared to other SGLT2 inhibitors.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mancini, Dr Sarah and Salt, Dr Ian
Authors: Hawley, S. A., Ford, R. J., Smith, B. K., Gowans, G. J., Mancini, S., Pitt, R. D., Day, E. A., Salt, I. P., Steinberg, G. R., and Hardie, D. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Diabetes
Publisher:American Diabetes Association
ISSN:0012-1797
ISSN (Online):1939-327X
Published Online:05 July 2016
Copyright Holders:Copyright © 2016 The American Diabetes Association
First Published:First published in Diabetes 65(9): 2784-2794
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
641891Inhibition of endothelial mitogen-activated protein kinases by amp-activated protein kinaseIan SaltBritish Heart Foundation (BHF)PG/13/82/30483RI CARDIOVASCULAR & MEDICAL SCIENCES