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 > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| 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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