The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels
Top Cited Papers
Open Access
- 5 July 2016
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 65 (9), 2784-2794
- https://doi.org/10.2337/db16-0058
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.Keywords
Funding Information
- British Heart Foundation
- Canadian Diabetes Association
- Canadian Institutes of Health Research
- Wellcome Trust (097726)
This publication has 46 references indexed in Scilit:
- AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net PhosphorylationCell Metabolism, 2013
- The Ancient Drug Salicylate Directly Activates AMP-Activated Protein KinaseScience, 2012
- Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trialInternational Journal Of Clinical Practice, 2012
- Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal ModelsPLOS ONE, 2012
- The role of AMP-activated protein kinase in the functional effects of vascular endothelial growth factor-A and -B in human aortic endothelial cellsVascular Cell, 2011
- Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy stateJCI Insight, 2010
- Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK ActivationCell Metabolism, 2010
- Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein KinasePublished by Elsevier BV ,2007
- 5′-AMP-Activated Protein Kinase (AMPK) Is Induced by Low-Oxygen and Glucose Deprivation Conditions Found in Solid-Tumor MicroenvironmentsMolecular and Cellular Biology, 2006
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001