2016
DOI: 10.2337/db16-0058
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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 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, empagl… Show more

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Cited by 323 publications
(272 citation statements)
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“…DAPA-mediated attenuation of TNFα-induced NFκB mRNA expression implicates DAPA in transcriptional regulation, a novel observation, and in keeping with recently identified 'off target' effects involving activation of cell signalling pathways independent of SGLT-2 by other members of the SGLT-2 class of agents. 5,15 Endothelial cell dysfunction is identified as a significant contributor to early atherogenesis particularly in the vulnerable type 2 diabetic patient population. 16,17 Upregulation of adhesion molecule expression is a marker of endothelial cell dysfunction and a precursor to the development of atherosclerosis.…”
Section: Discussionmentioning
confidence: 99%
“…DAPA-mediated attenuation of TNFα-induced NFκB mRNA expression implicates DAPA in transcriptional regulation, a novel observation, and in keeping with recently identified 'off target' effects involving activation of cell signalling pathways independent of SGLT-2 by other members of the SGLT-2 class of agents. 5,15 Endothelial cell dysfunction is identified as a significant contributor to early atherogenesis particularly in the vulnerable type 2 diabetic patient population. 16,17 Upregulation of adhesion molecule expression is a marker of endothelial cell dysfunction and a precursor to the development of atherosclerosis.…”
Section: Discussionmentioning
confidence: 99%
“…Although we are unable to explain the difference between our results and those obtained in the previous study, it is interesting to note that, using the same ACC phosphorylation-deficient mouse model, phosphorylation of ACC by AMPK was not required for regulation of FAO in heart (Zordoky et al., 2014). In a more recent study, canagliflozin, which was shown to activate AMPK in the liver, decreased RER independently of ACC phosphorylation (Hawley et al., 2016). These findings suggest that the relationship between AMPK, ACC phosphorylation, and the regulation of FAO is not a simple one and that other mechanisms, independent of AMPK phosphorylation and inhibition of ACC, regulate FAO in vivo.…”
Section: Discussionmentioning
confidence: 98%
“…Interestingly, other diuretics that cause hemoconcetration may similarly increase amputation risk, although this has not been carefully studied 99 . In addition, canagliflozin, but not empagliflozin, impacts mitochondrial AMP-kinase activity, which is involved in mitochondrial energy pathways 100 . In animals, canagliflozin associated AMP kinase activation was associated with inhibition of Complex I of the respiratory chain, leading to increases in cellular AMP and ADP.…”
Section: Sglt2 Inhibition and Potential Side Effectsmentioning
confidence: 99%