Hawley 2016 Diabetes

From Bioblast
Jump to: navigation, search
Publications in the MiPMap
Hawley SA, Ford RJ, Smith BK, Gowans GJ, Mancini SJ, Pitt RD, Day EA, Salt IP, Steinberg GR, Hardie DG (2016) The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes 65:2784-94.

» PMID: 27381369

Hawley SA, Ford RJ, Smith BK, Gowans GJ, Mancini SJ, Pitt RD, Day EA, Salt IP, Steinberg GR, Hardie DG (2016) Diabetes

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.

© 2016 by the American Diabetes Association.

Keywords: Mouse primary hepatocytes, HEK 293 cells

Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology 

Organism: Human, Mouse  Tissue;cell: Liver, HEK  Preparation: Permeabilized cells 

Regulation: Inhibitor  Coupling state: OXPHOS  Pathway: N, S  HRR: Oxygraph-2k