Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats.

Abstract

With an increasing prevalence of obesity and metabolic syndrome, exploring the effects and delineating the mechanisms of possible therapeutic agents are of critical importance. We examined the effects of SGLT2 inhibitor-dapagliflozin on insulin resistance, hepatic gluconeogenesis, hepatic injury and pancreatic ER stress in high-fat diet-induced obese rats. Male Wistar rats were fed with normal diet (ND) or high-fat diet for 16 weeks. Then high-fat rats were given vehicle (HF) or dapagliflozin (1 mg/kg/day; HFDapa) or metformin (30 mg/kg/day; HFMet) for another 4 weeks. We found that dapagliflozin ameliorated high-fat diet-induced insulin resistance. The fasting plasma glucose level was comparable among groups, although dapagliflozin treatment led to substantial glycosuria. Hepatic gluconeogenic enzymes, PEPCK, G6Pase and FBPase, expression was not different in HF rats compared with ND rats. Meanwhile, dapagliflozin-treated group exhibited the elevation of these enzymes in parallel with the rise of transcription factor CREB, co-factor PGC1α and upstream regulator SIRT1. Hepatic oxidative stress, inflammation and NAFLD activity score as well as hepatic and pancreatic ER stress and apoptosis in obese rats were attenuated by dapagliflozin. We conclude that dapagliflozin improved obesity-related insulin resistance, hepatic and pancreatic injury independent of fasting plasma glucose level. Of note, dapagliflozin-induced glycosuria apparently triggered the up-regulation of hepatic gluconeogenic enzymes to prevent hypoglycemia.