期刊
CLINICAL SCIENCE
卷 133, 期 23, 页码 2415-2430出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20190863
关键词
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资金
- Thailand Research Fund [TRF-RSA 6080015]
- Faculty of Medicine Research Fund [100-2562]
- scholarship for Doctoral degree in Physiology (International Program), Faculty of Medicine, Chiang Mai University
- Graduate Research Scholarship for the Fiscal Year 2561 Graduate School Chiang Mai University
- Functional Food Research Center for Well-being, Chiang Mai University
Background: 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. Materials and methods: 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. Results: 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 PGC1 alpha and upstream regulator SI RT1. 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. Conclusion: 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.
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