Sodium glucose co-transporter 2 inhibitors (SGLT2i) are antidiabetic drugs for type 2 diabetes that lower blood glucose levels and induce weight loss. However, the efficacy of SGLT2i is known to be affected by dietary factors such as carbohydrate and fat intake. In this study, we compared the effects of the SGLT2i (dapagliflozin) in eight-week-old male KK-Ay mice (a diabetic obese model) pair-fed a normal carbohydrate diet (NCD; carbohydrate 65, protein 23, fat 12%) or a low carbohydrate diet (LCD; carbohydrate 20, protein 45, fat 35%) for 8 weeks with or without dapagliflozin (5 mg/kg p.o.) (n=5-6). Dapagliflozin reduced body weight gain and blood glucose levels in the fed state in NCD and LCD, but reduced fasting blood glucose levels in NCD only. Likewise, dapagliflozin ameliorated glucose intolerance and enhanced hepatic gluconeogenesis in NCD only. Dapagliflozin decreased serum LDL cholesterol levels and subcutaneous fat in both groups, but decreased epidydimal fat (a visceral fat) in NCD only. We then investigated the metabolic effects of dapagliflozin and their underlying mechanisms in liver using transcriptomics (DNA microarray analysis) and metabolomics (Capillary Electrophoresis-Mass Spectrometry: CE-MS and Liquid Chromatography-Mass spectrometry: LC/MS). Dapagliflozin upregulated the expression of genes related to gluconeogenesis and β-oxidation in liver in both groups. In NCD, dapagliflozin increased several kinds of amino acids, and in LCD, it increased ketone bodies. Dapagliflozin upregulated the expression of genes related to bile acid metabolism in NCD only. Both groups showed a reduction in cholesterol ester, a major component of LDL cholesterol, in liver. Our results suggest that the efficacy of SGLT2i is attenuated under LCD, and that differences in liver metabolism between NCD and LCD under dapagliflozin treatment contribute to this outcome.
F. Furuya: None. Y. Fujita: Research Support; Self; AstraZeneca, Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, MSD K.K., Eli Lilly and Company. N. Matsuo: None. Y. Oguri: None. H. Minamino: None. K. Ikeda: None. S. Harashima: Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Sanofi K.K.. Speaker's Bureau; Self; Tanabe Mitsubishi KK. Advisory Panel; Self; Tanabe Mitsubishi KK. Speaker's Bureau; Self; Novartis Pharma K.K., Eli Lilly and Company, Ono Pharmaceutical Co., Ltd.. Y. Wang: None. Y. Liu: None. N. Inagaki: Research Support; Self; Daiichi Sankyo Company, Limited, AstraZeneca, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Japan Tobacco Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly and Company, Sanwa Chemical Industrial Co., Ltd., Teijin Pharma Limited.