1855-P: Effects of Dapagliflozin and/or Insulin Glargine on Hepatic Steatosis in db/db Mice

Abstract

Background: Although several studies have shown that SGLT2 inhibitors exert ameliorating effects on hepatic steatosis, the mechanism remains unknown. Therefore, we compare the glucose-lowering effects of the SGLT2 inhibitor, dapagliflozin on hepatic steatosis with those of insulin glargine. Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), and treated with both dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, blood glucose levels, liver triglyceride (TG) content and liver gene expression profiles were examined. Results: Fed blood glucose levels were significantly lower in the three treatment groups compared with the Placebo group (Placebo 904.2 ± 35.6, Dapa 425.0 ± 26.7, Gla 406.1 ± 25.8, Dapa+Gla 347.3 ± 24.0 mg/dL). HE staining and oil red O staining of the liver revealed that there was high fat and lipid droplets accumulation in the Gla group compared with that in the other three groups. The liver TG content was significantly increased in the Gla group compared with the others (Placebo 24.1 ± 5.7, Dapa 30.6 ± 6.4, Gla 128 ± 25, and Dapa+Gla 54.4 ± 7.1 mg per gram liver). Microarray analysis revealed that Cidea, Cidec and Mogat1 were upregulated in the Gla group compared with the Placebo group. Real-time quantitative PCR revealed that expression levels associated in fatty acid synthesis, such as Fas, Elovl6, Scd1 and Mogat1 significantly upregulated in the Gla group compared with the Placebo group. As for the expression levels of genes related to fatty acid uptake and storage, Cidea and Cidec, elevated in the Gla group compared with the Placebo group. Pparg2, which is associated with Fas, Elovl6, Scd1, Mogat1 and Cidec significantly increased in the Gla group compared with the Placebo group. Conclusion: Hepatic steatosis was prevented in db/db mice, after 8 weeks of treatment with dapagliflozin and/or insulin glargine, but not with insulin glargine alone. Disclosure K. Omori: None. A. Nakamura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. H. Nomoto: None. H. Kameda: None. K. Cho: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. T. Atsumi: Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding AstraZeneca