Difference in Hepatic Steatosis and Pancreatic Beta-Cell Mass between Dapagliflozin and Insulin Glargine Treatment at Comparable Levels of Glycemic Control

Abstract

Background: Although several studies have shown that SGLT2 inhibitors exert protective effects on pancreatic beta cells and hepatic steatosis, the mechanism remains unknown. Therefore, we compared the glucose-lowering effect of the SGLT2 inhibitor dapagliflozin (dapa) on pancreatic beta cell mass and 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 dapa (Dapa), treated with insulin glargine (Gla), or treated with both dapa and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined blood glucose levels, beta cell mass and liver triglyceride (TG) content. Results: Fed blood glucose levels were significantly lower in the treated groups compared with the Placebo group (Placebo 904.2 ± 35.6 mg/dL, Dapa 425.0 ± 26.7 mg/dL, Gla 406.1 ± 25.8 mg/dL, Dapa+Gla 347.3 ± 24.0 mg/dL). Immunohistochemical analysis revealed that pancreatic beta cell mass was significantly increased in the Dapa and Dapa+Gla groups, but not the Gla group, compared with the Placebo group (Placebo 2.25 ± 0.45 mg, Dapa 5.01 ± 0.52 mg, Gla 3.79 ± 0.32 mg, Dapa+Gla 5.19 ± 0.56 mg). Liver TG content was significantly increased in the Gla group compared with the others (Placebo 24.1 ± 5.7 mg, Dapa 30.6 ± 6.4 mg, Gla 128 ± 25 mg, and Dapa+Gla 54.4 ± 7.1 mg per gram liver). Microarray analysis revealed genes involved in hepatic steatosis such as Cidec and Pparg were significantly upregulated in the Gla group compared with the Placebo group. As for hepatic fatty acid composition, concentrations of C16:0 and C18:1n-9 were significantly increased in the Gla group compared with the Placebo group, while C18:0 was not significantly different between groups. There was no difference in safety including mortality. Conclusion: Beta cell mass was maintained, and hepatic steatosis was not induced, after 8 weeks of treatment with dapa, but with insulin glargine, in db/db mice. Disclosure K. Omori: None. A. Nakamura: Research Support; Self; Sanofi, Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisk Inc., Novartis Pharma K.K., AstraZeneca, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. H. Miyoshi: Speaker's Bureau; Self; Astellas Pharma US, Inc., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Kissei Pharmaceutical Co., Ltd., Novo Nordisk A/S, Sanofi. Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; MSD K.K.. K. Takahashi: None. N. Kitao: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi & Co., Ltd.. Speaker's Bureau; Self; Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited. T. Atsumi: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Astellas Pharma US, Inc., Takeda Pharmaceuticals U.S.A., Inc., Pfizer Inc., AbbVie Inc.. Research Support; Self; Astellas Pharma US, Inc., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceuticals U.S.A., Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Otsuka Holdings Co., Ltd..