Protective Effects of SGLT2 Inhibitor Luseogliflozin on Pancreatic Beta Cells in Obese Diabetic db/db Mice—"The Earlier and Longer, the Better”

Abstract

We previously reported that SGLT2 inhibitor luseogliflozin (Luseo) preserved beta-cell mass and function in obese diabetic db/db mice. The aim of this study is to compare the protective effects of Luseo on beta-cells between in an early and advanced stage of diabetes. We used 7-week-old and 16-week-old male db/db mice as an early and advanced stage model, respectively. Both mice received Luseo (0.01%) in chow or normal chow for 2 weeks. In addition, we set a long-term administration model (a long-term model) which received Luseo from 7 to 18 weeks old. Blood glucose levels were significantly decreased by Luseo treatment both in the early and advanced stage model. Various β-cell-related gene expression levels, insulin content in islets and glucose-stimulated insulin secretion (GSIS) were enhanced after Luseo treatment in the early stage model which was not clearly observed in the advanced stage model. Immunohistochemical staining showed that beta-cell ratio and percentage of Ki67-positve β-cells were significantly increased in the early stage model by Luseo treatment which was not clearly observed in the advanced stage model. Furthermore, in the long-term model, blood glucose levels, β-cell-related gene expression levels, insulin content, GSIS, beta-cell ratio and percentage of Ki67-positve β-cells were markedly enhanced by Luseo treatment. Various parameters were almost completely preserved in the long-term model even when the mice became 18 weeks old. Taken together, protective effects of Luseo on pancreatic β-cells were more effective in an early stage of diabetes compared to an advanced stage. Surprisingly, administration of Luseo for a prolonged period from an early stage preserved β-cell mass and function almost completely. These results suggest that long-term administration of Luseo from an early stage is important to maintain the β-cell mass and function. Disclosure T. Kimura: None. M. Shimoda: Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Taisho Pharmaceutical Co., Ltd. S. Nakanishi: Speaker's Bureau; Self; Sanofi. T. Mune: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Kaneto: Research Support; Self; Sanofi, Novo Nordisk Inc., Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Takeda Pharmaceuticals U.S.A., Inc., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Astellas Pharma US, Inc..