2054-P: Combination of Dipeptidyl Peptidase-4 (DPP-4) Inhibitor and Sodium–Glucose Cotransporter 2 (SGLT2) Inhibitor Substantially Protects Pancreatic ß-Cells Especially in Early Phase of Diabetes Rather than Advanced Phase
Authors: FUSHIMI YOSHIRO , OBATA ATSUSHI , SANADA JUNPEI , NOGAMI YUKA , IKEDA TOMOKO , OBATA YOSHIYUKI , SHIMODA MASASHI , NAKANISHI SHUHEI , MUNE TOMOATSU , KAKU KOHEI , KANETO HIDEAKI 
Published: June 2020

In diabetes treatment, it is important to protect pancreatic β-cells in addition to correct hyperglycemia. Although DPP-4 inhibitor and SGLT2 inhibitor are widely used nowadays, there is no report about β-cell protective effect by combination of both inhibitors. In this study, we examined the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cells and compared their effects between in early and advanced phase of diabetes. We used 7-week-old BKS. Cg-+ Leprdb/Jcl (db/db) mice as early phase and 16-week-old mice as advanced phase, and treated them for 2 weeks with oral administration of linagliptin 3 mg/kg (Lina group), empagliflozin 30mg/kg (Empa group), linagliptin + empagliflozin (L+E group), and 0.5% carboxymethylcellulose (Cont gourp). After 2-week treatment, blood glucose levels in Empa and L+E group were significantly lower than Cont group. OGTT after 1-week treatment showed that blood glucose levels were significantly lower in Empa and L+E group in both phases, and slightly lower in Lina group only in early phase. After 2-week treatment, islets size in L+E group was significantly larger than Cont group only in early phase. In GSIS using isolated islets, insulin levels in Lina, Empa and L+E group were significantly higher than Cont group in both phases. Furthermore, mRNA expression levels of ins1, ins2 and their transcription factors mafa, pdx-1, neurod and nkx6.1 were all higher in Lina and L+E group in early phase. Contrarily, mRNA expression levels of caspase3, 8 were lower in Lina and L+E group, and jnk and c-jun levels were lower in Empa and L+E group in early phase. Intriguingly, such changes were not observed in advanced phase. It seemed that DPP-4 inhibitor and SGLT2 inhibitor exerted beneficial effects on β-cells through some different mechanism.
In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor protects β-cells in early phase of diabetes.

Disclosure
Y. Fushimi: None. A. Obata: None. J. Sanada: None. Y. Nogami: None. T. Ikeda: None. Y. Obata: None. M. Shimoda: None. S. Nakanishi: None. T. Mune: None. K. Kaku: Advisory Panel; Self; Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc. Consultant; Self; Sanwa Kagaku Kenkyusho. Research Support; Self; Taisho Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Kaneto: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, 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, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.