1435-P: Dulaglutide Exerts More Beneficial Antiatherosclerotic Effects in Early Phase of Diabetes than in Late Phase in ApoE Knockout Mice with Diabetes
Authors: SANADA JUNPEI , OBATA ATSUSHI , OBATA YOSHIYUKI , FUSHIMI YOSHIRO , IKEDA TOMOKO , NOGAMI YUKA , SHIMODA MASASHI , NAKANISHI SHUHEI , MUNE TOMOATSU , KAKU KOHEI , KANETO HIDEAKI 
Published: June 2020

There is no report about the anti-atherosclerotic effects of GLP-1 receptor activator dulaglutide (Dula) and the difference of its effectiveness between intervention from early phase and late phase of diabetes. Therefore, we aimed to address such questions by using ApoE knockout mice. First, ApoE KO mice without diabetes were subcutaneously injected with either Dula (0.6mg/kg×2/week) or vehicle from 10 to 18 weeks of age. No significant differences in blood glucose, serum lipid levels, body weight and atherosclerotic lesion of aortic arch were observed between two groups. In abdominal aorta, mRNA expression levels of V-CAM, F4/80, MCP-1, IL-6 and TNF-α were significantly lower in Dula group. Second, streptozotocin (50mg/kg×5days) was intraperitoneally injected to ApoE KO mice at 8 weeks of age. Animals whose non-fasting glucose levels were over 300 mg/dL underwent experiments. Either Dula or vehicle was administered to ApoE KO mice with diabetes from 10 to 18 weeks of age. Atherosclerotic lesion of aortic arch in Dula group was significantly smaller compared with vehicle group. CD68-positive area of aortic root was significantly smaller in Dula group. In abdominal aorta, mRNA expression level of GLP-1 receptor was significantly higher, while mRNA expression levels of MCP-1, IL-6, F4/80 and CD68 were significantly lower in Dula group. Finally, ApoE KO mice with diabetes received Dula or vehicle from 18 to 26 weeks of age. Atherosclerotic lesion of aortic arch in Dula group was significantly smaller compared with vehicle group. However, no differences were observed in immunostaining of aortic root and mRNA expression levels of various factors in abdominal aorta.
In conclusion, Dula improved mRNA expressions of inflammatory and macrophage markers in a glucose-independent manner. Furthermore, our data suggest Dula exerts more beneficial anti-atherosclerotic effects in early phase of diabetes than in late phase.

Disclosure
J. Sanada: None. A. Obata: None. Y. Obata: None. Y. Fushimi: None. T. Ikeda: None. Y. Nogami: 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.