Tofogliflozin Suppresses the Progression of Atherosclerosis and Reduces Inflammation in Macrophages of STZ-Diabetic ApoE KO Mice due to Improvement of Glucose Tolerance

Abstract

Background: Selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) has become widely used for treatment of diabetes. Recently, EMPA-REG OUTCOME and CANVAS Program showed that SGLT2i reduce cardiovascular events in patients with type 2 diabetes, but the mechanism still remains uncertain. We investigated the mechanisms of vascular protection of Tofogliflozin (Tofo), one of the SGLT2i. Method: 1) Streptozotocin (STZ)-diabetic apolipoprotein-E-deficient (ApoE KO) mice were separated into two groups, one group were fed normal chow and the other were fed normal chow containing 0.005% Tofo for ad libitum. After 6weeks, all mice were administered thioglycolate intraperitoneally, and 4 days later, peritoneal macrophages were collected to investigate the expressions of inflammatory cytokines of peritoneal macrophages by real-time PCR. Histological analyses were carried out by Sudan IV, Oil Red O, and MOMA-2 staining. 2) The same experiment targeted were carried out towards nondiabetic ApoE KO mice. Results: 1) Tofo increased food and water intake and decreased blood glucose, but there were no significant changes in body weight, serum levels of free fatty acid, triglyceride and total cholesterol between two groups. The legions of atherosclerosis and macrophages accumulations were significantly suppressed in Tofo group. Moreover, the expression levels of TNF-α, IL-β were significantly suppressed in macrophages from Tofo group. 2) Nondiabetic ApoE KO mice showed similar increase in food and water intake, but failed to exhibit differences in blood glucose, Sudan IV staining, and expressions of inflammatory cytokines in macrophages, as observed in diabetic ApoE KO mice. Conclusion: Tofogliflozin suppresses the progression of atherosclerosis and reduces inflammation in macrophages of STZ- diabetic ApoE KO mice. These beneficial effects may be exerted due to improvement of glucose tolerance. Disclosure M. Iwamoto: None. N. Kubota: None. T. Kubota: None. Y. Sakurai: None. N. Wada: None. I. Takamoto: None. S. Shioda: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.