1143-P: A Single and Chronic SGLT2 Inhibitor Administration Did Not Alter Insulin Clearance in Type 2 Diabetes
Authors: SATO MOTONORI , TAMURA YOSHIFUMI , KAGA HIDEYOSHI , YAMASAKI NOZOMU , KIYA MAI , SUZUKI RURIKO , SUGIMOTO DAISUKE , KADOWAKI SATOSHI , FURUKAWA YASUHIKO , FUNAYAMA TAKASHI , SOMEYA YUKI , KAWAMORI RYUZO , WATADA HIROTAKA 
Published: June 2020

Reduced insulin clearance (IC) and hyperinsulinemia are observed in obesity with insulin resistance and considered as compensatory change against insulin resistance. On the other hand, several animal models showed that enhanced IC by genetic modification suppressed high fat diet induced weight gain and insulin resistance. Recently we found that 3-day low carbohydrate diet increased IC, suggesting low glucose availability may acutely increase IC. Given that SGLT2 inhibitors decrease glucose availability by increasing urinary glucose excretion, we hypothesized that SGLT2 inhibitors may acutely increase IC, and then induce body weight reduction and improve metabolic disorders. To test this hypothesis, we recruited 12 Japanese men with type 2 diabetes mellitus. We evaluated IC and tissue specific insulin sensitivity by hyperinsulinemic euglycemic clamp (insulin infusion rate; 40 mU/m2·min) on baseline, immediately after a single administration (n=12) and after 8-week administration (n=9) of SGLT2 inhibitor (Tofogliflozin). We also measured ectopic fat in muscle and liver and abdominal fat areas by 1H-MRS and MRI, respectively. IC was not altered immediately after a single administration of Tofogliflozin (594.7±67.7ml/min/m2 to 608.3±90.9ml/min/m2, p=0.61). Also, 8 weeks administration of Tofogliflozin did not alter IC (582.5±67.3ml/min/m2 vs. 602.3±67.0ml/min/m2, p=0.41), while body weight and subcutaneous fat area were significantly decreased by 1.7% and 6.4%, respectively. In addition, 8 weeks administration of Tofogliflozin significantly decreased HbA1c and fasting plasma glucose levels and increased fasting endogenous glucose production, while insulin sensitivity and ectopic fat in muscle and liver were not changed.
In conclusion, IC was not altered after a single and 8-week administration of Tofogliflozin. Decreased body weight and improved glycemic control by chronic administration of Tofogliflozin may occur independently of IC change.

Disclosure
M. Sato: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. H. Kaga: None. N. Yamasaki: None. M. Kiya: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. Y. Furukawa: None. T. Funayama: None. Y. Someya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding
Kowa Company, Ltd.