1135-P: Acute Increase in Endogenous Glucose Production by a Single Administration of Tofogliflozin Is Disappeared by Suppressing Its Glucose Lowering Effect in the Patients with Type 2 Diabetes Mellitus
Authors: YAMASAKI NOZOMU , TAMURA YOSHIFUMI , KAGA HIDEYOSHI , SATO MOTONORI , KIYA MAI , KADOWAKI SATOSHI , SUZUKI RURIKO , FURUKAWA YASUHIKO , SUGIMOTO DAISUKE , FUNAYAMA TAKASHI , SOMEYA YUKI , KAWAMORI RYUZO , WATADA HIROTAKA 
Published: June 2020

It has been shown that a single administration of SGLT2 inhibitor (SGLT2i) to the patients with type 2 diabetes mellitus (T2DM) decreases plasma glucose (PG), but increases endogenous glucose production (EGP); however, its underlying mechanism has been totally unknown. We hypothesized that a single administration of SGLT2i lowers PG, thereby suppresses insulin level and increases glucagon level, which in turn rises EGP. To test this hypothesis, we recruited 12 Japanese patients with type 2 diabetes mellitus without taking any hypoglycemic agents (BMI 24.9±2.5 kg/m2, HbA1c 7.7±0.9%). In each patient, by [6,6-2H2]-glucose infusion, we evaluated basal EGP and EGP under the conditions with: (i) no administration of drugs (CON), (ii) single administration of a SGLT2i, Tofogliflozin (TOF), and (iii) TOF + glucose adjustment (TOF+G) in which we adjusted PG level by exogenous glucose infusion to mimic PG level during CON. In each patient, we measured EGP under three condition at 1-2 week intervals. Also, we evaluated changes in insulin, glucagon and EGP between basal period and after each 3h condition. The decrement of PG during 3h experimental period in TOF was significantly greater than that in CON, and this change was inhibited by glucose infusion (delta PG: CON; -14.6 mg/dl, TOF; -26.4 mg/dl, TOF+G; -15.6 mg/dl). In CON, EGP was decreased by 11.1%, but it was significantly increased by 4.5% in TOF. However, similar to CON, EGP was decreased by 15.7% in TOF+G. In addition, insulin level was decreased by 24% and glucagon level was increased by 36% in TOF; however, these hormonal changes were not observed in CON and TOF+G.
In conclusion, acute EGP elevation by a single administration of SGLT2i was disappeared by suppression of glucose lowering effect of SGLT2i. Changes in insulin and glucagon by rapid decline of PG after SGLT2i administration may be a main inducer of EGP elevation.

Disclosure
N. Yamasaki: 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. M. Sato: None. M. Kiya: None. S. Kadowaki: None. R. Suzuki: None. Y. Furukawa: None. D. Sugimoto: 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.