2084-P: Hepatic Fat Accumulation Underlies the Inability of Glucokinase Activator to Achieve a Sustained Hypoglycemic Effect in db/db Mice

Abstract

Background: Previous clinical trials have demonstrated that glucokinase activators (GKAs) do not achieve a sustained hypoglycemic effect; however, the mechanism for this has not been determined. Aims: We aimed to clarify the mechanisms for the loss of GKA hypoglycemic effect. Method: Six-week-old db/db mice were fed standard chow and divided into three groups as follows: Untreated (UT), 0.04% GKA (G), or 0.005% ipragliflozin, a sodium-glucose cotransporter 2 inhibitor that has a long-term hypoglycemic effect in db/db mice (S). After measuring body weight (BW) and blood glucose (BG) for 28 days, pancreatic beta-cell mass and hepatic triglyceride (TG) content were analyzed. Results: The three groups did not differ in BW. A hypoglycemic effect persisted until Day 28 in S; however, in G it lasted only 6 days (Day 6: UT 454 ± 84 mg/dL, G 257 ± 85 mg/dL, S 224 ± 55 mg/dL, Day 28: UT 588 ± 102 mg/dL, G 508 ± 129 mg/dL, S 217 ± 30 mg/dL). Insulin sensitivity on insulin tolerance testing did not differ between Days 9 and 23. Glucose tolerance was improved in G and S on Days 4 and 11; however, this improvement had disappeared by Day 25. Only S exhibited increased fasting insulin-to-BG ratio on Days 11 and 25. On Day 28, pancreatic beta-cell mass and proliferation were increased in S, but not in G. Although the three groups did not differ in visceral or subcutaneous fat weight, liver weight was increased in G on Days 6 and 28. Hepatic TG content was increased in G on Day 6 (UT 130 ± 18 mg/g liver, G 226 ± 20 mg/g liver, S 39 ± 7 mg/g liver), and mRNA expression related to lipogenesis, including Fas, Elovl6 and Scd1, was upregulated in G. Conclusion: Our results indicate that GKA does not increase insulin secretion or pancreatic beta-cell mass in db/db mice. However, GKA does increase hepatic TG in db/db mice, suggesting that GKA increases glucose utilization in the liver. However, it might also promote lipogenesis and hepatic fat accumulation, leading to its hypoglycemic effect being unsustained. Disclosure S. Kawata: None. A. Nakamura: None. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk Inc., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., MDS CO. LTD., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. K. Tsuchida: None. K. Omori: None. K. Takahashi: None. H. Nomoto: None. H. Kameda: None. K. Cho: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk A/S, Sanofi. Consultant; Self; Astellas Pharma Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma 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., Kowa Company, Ltd., Medscape, Medtronic, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. T. Atsumi: Consultant; Self; Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline plc., Pfizer Inc., UCB Japan Co. Ltd. Speaker’s Bureau; Self; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB Japan Co. Ltd.