1736-P: Effect of Glucokinase Haploinsufficiency on Pancreatic Beta-Cell Function and Mass in High-Fat, High-Sucrose Diet-Fed Mice
Authors: SHIGESAWA IKUMI , NAKAMURA AKINOBU , YAMAUCHI YUKI , KAWATA SHINICHIRO , MIYAZAKI ASUKA , NOMOTO HIROSHI , KAMEDA HIRAKU , MIYOSHI HIDEAKI , TERAUCHI YASUO , ATSUMI TATSUYA 
Published: June 2023

Background and Aim: We previously found in db/db mice that glucokinase haploinsufficiency reduces excessive glucose signaling in beta-cells and optimizes intracellular metabolic patterns, thereby preserving pancreatic beta-cell function and mass, ultimately improving glucose tolerance. In the present study, we investigated the effect of glucokinase haploinsufficiency on beta-cell function and mass in high-fat, high-sucrose diet (HFHS)-fed mice.
Method: Four-week-old male wild-type (Gck+/+) and glucokinase haploinsufficient (Gck+/−) mice were fed normal chow (NC) or HFHS. Blood glucose levels were measured, and glucose tolerance, glucose-stimulated insulin secretion (GSIS), and pancreatic beta-cell mass were evaluated over time (16, 40, and 60 weeks of age).
Results: At 16 weeks of age, no difference was found in glucose tolerance between NC and HFHS feeding in both Gck+/+ and Gck+/− mice. At 40 weeks of age, Gck+/+ HFHS-fed mice exhibited increases in GSIS and beta-cell mass versus Gck+/+ NC-fed mice (7.0 ± 1.2 mg vs. 3.3 ± 1.6 mg; P &lt; 0.01), and glucose tolerance was preserved. Conversely, Gck+/− HFHS-fed mice displayed no increase in beta-cell mass (4.1 ± 0.5 mg vs. 3.9 ± 1.5 mg), a slight increase in GSIS, and worsening of glucose tolerance compared with Gck+/− NC-fed mice. At 60 weeks of age, Gck+/+ HFHS-fed mice displayed further increases in beta-cell mass (14.7 ± 2.0 mg) and GSIS with no worsening of glucose tolerance. In Gck+/− HFHS-fed mice, beta-cell mass (5.5 ± 1.4 mg) and GSIS were partially increased, and no further worsening of glucose tolerance was observed after 40 weeks of age.
Conclusion: Gck+/− mice fed HFHS displayed insufficient increases in beta-cell mass and GSIS, resulting in worsening of glucose tolerance. In the longer term, however, these mice did not exhibit subsequent declines in beta-cell mass and GSIS nor progressive worsening of glucose tolerance unlike the non-compensatory phase in people with type 2 diabetes.

Disclosure
I.Shigesawa: None. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. Y.Yamauchi: None. S.Kawata: None. A.Miyazaki: None. H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. H.Kameda: None. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. Y.Terauchi: Advisory Panel; Novo Nordisk, Eli Lilly Japan K.K., Sanofi, AstraZeneca, MSD Life Science Foundation, Consultant; Astellas Pharma Inc., Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo, Novo Nordisk, Eli Lilly Japan K.K., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Kyowa Kirin Co., Ltd., Speaker's Bureau; Kowa Company, Ltd., Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Novartis Pharmaceuticals Corporation, Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk, Eli Lilly Japan K.K., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., AstraZeneca, Taisho Pharmaceutical Holdings Co., Ltd., Medtronic, Teijin Pharma Limited, Roche Diagnostics, LifeScan Diabetes Institute, Terumo Corporation, Bayer Inc., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd.