1465-P: Metabolic Remodeling in Pancreatic Beta Cells in Japanese Patients with Type 2 Diabetes

Abstract

Background and Aims: It has been shown that metabolic remodeling from oxidative phosphorylation to glycolysis via activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) occurs in pancreatic beta cells in non-Asians with diabetes, resulting in impaired beta cell function. We used multiple autopsy pancreatic sections to investigate whether such changes occur in Japanese patients with type 2 diabetes (T2D) , and if so, which clinical and pathological features of islets relate to this remodeling. Methods: Autopsy pancreatic sections from patients with T2D and non-diabetic donors (ND) were stained with antibodies against PFKFB3, insulin, and glucagon. The PFKFB3-positive ratio of pancreatic beta cells and alpha cells between T2D and ND were compared. Next, the relationships between PFKFB3-postive beta cell ratio, patient background factors and pathological features of the islets were explored. Results: In total, 36 cases (18 cases each for T2D and ND) were enrolled and 50-100 islets/case were evaluated. Mean age was 70.6 ± 7.7 vs. 64.3 ± 12.8 years and body mass index (BMI) 22.4 ± 4.2 vs. 23.3 ± 4.5 kg/m2, respectively. T2D duration was 9.8 ± 9.9 years. The PFKFB3-positive beta cell ratio was significantly higher in T2D (29.7 ± 18.6% vs. 11.1 ± 8.7%, p<0.05) , whereas the PFKFB3-positive alpha cell ratio did not differ between groups. A negative correlation between PFKFB3-positive beta cell ratio and BMI was found only in the T2D group (r=-0.65, p<0.05) . No correlation was observed between PFKFB3-positive beta cell ratio and age/disease duration in the T2D group. Thioflavin T staining revealed a positive correlation between amyloid deposition in the islets of T2D and PFKFB3 positivity in beta cells (r=0.67, p<0.05) . Conclusion: Our results indicate that intracellular metabolic remodeling mediated by upregulation of PFKFB3 occurs in pancreatic beta cells of Japanese patients with T2D. Low BMI and amyloid deposition may affect PFKFB3 expression in beta cells from patients with T2D. Disclosure R.Izumihara: None. H.Nomoto: None. K.Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science , MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H.Kameda: None. K.Cho: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. H.Mizukami: None. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding JSPS KAKENHI Grant Number JP20281167.Japan Diabetes Society Junior Scientist Development Grant.MSD Life Science Foundation, Public Interest Incorporated Foundation.