1759-P: Relation between Metabolic Remodeling in Pancreatic ß-Cells and Pancreas Histology in Autopsy Cases with Type 2 Diabetes

Abstract

Background and Aims: Metabolic remodeling from oxidative phosphorylation to glycolysis via activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) occurs in pancreatic β-cells of non-Asian individuals with type 2 diabetes (T2D), resulting in impaired β-cell function. To elucidate the underlying mechanism of metabolic remodeling, we investigated the relationship between PFKFB3 expression in β-cells and histological features of the pancreas in Japanese adults with T2D. Methods: Autopsy pancreatic sections from cadaveric donors with T2D and those without diabetes (ND) were stained with antibodies against PFKFB3, insulin, and glucagon. Ratios of PFKFB3-positive pancreatic β-cells and α-cells were compared between T2D and ND groups. Next, the relationship between PFKFB3 positivity in β-cells and histological features of the islets and pancreas were explored. We conducted thioflavin-T staining to identify amyloid deposition in islets of the T2D group and Azan staining was applied to evaluate the extent of fibrosis in ​​the pancreas. Results: In total, 36 cases (18 cases each from T2D and ND) were analyzed and 100 islets/case were evaluated. Mean ages of T2D and ND individuals were 70.3 ± 7.7 and 64.3 ± 12.8 years, and body mass indexes were 22.7 ± 4.4 and 23.3 ± 4.5 kg/m2, respectively. The PFKFB3-positive β-cell ratio was significantly higher in the T2D group (23.9 ± 16.1% vs 8.7 ± 6.3%, p < 0.05), whereas the PFKFB3-positive α-cell ratio did not differ between groups. A negative correlation between PFKFB3-positive β-cell ratio and pancreatic β-cell mass was found (ρ = −0.34, p < 0.05). In the T2D group, amyloid deposition inside the islets and pancreatic parenchymal fibrosis correlated with β-cell PFKFB3 positivity (ρ = 0.50 and ρ = 0.84; p < 0.05, respectively). Conclusion: Intracellular metabolic remodeling mediated by PFKFB3 occurred in Japanese adults with T2D and histological features of the pancreas were correlated with such changes. Disclosure R.Izumihara: None. H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. K.Chiba: None. H.Kameda: None. 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. 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. H.Mizukami: None. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. Funding Japan Society for the Promotion of Science (JP20281167); Japan Diabetes Society; MSD Life Science Foundation; Public Interest Incorporated Foundation