2099-LB: Increased Expression of PFKFB3 in Diabetic Pancreatic ß-Cells May Compensate for the Maintenance of Glucose Metabolism

Background: In diabetic pancreatic β-cells, glycolysis is activated, and the up-regulation of the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3) has been suggested to be involved in these intracellular metabolic changes, but its physiological significance remains unclear. This study aims to clarify the role of PFKFB3 up-regulation in pancreatic β-cells under diabetic conditions. Methods: Streptozotocin (STZ)-induced diabetic C57B6/J mice were divided into two groups: mice receiving the PFKFB3 inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), and their control group. The body mass, glucose tolerance and insulin secretion were compared among the groups. PFKFB3 and MafA expressions in pancreatic islets were assessed through immunostaining. INS-1 cells were cultured for 48 hours in either 5.5mM or 22mM glucose conditions with or without Pfkfb3 gene silencing and compared for gene expression and glucose-responsive insulin secretion. Results: The inhibition of PFKFB3 by 3PO resulted in a reduction of insulin secretion during high glucose stimulation and exhibited elevated blood glucose levels, indicating impaired glucose tolerance. STZ increased the PFKFB3 expression in pancreatic islets, but it was decreased by 3PO administration. The expression of MafA in pancreatic islets decreased after STZ administration, and it was further impaired with 3PO administration. In INS-1 cells, the expression of Pdx-1 and Mafa decreased under high glucose conditions, and silencing Pfkfb3 did not affect this change. However, knockdown of Pfkfb3 led to decreased insulin secretion in response to high glucose stimulation. Conclusion: The inhibition of PFKFB3 in diabetic condition worsened insulin secretion and glucose tolerance, suggesting a potential role in compensating for glucose tolerance. Disclosure K. Chiba: None. H. Nomoto: Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk. Research Support; Kowa Company, Ltd. R. Izumihara: None. H. Kameda: None. A. Nakamura: Research Support; Kowa Company, Ltd. Speaker's Bureau; Novo Nordisk, Taisho Pharmaceutical Holdings Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation. Research Support; Abbott Japan Co., Ltd., Boehringer-Ingelheim. T. Atsumi: None.