2673-P: Defining the Role of P21 in β-Cell Senescence Using a Loss-of-Function Model

Introduction and Objective: As senescent β-cells accumulate with age, their presence can further lead to β-cell dysfunction and decreased proliferation. Although cyclin-dependent kinase (Cdk) p21 is a known marker and effector of cellular senescence, the role of p21 in the establishment of β-cell senescence remains unknown. We investigated the necessity of p21 in the development of β-cell senescence using a loss-of-function model. Methods: We used the p21-ATTAC mouse model, which allows for the clearance of p21-positive senescent cells upon injection of B/B homodimerizer (B/B). Isolated islets from p21-ATTAC mice were cultured with/without BB for 72 hours in vitro and analyzed with RT-qPCR. For in vivo experiments, p21-ATTAC mice under chow diet or high-fat diet (HFD) were administered B/B intraperitoneally biweekly for 4 weeks. Intact pancreas perfusions were performed. Results: After treating p21-ATTAC mouse islets with B/B in vitro, there was a clear decrease in p21 mRNA levels by 33% confirming feasibility of our model. Consistent with these results, in vivo experiments showed a decrease in p21 mRNA levels of up to 70% in islets isolated from B/B-treated p21-ATTAC male mice compared to untreated mice. Furthermore, HFD increased blood glucose levels, which were restored after p21 deletion in male mice, but not in chow diet. Deletion of p21 in male under HFD exhibited lower blood glucose levels during insulin tolerance test (ITT), indicating improved peripheral insulin sensitivity. Although female p21-ATTAC mice maintained normal blood glucose levels, they had a greater decrease in basal insulin secretion after B/B treatment compared to male mice, suggesting improved β-cell function. Conclusion: The clearance of p21-positive cells in p21-ATTAC mice improved glucose levels and decreased insulin resistance. The p21-ATTAC mouse model serves as a tool to further study cellular senescence in β-cells. Disclosure S. Le: None. K. Iwasaki: None. J. Hollister-Lock: None. C. Cahill: None. C. Aguayo-Mazzucato: Consultant; Ended; Novo Nordisk, Sanofi. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R25DK140752-01)