2679-P: Mechanisms and Consequences of IL-1β-Mediated Changes in β-Cell Function

Introduction and Objective: Chronic low-grade inflammation and activation of the NLRP3 inflammasome accompany obesity and aging and are associated with impaired glucose clearance. We hypothesize that this impairment is driven, at least in part, by IL-1β-mediated defects in insulin secretion or maturation. Methods: We used wild-type and immune cell-specific IL-1β knockout mice and isolated islets. The expression levels of key prohormone convertases, PC1/3 and PC2, were assessed following cytokine exposure. Islets were treated with the IL-1 receptor antagonist anakinra to determine the cytokine's effect on the islets. In parallel, mice were monitored longitudinally for up to two years with circulating insulin and proinsulin measured over time. Finally, pharmacological IL1R1 blockade was used to evaluate therapeutic potential in aged mice. Results: Aging mice exhibited increased insulin and proinsulin, accompanied by a reduced insulin-to-proinsulin ratio. At the same time, pancreatic islets of aged mice showed decreased proinsulin processing enzymes expression. Thus suggesting a progressive impairment in insulin maturation with aging. Ex vivo, IL-1β directly downregulated the processing enzymes in pancreatic islets. However, immune cell-specific IL-1β deletion did not show an improvement in the insulin-to-proinsulin ratio. Furthermore, short-term, systemic IL-1R1 antagonism failed to restore enzyme expression or insulin maturation in aged mice. Conclusion: Our work demonstrates that age-associated inflammatory signaling impairs proinsulin processing ex vivo. However, genetic and pharmacological targeting of IL-1β signaling was insufficient to restore insulin maturation in vivo, potentially reflecting limited treatment duration and/or the contribution of additional inflammatory pathways. Disclosure K. Sifoniou: None. L. Rachid: None. D.T. Meier: None. M. Donath: Advisory Panel; Ended; Novo Nordisk, Lilly. Board Member; Current; Olatec.