199-OR: Mutation in CELA2A Drives Impaired Pancreatic Islet Development and Function

Introduction and Objective: Loss-of-function mutations in the exocrine pancreatic enzyme chymotrypsin-like elastase (CELA2A) are associated with metabolic syndrome and diabetes. CELA2A is a ubiquitously expressed protein that enters circulation and enhances both insulin secretion and sensitivity. Mice with global deletion of Cela2a exhibit impaired glucose-stimulated insulin secretion, accompanied by reduced pancreatic islet size and number, suggesting a developmental defect. These phenotypes correlated with decreased islet cell proliferation, increased inflammation, and loss of extracellular matrix (ECM) proteins in pancreatic islets. However, the precise molecular mechanisms linking CELA2A to islet development and function remained unclear. Methods: Histological analysis revealed infiltration of both the exocrine and endocrine pancreas, as well as adipose tissue, with macrophages and monocytes in CELA2A knockout (KO) mice. Further investigations showed that CELA2A is expressed and secreted by monocytes and neutrophils and stimulates insulin secretion. In CELA2A KO mice, plasma inflammatory cytokines were elevated, while anti-inflammatory IL-10 levels were reduced, suggesting systemic inflammation caused by M1 macrophage polarization. Results: Transplantation of wild-type (WT) bone marrow into CELA2A KO mice restored pancreatic islet integrity, ECM composition, and vasculature, normalized macrophage polarization, and improved islet size and function. Conversely, transplantation of CELA2A bone marrow into WT recipients induced islet defects, confirming the critical role of macrophage-derived CELA2A in maintaining pancreatic islet homeostasis. Conclusion: Macrophage-derived CELA2A is essential for maintaining an anti-inflammatory state in islet macrophages, preserving ECM integrity, and supporting pancreatic islet structure and function. These findings highlight CELA2A as a key regulator of islet health and a promising therapeutic target for type 2 diabetes and related metabolic disorders. Disclosure J. Moon: None. A. Mani: None.