2670-P: Myocyte Enhancer Factor 2A (MEF2A) Is a Negative Regulator of Beta-Cell Maturation and Function

Introduction and Objective: Pancreatic beta cell endoplasmic reticulum (ER) function is essential for insulin synthesis and glucose homeostasis. Maladaptive ER stress during metabolic stress is a key driver of beta dysfunction in diabetes. We identified selective upregulation of myocyte enhancer factor 2a (Mef2a) under chronic ER stress. This study aimed to define the role of Mef2a in beta identity, maturation, and function. Methods: Primary mouse islet cells were exposed to mild, moderate, and severe ER stress. Bulk RNA sequencing identified gene networks altered during chronic stress, and bioinformatic analysis revealed dysregulation of the Mef2a activity. Functional studies included adenoviral overexpression and knockdown of Mef2a in primary mouse and human beta cells. The beta cell function was assessed using an ex vivo glucose-stimulated insulin secretion assay (GSIS), mitochondrial respiration via Seahorse XF analysis, and beta cell maturation and functional markers by quantitative PCR. Results: RNA-seq identified that Mef2a activity was induced selectively during maladaptive ER stress. Overexpression of Mef2a in mouse and human islet cells led to loss of beta cell identity, reduced glucose sensing and transport, impaired mitochondrial respiration, and complete loss of GSIS. Across primary mouse, human, and stem cell-derived beta cells, Mef2a expression was negatively correlated with beta cell maturation and function. Conversely, Mef2a knockdown during chronic ER stress reduced ER-stress signaling, preserved beta cell differentiation markers, and restored insulin secretion under basal and stress conditions. Conclusion: Mef2a functions as a Ca²+-sensitive regulator linking ER stress to beta cell dysfunction and failure. Inhibiting Mef2a mitigates ER stress-induced beta cell failure and restores insulin secretion, supporting Mef2a as a promising therapeutic target to prevent diabetes progression. Disclosure R. Sharma: None. C. Darko: None. Y. Wang: None. T. Lama: None. Funding Institutional Funds