2665-P: Hsa-miR-502-3p Promotes Mitochondrial Beta-Cell Apoptosis via Targeting SLC25A13 and Is Associated with Remission after Short-Term Intensive Insulin Therapy in Type 2 Diabetes

Introduction and Objective: Short-term intensive insulin therapy (SIIT) restores beta-cell function and induces remission in newly diagnosed type 2 diabetes (T2D), yet the mechanisms remain unclear. Our preliminary data indicated that lower baseline circulating hsa-miR-502-3p predicted long-term remission after SIIT. This study aimed to investigate the role of hsa-miR-502-3p in beta-cell dysfunction. Methods: Hsa-miR-502-3p expression was analyzed using GEO datasets and validated by FISH and RT-qPCR in islets from db/db mice and MIN6 cells exposed to glucolipotoxicity. Transcriptomic profiling, beta-cell apoptosis, proliferation, and GSIS were assessed following hsa-miR-502-3p overexpression. Mitochondrial function was evaluated by ROS and JC-1 assay. Target validation was performed via dual-luciferase reporter assay. Results: Hsa-miR-502-3p levels were elevated in serum (1.4-fold, P = 0.09) and islets (1.2-fold) of T2D patients compared with healthy controls. This upregulation was confirmed in db/db mouse islets and MIN6 cells exposed to glucolipotoxicity. Circulating hsa-miR-502-3p levels decreased following SIIT (P 0.05). Functional studies in MIN6 cell demonstrated hsa-miR-502-3p overexpression increased cleaved caspase-3 expression (2-fold), reduced EdU-positive cells by approximately 30%, and impaired GSIS (Insulin stimulation index: 1.33 vs 3.34 in controls). Concurrently, intracellular ROS levels increased while mitochondrial membrane potential decreased. The dual-luciferase assay confirmed hsa-miR-502-3p targeted the 3'UTR of SLC25A13, a key component of the malate-aspartate shuttle. GSVA revealed enrichment of mitochondrial apoptosis pathways. Conclusion: Glucolipotoxicity upregulates hsa-miR-502-3p, which induces mitochondrial beta-cell apoptosis by targeting SLC25A13. Lower baseline serum hsa-miR-502-3p levels may reflect greater residual beta-cell mass and predict sustained drug-free remission following SIIT. Disclosure S. Tang: None. W. Ke: None. Z. Zheng: None. Y. Li: None. L. Liu: None. Funding Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0531902)