1797-P: GLP-1/GLP-1 Receptor Autocrine Loop Mediates Glucagon Receptor Antagonism-Induced α-Cell Phenotype Conversion

Introduction and Objective: This study aimed to explore the mechanism of glucagon receptor (GCGR) antagonism-induced α-cell phenotype conversion. Methods: Streptozotocin-induced diabetic mice were treated with GCGR monoclonal antibody (mAb) or vehicle. ELISA, IF and transcriptomic analysis were evaluated to uncover the mechanism. Foxa2 knockdown α-cell line, GLP-1 receptor (GLP-1R) antagonist in mouse primary islets and global Glp1r knockout mice were used to clarify the pathway. Results: The number of glucagon+ cells, glucagon+ GLP-1+ cellls (indicating pro-α-cells), glucagon+Ngn3+ cells (indicating progenitors), and glucagon+insulin+ cells (indicating α-to-β cell transdifferentiation) were higher in GCGR mAb group, suggesting that GCGR antagonism promoted α-cell regeneration and induced α-cell-pro-α-cell-progenitor-β-cell conversion. Additionally, GLP-1 production and GLP-1R staining in α-cells were enhaced with GCGR mAb treatment in diabetic mice. GCGR mAb upregulated Ngn3 and Pcsk1 expression and GLP-1 production in mouse primary islets, while addition of GLP-1R antagonist reversed these effects. Notably, the glucagon+ cell area were boosted to a similar level in GCGR mAb-treated Flox/cre littermates and Glp1r-/- mice, while the numbers of glucagon+GLP-1+ cells and glucagon+insulin+ cells were both decreased in GCGR mAb-treated Glp1r-/- mice compared to GCGR mAb-treated littermates. By transcriptomic analysis, Foxa2 expression was found to decrease in isolated α-cells of GCGR antagonism group and its knockdown in α-cell line resulted in downregulation of mature α-cell markers, Arx and Pax6, and upregulation of Pcsk1, similarly to GCGR antagonism. Conclusion: GCGR antagonism could promote α-cell converting to GLP-1-producing pro-α-cells and to β-cells sequentially. Enhanced GLP-1/GLP-1R autocrine loop mediates GCGR antagonism induced-α-cell phenotype conversion and FoxA2 potentially participate in this process. Disclosure T. Wei: None. X. Cui: None. D. Wang: None. X. Liao: None. J. Yang: None. R. Wei: None. T. Hong: None. Funding Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507000, 2023ZD0506900), National Natural Science Foundation of China (82270843, 82400936)