1746-P: The Role of Cell–Cell Junction Associated Mediator in Glucose-Stimulated Insulin Secretion of Pancreatic Islets

Glucose-stimulated insulin secretion from β cells is essential in maintaining glucose homeostasis. Cell-cell communication within the pancreatic islets, mediated by cell-cell junctions and their mediators, regulates insulin secretion dynamics and glucose homeostasis. It has been reported that Nephrin-mediated intercellular junction between β cells is implicated in the regulation of insulin secretion, however, the underlying mechanisms are not fully understood. Here, we investigated the effects of Girdin, a cell-cell junction associated mediator, on insulin release. We found that Girdin was expressed in mouse pancreatic β cells and mediated glucose-stimulated insulin secretion, especially for the second phase. Next, we demonstrated that glucose-stimulated tyrosine phosphorylation of Girdin mediated Nephrin phosphorylation by recruiting Src kinase, which leads to the endocytosis of Nephrin. Furthermore, we observed the glucose-induced Girdin/Nephrin/Src signaling induced downstream Akt phosphorylation and activated Rac1-mediated cytoskeleton reorganization, allowing insulin secretory granules to access the plasma membrane for the second-phase secretion. Finally, we found that Girdin is downregulated in the diabetic islets, and rescue of Girdin restored impaired glucose-stimulated insulin secretion. Taken together, these data provide evidence that the cell-cell junction associated mediator play important roles in fusion of insulin secretory vesicles within the cell and establish a role for Girdin in regulating this process.