Grant: Operating Grant

In pancreatic islet beta-cells, only a small number of insulin secretory granules (SGs) are docked onto the plasma membrane (PM) and only a fraction of these docked SGs are competent or 'primed' for immediate release. Each of these sequential steps leading to secretion - release from a reserve pool within the cytoskeleton mesh just beneath the PM, insulin SG mobilization and docking onto the PM, where they undergo some time to get primed in order to become competent to undergo membrane fusion (exocytosis), are mediated by distinct sets of molecules. We recently found that majority of insulin SGs undergoing exocytosis actually arise from 'newcomer SGs' that undergo only minimal to no docking time on the PM before exocytosis; and that SGs could fuse with each other (SG-SG fusion) without having to all get to the PM to undergo exocytosis. These two novel modes of exocytosis are very efficient and could compensate for the secretory deficiency in diabetes believe to be due to the loss of fusion-competence of the pool of docked SGs. In the previous granting period, we found several of the molecules mediating the recruitment of newcomer SGs and SG-SG fusion, which we now would like to express in the pancreatic islets of diabetic rats by viral infection to see if this will improve glucose control and insulin secretion in diabetes. We also discovered and will further explore a novel protein (Septin 5) that is part of the cytoskeleton, which when disrupted could release more insulin SGs to undergo exocytosis. Insights gained from this work may reveal novel sites within these alternate pathways of exocytosis which could be targeted for drug design to optimize insulin secretion to achieve normal glycemic control in diabetes, and avert the ensuing acute and chronic diabetic complications.