Abstract

Pancreatic beta cells secrete insulin as a response to rises in blood glucose. Using INS-1 cells I identified EDEM1 as a critical signal for glucose-stimulated insulin secretion. EDEM1 is an endoplasmic reticulum (ER)-stress induced protein that targets misfolded glycoproteins for ER-associated degradation (ERAD). I demonstrated that overexpression of EDEM1 in beta cells accelerates ERAD, reduces the ER stress and facilitates proinsulin folding. In these cells, proinsulin released from the ER engages in a committed route towards the secretory vesicles, with an efficient conversion to insulin and secretion upon glucose-stimulation. Similarly, intact human islets transduced with EDEM1 released, on the average, twice as much insulin. This investigation showed that overexpression of EDEM1 can ameliorate beta cell function and support  EDEM1 as potential target for the treatment of diabetes. The project aim is to investigate the molecular mechanism by which EDEM1 increases insulin secretion in pancreatic beta cells and to transfer these results into a method that can be applied into the clinical trials, to humans as potential treatement of diabetes mellitus. This will allow the development of a  new method to treat diabetes mellitus using CRISPR Knock-In method designed to improve the physiology of the pancreatic cell.