Grant: Project Grant

Pancreatic beta cells make and release insulin, the hormone controlling blood glucose in humans. When people develop diabetes, it may be because their beta cells are producing less or no insulin, or possibly run out and die after trying to produce more insulin for a long period of time. A protein called PERK was found to be essential for beta cells to produce sufficient amount of active insulin and importantly, humans who carry non-functional PERK develop diabetes early in life. We recently found that mice lacking the protein Nck1 display powerful beta cells that produce and release more insulin than those of normal mice and this without any sign of fatigue. We discovered that Nck1 interacts with and decreases PERK activity. Thus, Nck1 counteracts PERK's beneficial effects on beta cells capacity to produce insulin, as well as survive to stress. Our objective is then to produce robust human beta cells by preventing Nck1 and PERK interaction. For this, we will decrease the levels of Nck1 or neutralize Nck1 in pancreatic beta cells to minimalize its interaction with PERK. We will determine whether these strategies improve beta cells function in producing active insulin and resisting to diabetes-related stress. Novel avenues to improve pancreatic beta cell function and survival to stress relevant to diabetes will benefit the prevention, treatment and even the cure of this disease. Given that PERK is of importance for healthy beta cells, our discovery that Nck1 through regulating PERK, not only modulates insulin production by the beta cells, but also their survival to stress is promising in the sense that any approach that weaken this interaction may lead to a slight increase in PERK activity that could be tremendously helpful to improve beta cells function and prevent their death associated with diabetes.