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 the cells have died after trying to produce too much insulin for too long a period of time. A protein called PERK is essential for beta cells to produce sufficient amounts of active insulin and importantly, humans who carry a PERK protein that does not work develop diabetes early in life. We recently found that mice lacking a protein called Nck1 have powerful beta cells that make and release more insulin than those of normal mice, without any signs of cell fatigue. We discovered that Nck1 normally interacts with and decreases PERK activity, inhibiting PERK's beneficial effects on beta cells to produce insulin and survive stress. Our goal is to produce robust human beta cells by preventing the Nck1 and PERK interaction. For this, we will decrease levels of Nck1 in pancreatic beta cells to minimize its interaction with PERK. We will then test whether these strategies improve the production of active insulin and protect against diabetes-related stresses. Given that PERK is important for healthy beta cells, our discovery that the Nck1/PERK interaction controls insulin production AND beta cell survival in the face of stress is promising. We propose that weakening this interaction could serve many purposes toward treating diabetes, including improving the function and health of beta cells in the body and those destined for transplantation.