Pancreatic cancer is one of the most deadly forms of cancer, but it is also one of the least well understood. We cannot design an intelligent cure for a disease that we know so little about. In particular, the exact events that initiate pancreatic cancer and accelerate its progression remain unclear. A growing body of evidence indicates that lifestyle factors like diet and obesity are important risk factors for pancreatic cancer. It has been suggested that the elevated levels of insulin caused by high-fat, high-sugar diets might promote rapid growth of cells in the pancreas, an event that could contribute to the development of pancreatic cancer. Over the past 5 years, our research team has made important discoveries on the effects of insulin on a small subset of pancreas cells that are not associated with the most common forms of pancreatic cancer. We have also developed the first animal model where manipulation of insulin genes renders mice resistant to the effects of a high fat diet on elevated insulin levels. We now plan to leverage this new model and our expertise to better understand the effects of insulin on pancreatic cancer cells. The overall goal of the proposed research is to determine whether elevated insulin increases pancreatic cancer and to understand how insulin produces these effects. Given the alarming rise in the incidence of obesity and hyperinsulinemia, it is critical to know exactly how these lifestyle factors affect pancreatic cancer risk. Together, these studies have the potential to increase our understanding of this devastating disease. Therefore, these investigations will improve our chances of finding effective treatments for pancreatic cancer.