PROJECT SUMMARY Diabetes afflicts 366 million worldwide and results in one death every 7 seconds, with 80% of deaths occurring in low- and middle-income countries. Additionally, diabetes creates $465 billion in healthcare costs every year. Central to the pathology of type 1 and 2 diabetes is dysfunction and death of insulin-producing beta cells. Our search for mechanisms to prevent beta-cell dysfunction and death, and to regenerate the lost beta-cell mass, led us to organisms with extreme metabolic physiology. Through millions of years of evolution, extreme organisms have arisen that thrive under conditions otherwise pathological to humans. One such group of organisms are binge-eating snakes, whose beta cells survive under conditions that are pathological to human beta cells. We have identified a group of such snakes whose beta cells can withstand hypoxia, hyperoxia, lipotoxic stress, and undergo non-pathologic hypertrophy when these snakes eat their large meals. Further, our data suggests that these snakes possess molecules that can induce desirable phenotypes in mammalian beta cells. The goal of this proposal is to identify the molecules that enhance human beta-cell mass and function. We also propose to delineate the signaling pathways that underlie the other extreme phenotypes exhibited by the beta cells of these snakes, with the ultimate aim of manipulate these pathways in human beta cells using small molecules.