Grant: Operating Grant

Type 2 diabetes is characterized by progressive loss of insulin producing beta-cells and formation of a toxic protein named islet amyloid that leads to increased blood glucose levels. Interestingly, it has been shown that toxic amyloid also forms in pancreatic islets during culture and following transplantation into type 1 diabetic patients, suggesting that formation of amyloid may also contribute to loss of transplanted islets. Fas is a protein on the surface of cells that upon activation by different toxic factors initiates activation of a group of enzymes named caspases leading to cell death. We hypothesize that amyloid kills beta-cells by activation of Fas protein and caspases and that inhibition of these enzymes may enhance survival and function of insulin producing islet beta-cells in type 2 diabetes as well as in transplanted human islets. We will perform studies in cultured cells and isolated islets from mice and cadaveric human donors to investigate the role of Fas in mediating amyloid toxicity. We will also perform experiments to investigate whether inhibition of Fas and caspase activation will protect insulin producing beta-cells from the toxic effects of islet amyloid during culture and following transplantation into diabetic mice. Through these experiments, we hope to gain a better understanding of how toxic amyloid fibrils kill beta-cells and identify potential targets for new therapies for type 2 diabetes as well as finding new ways to increase success of human islet transplantation in type 1 diabetic patients.