Grant: Operating Grant

Type 2 diabetes (T2D) is characterized by progressive dysfunction and death of insulin producing beta cells in the pancreas which results in elevated blood glucose levels. Patients with T2D require life-long oral treatment to control their blood glucose and eventually most of them will require insulin therapy. Islet amyloid deposits are protein aggregates formed by a small protein named islet amyloid polypeptide that is produced in the pancreatic beta cells. Amyloid deposits are toxic to beta cells and contribute to progressive beta cell death in patients with T2D. In patients with type 1 diabetes (T1D), beta cells are destroyed by the immune system leading to insulin deficiency and increased blood glucose levels. Patients with T1D require life-long insulin therapy or replacement of beta cells with human islet transplantation. Importantly, toxic amyloid deposits also form in islets transplanted into patients with T1D which is associated with beta-cell death and may eventually lead to islet graft failure. In these studies, we will use pancreatic islets (cluster of cells containing beta cells) from mice and cadaveric human pancreatic donors as well as mouse models of islet amyloid formation, to investigate the molecular mechanisms by which amyloid formation destroys beta cells. We will use various molecular techniques to identify the cellular proteins that contribute to amyloid-induced beta-cell death and the cellular regulators of these cell death pathways. Through these studies we hope to find new therapeutic approaches to preserve insulin producing beta cells in patients with T2D and prolong survival of islet grafts in patients with T1D and thereby improve the lives of diabetic patients.