(Scanned from the applicant's description) The overall aim of the studies proposed in this application is to establish the role of Islet Amyloid Polypeptide (IAPP) in the abnormal function of the pancreatic islets in Type-2 Diabetes. IAPP is a protein that is synthesized and secreted along with insulin by insulin secreting cells in the pancreatic islet. Non-diabetic humans do not have these deposits, although they also synthesize and secrete IAPP along with insulin and have similar levels circulating in their blood as people with Type-2 diabetes. The question arises therefore, why are these deposits present in people with Type-2 Diabetes, and do they contribute to the disease process? Type-2 Diabetes is characterized by a gradual onset with declining function of the insulin secreting cells in the islet. It is not clear if this is because there are not enough of these cells available or because they fail to function. The first specific aim of this application is to establish, in pancreas tissue obtained at autopsy from humans whether there is a deficiency in the number of insulin secreting cells. Also we will seek to establish if any change in the mass of these cells is due to increased cell death and/or decreased new cell and islet formation. The second specific aim of this application is to determine if excessive LAPP secretion by remaining insulin-secreting cells contributes to defective islet function in Type-2 diabetes. It is difficult to study the cause of IAPP amyloid deposits and their role in pancreatic islet failure in humans because of the location of the pancreas. We have developed transgenic models in mice and rats, which develop diabetes very comparable to that seen in humans. The third specific aim is to establish in these models exactly where IAPP forms deposits in the living islet and if it causes insulin-secreting cells to die excessively or prevents new cells forming. The fourth specific aim is to identify the link between aggregation of IAPP in the islet and cell death (or failed replication), and to develop methods to prevent this with long-term aim of developing strategies to prevent Type-2 diabetes.
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