Role of IAPP in islet dysfunction in diabetes

描述：（从申请人的描述扫描）的总体目标 本申请中提出的研究是确定胰岛淀粉样蛋白的作用 2型糖尿病胰岛功能异常与IAPP的关系 糖尿病IAPP是一种与胰岛素一起沿着合成分泌的蛋白质 由胰岛中的胰岛素分泌细胞分泌。而非糖尿病患者则不会 有这些存款，虽然他们也合成和分泌IAPP连同沿着 他们血液中的胰岛素水平与 2型糖尿病因此，问题就来了，为什么这些沉积物存在 在2型糖尿病患者中，它们是否促进了疾病的发展？ 2型糖尿病的特征是逐渐发作，伴随着糖尿病的功能下降。 胰岛中的胰岛素分泌细胞。目前尚不清楚这是否是因为 没有足够的这些细胞可用，或者因为它们不能发挥作用。 本申请的第一个具体目的是在胰腺组织中建立 从人体尸检中获得的是否存在数量不足， 胰岛素分泌细胞。此外，我们将寻求确定是否有任何变化， 这些细胞的质量是由于增加的细胞死亡和/或减少的新细胞 和胰岛形成。 本申请的第二个具体目的是确定是否存在过量的LAPP 剩余的胰岛素分泌细胞的分泌导致胰岛缺陷 2型糖尿病的治疗方法 很难研究IAPP淀粉样蛋白沉积的原因及其在炎症中的作用。 由于胰腺的位置，人类的胰岛功能衰竭。我们 已经在小鼠和大鼠中开发了转基因模型， 与在人类中看到的相似。 第三个具体目标是在这些模型中确定IAPP形成的确切位置 如果它导致胰岛素分泌细胞死亡 过度或阻止新细胞形成。 第四个具体目标是确定机构间采购方案汇总与 胰岛和细胞死亡（或复制失败），并开发方法， 预防这种情况的长期目标是制定预防2型糖尿病的战略 糖尿病

DESCRIPTION: (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.