Role of IAPP in Islet Dysfunction in Diabetes

本研究计划的总体目标是建立导致胰岛功能障碍的机制， 2型糖尿病，更广泛的目标是促进预防或治疗方法的合理设计， 逆转2型糖尿病2型糖尿病（T2 DM）患者的胰岛特征为胰岛细胞功能异常。 来源于胰岛淀粉样蛋白多肽（IAPR）的淀粉样蛋白，其是与胰岛淀粉样蛋白多肽共表达和分泌的蛋白质。 胰岛素人IAPP（h-IAPP）具有在溶液中形成寡聚体的倾向。这些低聚物导致 脂质膜中的非选择性离子通道，并可诱导细胞凋亡。 在之前的研究周期中，我们确定了T2 DM患者的p细胞质量减少了约65%， 至少部分是由于β-细胞凋亡增加约10倍。我们还报道了p细胞质量约为50% 在空腹血糖受损（IFG）的人中减少，这意味着p细胞质量的损失先于 高血糖症的发展。我们建立了h-IAPP转基因大鼠（HIP）和小鼠模型， 发展为特征在于由于增加的P细胞凋亡导致的P细胞质量的进行性缺陷的糖尿病。 初步研究表明，h-IAPP毒性是通过内质网应激介导的， 这在T2 DM患者中是有效的。 在拟议的研究中，我们试图解决以下问题。 1)IFG患者的0细胞凋亡是否增加？ 2)h-IAPP诱导0细胞凋亡的机制是什么，这种机制是否活跃 在IFG和T2 DM患者中？ 3)有毒的IAPP寡聚体是否在细胞内形成并引起内质网 膜渗漏？ 4)我们能预防HIP（h-IAPP转基因）大鼠糖尿病的发生吗？ 这项研究计划将使我们能够揭示人类p细胞丢失的根本原因， 并建立一个合理的方法来防止这种情况。

The overall goals of this research program is to establish the mechanisms leading to islet dysfunction in type 2 diabetes with a wider goal of facilitating rationale design of approaches designed to prevent or reverse type-2 diabetes. The islet in humans with type 2 diabetes mellitus (T2DM) is characterized by islet amyloid derived from islet amyloid polypeptide (IAPR), a protein that is co-expressed and secreted with insulin. Human IAPP (h-IAPP) has the propensity to form oligomers in solution. These oligomers cause non-selective ion channels in lipid membranes and can induce apoptosis. In the prior grant cycle we established that p-cell mass is decreased by ~65% in humans with T2DM, at least in part due to a ~10-fold increase in p-cell apoptosis. We also reported that p-cell mass is ~50% decreased in humans with impaired fasting glucose (IFG), implying that the loss of p-cell mass precedes development of hyperglycemia. We established h-IAPP transgenic rat (HIP) and mouse models which develop diabetes characterized by a progressive defect in p-cell mass due to increased p-cell apoptosis. Preliminary studies suggest h-IAPP toxicity is mediated through endoplasmic reticulum stress, and that this is active in patients with T2DM. In the proposed studies we seek to address the following questions. 1) Is 0-cell apoptosis increasedin humans with IFG? 2) What is the mechanism of h-IAPP induced0-cell apoptosis, and is this mechanism active in humans with IFGand T2DM? 3) Do toxic IAPP oligomers form intracellularly and cause endoplasmic reticulum membrane leakage? 4) Can weprevent development of diabetes in the HIP(h-IAPP transgenic) rat? This program of studies would allow us to shed light into the underlying cause of loss of p-cells in humans, and to establish a rationale approach to preventing this.