Role of IAPP in Islet Dysfunction in Diabetes

描述(由申请人提供)：这项研究计划的总体目标是建立导致2型糖尿病患者胰岛功能障碍的机制，更广泛的目标是促进旨在预防或逆转2型糖尿病的方法的基本设计。人类2型糖尿病(T2 DM)的胰岛是由胰岛淀粉样多肽(IAPR)衍生的胰岛淀粉样蛋白，IAPR是一种与胰岛素共表达和分泌的蛋白质。人IAPP(h-IAPP)在溶液中有形成低聚物的倾向。这些寡聚体在脂膜上形成非选择性离子通道，并可诱导细胞凋亡。在之前的资助周期中，我们发现患有T2 DM的人的b细胞质量减少了~65%，至少部分原因是b细胞凋亡率增加了约10倍。我们还报道了空腹血糖受损(IFG)的人的b细胞质量下降了约50%，这意味着b细胞质量的丧失先于高血糖的发展。我们建立了h-IAPP转基因大鼠(HIP)和小鼠的糖尿病模型，其特征是由于b细胞凋亡增加导致b细胞质量进行性缺陷。初步研究表明，h-IAPP的毒性是通过内质网应激介导的，这在T2 DM患者中是活跃的。在拟议的研究中，我们试图解决以下问题。2)h-IAPP诱导b细胞凋亡的机制是什么？这种机制在IFG和T2 DM患者中是否起作用？3)有毒的IAPP寡聚体是否在细胞内形成并导致内质网膜渗漏？4)我们能否预防HIP(h-IAPP转基因)大鼠糖尿病的发生？这项研究计划将使我们能够阐明人类b细胞丢失的根本原因，并建立防止这种情况的基本方法。

DESCRIPTION (provided by applicant): 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 b-cell mass is decreased by ~65% in humans with T2DM, at least in part due to a ~10-fold increase in b-cell apoptosis. We also reported that b-cell mass is ~50% decreased in humans with impaired fasting glucose (IFG), implying that the loss of b-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 b-cell mass due to increased b-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 b-cell apoptosis increased in humans with IFG? 2) What is the mechanism of h-IAPP induced b-cell apoptosis, and is this mechanism active in humans with IFG and T2DM? 3) Do toxic IAPP oligomers form intracellularly and cause endoplasmic reticulum membrane leakage? 4) Can we prevent 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 b-cells in humans, and to establish a rationale approach to preventing this.