Mechanisms of Cadmium Induced Dysglycemia and Type 2 Diabetes Mellitus

项目总结： 胰岛素抵抗中产生胰岛素的β细胞失败是2型的主要潜在原因 糖尿病。遗传易感性、年龄、生活方式和环境因素导致β细胞衰竭 在2型糖尿病中。其他人和我们之前发表的研究表明，低水平的慢性 在普通人群中接触非必需的过渡金属镉(Cd)与 糖尿病前期和2型糖尿病的风险增加。在最近的初步研究中，我们已经表明 在体内接触Cd会导致小鼠血糖升高，并伴随着胰岛素分泌的改变。我们 研究还发现，产生胰岛素的胰岛β细胞大量积聚镉，导致胰岛素受损。 分泌物和内质网应激征象增加。拟议研究的目标是 研究接触各种与环境有关的浓度镉的机制 会削弱胰岛细胞产生胰岛素的能力。具体地说，我们将以目前的初步数据为基础，探索 该假说认为Cd在产生胰岛素的β细胞中的积累通过损害 正常锌干预胰岛素处理，导致错误折叠的胰岛素积累和内质网应激。这个 这些研究的影响将是一个机械性的角色表征，低，但环境现实 镉在2型糖尿病发病中的浓度。

Project summary: Failure of insulin producing beta cells in the setting of insulin resistance is the main underlying cause for type 2 diabetes mellitus. Genetic susceptibility, age, lifestyle, and environmental factors contribute to beta cell failure in type-2 diabetes mellitus. Others and we previously published studies showing that low-level chronic exposure to the non-essential transition metal cadmium (Cd) in the general population is associated with an increase in the risk of prediabetes and type 2 diabetes mellitus. In recent preliminary studies, we have shown that in vivo exposure to Cd caused a rise in blood sugar accompanied by altered insulin secretion in mice. We also found that insulin-producing pancreatic beta cells accumulate Cd avidly, leading to impaired insulin secretion and an increase in signs of endoplasmatic reticulum stress. The goal of the proposed studies is to examine the mechanism by which exposure to various, environmentally relevant concentrations of cadmium impair insulin production from beta cells. Specifically, we will build on our current preliminary data and explore the hypothesis that accumulation of Cd in insulin producing beta cells causes beta cell toxicity by impairing normal zinc medicated insulin processing with resulting accumulation of misfolded insulin and ER stress. The impact of these studies will be a mechanistic characterization of the role of low, but environmentally realistic concentrations of Cd in the development of type 2 diabetes mellitus.