Mechanisms of Cadmium Induced Dysglycemia and Type 2 Diabetes Mellitus

项目概要： 在胰岛素抵抗的情况下，产生胰岛素的β细胞的失败是2型糖尿病的主要潜在原因。 糖尿病的遗传易感性、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。其他人和我们以前发表的研究表明，低水平的慢性 在一般人群中暴露于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，我们发现 在体内暴露于镉导致血糖升高，伴随着改变胰岛素分泌的小鼠。我们 还发现，产生胰岛素的胰腺β细胞大量积累镉，导致胰岛素受损， 分泌和内质网应激的迹象增加。拟议研究的目标是 研究暴露于各种环境相关浓度的镉的机制， 削弱β细胞胰岛素分泌。具体来说，我们将在现有初步数据的基础上， 假设镉在产生胰岛素的β细胞中的积累通过损害 正常锌介导的胰岛素加工，导致错误折叠的胰岛素和ER应激的积累。的 这些研究的影响将是一个低的作用机制表征，但环境现实 镉浓度在2型糖尿病的发展。

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.