Gene-Environment Interaction of ZnT8 and Cadmium - A Link to Diabetes Mellitus?

描述(由申请人提供) 2型糖尿病的主要潜在原因是胰腺中产生胰岛素的β细胞的正常功能下降。这种β细胞衰竭的原因被认为是遗传、环境和其他因素的综合作用。锌转运蛋白ZnT8中广泛流行的遗传变异已被证明是发生2型糖尿病的遗传危险因素。锌转运蛋白8是一种锌转运蛋白，在胰岛素分泌的β细胞功能中起着重要作用。这被认为与锌的独特作用以及β细胞中高锌含量和周转有关。研究人员和其他人之前已经证明，正确的锌转运蛋白8的功能对于β细胞的正常功能非常重要。镉已被证明在几个细胞转运系统和蛋白质结合部位与锌竞争。人类对环境镉的低水平暴露是普遍存在的。这种低水平的暴露很可能对大多数器官无害。然而，探索产生胰岛素的β细胞长期暴露于低水平环境镉的影响的研究很少。研究人员在目前的研究中证实，产生胰岛素的β细胞会大量积累镉。与先前的临床证据一致的是，慢性低水平镉暴露的人患2型糖尿病的几率增加，我们的初步数据显示，在低浓度镉暴露的原代小鼠胰岛中，胰岛素分泌受损，而不会导致全球细胞毒性。锌和镉在细胞系统中的这种相互作用导致了我们的假设，即环境中低水平的镉暴露可能会加剧锌T8基因变异的影响。研究人员推测，这种基因与环境的相互作用可能会增加携带锌锌基因变异的人患糖尿病的风险。这项研究的目的是描述镉在不引起全球细胞毒性的情况下损害胰岛细胞功能的机制。此外，他们还将研究镉暴露与导致β细胞功能受损的锌离子变化之间的相互作用。 公共卫生相关性：2型糖尿病的主要潜在原因是胰腺中产生胰岛素的β细胞的正常功能下降。先前的研究表明，基因ZnT8的遗传变异会损害产生胰岛素的β细胞的功能，从而增加患2型糖尿病的风险。我们的研究将检查微量工业重金属镉的摄入是否会加剧这种基因变异对β细胞的损害，从而显著增加携带这种基因变异的人患2型糖尿病的风险。

DESCRIPTION (provided by applicant) The main underlying cause of type 2 diabetes mellitus is a decline in the normal function of the insulin producing beta cells in the pancreas. The cause of this beta cell failure is thought to be combination of genetic, environmental, as well as other factors. A widely prevalent inherited variation in the zinc transporter ZnT8 has been shown to be genetic risk factors for developing type 2 diabetes mellitus. ZnT8 is a zinc transporter that plays an important role in the function of insulin producing beta cells. This is thought to be related to the unique roles of zinc and the high zinc content and turnover in beta cells. The investigators and others have previously shown that proper function of ZnT8 is important for a normal function of beta cells. Cadmium has been shown to compete with zinc in several cellular trafficking systems and protein binding sites. Low-level human exposure to environmental cadmium is widely prevalent. It is likely that this low level of exposure is not harmful to most organs. However, studies exploring the effect of chronic exposure of insulin producing beta cells to low levels of environmental cadmium are scarce. The investigators established in current studies that insulin- producing beta cells accumulate cadmium avidly. Consistent with prior clinical evidence for an increased incidence of type 2 diabetes mellitus in persons with a chronic, low level of cadmium exposure, our preliminary data show impaired insulin secretion without inducing global cell toxicity in primary murine islets exposed to low concentrations of cadmium. This interaction between zinc and cadmium in cellular systems lead to our hypothesis that low level environmental cadmium exposure may compound the effects of genetic variations in ZnT8. The investigators hypothesize that this gene-environment interaction may potentiate the risk of diabetes mellitus in carriers of the genetic variation in ZnT8. The goal of this study is to characterize the mechanism by which cadmium impairs beta cell function without inducting global cell toxicity. Furthermore, they will examine the interaction between cadmium exposure and variations in ZnT8 in causing impairment in beta cell function. Public Health Relevance: The main underlying cause of type 2 diabetes mellitus is a decline in the normal function of the insulin producing beta cells in the pancreas. Prior research has shown that an inherited variation in the gene ZnT8 increases the risk for type 2 diabetes by impairing the function of insulin producing beta cells. Our study will examine whether ingestion of trace amounts of the industrial heavy metal cadmium may compound the impairment of the beta cells caused by this genetic variation in ZnT8, thereby increasing the risk for type 2 diabetes significantly in people carrying this genetic variation.