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

ZnT8 和镉的基因-环境相互作用 - 与糖尿病有关吗？

• 批准号: 8608526
• 负责人: Malek El Muayed
• 金额: $ 13.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-09 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608526
• 关键词: Address; Age Factors; Amino Acids; Animals; Apoptosis; Arginine; Beta Cell; Binding Sites; Cadmium; Cadmium chloride; Cell Line; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Data; Diabetes Mellitus; Environment; Environmental Risk Factor; Epidemiology; Exposure to; Failure; Functional disorder; Future; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Heavy Metals; High Prevalence; Homeostasis; Hour; Human; Impairment; Incidence; Ingestion; Inherited; Inhibitory Concentration 50; Insulin; Insulin Resistance; Islet Cell; Lead; Link; Measures; Missense Mutation; Mission; Mus; National Institute of Environmental Health Sciences; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Persons; Play; Positioning Attribute; Predisposition; Production; Protein Binding; Reporting; Research; Research Personnel; Risk; Role; Structure of beta Cell of islet; System; Techniques; Toxic effect; Training; Tryptophan; United States National Institutes of Health; Variant; Wild Type Mouse; Zinc; blood glucose regulation; diabetes mellitus genetics; exposed human population; gene environment interaction; genetic risk factor; glucose production; in vivo; insight; insulin secretion; islet; lifestyle factors; non-diabetic; novel; overexpression; public health relevance; research study; risk variant; trafficking; translational study; zinc-binding protein

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.

描述（由申请人提供） 2 型糖尿病的主要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、环境以及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 型糖尿病的遗传风险因素。 ZnT8 是一种锌转运蛋白，在产生胰岛素的 β 细胞的功能中发挥着重要作用。这被认为与锌的独特作用以及β细胞中锌的高含量和周转率有关。 研究人员和其他人之前已经表明，ZnT8 的正常功能对于 β 细胞的正常功能非常重要。镉已被证明在多个细胞运输系统和蛋白质结合位点中与锌竞争。人类对环境镉的低水平暴露是普遍存在的。这种低水平的接触可能不会对大多数器官造成伤害。 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却很少。研究人员在当前的研究中证实，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，即长期、低水平镉暴露的人 2 型糖尿病发病率增加，我们的初步数据显示，在暴露于低浓度镉的原代小鼠胰岛中，胰岛素分泌受损，但没有诱导整体细胞毒性。细胞系统中锌和镉之间的这种相互作用导致我们假设低水平的环境镉暴露可能会加剧 ZnT8 遗传变异的影响。 研究人员推测，这种基因-环境相互作用可能会增加 ZnT8 遗传变异携带者患糖尿病的风险。本研究的目的是确定镉损害 β 细胞功能而不诱导整体细胞毒性的机制。 此外，他们还将研究镉暴露与 ZnT8 变异之间的相互作用，从而导致 β 细胞功能受损。 公共健康相关性：2 型糖尿病的主要原因是胰腺中产生胰岛素的 β 细胞正常功能下降。先前的研究表明，ZnT8 基因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。我们的研究将检验微量工业重金属镉的摄入是否会加剧由 ZnT8 基因变异引起的 β 细胞损伤，从而显着增加携带这种基因变异的人患 2 型糖尿病的风险。