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: 8225901
• 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/8225901
• 关键词: Address; Age Factors; Alleles; 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; 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，环境和其他因素的结合。 锌转运蛋白ZnT 8的一种广泛流行的遗传变异已被证明是发展2型糖尿病的遗传危险因素。 ZnT 8是一种锌转运蛋白，在产生胰岛素的β细胞的功能中起重要作用。这被认为与锌的独特作用以及β细胞中的高锌含量和周转有关。 研究人员和其他人先前已经表明，ZnT 8的正常功能对于β细胞的正常功能很重要。镉已被证明在几个细胞运输系统和蛋白质结合位点与锌竞争。人类低水平接触环境镉的情况普遍存在。这种低水平的暴露可能对大多数器官无害。 然而，研究探索胰岛素产生β细胞长期暴露于低水平的环境镉的影响是罕见的。研究人员在目前的研究中证实，产生胰岛素的β细胞大量积累镉。 与先前的临床证据一致，慢性低水平镉暴露的人2型糖尿病的发病率增加，我们的初步数据显示，在接触低浓度镉的原代小鼠胰岛中，胰岛素分泌受损，而不诱导整体细胞毒性。锌和镉在细胞系统中的这种相互作用导致我们的假设，低水平的环境镉暴露可能会复合ZnT 8的遗传变异的影响。 研究人员假设，这种基因-环境相互作用可能会增强ZnT 8遗传变异携带者患糖尿病的风险。本研究的目的是表征镉损害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ZnT 8变化之间的相互作用，从而导致β细胞功能受损。 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ZnT 8的遗传变异通过损害产生胰岛素的β细胞的功能来增加2型糖尿病的风险。我们的研究将检查摄入微量的工业重金属镉是否会加重ZnT 8基因变异引起的β细胞损伤，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。