Gene and environment interaction and insulin resistance

基因与环境相互作用与胰岛素抵抗

• 批准号: 8442907
• 负责人: Raquel Villegas
• 金额: $ 7.53万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442907
• 关键词: Affect; Area; Award; Body mass index; Cell membrane; Cells; Central obesity; China; Clinical; Cohort Studies; Consumption; Data; Defect; Development; Diabetes Mellitus; Diet; Dietary Factors; Dietary Fats; Disease; Environmental Risk Factor; Etiology; Failure; Fasting; Fatty Acids; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Glucokinase; Glucose; Glucose Transporter; Goals; Homeostasis; IGF1 gene; INSR gene; IRS1 gene; IRS2 gene; Incidence; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Investigation; Knowledge; Lead; Life Style; Measurement; Measures; Mediating; Mentored Research Scientist Development Award; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Parents; Participant; Pathogenesis; Pathway interactions; Physical activity; Play; Prevalence; Prevention; Prospective Studies; Proxy; Public Health; Research; Research Design; Research Personnel; Research Project Grants; Risk Factors; Role; Signaling Pathway Gene; Skeletal Muscle; Testing; Translating; United States; Variant; Waist-Hip Ratio; base; cohort; cost effective; enzyme activity; fasting glucose; gene discovery; gene environment interaction; gene function; genetic variant; genome wide association study; glucose metabolism; glucose transport; glucose uptake; hexokinase; insulin receptor substrate 1 protein; insulin secretion; insulin signaling; male; men; middle age; modifiable risk; non-diabetic; population based; prevent; prospective; skills; trait

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) affects more than 20 million people in the US, and its prevalence is increasing. Insulin resistance is a necessary condition for T2D to develop and results from an interaction between genetic and environmental factors. Understanding factors associated with insulin resistance and its genetic controls is of particular importance for the prevention of T2D, because insulin resistance is reversible. Major environmental risk factors for insulin resistance include obesity, central obesity, low physical activity, and dietary factors. Among dietary factors, dietary fat plays an important role in the induction of insulin resistance. The etiology of insulin resistance could derive from defects between insulin receptors and glucose transporter 4, and defects in the insulin receptor substrate may be a central feature of insulin resistance. However, there is limited evidence about the role of gene variants in the insulin-signaling pathway and prevalence of T2D or insulin resistance. Recent genome wide association studies (GWAS) have only identified a few new genes that appear to influence insulin resistance. This could be due to the failure to examine how environmental factors affect genetic susceptibility in the development of insulin resistance and/or T2D. In the proposed application we will explicitly evaluate the association of genetic polymorphisms in the first three genes in the insulin signaling pathway (the insulin receptor, INSR, and insulin receptor substrates 1 and 2, IRS1 and IRS2), glucose transporter 4 (GLUT4), and genes identified from GWAS of T2D quantitative traits with insulin resistance in the context of gene-environment interactions. Using fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) as proxies, we will analyze existing clinical and demographic data from 2000 non diabetic male participants of an ongoing, population-based prospective study conducted in Shanghai, China, for whom dietary factors, physical activity, anthropometric variables, and fasting glucose and insulin have already been measured. The goals of the proposed project are in concert with the parent K01 application's goal to determine gene-diet and gene-physical activity interactions associated with T2D. This application expands the overall goal of the K01 award by extending research in this important area of investigation to the study of quantitative traits associated with insulin resistance. Findings from this study can be used to aid in the prevention of T2D, since insulin resistance is a reversible condition.

描述（由申请人提供）：2型糖尿病（T2 D）影响美国超过2000万人，其患病率正在增加。胰岛素抵抗是2型糖尿病发生的必要条件，是遗传和环境因素相互作用的结果。了解与胰岛素抵抗及其遗传控制相关的因素对于预防T2 D特别重要，因为胰岛素抵抗是可逆的。胰岛素抵抗的主要环境危险因素包括肥胖、向心性肥胖、低体力活动和饮食因素。在膳食因素中，膳食脂肪在诱导胰岛素抵抗中起着重要作用。胰岛素抵抗的病因可能源于胰岛素受体和葡萄糖转运蛋白4之间的缺陷，胰岛素受体底物的缺陷可能是胰岛素抵抗的中心特征。然而，关于基因变异在胰岛素信号通路中的作用以及T2 D或胰岛素抵抗的患病率的证据有限。最近的全基因组关联研究（GWAS）只发现了一些新的基因，似乎影响胰岛素抵抗。这可能是由于未能研究环境因素如何影响胰岛素抵抗和/或T2 D发展中的遗传易感性。在拟议的申请中，我们将明确评估胰岛素信号传导途径中前三个基因（胰岛素受体、INSR和胰岛素受体底物1和2、IRS 1和IRS 2）、葡萄糖转运蛋白4（GLUT 4）和从T2 D数量性状的GWAS中鉴定的基因中遗传多态性与基因-环境相互作用背景下胰岛素抵抗的相关性。使用空腹胰岛素和胰岛素抵抗的稳态模型评估（HOMA-IR）作为代理，我们将分析来自2000名非糖尿病男性参与者的现有临床和人口统计学数据，该研究正在中国上海进行，以人群为基础的前瞻性研究，已经测量了饮食因素，体力活动，人体测量变量，空腹血糖和胰岛素。拟议项目的目标与父K 01应用程序的目标一致，即确定与T2 D相关的基因-饮食和基因-体力活动相互作用。该申请通过将这一重要研究领域的研究扩展到与胰岛素抵抗相关的数量性状的研究，扩大了K 01奖的总体目标。这项研究的结果可用于帮助预防T2 D，因为胰岛素抵抗是一种可逆的疾病。