Gene and environment interaction and insulin resistance

描述(由申请人提供)：2型糖尿病(T2D)在美国影响着2000多万人，而且其患病率正在上升。胰岛素抵抗是T2D发生的必要条件，是遗传因素和环境因素相互作用的结果。了解与胰岛素抵抗相关的因素及其遗传控制对于预防T2D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风险因素包括肥胖、中心性肥胖、低体力活动和饮食因素。在饮食因素中，饮食脂肪在胰岛素抵抗的诱导中起着重要作用。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，而胰岛素受体底物的缺陷可能是胰岛素抵抗的一个主要特征。然而，关于基因变异在胰岛素信号通路中的作用以及T2D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只发现了几个似乎影响胰岛素抵抗的新基因。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T2D的遗传易感性。在拟议的应用中，我们将在基因-环境相互作用的背景下，明确地评估胰岛素信号通路中的前三个基因(胰岛素受体、INSR和胰岛素受体底物1和2，IRS1和IRS2)、葡萄糖转运蛋白4(GLUT4)以及从T2D数量性状中鉴定的基因与胰岛素抵抗的关联。以空腹胰岛素和胰岛素抵抗稳态模型评估(HOMA-IR)为指标，我们将分析上海中国正在进行的一项基于人群的前瞻性研究的2000名非糖尿病男性参与者的现有临床和人口学数据，他们的饮食因素、体力活动、人体测量变量以及空腹血糖和胰岛素已经被测量。拟议项目的目标与父K01应用程序的目标一致，即确定与T2D相关的基因-饮食和基因-身体活动相互作用。这项申请扩大了K01奖的总体目标，将这一重要调查领域的研究扩展到与胰岛素抵抗相关的数量性状的研究。这项研究的发现可以用来帮助预防T2D，因为胰岛素抵抗是一种可逆的情况。

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.