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.

Public Health Relevance

Type 2 diabetes is major concern to public health. Insulin resistance is a necessary condition for type 2 diabetes to develop and because insulin resistance is potentially reversible, identification of risk factors for insulin resistance might hlp to prevent type 2 diabetes. We propose to study gene-environment interactions and the prevalence of insulin resistance among middle age non diabetic men.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Villegas, Raquel; Delahanty, Ryan; Williams, Scott et al. (2015) Genetic Variation and Insulin Resistance in Middle-Aged Chinese Men. Ann Hum Genet 79:357-365