The long-term objective of our research is to understand the mechanisms that cause type 2 diabetes (T2D) in relatively young Hispanic Americans in order to develop better approaches to prediction, prevention and early treatment. The specific objective of the BetaGene Study is to identify genes that predispose to T2D and understand how those genes contribute to development of diabetes. In the first five years of BetaGene, we performed oral (oGTT) and intravenous (ivGTT) glucose tolerance tests and body composition by DEXA on 1235 individuals from Mexican American families with probands who had either gestational diabetes (GDM) or normal glucose tolerance during pregnancy. In a separate cohort of Hispanic women with prior GDM, we have shown that T2D results from a progressive loss of pancreatic ?-cell function that occurs over the course of years on a background of chronic insulin resistance. The cross-sectional differences in ?-cell function that we and others have tested for association with putative T2D genes are, at best, surrogates for the more important longitudinal changes. The primary hypothesis underlying this proposal is that one or more T2D genes influence rates of change in ?-cell compensation for insulin resistance. We provide strong evidence for our hypothesis from preliminary studies of HNF4A. We will achieve three aims to test our hypothesis more fully. First, we will recruit and re-phenotype a random longitudinal cohort of 400 individuals from the BetaGene sample 3-5 years after their baseline exams. They will be our primary resource for association studies based on changes in ?-cell compensation. Second, we are already genotyping the entire BetaGene cohort for 20 genes for T2D and related quantitative traits. We will genotype the longitudinal cohort for relevant new genes underlying T2D and T2D-related phenotypes as they are discovered and for a panel of ancestrally informative markers to assess population substructure. Third, we will analyze data to test for association between variants underlying T2D and T2D-related phenotypes and rates of change in ?-cell compensation. We will also test for interactions between genetic effects and aspects of the ?-cell environment (e.g., obesity, insulin resistance, diet, physical activity) on rates of change in ?-cell compensation. Our results will provide unique information about genetic influences on the primary physiological abnormality that causes T2D in young Hispanic Americans. They will also provide unique information on the interplay among genetic variation and obesity, insulin resistance and ?-cell function. The information will help guide mechanistic studies of the genetic contribution to diabetes. It will also provide a basis for new clinical approaches to diabetes prediction, prevention and early treatment.

Public Health Relevance

This project is designed to determine how diabetes risk genes affect the major abnormalities that lead to type 2 diabetes in Mexican Americans. The results will be useful in guiding basic studies into the mechanisms of type 2 diabetes. The results will also help to guide the development of new approaches to the prediction, prevention and early treatment of type 2 diabetes in this high-risk ethnic group.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-EMNR-H (03))
Program Officer
Mckeon, Catherine T
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Palmer, Nicholette D; Wagenknecht, Lynne E; Langefeld, Carl D et al. (2016) Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium. Diabetes 65:2072-80
Palmer, Nicholette D; Goodarzi, Mark O; Langefeld, Carl D et al. (2015) Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium. Diabetes 64:1853-66
Black, Mary Helen; Wu, Jun; Takayanagi, Miwa et al. (2015) Variation in PPARG is associated with longitudinal change in insulin resistance in Mexican Americans at risk for type 2 diabetes. J Clin Endocrinol Metab 100:1187-95
Gao, Chuan; Wang, Nan; Guo, Xiuqing et al. (2015) A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS). PLoS One 10:e0134649
Sharma, Poonam R; Mackey, Aaron J; Dejene, Eden A et al. (2015) An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes. Endocrinology 156:3147-56
Chen, Z; Salam, M T; Karim, R et al. (2015) Living near a freeway is associated with lower bone mineral density among Mexican Americans. Osteoporos Int 26:1713-21
Goodarzi, Mark O; Langefeld, Carl D; Xiang, Anny H et al. (2014) Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans. Obesity (Silver Spring) 22:1157-64
Xiang, A H; Watanabe, R M; Buchanan, T A (2014) HOMA and Matsuda indices of insulin sensitivity: poor correlation with minimal model-based estimates of insulin sensitivity in longitudinal settings. Diabetologia 57:334-8
Ren, Jie; Xiang, Anny H; Trigo, Enrique et al. (2014) Genetic variation in MTNR1B is associated with gestational diabetes mellitus and contributes only to the absolute level of beta cell compensation in Mexican Americans. Diabetologia 57:1391-9
Chen, Zhanghua; Black, Mary Helen; Watanabe, Richard M et al. (2013) Self-reported physical activity is associated with β-cell function in Mexican American adults. Diabetes Care 36:638-44

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