Genetics of Beta Cell Failure in Mexican Americans

墨西哥裔美国人β细胞衰竭的遗传学

• 批准号: 8269634
• 负责人: Thomas A Buchanan
• 金额: $ 65.22万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-20 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269634
• 关键词: Affect; Alleles; Award; Beta Cell; Body Composition; Body fat; Candidate Disease Gene; Cell physiology; Cells; Chronic; Clinical; Cohort Studies; Cross-Sectional Studies; Data; Data Analyses; Deterioration; Development; Diabetes Mellitus; Diet; Dietary History; Dietary intake; Dual-Energy X-Ray Absorptiometry; Early treatment; Environment; Ethnic group; Failure; Family; Financial compensation; Food; Frequencies; Future; Genes; Genetic; Genetic Variation; Genotype; Gestational Diabetes; Glucose tolerance test; Goals; Hispanic Americans; Hispanics; Hyperglycemia; Individual; Individual Differences; Insulin; Insulin Resistance; Intravenous; Lead; Medical; Mexican Americans; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Pancreas; Pathway interactions; Phenotype; Physical activity; Physiological; Population; Pregnancy; Prevention; Recruitment Activity; Research; Research Personnel; Resources; Sampling; Sampling Studies; Scanning; Susceptibility Gene; Testing; Variant; Woman; base; cohort; design; diabetes risk; falls; gene environment interaction; gene interaction; genetic association; glucose tolerance; high risk; novel strategies; proband; response; trait

PROJECT SUMMARY/ABSTRACT 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.

项目摘要/摘要 我们研究的长期目标是了解导致2型糖尿病（T2D）的机制 与之相关的年轻西班牙裔美国人，以开发更好的预测，预防和早期方法 治疗。贝汀研究的具体目标是确定易受t2d和t2d的基因 了解这些基因如何促进糖尿病的发展。在Betagene的头五年中，我们 进行口服（OGTT）和静脉内（IVGTT）葡萄糖耐量测试和DEXA的身体组成 1235名来自墨西哥裔美国家庭的人患有妊娠糖尿病（GDM）或 怀孕期间正常的葡萄糖耐受性。在与先前GDM的另一批西班牙裔女性中，我们有 表明T2D是由于胰腺功能的进行性损失而导致的，该功能发生在整个过程中 在慢性胰岛素抵抗的背景下年。我们的横截面差异我们 其他人已经测试过与推定的T2D基因关联的，充其量是替代物的更重要的 纵向变化。该提案的主要假设是一个或多个T2D基因 影响胰岛素抵抗的变化率。我们提供有力的证据 我们从HNF4A的初步研究中的假设。我们将实现三个目标，以进一步检验我们的假设 首先，我们将招募和重新表型从Betagene组成的400个人的随机纵向队列 样本在基线考试后3 - 5年。它们将是我们基于协会研究的主要资源 关于 - 赔偿赔偿的变化。其次，我们已经在基因分型了整个Betagene队列20 T2D和相关定量性状的基因。我们将针对相关新基因的纵向队列进行基因型 在发现的基础T2D和T2D相关的表型中，以及一组祖先提供的信息 评估人口子结构的标记。第三，我们将分析数据以测试变体之间的关联 基础T2D和T2D相关的表型以及»细胞补偿的变化率。我们还将测试 遗传效应与细胞环境方面之间的相互作用（例如肥胖，胰岛素抵抗， 饮食，体育锻炼）关于 - 细胞补偿的变化率。我们的结果将提供独特的信息 关于对年轻西班牙裔T2D的主要身体异常的遗传影响 美国人。他们还将提供有关遗传变异和肥胖之间相互作用的独特信息， 胰岛素耐药性和 - 细胞功能。该信息将有助于指导通用的机理研究 对糖尿病的贡献。它还将为糖尿病预测的新临床方法提供基础， 预防和早期治疗。

项目成果

Longitudinal Increases in Adiposity Contribute to Worsening Adipokine Profile over Time in Mexican Americans.

• DOI: 10.1002/oby.22128
• 发表时间: 2018-04
• 期刊: Obesity (Silver Spring, Md.)
• 作者: Black MH;Shu YH;Wu J;Koebnick C;MacKay A;Watanabe RM;Buchanan TA;Xiang AH
• 通讯作者: Xiang AH

A diet high in sugar-sweetened beverage and low in fruits and vegetables is associated with adiposity and a pro-inflammatory adipokine profile.

• DOI: 10.1017/s0007114518002726
• 发表时间: 2018-12
• 期刊: The British journal of nutrition
• 作者: Koebnick C;Black MH;Wu J;Shu YH;MacKay AW;Watanabe RM;Buchanan TA;Xiang AH
• 通讯作者: Xiang AH

HOMA and Matsuda indices of insulin sensitivity: poor correlation with minimal model-based estimates of insulin sensitivity in longitudinal settings.

• DOI: 10.1007/s00125-013-3121-8
• 发表时间: 2014-02
• 期刊: DIABETOLOGIA
• 影响因子: 8.2
• 作者: Xiang, A. H.;Watanabe, R. M.;Buchanan, T. A.
• 通讯作者: Buchanan, T. A.