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.

项目概要/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 相对年轻的西班牙裔美国人，以便开发更好的预测、预防和早期治疗方法 BetaGene 研究的具体目标是确定易患 T2D 的基因和 了解这些基因如何促进糖尿病的发展 在 BetaGene 的前五年，我们 通过 DEXA 进行口服 (oGTT) 和静脉注射 (ivGTT) 葡萄糖耐量测试和身体成分 1235 名来自墨西哥裔美国人家庭的个体，其先证者患有妊娠期糖尿病 (GDM) 或 在另一组患有 GDM 的西班牙裔女性中，我们发现妊娠期间糖耐量正常。 表明 T2D 是由胰腺逐渐丧失引起的 ¿ - 过程中发生的细胞功能 慢性胰岛素抵抗背景下的年数 ¿ -我们的细胞功能 和其他人测试了与假定的 T2D 基因的关联，充其量只能替代更重要的基因 这一提议的主要假设是一个或多个 T2D 基因。 影响 ¿ 的变化率-我们为胰岛素抵抗的细胞补偿提供了有力的证据。 我们的假设来自于 HNF4A 的初步研究，我们将实现三个目标来进一步检验我们的假设。 首先，我们将从 BetaGene 招募 400 名个体的随机纵向队列并重新进行表型分析。 基线考试后 3-5 年后的样本，它们将成为我们基于关联研究的主要资源。 关于 ¿ 的变化-细胞补偿。其次，我们已经对整个 BetaGene 队列进行了 20 次基因分型。 我们将对相关新基因的纵向队列进行基因分型。 发现潜在的 T2D 和 T2D 相关表型以及一组祖先信息 第三，我们将分析数据以测试变异之间的关联。 潜在的 T2D 和 T2D 相关表型以及 ¿ 的变化率- 电池补偿。 遗传效应和各个方面之间的相互作用 ¿ -细胞环境（例如肥胖、胰岛素抵抗、 饮食、体力活动）对 ¿ 变化率的影响-细胞补偿。我们的结果将提供独特的信息。 关于遗传因素对导致年轻西班牙裔 T2D 的主要生理异常的影响 美国人还将提供有关遗传变异和肥胖之间相互作用的独特信息， 胰岛素抵抗和 ¿ -细胞功能将有助于指导遗传机制研究。 它也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.