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 相对年轻的西班牙裔美国人，以便开发更好的预测、预防和早期方法 治疗。Betagene研究的具体目标是确定易患T2D和T2D的基因 了解这些基因如何导致糖尿病的发生。在Betagene的前五年，我们 进行口服(OGTT)和静脉(IvGTT)葡萄糖耐量试验和身体成分 来自墨西哥裔美国家庭的1235人，他们的前妻患有妊娠期糖尿病(GDM)或 妊娠期糖耐量正常。在另一组有妊娠期糖尿病史的西班牙裔女性中，我们发现 表明T2D是胰腺细胞功能进行性丧失的结果，该过程发生在 多年的慢性胰岛素抵抗背景。细胞功能的横截面差异 而其他被测试的与假定的T2D基因的关联充其量也只能是更重要的 纵向变化。这一提议的主要假设是一个或多个T2D基因 影响胰岛素抵抗的细胞代偿的变化率。我们提供了强有力的证据 我们的假设来自对HNF4a的初步研究。我们将实现三个目标，以进一步验证我们的假设 完全是这样。首先，我们将从Betagene中招募400个人的随机纵向队列并对其重新表型 在他们的基线考试后3-5年内抽样。它们将是我们进行关联研究的主要资源 关于细胞薪酬的变化。其次，我们已经在对整个Betagene队列中的20个人进行基因分型 T2D及相关数量性状的基因。我们将对纵向队列中的相关新基因进行基因分型 潜在的T2D和T2D相关表型，因为它们被发现，并提供了一组祖先信息 用于评估种群亚结构的标记。第三，我们将分析数据以测试变量之间的关联 潜在的T2D和T2D相关的表型和细胞补偿的变化率。我们还将测试 遗传效应与细胞环境各方面之间的相互作用(如肥胖、胰岛素抵抗、 饮食、体力活动)对细胞补偿变化率的影响。我们的结果将提供独特的信息 关于导致西班牙裔年轻人T2D的主要生理异常的遗传影响 美国人。他们还将提供关于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。这些信息将有助于指导对基因的机械学研究 对糖尿病的贡献。它还将为糖尿病预测的新的临床方法提供基础， 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

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.

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