GENETICS OF BETA CELL FAILURE IN MEXICAN AMERICANS - PHASE II

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们研究计划的长期目标是了解相对年轻的墨西哥裔美国人中引起2型糖尿病（T2 DM）的机制，以开发更好的方法来预测，预防和早期治疗该疾病。本申请支持的BetaGene研究的具体目标是识别易患T2 DM的基因，并了解这些基因如何促进糖尿病的发展。在研究的前五年，我们仔细分型了209名患有妊娠期糖尿病（GDM）的T2 DM高危墨西哥裔美国妇女，沿着567名兄弟姐妹，298名堂兄弟姐妹和150名没有GDM的妇女。我们发现三个基因的变异，肝细胞核因子4a（HNF 4A，SNP rs 2144908），转录因子7样-2（TCF 7 L2，rs 12255372）和胰岛素样生长因子2 mRNA结合蛋白2（IGF 2BP 2，SNP rs 11705701），在其他研究中与T2 DM相关，也与胰腺B细胞功能差相关，在BetaGene队列的横断面分析中，T2 DM的主要原因。我们对HNF 4A的初步数据显示，随着时间的推移，遗传变异和B细胞功能变化率之间的关联比仅通过横断面分析检测到的关联更强。基于这一观察和我们先前对GDM后T2 DM生理学的研究，我们推测T2 DM基因有助于提高B细胞对胰岛素抵抗代偿的变化率。为了验证这一假设，我们建议在BetaGene队列中召回约400名具有HNF 4A TCF 7 L2和IGF 2BP 2变体特定基因型的个体，并重新测试它们以确定B细胞功能和其他两种重要的T2 DM相关表型，胰岛素抵抗和体脂的变化。我们还将描述饮食摄入和体力活动的特征，三个主要数据分析将比较三个感兴趣基因中每一个基因型之间B细胞sompensation（静脉内葡萄糖耐量试验的处置指数）的变化率。二次分析将检查（a）基因对B细胞补偿基因对口服葡萄糖的响应的潜在影响和（B）遗传效应对B细胞功能和胰岛素抵抗、肥胖、饮食摄入和体力活动变化的潜在相互作用。我们还将对其他糖尿病风险基因进行探索性分析，以获得有关它们的新信息。这些研究的结果将提供新的和独特的信息，在何种程度上和机制，具体的基因有助于T2 DM的病理生理学在墨西哥裔美国人。这一结果将有助于指导基础研究在适当的生理异常的糖尿病遗传机制。这一结果也将有助于我们开发更好的方法来预测和预防T2 DM。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term objective of our research program is to understand the mechanisms that casue type 2 diabetes mellitus (T2DM) in relatively young Mexican Americans in order to develop better approaches to prediction, prevention and early treatment of the disease. The specific objective of the BetaGene Study that this application supports is to identify genes that predispose to T2DM and understand how those genes contribute to development of the diabetes. In the first five years of the study, we carefully phenotyped 209 Mexican American women at high risk for T2DM becasue they had gestational diabetes mellitus (GDM), along with 567 of their siblings, 298 of their first cousins and 150 women who did not have GDM. We found that variation in three genes, hepatacyte neclear factor 4a (HNF4A, SNP rs2144908), transcription factor 7 like-2 (TCF7L2, rs12255372) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2, SNP rs11705701), that have been associated with T2DM in other studies also have weak associations with poor pancreatic B-cell functions, a main cause of T2DM on cross-sectional analysis in the BetaGene cohort. We have preliminary data forHNF4A showing that ther is a stronger association between the genetic variation and rates of change in B-cell funstion over time than can be detected by cross-sectional analysis alone. Based on that observation and our prior studies of the physilogy of T2DM after GDM, WE HPOTHESIZE THAT T2DM GENES CONTRIBUTE TO DIESEASE RISK INFLUENCING RATES OF CHANGE IN B-CELL COMPENSATION FOR INSULIN RESISTANCE. To test that hypothesis, we propse to call back ~400 individuals in the BetaGene cohort with specific genotypes for variants HNF4A TCF7L2 and IGF2BP2 and re-test them to determine changes in B-cell function and two other important T2DM-related phenotypes, insulin resistance and body fat. We will also characterize dietary intake and physical activity.The tree primary data analyses will compare rates of change in B-cell sompensation (the disposition indez from intravenous glucose tolerance tests) between genotypes for each of the three genes of interest. Secondary analysis will examine (a) potential influences of the genes on the genes on B-cell compensation in response to oralglucose and (b) potential interactions among genetic effects on change in B-cell function and insulin resistance, obesity, dietary intake and physical activity. We will also conduct exploratory analyses on other diabetes risk genes as new information on them becomes available. The results of these studies will provide new and unique information about the degree to which and mechanisms by which specific genes contribute to the pathophysiology of T2DM in Mexican Americans. The result will help direct basic research into genetic mechanisms for diabetes at the appropriate physiological abnormalities. The result wil also help us develop better approaches to predicting and prevention T2DM.