GENETICS OF PANCREATIC FUNCTION IN THE DEVELOPMENT OF DIABETES MELLITUS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。2型糖尿病是男性最常见的遗传性疾病之一，在高加索人群中估计患病率为8-10%。目前的证据表明，常见的2型糖尿病是由许多易感基因引起的，每一种基因都对糖尿病的发展、衰老和环境有一定的影响。2型糖尿病的特点是胰岛素抵抗和β细胞功能障碍。因此，2型糖尿病的候选基因包括那些与胰岛素分泌有关的基因。已知影响胰岛素分泌和/或胰腺发育的基因包括胰十二指肠同源盒因子-1 （PDX-1）、β 2/NeuroD、胰岛素受体底物-2 （IRS-2）和β -3-肾上腺素能受体（β 3ar）。在这些基因（PDX-1Asp76Asn, BETA2/NeuroD Ala45Thr, IRS2 Gly1057Asp，或beta3AR Trp64Arg）中已经发现了功能突变，它们有可能改变蛋白质的功能，从而单独或联合影响胰岛素分泌。在这项研究中，我们建议使用频繁采样的静脉葡萄糖耐量试验（FSIGTT）和胰岛素振荡研究，对前瞻性招募的年龄-性别和bmi匹配的非糖尿病受试者的胰岛素分泌进行特征描述，这些受试者具有以下一种或两种变体，PDX-1 Asp76Asn, BETA2/NeuroD Ala45Thr， IRS2 Gly1057Asp或beta3AR Trp64Arg，并确定具有与β细胞功能相关的基因的两种变体是否对胰岛素分泌具有累加性影响。

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. Type 2 diabetes mellitus is one of the most common inherited diseases in man with an estimated prevalence in Caucasian populations of 8-10%. Current evidence suggests that the common forms of type 2 diabetes result from a number of predisposing genes, ech of which contributes modestly to the development of diabetes as well as aging and the environment. Type 2 diabetes is characterized by insulin resistance and beta cell dysfunction. Therefore, candidate genes for type 2 diabetes include those involved with insulin secretion. Genes known to affect insulin secretion and/or pancreatic development include pancreatic duodenal homeobox factor-1 (PDX-1), Beta2/NeuroD, insulin receptor substrate-2 (IRS-2) and the beta-3-adrenergic receptor (beta3AR). Functional mutations have been identified in these genes (PDX-1Asp76Asn, BETA2/NeuroD Ala45Thr, IRS2 Gly1057Asp, or beta3AR Trp64Arg) which have the potential to alter the function of the protein, thereby, individually or in combination, effecting insulin secretion. In this study, we propose to characterize insulin secretion in prospectively recruited age-gender- and BMI-matched nondiabetic subjects with either one or two of the following variants, PDX-1 Asp76Asn, BETA2/NeuroD Ala45Thr, IRS2 Gly1057Asp, or beta3AR Trp64Arg, using the frequently sampled intravenous glucose tolerance test (FSIGTT) and insulin oscillation studies and to determine if having two variants in genes related to beta cell function have additive effects on insulin secretion.