Pathogenesis of youth onset pre diabetes and Type 2 diabetes.

项目摘要 该提案为研究导致β细胞功能快速丧失的机制寻求新的支持 我们召集了一大批多种族的 年轻人（n=1100），并与Leif Groop博士一起对他们进行基因分型，以确定已知的相关常见基因变异， 与GWAS成人中的T2 D相关。 发生在青年发病T2 D的自然病程早期。最近， 尽管相关T2 D易感基因的数量 尽管TCF 7 L2基因中的rs7903146 SNP一直在攀升，但它仍然是已知最强的遗传风险因素 对于T2 D。值得注意的是，我们在儿童中发现，T等位基因（rs7903146）的每一个拷贝都与一个基因相关。 1.914（1.474-2.486）增加了IGT/T2 D的校正比值（p=0.0001），使其成为最显著的 到目前为止，在青年中的T2 D遗传发现，其效应量大于成人中报告的效应量 (18，19，24，26）。此外，我们队列的最新初步数据表明，TCF 7 L2风险 基因型与倾向指数降低和高比值比相关（OR 2.372 95%CI 1.059 - 1.059）。 5.314; p= 0.03）维持IGT或进展为T2 D。基于我们令人兴奋的成果，我们计划 资本化和利用我们的大型彻底基因分型/表型队列来测试以下假设： rs7903146位点的风险等位基因有利于IGT的维持或其在青年中进展为T2 D，因为a） 功能性β细胞能力降低，B）肠促胰岛素作用降低或GLP-1刺激胰岛素的效率降低 分泌和c）增加的肝胰岛素抵抗。具体目标是： 目标1a。描述TCF 7 L2 rs7903146对肥胖患者功能性β细胞容量的影响 IGT青少年目标1b。为了确定TCF 7 L2中的风险基因型是否与 β细胞功能纵向恶化，从而影响葡萄糖耐量的变化。 方法：为了评估功能性β细胞能力（质量），我们将使用钳夹衍生的葡萄糖刺激的C- 肥胖者高血糖时肽分泌和对精氨酸的最大C肽反应（AIRmax） TT和CC TCF 7 L2基因型的青少年携带者。在2年的随访期后，OGTT和 将重复进行高血糖-AIRmax试验。 目标2.为了检查TCF 7 L2基因中的rs7903146变体对肠促胰岛素的功能作用， 作用和B）对患有IGT肥胖青少年中GLP-1诱导的胰岛素分泌的影响。方法：肠促胰岛素 将通过OGTT和IsoG-IVGT期间c肽的AUC来测量效果（29，30）。GLP-1刺激的胰岛素 将在GLP-1给药的高血糖钳夹期间评估分泌（31）。 目标3。确定TCF 7 L2 rs7903146 SNP对肥胖患者肝葡萄糖通量的功能性影响， IGT青少年方法：肝脏葡萄糖生成（6-6-D葡萄糖）代谢（2 H2O 技术）将在3小时高胰岛素-正常血糖钳夹期间使用C5至C2葡萄糖 比率（32-37）。

Project Summary Abstract This proposal seeks NEW support for studying mechanisms contributing to the rapid loss in beta cell function we assembled a large multiethnic cohort of youths (n=1100) and genotyped them together with Dr. Leif Groop for relevant common gene variants known to be associated with T2D in adults from the GWAS. occurring early in the natural history of youth onset T2D. Recently, Although the number of relevant T2D susceptibility genes has been climbing, the rs7903146 SNP in the TCF7L2 gene remains the single strongest known genetic risk factor for T2D. Remarkably, we found in children that each copy of the T allele (rs7903146) is associated with a 1.914 (1.474-2.486) increased adjusted odds for IGT/T2D (p=0.0001), making it one of the most significant genetic findings in T2D to date in youth, with an effect size greater than that reported in adults (18,19,24,26). Additionally, recent preliminary data from our cohort suggest that the TCF7L2 risk genotype is associated with a reduced Disposition Index and a high odds ratio (OR 2.372 95%CI 1.059 - 5.314; p= 0.03) of maintaining IGT or progressing to T2D. Building upon our exciting results we plan to capitalize and utilize our large thoroughly genotyped/phenotyped cohort to test the following Hypothesis: The risk allele at rs7903146 locus favors the maintenance of IGT or its progression to T2D in youth because of a) reduced functional beta cell capacity, b) reduced incretin effect or reduced efficiency of GLP-1 to stimulate insulin secretion and c) increased hepatic insulin resistance. The Specific Aims are: Aim 1a. To delineate the effects of TCF7L2 rs7903146 on functional Beta-Cell Capacity in obese adolescents with IGT. Aim 1b. To determine if the risk genotype in TCF7L2 is associated with worsening in beta cell function longitudinally, thereby affecting changes in glucose tolerance. Approach: To assess functional beta cell capacity (mass) we will use clamp-derived glucose-stimulated C- peptide secretion and maximal C-peptide response to Arginine during hyperglycemia (AIRmax) in obese adolescent carriers of the TT and CC TCF7L2 genotype. After a follow-up period of 2 years the OGTT and hyperglycemic–AIRmax tests will be repeated. Aim 2. To examine the functional effect of the rs7903146 variant in the TCF7L2 gene on a ) incretin effect and b ) on GLP-1-induced insulin secretion in obese adolescents with IGT. Approach: The incretin effect will be measured by AUC of the c-peptide during OGTT and IsoG-IVGTs (29,30). GLP-1 stimulated insulin secretion will be assessed during a hyperglycemic clamp with GLP-1 administration (31). Aim 3. To determine the functional effects of TCF7L2 rs7903146 SNP on hepatic glucose fluxes in obese adolescents with IGT. Approach: Hepatic glucose production (6-6-D glucose) gluconeogenesis (2H2O technique) will be quantified during a 3 hr hyperinsulinemic-euglycemic clamp using the C5-to-C2 glucose ratio (32-37).