Pathogenesis of youth onset pre diabetes and Type 2 diabetes.

青年发病前糖尿病和 2 型糖尿病的发病机制。

基本信息

批准号：
9257738
负责人：
SONIA CAPRIO
金额：
$ 73.42万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257738
关键词：
Adolescence Adolescent Adolescent obesity Adult Affect Alleles Arginine Beta Cell C-Peptide Cell physiology Child Childhood Coupled Data Defect Development Diabetes Mellitus Ethnic group Euglycemic Clamping Failure Foundations Functional disorder Genetic Genetic Variation Genotype Gluconeogenesis Glucose Glucose Clamp Goals Hepatic Hyperglycemia Incidence Insulin Insulin Resistance Link Maintenance Measures Methodology Natural History Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Odds Ratio Pathogenesis Pediatrics Peptides Peripheral Phenotype Prediabetes syndrome Preventive treatment Reporting Risk Series Staging Susceptibility Gene System TCF7L2 gene Techniques Testing Tracer Translational Research Variant Work Youth abstracting age effect cohort follow-up genetic risk factor genetic variant genome wide association study glucagon-like peptide 1 glucose production glucose tolerance impaired glucose tolerance indexing insight insulin secretion insulin sensitivity interest mathematical model metabolic abnormality assessment response risk variant

项目摘要

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 h r hyperinsulinemic-euglycemic clamp using the C5-to-C2 glucose ratio (32-37).

项目摘要摘要该提案寻求新的支持，以研究导致Beta细胞功能快速损失的机制我们组装了大型的多种多型队列年轻人（n = 1100），并与博士一起将它们分类。与GWA的成年人中的T2D有关。最近发生在青年发病的早期。尽管相关的T2D敏感基因的数量具有在攀登，TCF7L2基因中的RS7903146 SNP仍然是最强的已知遗传危险因素对于T2D。 1.914（1.474-2.486）IGT/T2D的调整赔率增加（p = 0.0001）迄今为止T2D的遗传发现在青年中，成人报告的效果大小较大（18,19,24,26）。基因型与降低的处置指数和高几率比（OR 2.372 95％CI 1.059-- 5.314；大写并利用了我们的GEGE，尽管已被基于基因分型/表型来检验以下假设：在RS7903146的危险等位基因风险基因座有利于IGT的维护或由于A的t2d的维持或其发展为T2D）功能性β细胞容量降低，b）降低肠6肠毒性效应或降低GLP-1刺激胰岛素的功效分泌和c）增加肝胰岛素抵抗。目的1a。 IGT的青少年。纵向β细胞功能的恶化，从而影响葡萄糖耐受性的变化。方法：为了评估功能β细胞容量（质量），我们将使用夹具衍生的葡萄糖诱导的C- 肥胖的高血糖（AIRMAX）期间肽分泌和最大C肽对Argineine的反应 TT和CC TCF7L2基因型的青少年载体。高血糖 - AIRMAX测试将重复。 AIM 2。检查A上TCF7L2基因中RS7903146变体的功能效应）效果和b）与IGT的肥胖青少年中GLP-1诱导的胰岛素分泌效果将通过OGTT ASOG-IVGTS期间的C肽AUC进行测量（29,30）分泌将在高血糖夹中评估使用GLP-1给药（31）。目标3。确定TCF7L2 RS7903146 SNP对肥胖中肝葡萄糖通量的功能效应 IGT的青少年。技术将在使用C5至C2葡萄糖的3 H R R R R R R R r糖胶状夹具中进行量化比率（32-37）。