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。

• 批准号: 10006541
• 负责人: SONIA CAPRIO
• 金额: $ 55.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10006541
• 关键词: Adolescence; Adolescent; Adolescent obesity; Adult; Affect; Alleles; Arginine; Beta Cell; C-Peptide; Cell physiology; Child; Childhood diabetes; Closure by clamp; Coupled; Data; Defect; Development; Diabetes Mellitus; Ethnic group; 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; Peripheral; Phenotype; Prediabetes syndrome; Preventive treatment; Reporting; Risk; Series; Susceptibility Gene; System; TCF7L2 gene; Techniques; Testing; Tracer; Translational Research; Variant; Youth; 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

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).

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民族队列 年轻人（n = 1100），并将其与Leif Groop博士一起使用了相关的常见基因变体已知 与GWA的成年人中的T2D有关。 发生在青年发病的自然历史早期。最近， 尽管相关T2D易感基因的数量具有 在攀登，TCF7L2基因中的RS7903146 SNP仍然是已知的唯一强遗传危险因素 对于T2D。值得注意的是，我们在儿童中发现，T等位基因的每个副本（RS7903146）与 1.914（1.474-2.486）IGT/T2D的调整赔率增加（p = 0.0001），使其成为最重要的一项 迄今为止T2D的遗传发现在青年中，其影响大小大于成人 （18,19,24,26）。此外，我们队列的最新初步数据表明TCF7L2风险 基因型与降低的处置指数和高几率比率有关（OR 2.372 95％CI 1.059- 5.314; p = 0.03）维持IGT或发展为T2D。以我们令人兴奋的结果为基础，我们计划 资本化并利用我们的大型基因分型/表型队列来检验以下假设： 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细胞的容量降低，b）降低效应或降低GLP-1的效率以刺激胰岛素 分泌和c）增加肝胰岛素抵抗。具体目的是： 目标1a。描述TCF7L2 RS7903146对肥胖功能β细胞容量的影响 具有IGT的青少年。目标1B。确定TCF7L2中的风险基因型是否与 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细胞的能力（MASS），我们将使用夹具衍生的葡萄糖刺激的C- 肥胖症中高血糖（AIRMAX）期间精氨酸的肽分泌和最大C肽反应 TT和CC TCF7L2基因型的青少年载体。经过2年的随访期后，OGTT和 高血糖 - AIRMAX测试将被重复。 目的2。检查TCF7L2基因中RS7903146变体对A）增加的功能效应 效果和b）对IGT肥胖青少年中GLP-1诱导的胰岛素分泌。方法：增加 效果将通过OGTT和ISOG-IVGTS期间的C肽AUC测量（29,30）。 GLP-1刺激胰岛素 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 具有IGT的青少年。方法：肝葡萄糖产生（6-6-D葡萄糖）糖异生（2H2O 技术）将在3小时的高胰岛素血糖夹中使用C5至C2葡萄糖进行量化 比率（32-37）。