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 这项建议寻求新的支持，以研究导致β细胞功能迅速丧失的机制。 我们聚集了一个庞大的多民族队列 年轻人(n=1100)，并与Leif Groop博士一起对他们进行了基因分型，以了解已知的相关常见基因变异 来自GWAS的成人的T2D与T2D有关。 发生在青春期T2D的自然病史早期。最近， 尽管相关的T2D易感基因的数量 在不断攀升的过程中，TCF7L2基因中的rs7903146 SNP仍然是已知的单一最强的遗传风险因素 用于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)与一个 1.914(1.474-2.486)IGT/T2D的调整后优势增加(p=0.0001)，使其成为最显著的 到目前为止，T2D在年轻人中的基因发现，其影响大小大于报告的成人 (18，19，24，26)此外，来自我们队列的最新初步数据表明，TCF7L2风险 基因分型与倾向指数降低和优势比高相关(OR 2.372，95%CI 1.059- 5.314；p=0.03)维持糖耐量低减或进展到T2D。在我们令人兴奋的结果的基础上，我们计划 利用我们大量的彻底基因分型/表型队列来检验以下假设： Rs7903146基因座的风险等位基因有利于IGT的维持或在青年时期进展为T2D，原因是a) 功能β细胞能力降低，b)胰岛素效应减弱或GLP-1刺激胰岛素的效率降低 分泌和c)增加肝脏胰岛素抵抗。具体目标是： 目标1a。TCF7L2 rs7903146基因对肥胖症患者β细胞功能的影响 患有IGT的青少年。目标1b。确定TCF7L2的风险基因是否与 β细胞功能纵向恶化，从而影响糖耐量的变化。 方法：为了评估功能性β细胞能力(MASS)，我们将使用钳夹衍生的葡萄糖刺激的C- 肥胖者高血糖时的多肽分泌和对精氨酸的最大C肽反应 TT和CC TCF7L2基因青少年携带者。经过2年的随访期，OGTT和 将重复进行高血糖-Airmax测试。 目的：检测TCF7L2基因rs7903146变异对a)分泌的功能影响。 对患有IGT的肥胖青少年GLP-1诱导的胰岛素分泌的影响。方法：不断创新 效应将通过在OGTT和IsoG-IVGTS(29，30)期间C-肽的AUC来衡量。GLP-1刺激的胰岛素 分泌物将在给予GLP-1的高血糖钳夹期间进行评估(31)。 目的：研究TCF7L2 rs7903146单核苷酸对肥胖大鼠肝脏葡萄糖代谢的影响。 患有IGT的青少年。方法：肝脏葡萄糖生产(6-6-D葡萄糖)糖异生(2H2O 技术)将在使用C5到C2葡萄糖的3小时高胰岛素-正常血糖钳夹期间进行量化 比率(32-37)。