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).

项目概要 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 我们聚集了一大群多种族的人 青少年 (n=1100) 并与 Leif Groop 博士一起对他们进行基因分型，以了解已知的相关常见基因变异 GWAS 发现与成人 T2D 相关。 发生在青年 T2D 自然史的早期。最近， 尽管相关 T2D 易感基因的数量已 一直在攀升，TCF7L2 基因中的 rs7903146 SNP 仍然是已知最强的单一遗传风险因素 对于 T2D。值得注意的是，我们在儿童中发现 T 等位基因 (rs7903146) 的每个副本都与一个 1.914 (1.474-2.486) 增加了 IGT/T2D 的调整赔率 (p=0.0001)，使其成为最重要的赔率之一 迄今为止，青少年 T2D 的基因发现，其影响大小大于成人报告的影响大小 (18,19,24,26)。此外，我们队列的最新初步数据表明 TCF7L2 风险 基因型与处置指数降低和高比值比相关（OR 2.372 95%CI 1.059 - 5.314； p= 0.03) 维持 IGT 或进展为 T2D。基于我们令人兴奋的成果，我们计划 利用我们庞大的彻底基因型/表型队列来检验以下假设： rs7903146 位点的风险等位基因有利于青年人维持 IGT 或其进展为 T2D，因为： 功能性 β 细胞容量降低，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) 增加肝脏胰岛素抵抗。具体目标是： 目标 1a。描述 TCF7L2 rs7903146 对肥胖者功能性 β 细胞容量的影响 患有 IGT 的青少年。目标 1b。确定 TCF7L2 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 细胞容量（质量），我们将使用钳源葡萄糖刺激的 C- 肥胖者高血糖 (AIRmax) 期间肽分泌和对精氨酸的最大 C 肽反应 TT 和 CC TCF7L2 基因型的青少年携带者。 2 年随访期后，OGTT 和 将重复高血糖-AIRmax 测试。 目标 2. 检查 TCF7L2 基因中的 rs7903146 变体对 a) 肠降血糖素的功能影响 b) 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：肠促胰岛素 效果将通过 OGTT 和 IsoG-IVGT 期间 c 肽的 AUC 来测量 (29,30)。 GLP-1刺激胰岛素 将在使用 GLP-1 进行高血糖钳夹期间评估分泌情况 (31)。 目标 3. 确定 TCF7L2 rs7903146 SNP 对肥胖者肝脏葡萄糖通量的功能影响 患有 IGT 的青少年。方法：肝脏葡萄糖生成（6-6-D 葡萄糖）糖异生（2H2O 技术）将在 3 小时高胰岛素正常血糖钳夹过程中使用 C5 至 C2 葡萄糖进行量化 比率（32-37）。