Metabolic architecture of insulin action in Southwest American Indians

西南美洲印第安人胰岛素作用的代谢结构

• 批准号: 10544900
• 负责人: Venkatesh Locharla Murthy
• 金额: $ 59.47万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544900
• 关键词: Acute; Adult; American; American Indians; Architecture; Arizona; Biological; Body Composition; Body measure procedure; Caucasians; Clinical; Clinical Research; Closure by clamp; Cohort Studies; Communities; Data; Ethnic Origin; Ethnic group; Functional disorder; Future; Gene Expression; Genetic; Genetic Risk; Glucose Clamp; Glucose tolerance test; Health; Insulin; Insulin Resistance; Link; Longitudinal Studies; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Molecular; Molecular Genetics; National Institute of Diabetes and Digestive and Kidney Diseases; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Oral; Pattern; Physiology; Pilot Projects; Population; Populations at Risk; Prospective cohort study; Quantitative Trait Loci; Resources; Risk; Rivers; Role; SNP genotyping; Severities; Skeletal Muscle; Therapeutic Studies; Variant; base; clinical epidemiology; clinical predictors; clinical risk; experience; follow-up; genetic architecture; genetic predictors; high risk; in vivo; insulin secretion; lifetime risk; metabolic abnormality assessment; small molecule

Project Summary Southwest American Indians (SWAI) suffer from the highest lifetime risk of type 2 diabetes (T2D) and its adverse health consequences of any ethnic group. Over the last two decades, our collaborators (led by Dr. C. Bogardus; NIDDK-Phoenix) have pioneered longitudinal studies of SWAls in the Gila River Indian Community in Phoenix, Arizona, to characterize clinical and genetic predictors of T2D in this at-risk population. Through careful integrative metabolic studies (e.g. measurement of insulin action using hyperinsulinemic-euglycemic clamp), they have defined insulin resistance (IR) and reduced acute insulin secretion (IS) as significant predictors of T2D. Of note, while these physiologies are linked to T2D in other ethnicities, SWAls have a greater degree of IR and IS at a similar level of obesity relative to other Americans, the mechanisms of which are elusive. While studies have found small molecule metabolites proximal and specific to metabolic dysfunction may presage T2D, these studies (1) do not identify precise biologic mechanisms of IR/IS due to lack of mechanistic measures of IR/IS (e.g., via clamp); (2) are focused on Caucasians, whose clinical risk and severity of T2D is lower relative to SWAls. Furthermore, pilot studies in Indians suggest that metabolites linked to T2D may not be the same as those found in Caucasians. Here, we identify metabolic pathways linked to T2D via their effect on IR/IS by measuring circulating metabolites in high-risk SWAls alongside exquisite characterization of in vivo insulin physiology and molecular genetics. We collaborate with the NIDDK-Phoenix Epidemiology/Clinical Research Branch to measure metabolites in SWAI adults to define the molecular architecture of metabolism, focused on insulin physiology. Our central hypothesis is that circulating metabolites will identify mechanisms of IR and IS in SWAls. We will study two different populations: (1) the Gila River Indian Cohort Study, a prospective cohort study of >650 SWAls with baseline measures of body composition and insulin physiology and longitudinal follow-up for T2D; (2) the Phoenix Cohort Study, a longitudinal study of >650 SWAls with oral glucose tolerance testing (OGTT) and ongoing clinical surveillance. In Aim 1, we will use measures of IR and IS based on the euglycemic-hyperinsulinemic- 3H-glucose clamp (HEC) and oral or IV glucose tolerance testing in the Gila River Indian Study to identify metabolic pathways linked to IR/IS in SWAls without T2D. In Aim 2, we will identify the genetic architecture of metabolism in SWAls via (1) association of metabolite patterns with >500,000 directly genotyped SNP variants and >4.5m imputed variants to identify quantitative trait loci for metabolism (mQTLs), with verification of derived genetic risk scores with T2D in a separate, large population of SWAls (N=6936) to demonstrate a causal role ininstrumental variables analysis; (2) studying relationship between IR and expression of genes implicated in metabolic pathways from skeletal muscle. If successful, this application defines underlying architecture of metabolism in SWAls, with resources accessible by the general scientific community for future discovery and comparison in broaderpopulations.

项目摘要 西南美洲印第安人（SWAI）患有2型糖尿病（T2 D）的最高终生风险， 任何种族群体的不利健康后果。在过去的二十年里，我们的合作者（由C博士领导）。 Bogardus; NIDDK-Phoenix）率先对吉拉河印第安社区的SWAL进行了纵向研究 在亚利桑那州凤凰城，描述T2 D的临床和遗传预测因素。通过 仔细的综合代谢研究（例如，使用高胰岛素血症-血糖正常 钳夹），他们将胰岛素抵抗（IR）和急性胰岛素分泌（IS）减少定义为显著 T2 D的预测因素。值得注意的是，虽然这些生理学与其他种族的T2 D有关，但SWA具有 与其他美国人相比，在类似的肥胖水平下，IR和IS的程度更高，其机制是 是难以捉摸的虽然研究发现小分子代谢物与代谢产物接近并特异于代谢产物， 功能障碍可能预示着T2 D，这些研究（1）没有确定IR/IS的精确生物学机制， 缺乏IR/IS的机械措施（例如，通过钳夹）;（2）集中于高加索人，其临床风险和 T2 D的严重程度相对于SWA较低。此外，在印度人中进行的初步研究表明， T2 D可能与高加索人中发现的不同。在这里，我们确定了与 通过测量高风险SWA中的循环代谢物以及精致的 体内胰岛素生理学和分子遗传学的表征。我们与NIDDK-Phoenix合作 流行病学/临床研究分支测量SWAI成人的代谢物，以确定分子 代谢的结构，重点是胰岛素生理学。我们的核心假设是循环代谢物 将识别SWAL中IR和IS的机制。我们将研究两个不同的种群：（1）吉拉河 印度队列研究，一项对>650例SWA进行的前瞻性队列研究，基线测量身体成分 和胰岛素生理学以及T2 D的纵向随访;（2）Phoenix队列研究， >650例SWA，口服葡萄糖耐量试验（OGTT）和持续的临床监测。在目标1中，我们将使用 基于正常血糖-高胰岛素血症-3H-葡萄糖钳夹（HEC）和口服或IV的IR和IS测量 Gila River Indian研究中的葡萄糖耐量试验，以确定与SWA中IR/IS相关的代谢途径 没有T2 D。在目标2中，我们将通过以下方式鉴定SWA 1中代谢的遗传结构：（1）与 具有> 500，000个直接基因分型SNP变体和>4.5m个插补变体的代谢物模式，以识别 代谢的数量性状基因座（mQTL），与验证衍生的遗传风险评分与T2 D在一个 单独的，大规模的SWA人群（N=6936），以证明在工具变量分析中的因果作用; (2)研究IR与骨骼肌代谢途径相关基因表达的关系 肌肉.如果成功，此应用程序将定义SWAL中代谢的基础架构， 一般科学界可以获得，以便将来在更广泛的人群中进行发现和比较。