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: 10647802
• 负责人: Venkatesh Locharla Murthy
• 金额: $ 59.43万
• 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/10647802
• 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; Collaborations; Communities; Data; Epidemiology; Ethnic Origin; Ethnic Population; Functional disorder; Future; Gene Expression; Genetic; Genetic Risk; Glucose Clamp; Glucose tolerance test; Health; Hyperinsulinism; 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; Role; SNP genotyping; Severities; Skeletal Muscle; Therapeutic Studies; Variant; clinical predictors; clinical risk; euglycemia; 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）遭受2型糖尿病（T2D）及其的终身风险最高 任何种族的不利健康后果。在过去的二十年中，我们的合作者（由C.领导。 bogardus; niddk-phoenix）在吉拉河印度社区的Swals进行了纵向研究 在亚利桑那州的凤凰城，在这种高危人群中表征了T2D的临床和遗传预测因子。通过 仔细的综合代谢研究（例如，使用高胰岛素 - 糖血糖测量胰岛素作用 夹具），他们定义了胰岛素抵抗（IR）和急性胰岛素分泌（IS）为显着 T2D的预测因子。值得注意的是，尽管这些生理与其他种族相关，但Swals有一个 IR的程度更高，相对于其他美国人的肥胖水平相似，其机制 难以捉摸。虽然研究发现小分子代谢产物近端，并且特异性为代谢 功能障碍可能会预示T2D，这些研究（1）无法确定IR/的精确生物学机制是由于 缺乏IR/IS的机械度量（例如，通过夹具）； （2）专注于高加索人，高加索人的临床风险和 T2D的严重程度相对于SWALS较低。此外，印第安人的试点研究表明代谢产物连接 到T2D可能与高加索人发现的情况不同。在这里，我们确定了与 T2D通过其对IR/的影响通过测量高风险Swals中的循环代谢物与精致 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成年人的代谢物以定义分子 新陈代谢的结构，重点是胰岛素生理。我们的中心假设是循环代谢物 将确定IR的机制，并处于Swals中。我们将研究两个不同的人群：（1）吉拉河 印度队列研究，一项> 650个SWALS的前瞻性队列研究，并采用了人体成分的基线度量 T2D的胰岛素生理学和纵向随访； （2）Phoenix队列研究，一项纵向研究 > 650个具有口服葡萄糖耐量测试（OGTT）和正在进行的临床监测的SWALS。在AIM 1中，我们将使用 IR的度量和基于尤基血糖 - 糖纤维素 - 3H-3H-葡萄糖夹（HEC）和口服或IV 吉拉河印度研究中的葡萄糖耐量测试，以识别与IR/IS相关的代谢途径 没有T2D。在AIM 2中，我们将通过（1）的关联确定SWALS中新陈代谢的遗传结构 具有> 500,000直接基因型SNP变体和> 450万的估计变体的代谢物模式 定量性状基因座用于代谢（MQTLS），并在A中用T2D验证了衍生的遗传风险评分 单独的大量SWALS（n = 6936），以证明因果变量分析的因果作用； （2）研究IR与与骨骼代谢途径有关的基因表达之间的关系 肌肉。如果成功，此应用程序定义了Swals中的代谢的基本体系结构，并用资源来定义 一般科学界可以在广泛的人群中进行未来的发现和比较。