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.

项目概要 西南美洲印第安人 (SWAI) 一生中患 2 型糖尿病 (T2D) 的风险最高 任何种族群体的不良健康后果。在过去的二十年里，我们的合作者（由 C. 博加杜斯； NIDDK-Phoenix）开创了吉拉河印第安社区 SWAL 的纵向研究 在亚利桑那州凤凰城，研究该高危人群中 T2D 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-正常血糖测量胰岛素作用 夹），他们将胰岛素抵抗（IR）和急性胰岛素分泌（IS）减少定义为显着 T2D 的预测因子。值得注意的是，虽然这些生理机能与其他种族的 T2D 有关，但 SWAL 具有 与其他美国人相比，在相似的肥胖水平下，IR 和 IS 的程度更高，其机制 是难以捉摸的。虽然研究发现小分子代谢物与代谢密切相关且具有特异性 功能障碍可能预示着 T2D，这些研究 (1) 没有确定 IR/IS 的精确生物学机制，因为 缺乏 IR/IS 的机械措施（例如，通过钳位）； (2) 重点关注白种人，他们的临床风险和 相对于 SWAL，T2D 的严重程度较低。此外，对印度人的初步研究表明，代谢物与 T2D 可能与白种人中发现的不同。在这里，我们确定了与以下相关的代谢途径 通过测量高风险 SWAL 中的循环代谢物以及精致的 T2D 对 IR/IS 的影响 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/临床研究部门测量 SWAI 成人的代谢物以确定分子 代谢结构，重点关注胰岛素生理学。我们的中心假设是循环代谢物 将确定 SWAL 中 IR 和 IS 的机制。我们将研究两个不同的种群：（1）希拉河 印度队列研究，一项对超过 650 个 SWAL 进行的前瞻性队列研究，以身体成分为基线测量 胰岛素生理学和 T2D 的纵向随访； (2) 凤凰队列研究，一项纵向研究 >650 个 SWAl，进行口服葡萄糖耐量测试 (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- 3H-葡萄糖钳夹 (HEC) 和口服或静脉注射的 IR 和 IS 测量 希拉河印第安人研究中的葡萄糖耐量测试，以确定与 SWAL 中 IR/IS 相关的代谢途径 没有 T2D。在目标 2 中，我们将通过 (1) 关联来确定 SWAL 中代谢的遗传结构 具有 >500,000 个直接基因分型 SNP 变体和 >4.5m 估算变体的代谢模式来识别 代谢数量性状位点 (mQTL)，并验证 T2D 的衍生遗传风险评分 单独的大量 SWAl (N=6936)，以证明工具变量分析中的因果作用； (2)研究IR与骨骼代谢途径相关基因表达之间的关系 肌肉。如果成功，该应用程序将定义 SWAl 中新陈代谢的底层架构，并提供资源 一般科学界均可使用，以便将来在更广泛的人群中进行发现和比较。