Metabolic architecture of insulin action in Southwest American Indians

项目摘要 西南美洲印第安人(SWAI)患有终生2型糖尿病(T2D)的风险最高，其 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(以C. Bogardus；NIDDK-Phoenix)率先在吉拉河印第安人社区对SWAL进行了纵向研究 在亚利桑那州凤凰城，研究这一高危人群中T2D的临床和遗传预测因素。穿过 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的作用 他们将胰岛素抵抗(IR)和急性胰岛素分泌减少(IS)定义为显著 T2D的预测因子。值得注意的是，虽然这些生理与其他种族的T2D有关，但SWAL有一个 与其他美国人相比，IR程度更高，处于类似的肥胖水平，其机制 是难以捉摸的。虽然研究发现小分子代谢物是新陈代谢的近端和特异的 功能障碍可能是T2D的先兆，这些研究(1)没有确定IR/IS的确切生物学机制，原因是 缺乏IR/IS的机械性措施(例如，通过钳夹)；(2)侧重于高加索人，他们的临床风险和 与SWAL相比，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可能与在高加索人中发现的不同。在这里，我们确定了与以下相关的代谢途径 T2D通过测量高危SWAL患者的循环代谢物和EQUICATE 体内胰岛素生理学和分子遗传学的特征。我们与NIDDK合作-凤凰城 流行病学/临床研究分会测量SWAI成人的代谢物以确定分子 新陈代谢的体系结构，侧重于胰岛素生理学。我们的中心假设是循环中的代谢物 将确定SWAL中IR和IS的机制。我们将研究两个不同的种群：(1)吉拉河 印度队列研究--一项对650名SWAL进行基线身体成分测量的前瞻性队列研究 和T2D的胰岛素生理学和纵向随访；(2)菲尼克斯队列研究，纵向研究 &gt；650例接受口服葡萄糖耐量试验(OGTT)和正在进行的临床监测的SWAL。在目标1中，我们将使用 IR和基于正常血糖-高胰岛素-~3H-葡萄糖钳夹(HEC)和口服或静脉注射的IR的测量 Gila River印度研究中的葡萄糖耐量试验以确定与SWAL的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 用&gt；500,000个直接分型SNP变异和&gt；450万个归属变异鉴定代谢物模式 代谢的数量性状基因座(MQTL)，并用T2D验证了衍生的遗传风险分数 分离的大量SWAL(N=6936)在工具变量分析中显示因果作用； (2)研究IR与骨骼代谢途径相关基因表达的关系 肌肉。如果成功，此应用程序定义了SWAL中的新陈代谢的基础架构，并提供了资源 供普通科学界查阅，以便今后在更广泛的人群中进行发现和比较。

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.