Cardiometabolic Health in Adolescents of South Asian Ancestry - the CHAriSmA study

项目摘要/摘要(来自上级奖励) 南亚人(SA)是美国增长最快的主要民族，也患有更严重的2型糖尿病 (T2 DM)和心血管疾病(CVD)风险相对较低的体重指数(BMI)与 欧洲和非洲血统。心脏代谢风险增加背后的机制(S)仍然存在 未定义。我们提交这项研究计划是为了回应美国国立卫生研究院的计划公告(PA-17- 021)征求解决NIDDK疾病健康差距的建议。心脏代谢增加 SA美国人的风险代表了一种研究不足的、不同的风险。进行的大多数是成人联合研究 在美国以外的国家，SA有更高的体脂百分比，内脏脂肪和腹部脂肪 考虑到体重指数高于其他民族。这些研究发现，在SA成年人中，胰岛素抵抗和 血脂异常以及胰岛素介导的葡萄糖处置减少(与内脏脂肪成反比)和 -细胞功能。我们建议对SA青年进行研究，以阐明其背后的早期机制变化 心脏代谢风险增加。鉴于SA独特的脂肪分布，我们建议将异位脂肪定义为 美国SA青少年脂肪代谢和细胞胰岛素分泌改变的沉积和测试。我们将 使用尖端的创新技术，包括MRI/MRS、游离脂肪酸(FFA)的数学建模 动力学和葡萄糖强化精氨酸试验(GPA)测量胰岛素分泌能力，方法不是 以前在SA青年中使用。我们已经组建了一支经验丰富的多机构(约翰霍普金斯大学， Chop、UPenn、CNMC)和具有成功协作记录的多学科团队，以执行 体重指数≥为80%的SA血统(n=50)12-21岁青年与欧洲人的横断面研究 血统(白人)(n=50)和非裔美国人(Aa)血统(n=50)具有相同的年龄、性别和BMI%。AA 众所周知，个人的心脏代谢风险也增加了，但内脏脂肪减少了， 这使他们成为一个独特的对比群体。目的：1.检查与祖先有关的体脂差异 分布(通过MRI/MRS)、FFA流量(通过3小时口服葡萄糖耐量试验和最小脂肪酸模型 动力学)，并比较不同祖先之间内脏肥胖和FFA流量之间的关系。2. 检查与祖先相关的细胞胰岛素分泌能力的差异(按GPA计算)，并比较 不同组间FFA流量与胰岛素分泌量的关系3.比较心血管疾病和2型糖尿病 3组的危险因素和血管末梢器官损伤(主动脉脉搏波速度)，并检验 FFA流量与心脏代谢风险特征之间关系的祖先相关差异。探索性的 目的：比较脂肪细胞来源的外切微RNA参与胰岛素信号转导的组间差异。 测量它们与细胞胰岛素分泌能力的关系，以产生假说。因此，这项提议 将调查异位脂肪、游离脂肪酸流量和细胞分泌之间的关联是否因祖先而不同 影响心脏代谢风险，预期这可能导致针对祖先的治疗选择。

Project Summary/Abstract (FROM PARENT AWARD) South Asians (SA), the fastest growing major ethnic group in the U.S., are also at greater type 2 diabetes (T2DM) and cardiovascular disease (CVD) risk at relatively lower body mass index (BMI) compared to those of European and African ancestry. The mechanism(s) underlying this increased cardiometabolic risk remain undefined. We are submitting this research proposal in response to an NIH program announcement (PA-17- 021) requesting proposals addressing health disparities in NIDDK diseases. The increased cardiometabolic risk in SA Americans represent an understudied and disparate risk. Mostly adult, associative studies performed outside the U.S. indicate that SA have higher % body fat, visceral adiposity, and abdominal adiposity for a given BMI than other ethnic groups. In SA adults, these studies have found increased insulin resistance and dyslipidemia as well as decreased insulin-mediated glucose disposal (inversely proportional to visceral fat) and -cell function. We propose to study SA youth, in order to elucidate early mechanistic changes underlying their increased cardiometabolic risk. Given the unique fat distribution of SA, we propose to define ectopic fat deposition and test for altered fat metabolism and -cell insulin secretion in SA adolescents in the U.S. We will use cutting-edge, innovative techniques, including MRI/MRS, mathematical modeling of free fatty acid (FFA) kinetics, and the glucose-potentiated arginine test (GPA) to measure insulin secretory capacity, methods not previously used in SA youth. We have assembled a highly experienced, multi-institutional (Johns Hopkins, CHOP, UPenn, CNMC), and multi-disciplinary team with a track record of successful collaboration, to perform a cross-sectional study of 12-21 yrs old youth of SA ancestry (n=50), BMI ≥80%ile, compared to European ancestry (White) (n=50) and African American (AA) ancestry (n=50) of comparable age, sex, and BMI%ile. AA individuals are known to also have increased cardiometabolic risk but have decreased visceral adiposity, making them a unique comparison group. Aims: 1.To examine ancestry-related differences in body fat distribution (by MRI/MRS), FFA flux (by 3-hour oral glucose tolerance test and Minimal Model of fatty acid kinetics), and to compare the relationships between visceral adiposity and FFA flux among ancestral groups. 2. To examine ancestry-related differences in -cell insulin secretory capacity (by GPA), and compare the relationship between FFA flux and insulin secretory capacity among groups. 3. To compare CVD and T2DM risk factors and vascular end organ injury (aortic pulse wave velocity) among the 3 groups, and test for ancestry-related differences in the relationships between FFA flux and cardiometabolic risk profile. Exploratory Aim: to compare adipocyte-derived exosomal microRNAs involved in insulin signaling among the groups, and measure their association with -cell insulin secretory capacity, for hypothesis generation. Thus, this proposal will investigate whether associations between ectopic fat, FFA flux, and -cell secretion vary by ancestry to impact cardiometabolic risk, with the expectation that this may lead to ancestry-specific treatment options.