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

项目总结/摘要 南亚人（SA）是美国增长最快的主要种族群体，2型糖尿病（T2 DM）的发病率也较高， 与欧洲人和非洲人相比，体重指数（BMI）相对较低时的心血管疾病（CVD）风险 祖先这种心脏代谢风险增加的潜在机制仍不明确。我们将提交这份 响应NIH项目公告（PA-17-021）的研究提案，该公告要求提出解决健康问题的提案 NIDDK疾病的差异。SA美国人的心脏代谢风险增加代表了一个研究不足， 不同的风险大多数成年人，在美国以外进行的相关研究表明，SA具有较高的体脂百分比， 内脏肥胖和腹部肥胖的比例高于其他种族。这些研究还发现， 增加胰岛素抵抗和血脂异常以及减少胰岛素介导的葡萄糖处置（相反 与内脏脂肪成比例）和SA成人中的β细胞功能。我们建议研究SA青少年，以阐明 早期机械变化导致心脏代谢风险增加。鉴于SA的独特脂肪分布，我们 建议定义异位脂肪沉积，并检测SA青少年脂肪代谢和β细胞胰岛素分泌的改变 我们将使用尖端的创新技术，包括MRI/MRS，游离脂肪酸的数学建模， 酸（FFA）动力学和葡萄糖增强精氨酸试验（GPA）测量胰岛素分泌能力，方法不 曾用于青少年。我们已经组建了一个经验丰富的，多机构（CNMC，CHOP，NIH）， 和多学科团队，具有成功合作的记录，进行12-21的横断面研究 SA血统的10岁青少年和年轻成年人（n=50），BMI ≥ 85%ile，与欧洲青少年相比， 年龄、性别和BMI百分比相似的血统（白色）（n =50）和非裔美国人（AA）（n=50）。AA 已知个体也具有增加的心脏代谢风险，但具有降低的内脏肥胖，使其成为 独特的对照组。目的：1.为了检查与祖先相关的体脂分布差异（通过MRI/MRS），FFA 通过3小时口服葡萄糖耐量试验和脂肪酸动力学最小模型，并比较它们之间的关系 内脏肥胖和FFA之间的关系2.为了检查β细胞中与祖先相关的差异， 胰岛素分泌能力（GPA），并比较FFA通量与胰岛素分泌能力的关系 在群体之间。3.比较CVD和T2 DM风险因素与血管终末器官损伤（主动脉脉搏波速度） 在三组之间，并测试FFA通量与 心脏代谢风险特征。探索性目的：比较脂肪细胞来源的外泌体microRNA参与胰岛素 信号传导，并测量其与β细胞胰岛素分泌能力的相关性，用于假设 一代因此，本研究将探讨异位脂肪、FFA通量和β细胞分泌之间的关系， 因血统而异，以影响心脏代谢风险，预计这最终可能导致血统特异性 治疗方案。

Project Summary/Abstract 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. These studies have also found increased insulin resistance and dyslipidemia as well as decreased insulin-mediated glucose disposal (inversely proportional to visceral fat) and β-cell function in SA adults. We propose to study SA adolescents, 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 β-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 adolescents. We have assembled a highly experienced, multi-institutional (CNMC, CHOP, NIH), and multi-disciplinary team with a track record of successful collaboration, to perform a cross-sectional study of 12-21 year old adolescents and young adults of SA ancestry (n=50), BMI ≥ 85%ile, compared to adolescents of 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 β-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 three 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 β-cell insulin secretory capacity, for hypothesis generation. Thus, this proposal will investigate whether associations between ectopic fat, FFA flux, and β-cell secretion vary by ancestry to impact cardiometabolic risk, with the expectation that this may eventually lead to ancestry-specific treatment options.