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

南亚血统青少年的心脏代谢健康 - CHARiSmA 研究

• 批准号: 10190921
• 负责人: SHEELA NATESH MAGGE
• 金额: $ 66万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-04 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190921
• 关键词: 21 year old; Address; Adipocytes; Adolescent; Adolescent and Young Adult; Adult; Affect; African; African American; Age; Arginine; Asian Americans; Bangladesh; Beta Cell; Bhutan; Blood Vessels; Body Composition; Body fat; Body mass index; Cardiovascular Diseases; Cell physiology; Cell secretion; Collaborations; Cross-Sectional Studies; Data; Deposition; Disease; Dyslipidemias; Environmental Exposure; Ethnic Origin; Ethnic group; European; Fatty Acids; Fatty acid glycerol esters; Free Association; Future; Generations; Glucose; Health; Hour; India; Individual; Inflammation; Insulin; Insulin Resistance; Investigation; Kinetics; Lead; Lipids; Lipoproteins; Magnetic Resonance Imaging; Maldives; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; MicroRNAs; Modeling; NIH Program Announcements; National Institute of Diabetes and Digestive and Kidney Diseases; Nepal; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; OGTT; Obesity; Pakistan; Pathology; Pathway interactions; Pattern; Physiologic pulse; Plant Roots; Population; Request for Proposals; Research Proposals; Risk; Risk Factors; South American; South Asian; Sri Lanka; Techniques; Testing; United States National Institutes of Health; Visceral; Visceral fat; abdominal fat; adipokines; base; cardiometabolic risk; cardiometabolism; cardiorespiratory fitness; cardiovascular disorder risk; clinical phenotype; comparison group; expectation; experience; fatty acid metabolism; glucose disposal; glucose tolerance; health disparity; inflammatory marker; innovation; insight; insulin regulation; insulin secretion; insulin signaling; lipid metabolism; mathematical model; multidisciplinary; novel; organ injury; particle; response; sex

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.

项目概要/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 (T2DM) 和 与欧洲和非洲人相比，体重指数 (BMI) 相对较低的心血管疾病 (CVD) 风险 祖先。这种心脏代谢风险增加的机制仍不清楚。我们正在提交这个 响应 NIH 计划公告 (PA-17-021) 的研究提案，要求提出解决健康问题的提案 NIDDK 疾病的差异。南澳美国人心脏代谢风险增加是一个尚未得到充分研究和研究的问题 不同的风险。在美国境外进行的大多数成人相关研究表明，南非人的体脂百分比较高， 对于给定的体重指数，内脏肥胖和腹部肥胖高于其他种族。这些研究还发现 胰岛素抵抗和血脂异常增加，以及胰岛素介导的葡萄糖处理减少（相反 与内脏脂肪成正比）和 SA 成人的 β 细胞功能。我们建议对南非青少年进行研究，以阐明 心脏代谢风险增加的早期机制变化。鉴于 SA 独特的脂肪分布，我们 提议定义异位脂肪沉积并测试 SA 青少年脂肪代谢和 β 细胞胰岛素分泌的改变 在美国，我们将使用尖端的创新技术，包括 MRI/MRS、游离脂肪的数学模型 酸（FFA）动力学，以及葡萄糖强化精氨酸试验（GPA）来测量胰岛素分泌能力，方法不 以前用于 SA 青少年。我们组建了一支经验丰富的多机构（CNMC、CHOP、NIH）、 和具有成功合作记录的多学科团队，对 12-21 进行横断面研究 与欧洲青少年相比，南非血统的 2 岁青少年和年轻人 (n=50)，BMI ≥ 85%ile 具有可比年龄、性别和 BMI %ile 的白人 (白人) (n=50) 血统和非裔美国人 (AA) 血统 (n=50)。 AA 众所周知，个体的心脏代谢风险也增加，但内脏脂肪减少，使他们成为 独特的对照组。目的： 1. 检查与血统相关的身体脂肪分布差异（通过 MRI/MRS）、FFA 通量（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），并比较关系 祖先群体中内脏肥胖和 FFA 通量之间的关系。 2. 检查 β 细胞的血统相关差异 胰岛素分泌能力（按GPA），并比较FFA通量与胰岛素分泌能力之间的关系 群体之间。 3. 比较CVD和T2DM危险因素和血管终末器官损伤（主动脉脉搏波速度） 三组之间的差异，并测试 FFA 通量与血统之间关系的差异 心脏代谢风险状况。探索性目标：比较脂肪细胞来源的外泌体 microRNA 参与胰岛素的作用 各组之间的信号传导，并测量它们与 β 细胞胰岛素分泌能力的关联，以进行假设 一代。因此，该提案将研究异位脂肪、FFA 通量和 β 细胞分泌之间是否存在关联 因血统不同而影响心脏代谢风险，预计这最终可能导致血统特异性 治疗方案。