Metabolic Responses to an Oral Mixed Meal Tolerance Test: Intra-individual changes, correlates, and prognostic significance

口服混合膳食耐受性测试的代谢反应：个体内变化、相关性和预后意义

• 批准号: 10471798
• 负责人: Matthew G. Nayor
• 金额: $ 60.55万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471798
• 关键词: Address; Adipose tissue; Age; Bioinformatics; Biological; Biological Assay; Biometry; Blood; Blood specimen; Body mass index; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Categories; Cessation of life; Communities; Consumption; Coronary Artery Risk Development in Young Adults Study; Coronary heart disease; Data Analyses; Development; Diabetes Mellitus; Disease Outcome; Drug Modulation; Epidemiology; Event; Fasting; Fatty acid glycerol esters; Framingham Heart Study; Functional disorder; Funding; Future; Generations; Genetic Variation; Glucose; Goals; Health; Heart Diseases; Heterogeneity; Hour; Human; Human Biology; Impairment; Individual; Insulin Resistance; Intake; Kidney; Link; Liver; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Molecular; Neurologic; Obesity; Oral; Pancreas; Participant; Pathway interactions; Pattern; Persons; Phenotype; Physiological; Populations at Risk; Positioning Attribute; Process; Proteins; Public Health; Reproducibility; Research; Research Personnel; Resources; Rest; Risk; Risk Factors; Sampling; Skeletal Muscle; Standardization; Stress; System; Testing; base; body system; cardiometabolic risk; cardiometabolism; cardiovascular disorder epidemiology; cardiovascular risk factor; clinical risk; cohort; diabetes risk; disorder risk; endophenotype; energy balance; experience; flexibility; genetic epidemiology; genetic variant; gut microbiome; health definition; heart disease risk; high dimensionality; improved; innovation; insight; metabolome; metabolomics; microbiome composition; molecular marker; multi-racial; novel; novel marker; patient oriented research; preservation; prognostic; prognostic significance; response; risk prediction; sex; small molecule; stressor; trait; translational study; young adult

PROJECT SUMMARY/ABSTRACT Cardiometabolic disease (CMD), including diabetes, obesity, and cardiovascular disease (CVD), represents an enormous public health burden. Although a large number of clinical risk factors and molecular biomarkers are known to contribute to CMD risk at the population level, individual-level risk prediction remains challenging and there is an unmet need to identify individuals during earlier, and thus more modifiable, subclinical stages in the development of CMD. The systemic response to discrete physiologic perturbations (or ‘stresses’) can unmask abnormal metabolic and homeostatic functions that are not apparent in a resting state. Therefore, we propose to systematically assess responses to an oral mixed meal tolerance test (MMTT), which represents a standardized, reproducible, and physiologic metabolic challenge. Preservation of energy balance and efficient storage of fuel substrates after a meal requires a coordinated multi-organ systemic response. Subclinical organ system dysfunction can alter post-meal metabolism leading to distinct circulating metabolic signatures. In this application, we will capture integrated responses to a MMTT by assaying dynamic changes (from fasting to 2 hours post-prandial) in ≈600 circulating small molecules providing broad coverage of the human metabolome. Fasting metabolite profiles are associated with key CMD risk factors and events, but how intra-individual changes in these metabolites after a meal reflect subtle differences in metabolic health is largely unknown. Accordingly, we hypothesize that the metabolic response to a MMTT can reveal cardiometabolic dysfunction that is not evident by fasting blood measures. To test this hypothesis, we will characterize MMTT responses in 3037 Framingham Heart Study (FHS) participants at the fourth exam of the Generation 3/ Omni 2 cohorts. Our specific aims are: (1) to characterize metabolomic responses to a MMTT and their relations to CM traits and insulin resistance; (2) to relate post-MMTT metabolite responses (and baseline levels of metabolites with large post-meal excursions) to cardiometabolic and CVD and outcomes in the FHS and in the Coronary Artery Risk Development in Young Adults (CARDIA) Study; (3) to assess molecular determinants of post-MMTT metabolite responses including genetic variation, antecedent metabolite trajectories, and the gut microbiome composition. Our application will systematically evaluate metabolic responses to a MMTT in the community with the goals of identifying abnormal responses not accessible by standard fasting measures that provide innovative insights regarding future CMD risk and of discovering novel biological pathways that may be amenable to drug modulation. Our study team includes experts in the fields of epidemiology, metabolomics, diabetes, high- dimensional molecular assays and data analysis, and bioinformatics. By systematically assessing metabolic responses to a standardized oral meal in community-dwelling individuals with varying cardiovascular risk profiles, we will provide an important resource to the scientific community.

项目总结/摘要 心脏代谢疾病（CMD），包括糖尿病、肥胖症和心血管疾病（CVD），代表了一种 巨大的公共卫生负担。虽然大量的临床危险因素和分子生物标志物是 已知在人群水平上会导致CMD风险，但个体水平的风险预测仍然具有挑战性， 在较早的、因此更易改变的亚临床阶段， CMD的发展。对离散生理扰动（或“应激”）的系统反应可以揭示 在静止状态下不明显的不正常的新陈代谢和自我平衡功能。所以我们提出 系统评估对口服混合餐耐受性试验（MMTT）的反应，该试验代表了 标准化、可重复和生理代谢挑战。保持能源平衡和效率 餐后燃料底物的储存需要协调的多器官系统反应。亚临床器官 系统功能障碍可以改变餐后代谢，导致不同的循环代谢特征。在这 应用程序，我们将通过分析动态变化（从禁食到2 餐后24小时）在100600个循环小分子中，提供了对人代谢组的广泛覆盖。 空腹代谢产物谱与关键CMD风险因素和事件相关，但个体内如何 餐后这些代谢物的变化反映了代谢健康的微妙差异，这在很大程度上是未知的。 因此，我们假设对MMTT的代谢反应可以揭示心脏代谢功能障碍 这在空腹血液测量中并不明显。为了检验这一假设，我们将描述MMTT反应， 3037名FHS参与者参加了第3代/ Omni 2队列的第4次检查。我们 具体目标是：（1）表征对MMTT的代谢组学反应及其与CM性状的关系， 胰岛素抵抗;（2）与MMTT后代谢物反应（以及代谢物的基线水平与大剂量胰岛素抵抗相关）相关。 餐后波动）与心脏代谢和CVD以及FHS和冠状动脉风险结局的关系 年轻成人发育（CARDIA）研究;（3）评估MMTT后代谢物的分子决定因素 这些反应包括遗传变异、前期代谢物轨迹和肠道微生物组组成。 我们的申请将系统地评估社区中对MMTT的代谢反应，目标是 识别标准空腹测量无法获得的异常反应，提供创新见解 关于未来的CMD风险和发现新的生物学途径，可能适合药物治疗 调变我们的研究团队包括流行病学，代谢组学，糖尿病，高血压等领域的专家， 三维分子测定和数据分析以及生物信息学。通过系统评估代谢 不同心血管风险的社区居民对标准化口服餐的反应 简介，我们将为科学界提供一个重要的资源。