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: 10178458
• 负责人: Matthew G. Nayor
• 金额: $ 64.21万
• 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/10178458
• 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; 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.

项目摘要/摘要 心脏代谢疾病（CMD），包括糖尿病，肥胖和心血管疾病（CVD），代表 巨大的公共卫生伯恩。尽管大量的临床危险因素和分子生物标志物是 已知在人口一级有助于CMD风险的贡献，个人级别的风险预测仍然是挑战，并且 在早期期间识别个人的需求未满足，因此在 CMD的开发。对离散生理扰动（或“压力”）的全身反应可以揭露 在静止状态下并不明显的异常代谢和稳态功能。因此，我们提出 系统地评估对口服混合进餐测试（MMTT）的反应，这代表 标准化，可重现和生理代谢挑战。能源平衡和高效 用餐后的燃料底物的存储需要协调的多器官全身响应。亚临床器官 系统功能障碍会改变餐后代谢，从而导致独特的循环代谢特征。在这个 应用程序，我们将通过分析动态更改来捕获对MMTT的集成响应（从禁食到2 后派的小时）在≈600个循环小分子中，提供了人类代谢组的广泛覆盖范围。 禁食代谢物概况与关键CMD风险因素和事件有关，但个体内部如何 一顿饭后这些代谢产物的变化反映了代谢健康的细微差异在很大程度上尚不清楚。 据此，我们假设对MMTT的代谢反应可以揭示心脏代谢功能障碍 这不是禁食血液测量的证据。为了检验这一假设，我们将表征MMTT的响应 3037 Framingham心脏研究（FHS）参与者在第三代/ OMNI 2 COLOTS的第四次考试中。我们的 具体目的是：（1）表征对MMTT的代谢组反应及其与CM特征的关系以及 胰岛素抵抗； （2）关联MMTT后代谢物反应（以及代谢物的基线水平， 在FHS和冠状动脉风险中的心脏代谢和CVD以及冠状动脉局的结果以及结果 年轻人的发展（CARDIA）研究； （3）评估MMTT代谢产物后的分子决定剂 包括遗传变异，先行代谢物轨迹和肠道微生物组组成的反应。 我们的应用程序将系统地评估社区中对MMTT的代谢反应 确定通过提供创新见解的标准禁食措施无法获得的异常响应 关于未来的CMD风险以及发现可能适合药物的新型生物学途径 调制。我们的研究团队包括流行病学，代谢组学，糖尿病，高级领域的专家 尺寸分子测定和数据分析以及生物信息学。通过系统评估代谢 对具有不同心血管风险的社区居民中标准化口服餐的反应 个人资料，我们将为科学界提供重要的资源。