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

项目摘要/摘要 心脏代谢性疾病(CMD)，包括糖尿病、肥胖和心血管疾病(CVD)，是一种 巨大的公共卫生负担。尽管大量的临床危险因素和分子生物标志物 已知在人群水平上会导致CMD风险，个人水平的风险预测仍然具有挑战性 还有一种未得到满足的需求，即在更早的、因此更可修改的亚临床阶段识别个体 CMD的发展。系统对离散的生理扰动(或压力)的反应可以揭开面纱 静息状态下不明显的代谢和内环境平衡功能异常。因此，我们建议 为了系统地评估对口服混合餐耐量试验(MMTT)的反应，该试验代表着一种 标准化、可重复性和生理性代谢挑战。保持能源平衡和高效 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 系统功能障碍会改变餐后代谢，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 餐后数小时)在≈600循环小分子中提供对人体代谢组的广泛覆盖。 空腹代谢物特征与关键的CMD风险因素和事件相关，但个体内部 餐后这些代谢物的变化反映出代谢健康的细微差异在很大程度上是未知的。 因此，我们假设Mmtt的代谢反应可以揭示心脏代谢功能障碍。 通过禁食血液指标，这一点并不明显。为了验证这一假设，我们将在 3037名弗雷明翰心脏研究(FHS)参与者参加第三代/OMNI 2世代队列的第四次考试。我们的 具体目标是：(1)表征代谢反应及其与CM性状的关系。 胰岛素抵抗；(2)与MMTT后代谢物反应相关(以及基础代谢物水平与大量 餐后短途旅行)心脏代谢和心血管疾病与FHS和冠状动脉风险的结局 青年发展(CARDIA)研究；(3)评估MMT后代谢物的分子决定因素 反应包括遗传变异、前驱代谢物轨迹和肠道微生物组组成。 我们的应用程序将系统地评估社区对MMT的代谢反应，目标是 识别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CMD的风险和发现可能适用于药物的新的生物途径 调制。我们的研究团队包括流行病学、代谢组学、糖尿病、高脂血症等领域的专家。 维度分子分析和数据分析，以及生物信息学。通过系统地评估代谢 具有不同心血管风险的社区居民对标准化口服餐的反应 我们将为科学界提供一个重要的资源。

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.