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

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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.