Friday, March 21, 2025
3/21/2025
PROJECT SUMMARY/ABSTRACT Tight regulation of circulating nutrients within a narrow physiological range is a critical function of metabolism, and eating is a regular perturbation of this homeostasis. Growing evidence suggests that changes in circulating metabolites after a standardized mixed meal tolerance test (MMTT) may reflect underlying cardiometabolic (CM) health beyond what is revealed during fasting. Thus far, there have been very few broad characterizations of metabolomic changes after a standardized meal in a large cohort of community-dwelling individuals with a range of CM risk. In recently published human data, the applicant identified >30 circulating metabolites whose 2-hour changes after a MMTT are different in people with diabetes vs. those without even after accounting for fasting differences. A subset of these metabolites is associated with premature death in a large population-based cohort. The applicant will now extend these pilot findings in the Framingham Heart Study (FHS), where >2,400 participants will undergo a MMTT and metabolomic profiling of ≈800 targeted metabolites and ≈5,000 unknown compounds by liquid chromatography tandem mass spectrometry. We will test whether specific metabolites’ responses after a MMTT are associated with a range of CM risk factors such as insulin resistance, dyslipidemia, obesity, and unhealthy diet, and novel glycemic traits by continuous glucose monitoring (Aim 1). We will then assess broader epidemiologic implications of these post-MMTT metabolite responses by examining their associations with incident cardiometabolic disease (CMD) in the FHS, relating their fasting levels to incident diabetes and cardiovascular disease (CVD) in racially and ethnically diverse external cohorts, and testing whether post-MMTT metabolite responses may be causally related to CMD by leveraging genetics (Aim 2). Finally, we will translate the paradigm of using a MMTT to assess CM health from individuals in the community with average CM risk to a hospital-based cohort of individuals with overt CMD (i.e., heart failure with preserved ejection fraction [HFpEF]). We will assess whether post-MMTT metabolite responses are related to markers of HFpEF disease status and if post-MMTT metabolite responses improve after treatment with sodium-glucose cotransporter 2 inhibitors, which are theorized to improve outcomes in HFpEF through metabolic modulation (Aim 3). The applicant is an early career investigator and cardiologist with a research focus on leveraging evolving biochemical profiling techniques in precision nutrition to improve CVD prevention and treatment. This proposal will further the applicant’s career development through training in nutrition science, state-of-the-art metabolomics technology, advanced biostatistics and bioinformatics methods for analyzing metabolomics and genomics data, and the conduct of patient-oriented research in diverse settings. The applicant’s outstanding mentoring team of senior investigators with distinguished mentoring records and internationally recognized expertise in nutrition, metabolomics, genetics, and epidemiology will support the candidate as he transitions to research independence during the award.
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