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.