PROJECT SUMMARY/ABSTRACT Background: The increasing incidence and prevalence of type 2 diabetes (T2D) can be mitigated by successful prevention with behavioral changes or pharmacotherapy in individuals that are at high risk. Identifying a specific individual’s risk for diabetes and which preventive treatment will be most effective, however, remains a clinical dilemma. Metabolite biomarkers represent a novel approach to addressing these clinical challenges and may also reveal mechanisms of disease development. This five-year mentored career development proposal details a translational research training program in biomarker discovery and clinical study implementation with a goal of identifying metabolite predictors of diabetes and preventive treatment effect. Candidate: The applicant is a recently appointed Endocrinology faculty member at Beth Israel Deaconess Medical Center with a long-term goal to become a physician-scientist who investigates metabolic pathways involved in T2D development and progression. She has 2.5 years of experience in molecular profiling in large human studies and the outlined proposal builds on this background to provide new domains of expertise including prediction modeling, genetics, and clinical study design. Training: The applicant’s development will occur through a blend of laboratory training, didactic courses (including an ongoing MPH), and scientific conferences. The candidate’s mentor is a recognized leader in molecular profiling, integrative “omics”, and cardiometabolic diseases. Her co-mentor is a leader in T2D genetics, and the members of her advisory committee have a distinguished mentoring record and vast expertise in T2D, non-targeted metabolomics, statistical modeling, and clinical trials. Research: Recently, the applicant identified unique metabolite profiles associated with T2D in a large, randomized control trial that compared lifestyle changes and metformin therapy for T2D prevention in individuals with impaired glucose regulation. These associations, including specific phosphatidylcholines and cholesterol esters, remained after adjustments for traditional clinical risk factors suggesting they could serve as predictors of T2D. Furthermore, these metabolites were associated with different rates of T2D progression after lifestyle or metformin treatment and may help guide T2D prevention decisions. The applicant proposes to further extend these findings by (Aim 1) creating metabolite multi-marker prediction models to assess the ability of these metabolites to prospectively predict diabetes development, (Aim 2A) integrate these findings with genetics to uncover metabolic pathways that underly these associations and if they cause diabetes, (Aim 2B) leverage genetics to also identify completely novel circulating small molecules associated with T2D, and (Aim 3) conduct a small prospective cohort study to externally validate these metabolites as predictive biomarkers in a real-world clinical setting. This work wi...