PROJECT SUMMARY Dr. Latha Palaniappan, MD, MS is a well-recognized clinical researcher with a long track record of funding, expertise, and mentoring in patient-oriented research (POR) in cardiometabolic disease. As a newly-appointed Professor of Medicine at Stanford University, her extensive clinical research and teaching experience will help her mentor and train the next generation clinical and translational scientists in POR. Although Dr. Palaniappan is currently the lead investigator of two NIH-funded clinical trials, she is seeking support to pursue novel mechanistic research directions in cardiometabolic health, particularly in adults of normal weight with Type 2 diabetes, which affects over 3 million Americans and is associated with higher cardiovascular mortality. In addition, this K24 proposal will leverage Dr. Palaniappan’s breadth of experience to provide an innovative and dynamic setting to train mentees in POR. Her mentees can leverage the existing research platform available through two large, randomized clinical trials (RCTs), namely STRONG-D (normal weight) and IMPACT (overweight/obese), and an existing institutional biobank (Stanford GenePool). These biobanked samples will provide the basis for her future research direction which will focus on mechanistic differences in cardiometabolic health in three groups: normal-weight patients with diabetes (STRONG-D), overweight/obese (IMPACT) individuals with diabetes, and normal weight normoglycemic individuals (Stanford GenePool). She will use human induced pluripotent stem cells, metabolomics, and exosome profiling. The Specific Aims are as follows: Aim 1: Characterize cardiometabolic health across the three groups (n=40 in each group). We hypothesize that normal-weight people with diabetes (NWD) will be most cardiometabolically unhealthy followed by overweight/obese PWDs, followed by normal-weight normoglycemia. Aim 2: Investigate the functional differences in human induced pluripotent stem cells (iPSCs), specifically in cardiomyocytes and endothelial cells across the three groups (n=3 in each group). We hypothesize that individuals with normal weight diabetes will exhibit more dysfunction in cardiomyocytes (less cardiac contractility) and endothelial cells (less nitric oxide output). Aim 3: Examine metabolite profiles across the three groups (n=40 in each group). We hypothesize that NWDs will have more hepatic gluconeogenesis metabolites than overweight or obese individuals with diabetes. Aim 4: Evaluate and compare exosome profiles across the three groups (n=40 in each group). We hypothesize that NWDs will express more anti-angiogenesis miRNAs (miR-320) than overweight/obese individuals with diabetes after controlling for weight. This proposal will identify new pathways for intervention to predict, prevent and treat mortality and morbidity in normal weight diabetes.