Visceral Adiposity and Diabetes: Translating Form to Function Using Imaging



 DESCRIPTION (provided by applicant): My career goal is to become an independent NIH R01-funded investigator contributing to a better understanding of the pathophysiology underpinning the heterogeneous diabetes and metabolic risks associated with obesity. My work to date has been primarily focused on static assessments of adipose tissue structural distribution, culminating in many first-author publications and research awards. The two immediate research goals necessary to advance the field and my own career development are to 1) acquire new skills in the longitudinal assessment of changes in visceral adipose tissue (VAT) distribution and 2) extend my research program from study of adipose tissue distribution to that of adipose tissue function using novel imaging techniques, in order to better understand mechanisms by which excess VAT contributes to metabolic disease. To achieve these goals, I have formed a dedicated and rigorous career development plan that will include multi-disciplinary mentorship, coursework in epidemiology, biostatistics, and biomedical imaging, culminating in completion of a Master's degree in Clinical Sciences, and direct training in the analysis and interpretation of adipose tissue imaging and translational methods. I will continue my successful mentored relationship with Dr. James de Lemos and have initiated a mentored collaboration with Dr. Craig Malloy, an expert in metabolic imaging and Director for the Advanced Imaging Research Center (AIRC) at UTSW. Additionally, I will continue collaborative relationships with Dr. Gloria Vega and Dr. Scott Grundy with whom I will work to train in imaging techniques and analysis of body fat distribution. In the context of this grant, I will formalize ne relationships with Dr. Helen Hobbs, the primary investigator for the Dallas Heart Study (DHS) and an expert in metabolic disease, as well as Dr. Jorge Plutzky, a renowned researcher in diabetes and lipid metabolism. My long term goal is to understand how VAT contributes to diabetes risk and to identify strategies to reduce the metabolic consequences of excess VAT. The objectives of this proposal are to characterize the relationship between changes in VAT and diabetes risk and elucidate the mechanistic relationship between VAT and abnormal glucose homeostasis. Here, I will test the central hypothesis that visceral adiposity plays a key role in te pathogenesis of insulin resistance and diabetes in the DHS, a multiethnic cohort study in which VAT has been serially measured with dual x-ray absorptiometry and diabetes outcomes have been collected over 10 years of follow-up. These epidemiologic studies will be complemented by functional studies of glycerol metabolism in hepatic gluconeogenesis using a well-validated nuclear magnetic resonance (NMR) spectroscopy platform. I will achieve the scientific objectives of this proposal by pursuing the following three specific aims: 1) Characterize the associations between changes in VAT and diabetes risk over a 10 year period in in the Dallas Heart Study, 2) Elucidate the relationship between VAT mass and glucose homeostasis by measuring enrichment of glycerol in blood glucose by NMR spectroscopy, and 3) Determine the effect of empagliflozin, a novel diabetes drug shown to reduce markers of VAT, on glucose homeostasis in non-diabetic obese adults with differing VAT mass. These studies are expected to have an important positive impact, because the identified relationships are highly likely to improve assessment of diabetes risk, lead to new targets for preventive and therapeutic interventions for diabetes, and fundamentally advance the field of adiposity research. UT Southwestern combines extraordinary epidemiologic and translational research opportunities and faculty development programs that will ensure the PI's successful clinical research career. These include the DHS (led by Drs. de Lemos and Hobbs), the AIRC (led by Dr. Malloy), the Center for Human Nutrition (led by Drs. Grundy and Vega), the Taskforce for Obesity Research, the Department of Clinical Sciences, the Center for Translational Medicine, and the Touchstone Center for Diabetes Research. Based on my training, experience, collaborative relationships, and institutional environment, I believe that I am uniquely positioned to achieve the objectives of this career development project and mature into an independent investigator able to apply novel imaging and translational techniques that directly interrogate the structure and function of VAT to answer important epidemiological and clinical questions regarding the role of excess VAT as a target for reducing diabetes and metabolic disease.