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.

Public Health Relevance

This project aims to evaluate the role of visceral adipose tissue in diabetes pathogenesis. Two studies are proposed: 1) characterization of the epidemiology of changes in visceral adipose tissue over time and its relation to the development of pre-diabetes and diabetes in a multiethnic population, and 2) a study elucidating the mechanism behind how visceral adipose tissue alters glucose homeostasis and exploration of a possible therapeutic intervention targeting this mechanism. These studies are relevant to public health because they may improve the clinical assessment of diabetes risk in the general population and may lead to new therapies for obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK106520-05
Application #
9782919
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2015-09-15
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Neeland, Ian J; Singh, Shruti; McGuire, Darren K et al. (2018) Relation of plasma ceramides to visceral adiposity, insulin resistance and the development of type 2 diabetes mellitus: the Dallas Heart Study. Diabetologia 61:2570-2579
Neeland, Ian J; Poirier, Paul; Despr├ęs, Jean-Pierre (2018) Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management. Circulation 137:1391-1406
Mehta, A; Marso, S P; Neeland, I J (2017) Liraglutide for weight management: a critical review of the evidence. Obes Sci Pract 3:3-14
Pham, David; Albuquerque Rocha, Natalia De; McGuire, Darren K et al. (2017) Impact of empagliflozin in patients with diabetes and heart failure. Trends Cardiovasc Med 27:144-151
Neeland, Ian J; Das, Sandeep R; Simon, DaJuanicia N et al. (2017) The obesity paradox, extreme obesity, and long-term outcomes in older adults with ST-segment elevation myocardial infarction: results from the NCDR. Eur Heart J Qual Care Clin Outcomes 3:183-191
Shemisa, Kamal; Bhatt, Anish; Cheeran, Daniel et al. (2017) Novel Biomarkers of Subclinical Cardiac Dysfunction in the General Population. Curr Heart Fail Rep 14:301-310
Lew, Jeanney; Sanghavi, Monika; Ayers, Colby R et al. (2017) Sex-Based Differences in Cardiometabolic Biomarkers. Circulation 135:544-555
Yano, Yuichiro; Neeland, Ian J; Ayers, Colby et al. (2017) Hemodynamic and Mechanical Properties of the Proximal Aorta in Young and Middle-Aged Adults With Isolated Systolic Hypertension: The Dallas Heart Study. Hypertension 70:158-165
Neeland, Ian J; Kozlitina, Julia (2017) Mendelian Randomization: Using Natural Genetic Variation to Assess the Causal Role of Modifiable Risk Factors in Observational Studies. Circulation 135:755-758
Gupta, Arjun; Pandey, Ambarish; Ayers, Colby et al. (2017) An Analysis of Individual Body Fat Depots and Risk of Developing Cancer: Insights From the Dallas Heart Study. Mayo Clin Proc 92:536-543

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