Insulin Resistance, Pre-Diabetes, and Diabetes in Obesity-Associated Asthma

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PROJECT SUMMARY AND ABSTRACT Asthma and obesity are prevalent conditions in the United States. Obese individuals with asthma are at risk for obesity-associated asthma, a distinct phenotype that is more severe and exacerbation prone. Insulin resistance, pre-diabetes, and diabetes, a spectrum of disorders in glucose metabolism that is enriched in obesity, have been implicated as contributing to the excess morbidity observed in obesity-associated asthma. In general populations, these conditions have been associated with diminished lung function and respiratory symptoms, supporting a pathologic role in pulmonary health. However, there are significant limitations in literature, and its relevancy to asthma control and severity in humans, and among individuals with obesity, is uncertain. In this application, we propose to examine the association of insulin resistance, pre-diabetes, and diabetes with asthma exacerbations, asthma control, and lung function, as well as effect modification of this association by obesity. We will perform this analysis in two complementary aims, (1) a “big data” applied epidemiology project leveraging the electronic health record of two major health systems in the United States, combining cohort analyses with pharmaco-epidemiologic techniques to investigate the hypothesized pathway, and (2) a prospectively enrolled cohort study of obese participants with asthma who undergo bariatric surgery, with repeated measurements of insulin resistance, lung function, and patient-reported asthma outcomes. The results of these analyses will build evidence for a deleterious role of insulin resistance, pre-diabetes, and diabetes within obesity-associated asthma. This is especially important, as this common asthma phenotype has few specific treatment options. This project proposal will provide mentored training for the applicant to develop skills in the conduct of a patient-oriented clinical study, pharmacoepidemiology, EHR analytic techniques, and biostatistics. These skills will be pivotal toward the applicant's goal of becoming an independent physician-scientist and clinical epidemiologist with expertise in asthma and obesity-associated asthma. He is overseen by a mentorship team comprised of experts in asthma, patient-oriented research, EHR epidemiology, and biostatistics. The career development plan is a natural continuation of research activities in fellowship and serves to establish an expertise distinct from his principal mentor. The research strategy and career development plan will be operationalized within the Division of Pulmonary and Critical Care Medicine at the Johns Hopkins University, leveraging a collaborative and productive research environment with a strong history of successful development of junior faculty.