PROJECT SUMMARY Sleep disordered breathing (SDB) is a highly prevalent disease that is associated with increased risk for incident diabetes. Mechanisms of SDB-induced dysglycemia have not been elucidated. Hypoxemia has been implicated as a key pathogenic factor in the development of glucose intolerance and diabetes. High altitude populations, who experience chronic hypoxia, represent unique cohorts to study the role of nocturnal hypoxemia in the pathogenesis of SDB-related diabetes. Our group previously demonstrated that severity of nocturnal hypoxemia, independent of daytime oxyhemoglobin saturation, was associated with elevated hemoglobin A1c. To date, no study has shown that targeting nocturnal hypoxemia improves glucose control. In this application, we will investigate the hypothesis that nocturnal hypoxemia causes dynamic nocturnal glucose elevations, that are mitigated by oxygen. We will employ continuous glucose monitoring to examine the temporal association between glucose and oxygenation dynamics in an observational study and examine the effects of nocturnal oxygen supplementation in a randomized cross-over study. Successful completion of this proposal will provide mechanistic proof that nocturnal hypoxia is a reversible cause of dysglycemia in highlanders. The applicant, Dr. Luu Pham, is a physician in Pulmonary, Critical Care and Sleep Medicine, who seeks to develop a research career focused on the pathogenesis of SDB-related metabolic diseases. This proposal would allow the applicant dedicated time to conduct the outlined research project, as well as pursue didactic training in design and conduct of clinical trials and further quantitative methods relevant to this project and future research plans. The data generated from this research proposal will form the basis for an R01 application to examine the impact of treating of hypoxemia in the pathogenesis diabetes. The career development plan for this applicant includes a structured approach to mentoring, didactic coursework focused on a specific research goal, participation in local and national meetings and identification and regular assessment of career milestones. The research environment provided by Johns Hopkins University as well as the mentorship team described in this application will assist in Dr. Pham’s successful completion of his career and research goals. The Division of Pulmonary and Critical Care Medicine and Johns Hopkins University have a long history of training successful young clinical researchers. The pre-existing high-altitude research infrastructure and trained field staff, as well as the applicant’s established and ongoing collaboration with his team of mentors, will ensure that the study goals will be completed within the timeframe of this award. We have assembled a mentoring team of established faculty with distinct, complementary strengths in high altitude research, clinical trials, metabolic sequelae of SDB and biostatistics, relevant to this proposal. In add...