Impact of Nocturnal Hypoxemia on Glucose during Sleep in High Altitude Sleep Disordered Breathing

项目摘要 睡眠呼吸障碍（SDB）是一种高度流行的疾病， 糖尿病SDB诱导的功能障碍的机制尚未阐明。低氧血症与 作为葡萄糖耐受不良和糖尿病发展的关键致病因素。高海拔人群， 经历慢性缺氧的人，代表了研究夜间低氧血症在 SDB相关糖尿病的发病机制。我们的研究小组以前证明了夜间低氧血症的严重性， 独立于日间氧合血红蛋白饱和度，与血红蛋白A1c升高相关。至今没有 研究表明，针对夜间低氧血症改善葡萄糖控制。 在本申请中，我们将调查夜间低氧血症引起动态夜间血糖的假设 海拔高度，这是缓解氧气。我们将采用连续血糖监测来检查时间 葡萄糖和氧合动力学之间的联系，并检查 在一项随机交叉研究中进行夜间吸氧。成功完成此提案将 为夜间缺氧是高地人精神障碍的可逆原因提供了机械证据。 申请人Luu Pham博士是一名肺部、重症监护和睡眠医学医生，他寻求 发展专注于SDB相关代谢疾病发病机制的研究事业。这项建议将 允许申请人专门的时间来进行概述的研究项目，以及追求教学培训， 设计和开展临床试验，并进一步量化与本项目和未来研究相关的方法 布局本研究建议书所产生的数据将作为R01申请的基础， 低氧血症在糖尿病发病中的作用。此申请人的职业发展计划 包括一个结构化的指导方法，教学课程集中在一个特定的研究目标， 参加地方和国家会议，确定和定期评估职业里程碑。 约翰霍普金斯大学提供的研究环境以及 此申请将有助于范博士成功完成其职业生涯和研究目标。司 肺部和重症监护医学和约翰霍普金斯大学有着悠久的成功培训历史 年轻的临床研究人员。现有的高海拔研究基础设施和训练有素的实地工作人员，以及 由于申请人与他的导师团队建立和持续的合作，将确保研究 目标将在该奖项的时间范围内完成。我们已经组建了一个指导团队， 教师在高海拔研究，临床试验，SDB代谢后遗症方面具有独特的互补优势 和生物统计学，与本提案有关。此外，指导委员会的每个成员都是 为申请人的职业发展成为一个独立的调查员的优秀榜样。

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 addition, each member of the mentoring committee serves as an excellent role model for the applicant’s career development into an independent investigator.