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

项目总结 睡眠障碍呼吸(SDB)是一种高度流行的疾病，与事故风险增加有关 糖尿病。SDB引起的血糖异常的机制尚未阐明。与低氧血症有牵连 作为糖耐量异常和糖尿病发生的关键致病因素。高海拔人口， 谁经历了慢性缺氧，代表了独特的队列研究夜间低氧血症在 SDB相关糖尿病的发病机制。我们小组之前证明了夜间低氧血症的严重性， 与日间氧合血红蛋白饱和度无关，与血红蛋白A1c升高有关。到目前为止，没有 研究表明，以夜间低氧血症为靶点可以改善血糖控制。 在这项应用中，我们将研究夜间低氧血症导致夜间动态血糖的假设。 被氧气降低的海拔高度。我们将使用连续的血糖监测来检查颞叶 在一项观察性研究中血糖和氧合动力学之间的关系，并检查 夜间补充氧气的随机交叉研究。成功完成这项提案将 提供机制证据，证明夜间低氧是高地人血糖紊乱的可逆原因。 申请人鲁凡博士是一名肺部、重症监护和睡眠医学的内科医生，他寻求 发展专注于SDB相关代谢性疾病发病机制的研究事业。这项提议将 让申请者有专门的时间进行概述的研究项目，以及进行教学培训 设计和实施与本项目和未来研究相关的临床试验和进一步的量化方法 计划。此研究提案生成的数据将成为R01应用程序检查 低氧血症的治疗在糖尿病发病机制中的作用。应聘者的职业发展计划 包括结构化的指导方法，专注于特定研究目标的教学课程， 参加地方和国家会议以及确定和定期评估职业发展里程碑。 约翰霍普金斯大学提供的研究环境以及 这份申请将有助于范博士成功完成他的职业生涯和研究目标。分部 肺和重症监护医学和约翰霍普金斯大学在培训成功方面有着悠久的历史 年轻的临床研究人员。既有的高海拔研究基础设施和训练有素的实地工作人员 由于申请者与他的导师团队建立和持续的合作，将确保这项研究 目标将在本奖项的时间框架内完成。我们已经组建了一支由著名的 在高原研究、临床试验、SDB的代谢后遗症方面优势截然不同、优势互补的教师 和生物统计学，与这项提议相关。此外，指导委员会的每一位成员都是 优秀的榜样申请人的职业发展成为一名独立的调查员。

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.