Obstructive Sleep Apnea and Glycemic Variability in Type 2 Diabetes

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）和2型糖尿病是常见的医学疾病，每种疾病都有显著的不良后果。在过去的十年中，大量的经验证据表明，阻塞性睡眠呼吸暂停在糖尿病患者中普遍存在，并且这两种疾病之间的关联与肥胖无关。动物和临床研究表明，间歇性低氧血症和睡眠中断可能会改变葡萄糖稳态，损害血糖控制。然而，阻塞性睡眠呼吸暂停和糖尿病之间的关系仍然存在一些问题。缺乏表征OSA严重程度对餐后高血糖和血糖变异性影响的研究。众所周知，虽然糖化血红蛋白水平（HbA1c）等血糖控制的整体指标可以预测血管并发症，但餐后高血糖和血糖大幅漂移可以独立预测糖尿病患者的血管并发症，包括颈动脉内膜-中膜厚度、动脉粥样硬化和大血管疾病。本研究的第一个目的是在糖尿病患者队列中表征OSA严重程度、血糖控制、餐后高血糖和血糖变异性之间的横断面关联。表征这些相关性是实现本研究第二个目标的核心——确定糖尿病患者持续气道正压通气（CPAP）治疗OSA是否与血糖控制、餐后高血糖和血糖变异性的改善有关。为了实现这些目标，糖尿病患者将接受睡眠测试来识别和分类OSA严重程度。将获得活动记录仪监测（量化睡眠时间）、热量摄入和葡萄糖稳态的几个指标（连续血糖监测、7点自我监测血糖谱和糖化血红蛋白）。OSA严重程度的指标将与血糖负荷指标相关，并仔细考虑混杂因素。因此，两种平行且独特的科学探究方式——横断面研究和介入性研究——将被用于更全面地了解OSA作为葡萄糖代谢调节剂的相关性。也许，本研究最具创新性和实际意义的贡献是评估CPAP治疗是否可以改善血糖控制，并被认为是糖尿病治疗领域的“辅助”。如果在本应用中提出的假设是正确的，那么所得到的数据将对糖尿病管理产生范式转变的影响。K23指导患者导向研究职业发展奖是成功开展上述建议调查的理想平台，也是实现我成为睡眠障碍医学独立临床研究者的长期职业目标和职业抱负的理想平台。通过K23机制，我期望在获得奖项的过程中，通过成功完成以下每一个短期目标，向我的长期目标迈进：1)通过彭博公共卫生学院的临床研究研究生培训计划获得健康科学硕士学位，获得临床研究方面急需的正式培训；2)与我的专家和专业导师团队密切合作，执行拟议的研究；3)在科学会议上展示研究结果，并在同行评议的期刊上发表。我坚定不移地致力于成为一名独立的睡眠医学临床研究者，这证明了我决定改变我的职业方向，搬到约翰霍普金斯大学，在那里我可以沉浸在一个支持和专注的学术环境中，拥有无与伦比的导师团队。约翰霍普金斯大学医学院、布隆伯格公共卫生学院和肺科和重症医学系的知识和临床环境非常适合开展拟议的研究并培养临床职业生涯

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) and type 2 diabetes mellitus are prevalent medical conditions each with significant adverse consequences. Over the last decade, a large body of empirical evidence has shown that OSA is prevalent in patients with diabetes and that the association between these two conditions is independent of adiposity. Animal and clinical studies have demonstrated that intermittent hypoxemia and sleep disruption in OSA may alter glucose homeostasis and impair glycemic control. Several questions remain, however, about the association between OSA and diabetes. Research characterizing the impact of OSA severity on post-prandial hyperglycemia and glycemic variability are lacking. It is well established that, while global measure of glycemic control, such as glycosylated hemoglobin levels (HbA1c), can predict vascular complications, post-prandial hyperglycemic with large glycemic excursions are independently predictive of vascular complications including carotid intima-media thickness, atherosclerosis, and macrovascular disease in individuals with diabetes Accordingly, the first aim of the current proposal is to characterize the cross-sectional association between OSA severity, glycemic control, post-prandial hyperglycemia, and glycemic variability in a cohort of patients with diabetes. Characterizing these associations is central in accomplishing the second aim of the proposed investigation - determining if treatment of OSA with continuous positive airway pressure (CPAP) therapy in patients with diabetes is associated with improvements in glycemic control, post-prandial hyperglycemia, and glycemic variability. To accomplish these aims, patients with diabetes will undergo sleep testing to identify and classify OSA severity. Actigraph monitoring (to quantify sleep duration), caloric intake, and several metrics of glucose homeostasis (continuous glucose monitoring, 7- point self-monitoring blood glucose profiles, and HbA1c) will be obtained. Indices of OSA severity will be related to metrics of glycemic load with careful consideration of confounders. Thus, two parallel and unique lines of scientific inquiry - a cross-sectional and an interventional study - will be utilized to gain a ore comprehensive understanding of the relevance of OSA as a modifier of glucose metabolism. Perhaps, the most innovative and practically relevant contribution of this research is the assessment of whether CPAP therapy could improve glycemic control and be considered an "adjuvant" in the therapeutic armamentarium for diabetes. If the hypotheses proposed in this application are correct, the resulting data will have a paradigm shifting effect on diabetes management. The K23 Mentored Patient-Oriented Research Career Development Award is the ideal platform to successfully carry out the proposed investigations outlined above and fulfill my long-term career goal and professional aspiration of becoming an independent clinical investigator in sleep disorders medicine. Through the K23 mechanism, I anticipate progressing towards my long-term objective by successfully completing each of the following short-term goals over the course of the award: 1) obtaining much needed formal training in clinical investigation by pursuing a Masters in Health Science degree through the Graduate Training Program in Clinical Investigation at the Bloomberg School of Public Health, 2) working closely with my expert and dedicated mentorship team to execute the proposed research, and 3) presenting the findings at scientific meetings and through publication in peer-reviewed journals. My unwavering commitment towards becoming an independent clinical investigator in sleep medicine is evidenced by my decision to redirect my career and move to Johns Hopkins University, where I could be immersed in a supportive and dedicated academic environment with an unparalleled mentorship team. The intellectual and clinical environments at the Johns Hopkins School of Medicine, Bloomberg School of Public Health, and Division of Pulmonary and Critical Care Medicine are ideal to carry out the proposed research and foster a career in clinical research.