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型糖尿病是普遍存在的疾病，每种疾病都有严重的不良后果。在过去的十年里，大量的经验证据表明，OSA在糖尿病患者中很普遍，这两种情况之间的联系与肥胖无关。动物和临床研究表明，OSA的间歇性低氧血症和睡眠障碍可能会改变血糖稳态，损害血糖控制。然而，关于阻塞性睡眠呼吸暂停综合征和糖尿病之间的联系，仍有几个问题。有关阻塞性睡眠呼吸暂停严重程度对餐后高血糖和血糖变异性的影响的研究尚缺乏。众所周知，虽然血糖控制的全球指标，如糖化血红蛋白水平(HbA1c)可以预测血管并发症，但餐后高血糖伴大血糖漂移可以独立预测血管并发症，包括糖尿病患者的颈动脉内膜中层厚度、动脉粥样硬化和大血管疾病，本研究的第一个目的是表征OSA严重程度、血糖控制、餐后高血糖和糖尿病患者血糖变异性之间的横断面关联。确定这些相关性是实现拟议研究的第二个目标的核心--确定糖尿病患者采用持续气道正压(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，以确定和分类OSA的严重程度。将获得活动监测(量化睡眠持续时间)、卡路里摄入量和葡萄糖稳态的几个指标(连续血糖监测、7点自我监测血糖曲线和HbA1c)。OSA严重程度指数将与血糖负荷指标相关，并仔细考虑混杂因素。因此，将利用两条平行而独特的科学研究路线--横断面研究和干预性研究--来更全面地了解OSA作为葡萄糖代谢调节剂的相关性。也许，这项研究最具创新性和实际意义的贡献是评估CPAP疗法是否可以改善血糖控制，并被认为是糖尿病治疗工具中的“辅助剂”。如果本申请中提出的假设是正确的，由此产生的数据将对糖尿病管理产生范式转换效应。K23导师以患者为导向的研究职业发展奖是成功开展上述拟议研究的理想平台，并实现了我长期的职业目标和职业抱负，即成为睡眠障碍医学的独立临床研究员。通过K23机制，我预计将朝着我的长期目标前进，在获奖过程中成功完成以下每一个短期目标：1)通过彭博公共卫生学院临床调查研究生培训计划攻读卫生科学硕士学位，获得急需的临床调查正式培训；2)与我的专家和专门的指导团队密切合作，实施拟议的研究；3)在科学会议上展示研究结果，并通过在同行评议的期刊上发表研究结果。我坚定不移地致力于成为一名睡眠医学的独立临床研究员，这证明了我决定改变我的职业方向，转到约翰·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，有一个无与伦比的指导团队。约翰霍普金斯医学院、彭博公共卫生学院以及肺部和重症监护医学部的智力和临床环境是开展拟议研究和培养临床职业生涯的理想选择 研究。

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.