快速眼球运动睡眠的呼吸暂停事件在2型糖尿病发生中的作用机制研究

Obstructive sleep apnea(OSA) can contribute independently to the development of insulin resistance(IR) and type 2 diabetes(T2DM). However, recent studies showed that the insufficient CPAP use, leaving most obstructive events during rapid eye movement(REM)sleep untreated, had no significant impact on glycemic control and IR in patients with OSA and hyperglycemia. The continuous glucose monitoring of patients with OSA and T2DM revealed that the nocturnal blood glucose gradually elevated during the dawn hours and then leaded to fasting hyperglycemia, which matched the feature of the dawn phenomenon. The dawn hours are typically the time during the sleep period where REM sleep predominates. These results reflect that REM OSA may have more close relationship with hyperglycemia and IR. The increased activity of sympathetic nervous system and hypothalamic-pituitary-adrenal axis and chronic systemic inflammation are the predominant mechanisms involved in the link between OSA and IR or T2DM. In the current proposal, we plan to use simultaneously nightly polysomnography and continuous glucose monitoring system, combining the measurement of insulin, catecholamine, cortisol and inflammatory markers, to determine if REM OSA has a greater effect on the aforementioned pathologic mechanisms and further results in more severe IR and metabolic dysfunction than non-REM OSA. The outcomes of research would be valuable in providing theoretical basis for choosing the optimal timing of CPAP therapy.

阻塞性睡眠呼吸暂停(OSA)可导致胰岛素抵抗和2型糖尿病(T2DM)的发生。然而，近期研究显示，没有充分覆盖快速眼动睡眠(REM)的持续正压通气(CPAP)治疗并没有改善血糖水平和胰岛素抵抗。对OSA合并T2DM患者的连续血糖监测发现，睡眠期间血糖于黎明时分逐渐升高导致空腹高血糖，符合T2DM的黎明现象且主要发生在REM为主的睡眠期。这些结果表明，REM睡眠的OSA事件可能与血糖升高和胰岛素抵抗关系更为密切。交感神经系统和下丘脑-垂体-肾上腺轴过度活跃及系统性炎症反应是OSA导致胰岛素抵抗和T2DM发生的关键机制。本研究将同步使用多导睡眠图和动态血糖监测系统，结合胰岛素、儿茶酚胺、皮质醇及相关炎症因子的测定阐明REM相关的OSA事件在OSA导致T2DM的病理生理机制中作用更明显，最终表现为REM睡眠期胰岛素抵抗更重、糖代谢紊乱程度更高，为调整CPAP治疗时机提供理论依据及指导方向。

阻塞性睡眠呼吸暂停(OSA)的快速眼动睡眠(REM)的呼吸事件（OSA）可能在2型糖尿病发生发展中发挥更显著的影响，明确这一特点有助于为以后的干预治疗提供理论依据及指导方向。本项目通过建立患者数据库，评估了不同睡眠阶段的呼吸事件和微觉醒与血糖异常及其病理生理机制的关系。研究发现：① 与NREM睡眠期相比，REM期的睡眠呼吸低通气指数（AHI）确实与血糖升高更为密切；② REM和NREM睡眠期的睡眠呼吸低通气指数均与胰岛素抵抗的相关指标呈独立正相关。然而，在血糖异常的早期阶段，无论在REM和NREM睡眠期，胰岛β细胞功能的相关指标并未随AHI的增加而减退，反而随AHI的增加而增加； ③ 不管REM期还是NREM睡眠期，体现交感神经活性的去甲肾上腺素和肾上腺素以及炎性因子IL-6和CRP水平均随AHI的升高而升高。而与NREM睡眠期相比，REM睡眠期的相关系数更大，提示REM期的呼吸事件可能对交感神经活性及系统性炎症的影响更大；④ 胰岛素抵抗随系统性炎症的加重而加重。在血糖异常的早期阶段，胰岛β细胞的基础胰岛素分泌功能并未随系统性炎症水平的升高而减退，然而餐后早相胰岛素分泌功能有减退的趋势。通过患者数据库，我们还发现，在OSA相关的夜间低氧参数中，AHI可能是预示伴有OSA的2型糖尿病发生微血管并发症的最重要的指标；而且与老年人相比，OSA对青中年患者发生微血管并发症可能产生更大的不利影响。这些数据具有一定的临床指导意义，为将来疾病的风险评估及治疗提出了可能的新思路。

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