临床医学进展  >> Vol. 11 No. 2 (February 2021)

2型糖尿病与睡眠障碍的相关研究
Study on Type 2 Diabetes and Sleep Disorders

DOI: 10.12677/ACM.2021.112088, PDF, HTML, XML, 下载: 22  浏览: 62 

作者: 吴 燕, 刘 冀*:青海大学,青海 西宁

关键词: 2型糖尿病睡眠障碍机制Type 2 Diabetes Sleep Disorders Mechanisms

摘要: 可由多种原因诱发,以慢性高血糖症状为主要表现特点的糖尿病,近年来其患病率大幅激增,给我国经济社会造成了沉重的压力和负担。同时,随着信息化时代的进步,科技发达,人们的工作生活方式也在很大程度上发生了改变,导致整个睡眠质量的普遍下降。流行病理学和临床研究结果表明,糖尿病的发生、进展与睡眠障碍息息相关,有可能使其陷入恶性循环:一方面,糖尿病的患者,特别是对于血糖的控制很差的,往往会使其伴有严重的睡眠障碍;另外一个方面,睡眠障碍可能促进糖尿病的早期发生、发展。该文将基于2型糖尿病与睡眠障碍之间的相互作用进行研究、探讨,为未来2型糖尿病的早期临床诊断和早期预防工作提供一种全新的诊断方法和治疗策略。
Abstract: Diabetes mellitus, which can be induced by many reasons and characterized by chronic hyperglycemia, has caused heavy pressure and burden to our economy and society in recent years. At the same time, with the progress of the information age and the development of science and technology, people’s working and life style has also changed to a great extent, which leads to the general decline of the whole sleep quality. Epidemiological and clinical studies have shown that the occurrence and progression of diabetes are closely related to sleep disorders and may lead to a vicious circle: on the one hand, patients with diabetes, especially those with poor control of blood sugar, tend to be accompanied by severe sleep disorders; on the other hand, sleep disorders may promote the early occurrence and development of diabetes. This paper will be based on the interaction between type 2 diabetes and sleep disorders, and provide a new diagnostic method and treatment strategy for early clinical diagnosis and early prevention of type 2 diabetes in the future.

文章引用: 吴燕, 刘冀. 2型糖尿病与睡眠障碍的相关研究[J]. 临床医学进展, 2021, 11(2): 604-610. https://doi.org/10.12677/ACM.2021.112088

1. 引言

2型糖尿病(T2DM)是一种以高血糖症、胰岛素抵抗及胰岛素分泌相对受损为特点的代谢性疾病。根据《国际糖尿病联合会糖尿病图集》第9版估计,2019年共有4.63亿人患有糖尿病,占目前全球总成年人口(20~79岁)的9.3%。这一数字预估将在2030年增长至5.78亿(10.2%),在2045年增加到7亿(10.9%) [1]。异常睡眠时间或睡眠中出现异常情况被称为睡眠障碍,其中包括睡眠呼吸暂停、失眠、嗜睡症和不宁腿综合征等。近年来的多项研究表明 [2] [3],糖尿病与睡眠障碍之间往往存在双向关系,一方面,T2DM患者容易患有睡眠障碍,产生焦虑、抑郁等严重的心理性疾病;另外一面,胰岛素敏感性和葡萄糖耐量会受到睡眠障碍的影响而降低,血糖水平将会变化。

2. 睡眠的生理过程

睡眠是人体的基本需求,但是它是一个复杂的行为和生理过程,健康的睡眠要求具有足够的持续时间、良好的质量、适当的时间与规律,以及不存在任何睡眠障碍或紊乱 [4]。由非快速眼动(non-rapid eye movement, NREM)和快速眼动(rapid eye movement, REM)两种不同的状态组成睡眠。非快速眼动睡眠又可分为3个阶段(N1、N2、N3),其特征是皮质神经元活动越来越同步,自主神经功能稳定,觉醒阈值增加。相比之下,脑电图显示快速眼动睡眠期间为低电压、混合频率的脑电波活动,与更同步的非快速眼动脑电图相比,更类似于放松清醒时的脑电图 [5]。人体在非快速眼动阶段时,降低交感神经的活跃,增高迷走神经的活跃,具体表现为心率减慢、血压降低、生长激素的释放增加、大脑对葡萄糖的吸收和利用率降低、下丘脑–垂体–肾上腺(HPA)轴的活性将被抑制。

3. 睡眠障碍对2型糖尿病的影响

睡眠由两种不同的状态所构成:非快速眼动(NREM)和快速眼动(REM)。在非快速眼动阶段,人体会降低交感神经的兴奋性,增高迷走神经的兴奋性,具体表现为心率减慢、血压降低、生长激素的释放增加、大脑对葡萄糖的吸收和利用率降低、下丘脑–垂体–肾上腺(HPA)轴的活性将被抑制。而当机体出现睡眠障碍时,则会直接引起交感神经系统活性升高、肾上腺皮质分泌增多,从而降低对胰岛素的敏感性 [6]。目前的临床研究结果表明,睡眠时间和睡眠质量都与T2DM之间有密切的联系。

3.1. 睡眠时间与T2DM

近年的多项研究已经将睡眠时间短和睡眠时间长与糖尿病患者的胰岛素抵抗、糖尿病的诱发事件和血糖控制不佳联系起来 [7] [8] [9] [10]。张盼 [11] 等收集了771例首次检测和确诊的2型糖尿病患者的正常睡眠时间、生活习惯、疾病史等相关信息,结果发现正常睡眠时间<6 h的患者发生糖尿病的风险是睡眠时间为6~8 h的3.29倍。近年的多项Meta分析指出 [12] [13] [14] [15],睡眠时间的长短与糖尿病的发生风险呈“u型”关系,每日持续睡眠时间在7~8 h时发生糖尿病的危害和风险最低,无论睡眠时间减少还是增加,糖尿病的患病风险均会随之增加。此外通过对317例未进行治疗的2型糖尿病患者的临床研究 [16],西班牙学者Full发现睡眠时间与糖化血红蛋白之间为负相关关系。而2017年发表的由不同的美国西班牙裔/拉丁裔成年人共同组成的大样本的研究结果表明 [17],无论是在糖尿病患者还是非糖尿病患者,较晚晚睡时间都有相对较高的胰岛素抵抗。根据这一研究,可以发现夜班工作也与较差的血糖控制有关 [18]。

3.2. 睡眠质量与T2DM

对于睡眠质量的衡量,匹兹堡睡眠质量指数(PSQI)量表是目前国内外最常使用的。于1989年由Buysse [8] 等在概括之前的相关文献和一些有关测试工具的基础上进一步得出,主要用于评价被调查者最近1个月的整体睡眠状态和质量。PSQI的得分值越高代表睡眠质量越差。国内学者 [19] 认为该量表具有良好的有效性、可靠性。通过对622名2型糖尿病患者(平均年龄56.1 ± 9.56岁)进行横断面研究,同时设立622名性别和年龄相互对应的对照组,日本学者Narisawa [20] 等研究发现在2型糖尿病组中有253名(43.9%)睡眠不良者,其PSQI总分>5.5,精神量表(包括流调用抑郁量表及生活质量简明量表等)的得分水平也相对偏低。2型糖尿病组的平均PSQI总分水平较高,睡眠维持较差。此外一项关于近年台湾地区46名糖尿病患者睡眠质量的临床研究发现 [21],受试者者的糖化血红蛋白水平 > 7%与PSQI评分 > 8密切相关,睡眠质量差和睡眠效率低与血糖控制显著相关。

睡眠障碍中还有一种重要的类型,即睡眠呼吸障碍,其中阻塞性睡眠呼吸暂停低通气综合征(OSAHS)是所有睡眠呼吸障碍疾病中发病率最高的,其明显特征为患者睡眠期间咽部反复出现塌陷,导致机体间歇性缺氧、睡眠中断和白天过度嗜睡。已有大量研究表明 [22] [23] [24],OSAHS与T2DM、胰岛素抵抗、葡萄糖不耐受或代谢综合征等葡萄糖代谢相关疾病之间存在独立联系。通过对来自社区的1453名无糖尿病参与者进行了家庭多导睡眠评估,Nagayoshi等人对此进行了一项前瞻性分析,结果发现在13年的中位随访期间,患有严重阻塞性睡眠呼吸暂停的参与者比认为是正常的人更容易患上糖尿病。提示患有OSAHS的患者存在较大的糖尿病发病风险,且与肥胖无关 [25]。越来越多的研究支持阻塞性睡眠呼吸暂停(OSA)与胰岛素抵抗之间存在独立联系,例如通过对186名无明显共病的男性受试者进行病例对照研究,并按照体重划分为不同的类别,Murphy等人发现在所有类别中,OSAHS的严重程度依旧是胰岛素抵抗的独立预测因素 [26]。近期的一项研究表明,如果妊娠妇女患有阻塞性睡眠呼吸暂停,其葡萄糖代谢将受影响。如对参加流行病学观察研究的9795名参与者进行荟萃分析发现,经体重指数调整后,睡眠呼吸障碍(SDB),即阻塞性睡眠呼吸暂停综合征或存在打鼾的妇女,与没有SDB的妇女相比,患妊娠糖尿病的风险将会增加三倍多 [27]。欧洲睡眠呼吸暂停数据库的队列数据,支持OSAHS的存在也可能会导致T2DM患者糖尿病控制不佳这一观点,该队列包含有1100多名参与者,证明OSAHS的严重程度与糖化血红蛋白(HbA1c)水平之间存在独立联系 [23]。

4. 睡眠影响T2DM的机制

4.1.交感神经系统活性升高

正常的睡眠与交感神经活动减少有关 [28],而睡眠碎片会大大地增加交感神经活动,交感神经活动可以通过对胰岛素敏感性的降低来提高体内的血糖水平 [29]。其机制是,睡眠障碍会兴奋交感神经系统,紊乱自主神经系统节律,诱发低氧血症,高碳酸血症等,并且导致骨骼肌血管的收缩增强,骨骼肌对葡萄糖的摄取降低;增加糖原分解,增强糖异生作用,从而升高血糖 [30]。

4.2. 下丘脑–垂体–肾上腺轴(HPA轴)功能改变

睡眠障碍的患者大多都会存在不良的精神情绪问题,比如焦虑、抑郁,这些情绪问题会影响到下丘脑的活性,尤其是下丘脑–垂体–肾上腺轴(HPA轴) [31] [32]。当HPA轴异常活跃时,机体内的胰岛素拮抗激素水平会随之增加,如生长激素、皮质激素水平增加,进一步加重胰岛素抵抗。经过研究调查发现,当睡眠剥夺后,血清和尿液中的肾上腺素和去甲肾上腺素水平均增高,糖异生增强,血糖进一步升高 [33]。既往通过对大鼠模型的研究发现,睡眠不足对HPA轴存在影响 [34]。

4.3. 食欲调节激素的改变

食欲调节激素包括瘦素和胃饥饿素。瘦素主要是一种从人体内脂肪细胞中衍生的抑制食欲的激素,胃饥饿素主要是一种胃衍生的肽,能刺激食欲。睡眠障碍时,食欲的神经内分泌系统将会紊乱 [35],其中最主要的机制是食欲素系统活性增高。一般情况下,当我们的机体储存的能量消耗或者胃部食物排空时,则会大幅度增加胃饥饿素水平,降低瘦素水平,刺激食欲,摄取食物增加;当机体储存足够的能量时,瘦素就会增加、胃饥饿素会下降。食欲素系统在睡眠剥夺期间过于活跃,促饥饿激素胃饥饿素的循环水平有所增加,而作为饱腹感因素的瘦素水平下降 [36]。临床研究也证实这一观点,如通过对12名健康男性测量白天血浆瘦素和胃饥饿素水平以及饥饿和食欲的主观评分进行的随机对照研究发现,当受试者机体处于睡眠剥夺时,体内的胃饥饿素将逐渐上升28%,瘦素逐渐下降18%,明显增加受试者的食欲,摄食量也增加 [37]。

4.4. 褪黑激素的降低

褪黑激素主要是由松果体在夜间产生的一种神经激素 [38]。它可以介导内源性昼夜节律的光周期夹带,还参与许多其他功能,比如能量平衡调节 [39] [40]。目前已有研究表明在人类和动物的葡萄糖调节、T2DM中褪黑激素也发挥作用 [41]。如在T2DM大鼠和人类中,当褪黑激素水平降低时,可以观察到高水平的胰岛素 [42]。以及在一项病例对照研究中发现,6-硫酸氧基甲氨蝶呤作为尿中褪黑激素的主要代谢物,其水平的高低与发生T2DM的风险相关,因此褪黑激素分泌水平较低,则T2DM发生的风险较高 [43]。从基因层面上来看,已经初步证实褪黑激素受体1B (MTNR1B)基因的一个常见变异体为2型糖尿病发病风险等位基因 [44] [45]。

4.5. 炎症因子水平升高

目前已经发现有许多临床研究结果表明,睡眠时间减少及睡眠剥夺会直接引起体内炎症反应明显加剧,白细胞和单核上皮细胞数量增多 [46],从而导致体内白介素-1β (IL-1β)、白细胞介素-6 (IL-6)、肿瘤坏死因子(TNF-α)、超敏C-反应蛋白(Hs-CRP)等炎症因子明显增多 [47]。炎症因子水平的升高,会在一定程度上增加游离脂肪酸的释放,减少脂联素的合成,从而影响分泌胰岛素的传到信号,最终产生胰岛素抵抗 [48]。

5. T2DM影响睡眠

另一方面,在关于T2DM对睡眠障碍的影响问题进行研究时,按照相关的临床研究表明,相比于一般正常人而言,2型糖尿病患者的持续睡眠时间缩短,造成糖尿病引起睡眠障碍的病因和机制也非常复杂。随着糖尿病病情的进一步发展,会出现多系统功能障碍或对体内各脏器造成损害,导致睡眠调节机制失衡。首先,中枢神经系统的各种神经递质都受到了严格限制,导致自主神经功能障碍,影响患者的睡眠 [49]。其次,内分泌系统紊乱进一步加重病情,导致睡眠障碍的HPA轴功能明显亢进 [50]。此外,T2DM患者的高血糖、代谢性炎症、胰岛素抵抗等多种危险因素会进一步诱发糖尿病周围神经病变 [51],这也是导致睡眠障碍的一个重要因素。T2DM也与肥胖紧密联系,肥胖人群容易患有OSAHS或是其他睡眠障碍。

6. 结语

从以上讨论的所有内容分析,很明显T2DM和睡眠障碍是一个恶性循环,这些发生的机制仍在进一步研究中,但我们已经有了一些特定途径的证据,可以总结如下。睡眠通过影响包括瘦素、生长素、胰岛素和皮质醇在内的激素的平衡和水平,对葡萄糖代谢产生显著的调节作用。但是我们很难从这种神经–内分泌–代谢失衡中找出原因和结果,因为睡眠特征(障碍或持续时间)可能影响神经和内分泌系统,促进T2DM,而T2DM也可能影响睡眠。因此,短睡眠时间或睡眠障碍有利于T2DM病并使其加重,但睡眠可能会受到这种普遍代谢状况的损害。考虑到所有呈现的数据,我们得出结论,通过选择更健康的生活方式,适当的食物、体育活动以及充足的睡眠质量和持续时间,T2DM的发展可能被阻止,T2DM的代谢控制可能被改善。此外,诊断和积极治疗睡眠障碍有可能会进一步提高糖尿病患者的生活质量和改善代谢问题。另一方面,T2DM的代谢改善可能会改善睡眠质量,使其更容易保持良好的代谢控制。

NOTES

*通讯作者。

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