修回日期: 2016-05-10
接受日期: 2016-05-16
在线出版日期: 2016-06-18
糖尿病性胃肠功能紊乱是糖尿病患者常见的并发症, 大多数症状与胃肠功能受损有关. 其发病机制复杂, 糖尿病性胃肠功能紊乱的病因是多方面的, 不仅包括副感神经和交感神经系统, 而且肠神经元、平滑肌细胞、Cajal间质细胞网络、胆碱能受体、神经元型一氧化氮合酶等在糖尿病相关的胃肠功能紊乱也起着重要的作用. 本文对糖尿病性胃肠功能紊乱的发病机制作一综述.
核心提示: 糖尿病性胃肠功能紊乱的病因是多方面的, 不仅包括副感神经和交感神经系统, 而且肠神经元、平滑肌细胞、Cajal间质细胞网络、胆碱能受体、神经元型一氧化氮合酶等在糖尿病相关的胃肠功能紊乱也起着重要的作用.
引文著录: 王晓青, 胡敏敏, 王伟, 高璠, 张林明, 闫福媛, 琚坚. 糖尿病性胃肠功能紊乱发病机制的研究进展. 世界华人消化杂志 2016; 24(17): 2682-2687
Revised: May 10, 2016
Accepted: May 16, 2016
Published online: June 18, 2016
Diabetic gastrointestinal dysfunction is a common complication in patients with diabetes mellitus. Most of the symptoms are related to impaired gastrointestinal function. The pathogenesis and etiology of diabetic gastroenteropathy are complex, involving the parasympathetic and sympathetic nervous systems, enteric neurons, smooth muscle cells, the network of interstitial cells of Cajal, cholinergic receptors and neuronal nitric oxide synthase. This article reviews the pathogenesis of diabetic gastrointestinal dysfunction.
- Citation: Wang XQ, Hu MM, Wang W, Gao F, Zhang LM, Yan FY, Ju J. Pathogenesis of diabetic gastrointestinal dysfunction. Shijie Huaren Xiaohua Zazhi 2016; 24(17): 2682-2687
- URL: https://www.wjgnet.com/1009-3079/full/v24/i17/2682.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i17.2682
糖尿病性胃肠功能紊乱(diabetic gastrointestinal dysfunction, DGD)是糖尿病患者常见的并发症之一, 表现为糖尿病性胃轻瘫(diabebetetic gastroparesis, DGP)和糖尿病性肠病(diabetes enteropathy, DE). 其发病机制复杂, 目前大量研究表明其发病机制主要包括高血糖、胃肠自主神经病变、胃肠道微血管病变、胃肠平滑肌变化、Cajal间质细胞(interstitial cells of Cajal, ICCs)变化、胃肠激素的变化、幽门螺杆菌(Helicobacter pylori, H. pylori)感染、肠道菌群失调、精神因素、炎症等[1,2]. 糖尿病患者中大约5%-12%的患者伴有胃轻瘫的症状[3], 虽然糖尿病伴有胃轻瘫的患者没有足够证据显示寿命缩短, 但可以影响患者的生活质量. 重度胃轻瘫可以导致患者发生电解质紊乱、营养不良等, 需急诊至医院治疗[4], 不仅造成患者的痛苦, 而且花费大量人力、财力, 给患者及其家庭带来沉重的负担. DE是糖尿病患者另一个常见并发症, 与胃肠道植物神经的病变密切相关, 发病率为10%-20%. DE患者临床上通常表现为便秘、腹泻、腹痛, 或腹泻与便秘交替出现等不适, 随着病程的进展, 可以出现严重腹泻, 甚至脂肪泻等. 如果能针对DGD发病机制早期预防及治疗, 阻断其发展, 会改善患者预后.
在发达国家, 糖尿病是胃肠道自主神经病变最常见的原因[5]. 胃肠道自主神经病变是糖尿病患者一种严重而常见的并发症, 经常与其他周围神经病变和糖尿病其他并发症并存[6]. 在糖尿病患者中, 常同时存在胃轻瘫、直肠敏感性降低及心律失常等, 证实了糖尿病自主神经病变为弥漫性障碍[7,8]. DGD患者胃肠自主神经及营养神经的血管发生病变, 导致神经营养障碍及自主神经脱髓鞘, 使胃肠道内的自主神经功能发生变化, 影响胃肠道运动功能, 造成胃肠道功能紊乱. 糖尿病性神经病变有报道称是通过多元醇途径的作用, 细胞内的山梨醇增加和肌醇减少, 导致神经细胞变性、神经细胞中的氧化氮合酶表达缺失、胃肠道神经元表达缺失, 进而导致自主神经发生阶段性脱髓鞘的改变. 另有研究发现胃肠道蠕动和脑-肠轴有关, 可以针对这一机制为治疗提供方案[9].
在身体或心理压力下氧化应激是胃肠道损害的主要原因[10]. 氧化应激和细胞凋亡增加导致结肠神经元的损失, 可能会导致糖尿病性运动障碍, 抗氧化剂可能对预防糖尿病性运动障碍有治疗价值[11]. 相关试验也证实了抗氧化剂硫辛酸能防止和逆转这一病理机制[12].
糖尿病合并消化道功能障碍, 至少部分与血糖受损有关, 血液中的葡萄糖浓度变化可逆性的影响人类的肠道蠕动, Chandrasekharan等[11]报告证实了这个观点, 无论在体外体内高血糖条件下啮齿动物肠道神经元细胞凋亡, 与PI3K活性和神经胶质细胞线源性神经营养因子受损有关[13]. 强化血糖控制后胃肠自主神经功能障碍可改善[7]. 为减少糖尿病胃肠道并发症的风险和减少高血糖对胃肠道功能的急性影响, 血糖控制将继续是最重要的治疗目的[9]. 自主神经病变在糖尿病患者中是常见的, 除了严格的血糖控制, 没有进一步的治疗、预防这种现象方法[14]. 对胃排空延迟的调节可以通过加强血糖控制解决[15]. 有研究表明糖尿病胃病可能是在高血糖期间急性产生的. 空腹血糖受损(impaired fasting glucose, IFG)及糖耐量受损(impaired glucose tolerance, IGT)患者胃排空延迟可能继发于急性高血糖[16]. 自发性和胰高血糖素诱导的高血糖导致小肠慢波节律失常[17]. 但也有研究表明糖尿病患者胃肠道症状的变化与血糖控制不相关, 而与抑郁的变化呈正相关[18].
有学者研究了神经内分泌肽与DGD有不同程度的相关性, 在患者中餐后催产素(oxytocin, OT)分泌减少与胃排空延迟有关, 伴有食管动力障碍的患者胆囊收缩素(cholecystokinin, CCK)分泌增加, 自主神经病变患者血清胃泌素水平升高, 表明神经内分泌肽的分泌可能是糖尿病患者消化系统并发症的病理生理的一部分[19].
胰高血糖素样肽-1(glucagon-like peptide1, GLP-1)可能通过迷走神经扩张人的胃体积[20]. 结肠平滑肌细胞内源性GLP-1缺乏导致干细胞因子表达减少, 从而导致胃肠功能紊乱[21].
血浆胃动素浓度随糖尿病患者食管动力异常的变化而变化, 但不随胃排空异常而变化[22].
糖尿病患者表现出低水平的一氧化氮(nitric oxide, NO)[23]. 研究发现从神经到肌肉一氧化氮信号的损失引起胃排空延迟[24]. 糖尿病大鼠胃底非肾上腺素能、非胆碱能(non-adrenergic non-cholinergic, NANC)神经反应受损对胃肠自主神经病变有潜在的治疗作用[12]. NO是在胃肠道内一个主要的抑制NANC的神经递质, 响应于肌间神经丛的神经刺激释放的NO导致平滑肌的松弛[25]. NO与一氧化氮合酶(nitric oxide synthase, NOS)通过激活神经元在肌间神经丛被合成. 被释放的NO在胃肠道的各个部分中起着重要的生理作用, 对食管下段、胃幽门括约肌、Oddi括约肌、肛门的肌张力进行调节. NO也调节眼底反射和和肠蠕动反射. 以前的研究已经表明, NOS抑制剂延迟胃排空及结肠传输. nNOS的表达减少, 与局部NO生产受损有关, 可能与胃肠动力障碍有关. 有证据表明在肌间神经丛NO神经元功能障碍可引起多种胃肠道疾病. 肌间神经丛nNOS合成受损似乎是贲门失弛缓症、糖尿病胃轻瘫、婴儿肥厚性幽门狭窄、先天性巨结肠一个重要的因素. 减少NO的释放和/或nNOS表达可能是功能性消化不良患者的原因. 虽然假性肠梗阻的病因仍不清楚, 外源性神经损伤可能使nNOS的表达上调, 从而增强肌肉的松弛. 结肠炎动物模型显示在结肠肌间神经丛nNOS表达受损. 另一个研究结果也表明, 糖尿病引起的L-精氨酸的缺乏和随之而来的在胃肠道组织中低水平的NO可能为消化不良的原因, 应用左旋精氨酸可预防. 此外, 糖尿病大鼠胃和空肠肌间神经丛神经元的氮能逐渐降低, 而胆碱能神经数量并没有改变, 在空肠壁有短暂的炎性浸润. 在糖尿病大鼠小肠运动改变与肌间nNOS表达缺失有相关性, 而不依赖于高血糖或迷走神经功能障碍, 并和一过性肠道炎症反应有关[26]. 糖尿病女性患者比男性患者氮系统更易受影响 , 表明女性糖尿病患者更易发生胃功能障碍[27]. 新的治疗方法, 应该旨在增强一氧化氮的信号.
ICC的数量已被证明在糖尿病中减少[36]. ICC的损伤可能在糖尿病性胃肠病的发病机制中起关键作用[37]. 他是目前公认的这些细胞损失或损伤后会导致严重的运动功能障碍[38]. ICC是在整个胃肠道的间质细胞, 在胃产生电起搏活性, 介导运动神经传递, 提供正常胃肠蠕动的功能, 包括产生和传播慢波和调解自主神经与平滑肌细胞之间的双向通信. 通过这些功能, 并与胃肠肌肉其他类型的细胞协同, ICC支持基本的胃肠道功能, 如消化, 吸收和废物清除. ICC丧失或功能障碍已被证明会导致胃电节律紊乱、胃轻瘫、结肠慢传输. 这些研究结果和越来越多的证据表明糖尿病ICC网络的中断表明可能是一个主要的致病因素[2].
研究[39]表明H. pylori常存在于糖尿病伴有自主神经功能紊乱的被检测者中, 这一发现可能与自主神经病变引起胃的机械或电功能障碍有关. 糖尿病患者H. pylori的感染不仅与自主神经功能紊乱有关, 也和胃对细菌的清除受损有关[39]. 12 mo随访H. pylori的复发率与对照组相比糖尿病患者显著增高, H. pylori的感染者淋巴细胞活性减小, 中性粒细胞趋化功能的衰竭, 也可能解释这些患者感染率较高原因[40]. H. pylori感染在糖尿病患者的胃排空起着重要作用, 也对血糖控制有影响[41].
炎症在糖尿病中的角色及其炎症相关的并发症越来越被人重视[42-45]. 炎症可导致胃肠功能紊乱[46]. p38丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)已被证明是参与促炎性介质的产生. p38-MAPK通路阻断剂可改善糖尿病大鼠胃排空延迟. SB203580是一个特定的p38 MAPK抑制剂[47,48], 用SB203580阻断p38-MAPK途径, 通过抑制诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)、肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)和白介素(interleukin, IL)-1β的表达, 改善糖尿病大鼠胃排空延迟. 因此, p38-MAPK可能成为糖尿病相关的胃肠动力障碍治疗的新靶点[49].
DGD以胃肠道内的微血管病变为主, 且常合并视网膜和肾脏等小血管的病变. 胃肠道的微血管由于糖化血红蛋白的持续沉积, 造成胃肠道平滑肌细胞的营养障碍, 并且沉积于胃肠道微血管内糖化血红蛋白引起氧化应激反应, 病理表现血管内皮细胞增生、基底膜增厚, 导致胃肠道血流量减少, 甚至缺血, 影响胃肠道的运动功能紊乱、感觉异常[50].
糖尿病胃肠功能紊乱患者常合并肠道菌群失调, 有害菌过度繁殖, 加重DE患者的临床症状. 益生菌能够改善肠道的菌群, 抑制肠道有害菌过度繁殖, 调节肠道微生态平衡, 从而缓解DGD患者的腹泻及便秘等症状[51-54].
DGD是糖尿病患者常见的并发症. 其发病机制复杂, 大量研究表明, 副交感神经和交感神经系统、肠神经元、平滑肌细胞、ICC网络、胆碱能受体、神经元型一氧化氮合酶等在糖尿病相关的胃肠肠功能紊乱起着重要的作用.
糖尿病患者中大约5%-12%的患者伴有胃轻瘫的症状, 虽然糖尿病伴有胃轻瘫的患者没有足够证据显示寿命缩短, 但可以影响患者的生活质量. 重度胃轻瘫可以导致患者发生电解质紊乱、营养不良等, 需急诊至医院治疗, 不仅造成患者的痛苦, 而且花费大量人力、财力, 给患者及其家庭带来沉重的负担.
李玲, 副教授, 副主任医师, 东南大学附属中大医院内分泌科; 高凌, 副教授, 副主任医师, 武汉大学人民医院内分泌科
糖尿病性胃肠功能紊乱(diabetic gastrointestinal dysfunction, DGD)的病因是多方面的, 不仅包括副交感神经和交感神经系统, 而且肠神经元、平滑肌细胞、Cajal间质细胞网络、胆碱能受体、神经元型一氧化氮合酶等在糖尿病相关的胃肠功能紊乱也起着重要的作用.
本文结合国内外最新报道旨在全面总结DGD的发病机制.
针对DGD发病机制早期预防及治疗, 阻断其发展, 会改善患者预后.
本文综述选题尚存在一定的创新性, 对DGD发病机制研究有一定的帮助作用.
编辑:郭鹏 电编:都珍珍
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