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  开放获取

  编辑:

  张欣远,
北京同仁医院,首都
中国医科大学

  审阅:

  卜雅山,
香港大学
中国香港
  Kofi Asiedu,
新南威尔士大学
  澳大利亚

  *通讯作者

  谢立新

  专业部分

本文提交给《临床糖尿病》杂志,
期刊的一部分
Frontiers in Endocrinology
收到日期:2022 年 10 月 25 日
接受日期:2022 年 12 月 2 日
发表于 2022 年 12 月 16 日

  引用

周勤, 杨柳, 王强, 李洋, 魏晨和谢琳 (2022) 糖尿病眼表疾病的机制研究
Front. Endocrinol. 13:1079541.
doi: 10.3389/fendo.2022.1079541
© 2022 周, 杨, 王, 李, 魏和谢。本研究按照知识共享 Attribution License (CC BY) 发行。任何论坛的使用、分发或再版均须遵守该许可证条款,须在使用时署名原始作者和版权拥有者,并在其他论坛引用时在此期刊中指出原始发表,符合学术惯例。任何不符合这些条款的使用、分发或再版均被禁止。

糖尿病眼表疾病的机制研究

周青 jun 1 , 2 1 , 2 ^(1,2){ }^{1,2} , 杨凌 ling 1 , 2 1 , 2 ^(1,2){ }^{1,2} , 王群 1 , 2 1 , 2 ^(1,2){ }^{1,2} , 李 ya 1 , 2 1 , 2 ^(1,2){ }^{1,2} , 魏超 1 , 2 1 , 2 ^(1,2){ }^{1,2} 和 谢利 xin 1 , 2 1 , 2 ^(1,2**){ }^{1,2 *} 1 1 ^(1){ }^{1} State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China, 2 2 ^(2){ }^{2} Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China 

  摘要

随着近几十年糖尿病在全球范围内的流行,越来越多的患者遭受各种糖尿病并发症的影响,包括可能严重影响生活质量甚至视力的糖尿病眼表疾病。主要的糖尿病眼表疾病包括糖尿病性角膜病变和干眼症。糖尿病性角膜病变的特点是角膜上皮伤口愈合延迟、角膜神经密度降低、角膜感觉减退以及烧灼感或干燥感。糖尿病干眼症表现为泪液分泌减少伴随眼部不适。早期临床症状包括干眼和角膜神经退化,提示早期诊断应重点关注共聚焦显微镜检查和干眼症状。糖尿病性角膜病变的发病机制涉及晚期糖基化终产物的积累、神经营养性神经功能受损、角膜缘干细胞功能障碍以及生长因子信号和炎症改变。糖尿病干眼症可能与交感神经系统过度激活导致泪腺的异常线粒体代谢有关。 考虑到密集的神经支配在维持角膜和泪腺稳态中的重要作用,进一步研究神经上皮和神经免疫的相互作用将揭示糖尿病眼表并发症的主要致病机制,并发展针对性的干预策略。

  关键词

糖尿病性角膜病变、干眼、神经病变、上皮病变、泪腺、发病机制

  引言

Diabetes mellitus (DM) is an endemic disease that occurs all over the world, imposing extensive health burden on society (1, 2). Diabetics with prolonged periods of hyperglycemia suffer from numerous complications affecting almost every organ system, including the ocular tissues ( 3 , 4 ) ( 3 , 4 ) (3,4)(3,4). DM-related ocular complications are the leading cause of blindness, especially in developed countries. Although diabetic 
retinopathy is the most common and well-known ophthalmic complication, DM also has profound clinically relevant effects on the ocular surface ( 5 , 6 ) ( 5 , 6 ) (5,6)(5,6). 
The corneal tissue composes five stratified layers: the epithelium, Bowman’s layer, stroma, Descemet’s membrane and the endothelium ( 7,8 ). Corneal epithelium is the cornea’s outermost layer, whose integrity is essential to maintaining healthy vision. Corneal stroma, which is populated by keratocytes, represents almost 90 % 90 % 90%90 \% of the thickness of the cornea. Corneal endothelium, a single cell layer between the corneal stroma and anterior chamber, exhibits barrier and ‘pump’ functions to maintain corneal dehydration. In addtition, to maintain a healthy ocular surface, the lacrimal gland and meibomian glands produce tears and lipids to prevent excessive evaporation of the tear film. Dysfunctions of these glands will cause dry eye disease ( 9 , 10 ) ( 9 , 10 ) (9,10)(9,10). 
虽然眼表结构相对简单,但任何一个组成部分的问题都可能产生严重后果。对于糖尿病相关的眼部并发症,各种主要的病理表现包括角膜敏感度下降、角膜擦伤后上皮愈合延迟、基底膜异常、角膜神经病变和内皮失代偿(11, 12)。通常,这些变化被称为糖尿病性角膜病变或糖尿病性神经性角膜病变。眼表另一个常见的糖尿病并发症是干眼,涉及泪液功能单位功能障碍(LFUD)(13)。这些并发症严重影响患者的生活质量,且经常被误诊和低估。
目前治疗糖尿病性角膜病变(DK)的主要方法包括使用润滑剂、抗生素软膏、遮盖、包扎软接触镜和角膜移植(14)。然而,即使这些治疗方法联合使用,对于严重的 DK 来说,通常也是无法治愈的。对于干眼症的治疗,找到有效的药物仍然是一个迫切的挑战。因此,研究新的药物靶点对于预防和治疗糖尿病对眼表的并发症至关重要。
本文回顾了糖尿病性角膜病变和干眼症的发病机制的最新进展,同时也评估了诊断和治疗方法的进步。这些新的发现将为糖尿病眼表并发症的干预策略提供新的思路。

  糖尿病性角膜病变

糖尿病性角膜病变是糖尿病影响眼表最常见的临床疾病。它是一种潜在的视力威胁性疾病,主要涉及上皮病变、神经病变和内皮病变。

糖尿病性角膜上皮病变

角膜上皮由 5-7 层非角质化的 stratified squamous epithelium 构成,它在维持角膜透明性和稳定性方面起着关键作用。由于角膜没有血管,糖尿病患者房水和血清中的葡萄糖水平远高于泪液中的葡萄糖水平(15, 16),因此认为角膜上皮细胞中的葡萄糖主要来源于房水(17)。糖尿病患者的角膜中糖基化水平显著增加(18),并且观察到糖尿病患者角膜上皮细胞中存在糖原颗粒的积累(19)。在糖尿病患者中,角膜上皮细胞长期暴露在高浓度的葡萄糖环境中,导致出现各种临床上皮异常。
Several studies have found that corneal epithelium in diabetic patients tends to have increased fragility, lower cell density, thinner thickness and reduced barrier function (20-22). An electron-microscopic examination of corneal epithelium showed an increased epithelial fragility in specimens of diabetic patients (23). Saini and Khandalavla measured the corneal epithelial fragility of healthy people and diabetic patients using an esthesiometer (20). The results revealed that the average corneal epithelial fragility of diabetic patients was significantly higher than that of healthy people, and that the epithelial fragility of diabetic retinopathy patients increased more significantly. Increased corneal epithelial fragility was also found in Goto Kakizaki rats with type 2 DM (24). A few studies reported that there was no statistical significance in the reduction of corneal basal epithelial cell density in diabetic patients ( 25 , 26 ) ( 25 , 26 ) (25,26)(25,26). However, more clinical studies have demonstrated that the density of corneal basal epithelial cells was significantly reduced in type 1 and type 2 diabetic patients (21, 27-29), which may be related to the reduction of corneal innervation, impaired of basement membrane and higher turnover rate (21). In the diabetic patients, the mean corneal epithelium thickness was thinner ( 22 , 30 ) ( 22 , 30 ) (22,30)(22,30) which is associated with the stage of the disease. Similarly, Cai et al. verified the characteristics of the thinning of corneal epithelium and the decreasing density of basal epithelial cells in the rodent model of type 1 diabetes induced by streptozotocin (31). The changes of corneal epithelial density and thickness reflect the imbalance between cell proliferation, differentiation, migration and death. The corneal epithelium has a strong barrier function, making it the first line of defense for the eyeball to resist the external environment. It has long been found that the barrier function of diabetic corneal epithelium is weakened (32-34) which is related to the increase of glycosylated hemoglobin level (34), and correspondingly, diabetic corneas are more prone to infection than healthy people (35-39). In vitro studies have proven that high glucose exposure leads to the impairment of the human 
角膜上皮细胞屏障功能发生变化,但这种变化并非由紧密连接蛋白表达减少引起(40)。
临床表现为点状上皮性角膜炎、反复上皮性侵蚀、持续性上皮缺损和延迟且常不完全的伤口愈合。在我们之前的综述中,根据塞梅拉罗的分类标准(41),我们总结了在我院发现的轻度、中度和重度糖尿病角膜上皮病变的表现(4)。糖尿病患者的角膜擦伤可能导致更严重的损伤,在某些情况下会导致基底膜脱离,在其他情况下则会导致反复性角膜侵蚀(42)。上皮伤口愈合对于损伤后恢复角膜屏障功能至关重要。糖尿病患者的角膜上皮损伤往往愈合时间更长,甚至不愈合,这也是糖尿病性角膜侵蚀难以治疗的主要原因(14)。
糖尿病患者的手术治疗往往会引发后续的上皮病变,如上皮细胞的长期侵蚀和上皮细胞缺损的不良愈合。已证实,接受角膜屈光手术的糖尿病患者更容易发生各种上皮疾病(43-45)。因此,一些眼科医生建议,对于血糖控制不佳的糖尿病患者,应谨慎考虑进行屈光手术(44-47)。最近的一项研究显示,糖尿病是玻璃体视网膜手术后角膜上皮缺损的重要风险因素(48)。通常,白内障手术后出现的上皮性角膜炎患者具有快速进展、严重的上皮损伤和缓慢的角膜上皮愈合的特点(49)。糖尿病患者由于上皮伤口愈合受损,更容易发生上皮剥脱(50)。

糖尿病性角膜神经病变

Corneal nerves, a branch of the ophthalmic division of the trigeminal nerve, enter the peripheral cornea in a radial fashion parallel and then penetrate Bowman’s layer to form the corneal sub-basal nerve plexus, which terminate in free nerve endings in the corneal epithelium and comprises the outermost layer of the cornea and protects cornea from microbial invasion ( 51 , 52 ) ( 51 , 52 ) (51,52)(51,52). Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, affecting up to 50 % 50 % 50%50 \% of diabetic patients (53). Recent study reported that the density of corneal nerve fiber and branch, and the corneal nerve fiber length are significantly decreased in diabetic patients (12). Moreover, the loss of 6 % 6 % 6%6 \% or more of corneal nerve fibers per year has been found in 17 % 17 % 17%17 \% of diabetic patients ( 54 , 55 ) ( 54 , 55 ) (54,55)(54,55). Approximately 39 % 39 % 39%39 \% of diabetic patients experience painful DPN when left untreated (56). 
在 1 型和 2 型糖尿病患者及动物模型中,角膜上皮附近的角膜下基质神经丛中的神经纤维长度、分支和密度已被发现
to be reduced, which relates to the severity of diabetic polyneuropathy (24, 31, 57-63). Detailed examination by in vivo confocal microscopy has revealed increased corneal nerve tortuosity and thickness in diabetic patients (60, 64-68). Moreover, reduced corneal sensitivity is observed in diabetic patients and animals, and the degree is correlated with the severity of diabetes ( 60 , 63 , 67 , 69 71 60 , 63 , 67 , 69 71 60,63,67,69-7160,63,67,69-71 ). Pritchard et al. reported that corneal sensation threshold was significantly higher for patients with neuropathy compared to those without neuropathy and controls (72). Recent studies have identified corneal sensitivity as a potential marker of diabetic neuropathy (73). In addition, the regeneration of corneal subbasal nerves is significantly slower in diabetic animals during corneal epithelial wound healing ( 24 , 74 ) ( 24 , 74 ) (24,74)(24,74). Importantly, the reduction of sub-basal nerve plexus density and corneal sensitivity, which precedes other clinical and electrophysiology tests, could be used as markers for DPN assessment (75, 76). In addition, patients with diabetes often have burning, dryness or painful feeling in the eye (77). 

  病理机制

The pathogenesis is difficult to investigate through human epidemiological studies due to too many confounding factors. Therefore, researchers often use animal diabetes models and in vitro cell models to study pathogenesis ( 78 , 79 ) ( 78 , 79 ) (78,79)(78,79). The changes in growth factors, immune cells and signal pathways in diabetic keratopathy have been elaborated in previous reviews ( 4 , 14 , 17 4 , 14 , 17 4,14,174,14,17, 78, 80). Here, we mainly discuss the following aspects. 

  慢性炎症

As a significant characteristic of DM, low-grade chronic inflammation is regarded as an important mechanism for the development of DM and its complications, including diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy ( 81 , 82 ) ( 81 , 82 ) (81,82)(81,82). These chronic inflammatory scenarios was triggered and sustained by immune cells and structural cells of specific organs/tissues, which activated innate immunity mainly through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)like receptors (NLRs) ( 82 , 83 ) ( 82 , 83 ) (82,83)(82,83). Therefore, chronic inflammation theoretically also contributes to the development of DK. Several compelling evidence we found consolidated the pathogenic involvement of chronic inflammation in the development of DK (Figure 1). 
NOD-like receptor protein 3 (NLRP3) inflammasome, a fully characterized inflammasome, contains NLRP3, adaptor protein ASC, and pro-caspase-1(pro-CASP1), and can be activated by various stimuli, including pathogenic molecules, sterile insults, and metabolic products ( 84 , 85 ) ( 84 , 85 ) (84,85)(84,85). NLRP3 inflammasome-mediated inflammation plays key roles in the development and progression of DM and its complications, such as diabetic nephropathy (83),