邱贵娟 张韶君
1.山西医科大学,山西太原 030012;2.山西医科大学附属人民医院,山西太原 030012
维生素D与糖尿病视网膜病变关系的研究进展
邱贵娟1张韶君2
1.山西医科大学,山西太原030012;2.山西医科大学附属人民医院,山西太原030012
糖尿病目前已成为威胁人类健康的主要慢性病之一,而糖尿病并发症严重影响着人类的健康和生活质量,尤其是糖尿病视网膜病变(diabetic retinopathy,DR)的发病率逐年递增,并且是造成失明的主要原因之一,所以对于DR的早期发现及治疗至关重要。而最近发现维生素D与DR的发病有着密切的关系,其可能通过多种途径改善DR,可能对DR有保护作用。本文旨在深入探讨维生素D的作用机制,进而为DR的预防及治疗提供新的思路。
维生素D;糖尿病;糖尿病视网膜病变;治疗
[Abstract]Diabetes is currently one of themain chronic diseases threatening people's health,and the complications of diabetes is severely affecting people's health and life quality.In particular,the incidence rate of diabetic retinopathy (DR)is gradually increasing year by year,and it is one of themain reasons causing blindness.Therefore,early detection and treatment of DR are pivotal.According to recent findings,vitamin D is closely associated with DR,and vitamin D may be able to improve DR bymultiple routes,whichmay be protective to DR.The text aims to explore themechanism of action of vitamin D,and provide new thoughts on the prevention and treatment of DR.
[Key words]Vitamin D;Diabetes;Diabetic retinopathy;Treatment
全球糖尿病视网膜病变(diabetic retinopathy,DR)的患病人数大约为9300万人[1],据世界卫生组织估计DR约占全球失明患病率的5%,在发达国家中急剧上升至15%~17%[2]。DR的病因目前不是完全清楚,认为高血糖、高血压、糖尿病病程、氧化应激和自由基、炎症反应、多元醇途径、细胞因子、细胞的凋亡及增殖等多方面与其发生有关,且最新研究表明维生素D与DR有着不可分割的关系,故现对此予以综述。
Huldschinsky于1919年发现暴露于太阳下可以治疗佝偻病,由此发现了维生素D。维生素D包括维生素D2和维生素D3,是一组脂溶性类固醇衍生物。维生素D2主要来源于植物,而维生素D3大多经由其前体7-脱氢胆固醇在波长为290~310 nm的紫外线作用下在皮肤合成,少量来源于食物。维生素D经过肝脏25-羟化酶生成25-羟维生素D[25-hydroxyvitamin D,25(OH)D]、肾脏1α-羟化酶生成1,25-双羟维生素D[1,25-dihydroxyvitaminD,1,25-(OH)2D3],后者与各种靶细胞内特异性受体结合后产生生理作用:维持钙磷的体内平衡,有助于骨骼和肌肉的健康[3]。最近大量研究表明维生素D还可以抑制肿瘤细胞增殖、调节免疫细胞生长和分化、血管生成[4]以及基因调节[5],抑制胰岛β细胞凋亡,对2型糖尿病患者胰岛β细胞有保护作用[6]。因此考虑与其他很多代谢性疾病相关,包括糖尿病、恶性肿瘤、心血管疾病、代谢综合征、自身免疫性疾病等[7-10]。
DR无论是在1型糖尿病还是2型糖尿病患者中均是致残的主要原因之一,在全世界范围内DR患病率估计为34.6%,增生性糖尿病视网膜病变患病率为7.0%[1]。据世界卫生组织统计,DR占每年全球3700万人失明原因的4.8%[11],是全球失明最常见的原因之一[12],除了血管改变,糖尿病性视网膜病变的早期阶段主要为功能神经退行性变,如神经节细胞退行性变,胶质反应增加,视网膜变薄[13]。此外,最近的临床和实验研究[14-16]已经观察到,这些神经退行性变导致视网膜电图、对比敏感度、暗适应和微视野检查异常。还有报道[17]DR与视网膜神经纤维层变薄有关。组织学和免疫组织化学研究[18,19]表明,糖尿病视网膜病变导致视网膜神经节细胞、星形细胞、无轴突细胞、视网膜光感受器数量在视网膜神经纤维层显著下降。
维生素D被发现有很多其他角色,如免疫调节、血压控制、抗肿瘤的效应和胰岛β细胞的调节。许多研究表明维生素D在1型糖尿病和2型糖尿病的发病机制中都有作用[20]:二者维生素缺乏的发生率更高,其胰腺组织尤其是胰岛β细胞和免疫细胞表达维生素D受体和配体,维生素D基因多态性与糖耐量、胰岛素敏感性、胰岛素分泌有关。1,25-(OH)2D3通过降低主要组织相容性复合体1的表达进而起到保护胰岛β细胞的作用[21],其中主要表现为A20蛋白的凋亡和Fas蛋白的表达下降[22,23],维生素D可能通过刺激胰岛素受体的表达进而提高胰岛素对血糖的反应性[24]。有研究发现25(OH)D可减轻DR的进展[25],低水平维生素D与包括糖尿病不同的糖代谢损害相关。在一项研究中发现每天摄入511U或者更多维生素D的健康妇女发生2型糖尿病的风险明显比每天摄入159 U或更少者要低[26]。一些研究还表明[27,28]维生素D对DR有抑制作用,但其机制尚不明确,可能通过以下几方面发挥作用。
3.1维生素D受体基因多态性与DR
糖尿病控制及其并发症的流行病学数据(DCCT)和英国前瞻性糖尿病研究表明:高血糖、高血压、糖尿病和糖尿病持续时间是DR发展的主要危险因素[29,30],其他DR的危险因素包括患糖尿病的年龄、高脂血症、性别、种族[31]。强有力的证据表明良好的糖尿病控制有助于防止DR,但是一些糖尿病患者即使血糖控制良好,但仍发生DR,而有些糖尿病患者即便病史长或者未进行良好的血糖控制却没发生DR,表明遗传因素可能影响糖尿病患者对视网膜病的易感性[32]。钟兴等[33]发现在安徽地区汉族人中存在VDR基因Fok I位点多态性,可能与安徽地区汉族人群DR的发病具有相关性。Zhong X等[34]发现在中国汉族2型糖尿病患者中VDR的rs2228570 T等位基因与DR的危险性相关。Hong YJ等[35]发现在韩国2型糖尿病患者中发现维生素D受体基因Bsm1多态性与DR有关联,B等位基因与DR低风险明显相关。
3.2维生素D炎症通路与DR
Ren Z等[36]发现在SD大鼠糖尿病视网膜水肿模型中,其在1,25-(OH)2D3作用13周后视网膜水肿程度减轻,并且发现血管内皮生长因子(vascular endothelialgrowth factor,VEGF)、转移生长因子(transforming growth factor-b1,TGF-b1)在糖尿病组和1,25-(OH)2D3组中都明显增加,但在1,25-(OH)2D3组中比糖尿病组低,在动物水平证明了1,25-(OH)2D3可能具有改善DR的作用,其机制可能是1,25-(OH)2D3抑制了VEGF、TGF-b1的表达。还有研究[37]表明维生素D通过增加单核细胞的分化、抑制淋巴细胞增殖、抑制细胞因子白介素-2、干扰素-γ、白介素-12的分泌而发挥免疫抑制作用,而DR的发生与此有关。吴冕[38]研究发现在SD大鼠中给予维生素D3干预能显著减轻糖尿病大鼠视网膜屏障破坏,维护视网膜正常结构和功能,抑制NLRP3炎症小体表达,在细胞水平发现1,25-(OH)2D3减轻因高糖孵育48 h所造成的视网膜微血管内皮细胞凋亡及氧化应激,并且能显著降低高糖诱导的NLRP3表达增加,同时降低NLRP3炎症通路其他蛋白包括凋亡相关微粒蛋白、硫氧还原相互作用蛋白和白介素-1的表达。
3.3维生素D与DR病理改变
目前关于维生素D与DR病理改变的研究较少,仅有研究[39]发现糖尿病小鼠第2周的脉络膜萎缩明显,并随时间延长萎缩情况加剧,经维生素D3干预(5mg/kg,每周注射1次),4周时脉络膜萎缩趋势明显减缓,且在维生素D3用药后各周脉络膜厚度均大于对照组,表现出对脉络膜的保护作用。Gungor A等[40]发现在以25(OH)D低于20 ng/mL定义为25(OH)D缺乏,在伴有早期糖尿病视网膜病变的糖尿病患者中25(OH)D缺乏组的视网膜神经纤维层厚度明显比无25(OH)D缺乏组薄,提示25(OH)D可能是视网膜神经保护物质,具体机制尚不清楚,有待进一步研究。
综上,DR是严重威胁人类生活质量的疾病之一,由于其机制尚未完全明确,因而其预防与治疗也成为了世界难题,而维生素D在DR的发生发展中可能起着重要作用,所以维生素D可能成为预防及治疗DR的重要手段,这需要未来对维生素D和DR的关系进行进一步的研究。
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Research development of relationship between vitam in D and diabetic retinopathy
QIU Guijuan1ZHANG Shaojun2
1.ShanxiMedical University,Taiyuan030012,China;2.The Affiliated People's Hospital of ShanxiMedical University,Taiyuan030012,China
R587.1;R774.1
A
1673-9701(2016)20-0158-04
2016-05-05)