糖尿病视网膜病变患者神经血管单元损伤的机制研究进展

糖尿病视网膜病（DR）是一种高度组织特异性的神经血管并发症，视网膜神经血管单元（NVU）正常结构及功能受损直接介导DR的病程进展。在糖尿病状态下，Müller细胞功能障碍，使谷氨酸浓度增加，出现谷氨酸兴奋性毒性，导致视网膜神经元不可逆损伤；氧化应激介导神经胶质细胞异常分泌众多炎症因子，使视网膜长期处于炎症状态，诱发视网膜神经细胞凋亡和微血管病变；视网膜神经保护因子失衡会打破视网膜内环境稳定，致使视网膜神经变性，诱导早期微血管病变；长期高糖亦能引起视网膜局部微血管异常，与视网膜神经变性相互影响，最终加重视网膜NVU破坏，造成不可逆的DR。针对NVU损伤这一DR早期事件，及早干预、采取有效防治措施有望降低DR发病风险。     

乌索酸及其同分异构体齐墩果酸治疗2型糖尿病及相关并发症机制的研究进展

乌索酸及其同分异构体齐墩果酸是一种广泛存在于植物中的五环三萜类化合物。近来的研究逐渐揭示乌索酸和齐墩果酸对各种疾病的治疗作用,而在防治2型糖尿病及相关并发症中的疗效尤为显著,例如非酒精性脂肪性肝炎、肾病、视网膜病变、动脉粥样硬化等,并且随着研究的深入,乌索酸和齐墩果酸对疾病治疗作用的相关分子机制也逐渐得到揭示。随着全世界范围内2型糖尿病发病率的急速增加,2型糖尿病已经成为人们主要关注的疾病之一。靶向治疗2型糖尿病中改变的信号通路可以有效地防治糖尿病及其并发症,天然及衍生型的乌索酸和齐墩果酸是改善这些通路的潜在治疗药物。该研究从有关这些化合物的体内外试验中揭示以下发现:(1)改善胰岛素信号,减少高血糖症;(2)通过上调抗氧化剂减少氧化应激;(3)通过抑制促炎性因子减少炎症反应。该文通过讨论这些治疗作用的分子机制,为应用乌索酸和齐墩果酸防治2型糖尿病及相关并发症提供理论依据。     

糖尿病视网膜病变的发病机制及其防治研究进展

糖尿病视网膜病变 (DR)是糖尿病常见且严重的并发症之一 ,其发病机制主要涉及多元醇通路的激活、肌醇耗竭、蛋白的非酶性糖基化、自由基损伤及二酰基甘油 蛋白激酶C系统的活化等方面。此外 ,视网膜局部的血流动力学异常及视网膜局部炎症反应也参与DR的发生和发展 ,本文对DR的发病机制及其防治作一综述。     

糖尿病血管老化过程中调控NLRP3炎症小体活性的信号通路研究进展

糖尿病相关的代谢异常可导致糖尿病性血管老化,引发一系列血管并发症。糖尿病性血管老化与炎症反应密切相关,核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体参与慢性无菌性炎症反应、氧化应激等进程,是糖尿病发展的重要环节。调控NLRP3炎症小体活性的信号通路可分为促进激活与抑制激活两类,核因子κB、活性氧簇（ROS）/硫氧还蛋白互作蛋白信号通路具有促进NLRP3炎症小体的转录、翻译与修饰以及促进ROS生成的作用,能够激活NLRP3炎症小体、诱导炎症反应与氧化应激,从而加速血管内皮细胞的老化;磷酸腺苷活化蛋白激酶、核因子红细胞系2相关因子2信号通路具有抑制NLRP3翻译与转录、阻断炎症小体组装与调节自噬等作用,对NLRP3炎症小体的激活进行负向调节,从而抑制炎症反应、氧化应激反应与细胞焦亡,可有效延缓血管老化。在糖尿病环境下,干预NLRP3炎症小体的启动、激活与分泌,可抑制糖尿病性血管老化的进展,是防治糖尿病慢性血管并发症的潜在靶点。     

糖尿病视网膜病变的内科防治现状及研究进展

糖尿病视网膜病变（DR）是常见微血管并发症,是糖尿病（DM）患者致盲和视力受损的主要原因。近年来,DM及DR发病率呈上升趋势,已成为世界性难题。DR的发生机制尚未完全明了,其病理基础主要是各种危险因素引起视网膜微血管系统损害,使毛细血管肿胀变形,破坏血一视网膜屏障,引起视网膜渗漏、黄斑水肿,使视力受损;如不及时治疗可形成新生血管,引发玻璃体出血和视网膜脱离,导致失明。目前认为,DR的发生和发展可能与DM病程、血糖、血压及血脂等因素有关。因此,控制血糖、血脂、血压,对延缓DR发生、发展有重要作用。     

2型糖尿病视网膜病变患者血清超敏C反应蛋白与胰岛素抵抗的相关性

<正>糖尿病视网膜病变(DR)是糖尿病常见严重的微血管并发症,是致盲的主要原因之一。其发生是个复杂的过程,目前发病机制尚未明确。近年来对高血糖、氧化应激、糖基化终末产物、多元醇途径和炎症反应等在DR发生发展中的作用有了新的发现,越来越多的学者认为炎症反应与胰岛素抵抗(IR)及糖尿病(DM)的发生发展及预后有密切的关系〔1,2〕。超敏C-反应蛋白(hs-CRP)是临床上敏感的非特异性炎症标志物。本研究了解2型DM(T2DM)视网膜病变患者血清hs-CRP与IR之间的关系。     

2型糖尿病并视网膜病变患者红细胞山梨醇含量及血浆内皮素水平的研究

糖尿病视网膜病变（DR）是糖尿病患者常见的慢性并发症之一，是影响成人视力与致盲的主要原因，但其发病机理至今尚未完全清楚。我们对46例2型糖尿病并DR患者的红细胞山梨醇（ES）含量和血浆内皮素（ET）水平的变化进行了研究，旨在探究二者在DR发生发展中的可能作用。对象与方     

炎症因子——核因子-κB对糖尿病心肌病的影响

糖尿病心肌病是糖尿病性心脏病的特异性病变,糖脂代谢紊乱、胰岛素抵抗、氧化应激、细胞凋亡、微血管病变、心肌纤维化等都参与其发生发展,而炎症反应可能在其中发挥重要作用。核因子κ-B(NF-κB)作为炎症信号通路的关键因子,参与了多种炎症因子转录的调控,从而对糖尿病心肌病产生影响。该文阐述了炎症因子NF-κB在糖尿病心肌病病理生理中的作用以及对NF-κB通路的阻断策略。     

亲环素A启动单核细胞炎症性募集的机制

目的　探讨亲环素A在单核细胞参与氧化应激炎症反应中的作用。方法　人类单核细胞系THP-1细胞常规体外培养，以亲环素A作为氧化应激炎症反应的主要活性氧诱导刺激因子，Transwell法检测亲环素A对单核细胞迁移趋化的影响；ELISA检测单核细胞培养液中主要炎症反应因子白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）的含量变化；明胶酶谱法测定基质金属蛋白酶9（MMP-9）的活性变化；Western　blot检测核因子кB（NF-кB）炎症信号通路、丝裂原活化蛋白激酶（MAPK）炎症信号通路的激活。结果　亲环素A可以诱导单核细胞迁移趋化，促进单核细胞分泌炎症反应因子IL-6；亲环素A通过MAPK-NF-кB炎症信号通路增强MMP-9活性。结论     

小胶质细胞在糖尿病视网膜病变中的作用

糖尿病视网膜病变(DR)是糖尿病常见的微血管慢性并发症之一,其发病机制复杂,一直是国内外研究的热点之一。近年来,越来越多的证据表明DR可能是一种小胶质细胞参与的慢性低度炎性疾病。视网膜小胶质细胞是视网膜的免疫细胞,参与DR神经变性和血视网膜屏障破坏。了解视网膜小胶质细胞的功能、活化、调节及其参与DR发病及治疗机制,可更好地为DR的预防和治疗开辟新途径。     

江苏省2型糖尿病病人视网膜病变调查及相关危险因素分析

目的了解江苏省2型糖尿病患者视网膜病变患病情况并分析其发生的相关危险因素。方法采用横断面研究方法,以调查问卷形式收集患者年龄、性别、病程、相关并发症、降糖药物的使用情况等,留取血标本检测HbA1c。并用单因素）（2检验和多因素Logistic回归分析筛选和判定DR发生的危险因素。结果在受调查的2966例糖尿病患者中,1528例有应答,应答率为51．5％,应答者平均年龄（57．71±11．12）岁,应答者中患糖尿病视网膜病变者199例,患病率为13．0％。年龄、糖尿病病程、高血压、尿微量白蛋白异常是糖尿病视网膜病变的显著危险因素。结论江苏省2型糖尿病患者中视网膜病变较2006年全国糖尿病视网膜病发病率低,早期规律的眼底检查及危险因素的预防对阻止DR的发生发展至关重要。     

Diabetic retinopathy,a vascular and inflammatory disease: Therapeutic implications

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in the working-age population in the Western world. Diabetic macular oedema (DME) is one of the major complications of DR. Therapy with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs has become the gold standard treatment for DR and its complications. However, these drugs have no effect on the pathogenesis of DR and must be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. Indeed, an increasing volume of data supports the role of the inflammatory process in the pathogenesis of DR itself and its complications, including both increased retinal vascular permeability and neovascularization. Inflammation may also contribute to retinal neurodegeneration. Evidence that low-grade inflammation plays a critical role in the pathogenesis of DME has opened up new pathways and targets for the development of improved treatments. Anti-inflammatory compounds such as intravitreal glucocorticoids, topical non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants, inflammatory molecule inhibitors, renin–angiotensin system (RAS) blockers and natural anti-inflammatory therapies may all be considered to reduce the rate of administration of antineovascularization agents in the treatment of DR. This report describes the current state of knowledge of the potential role of anti-inflammatory drugs in controlling the onset and evolution of DR and DME.     

Corneal changes in diabetes mellitus

Diabetes mellitus is a major disease worldwide, and the prevalence of diabetes has risen significantly in the past several decades. Although one of the major complications of diabetic eyes is diabetic retinopathy (DR), corneal diseases can not only develop in diabetic patients but are also difficult to manage. Diabetic neurotrophic keratopathy is a component of diabetic polyneuropathy and is recognized to be the cause of the morbidity of the cornea in diabetic patients. In addition, corneal endothelial cell damage can cause disturbances in the management of proliferative DR before and after surgeries because of endothelial decompensation with bullous keratopathy. However, there have been only a limited number of studies that have focused on the importance of corneal diseases in diabetic patients. This review describes the pathophysiological roles of different factors that have been found to be causative factors of diabetic corneal keratopathy and endothelial cell dysfunction in diabetic patients. In addition, the clinical features of the corneal changes in diabetic patients and recent studies related to the development of therapies for the management of corneal diseases are presented.     

Role of cytokines and trophic factors in the pathogenesis of diabetic retinopathy

Diabetic retinopathy (DR) is one of the most frequent complications of diabetes and the leading cause of acquired blindness in developed countries. A note worthy problem in DR is the formation of fibrovascular epiretinal membranes (ERMs) which can cause tractional retinal detachment in the progressed stage of DR. Ocular vitreous fluid and ERMs, which can be obtained during vitrectomy, allow laboratory studies investigating the pathogenesis of DR. Recent studies have shown a significant association between clinical grades of DR and the expression levels of specific cytokines, such as vascular endothelial growth factor (VEGF), in the intraocular fluid. In addition, expression of various trophic factors and their receptors are reported in ERMs. ERM is composed of many cell types including endothelial cells, which is the primary target of glucose-induced dysfunction in the retina. However, some trophic factor receptors are observed in other cell types such as the glial cells, and their role in ERMs is unclarified. These findings may uncover the detailed pathogenesis of DR, which may lead to new therapeutic strategies. This review briefly summarizes recent research regarding the clinical and laboratory findings of DR.     

Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy

One of the major complications in patients with diabetes is diabetic retinopathy (DR), a leading cause of blindness worldwide. It takes several years before any clinical signs of retinopathy appear in diabetic patients, which gives an ample opportunity for scientists to uncover biochemical and molecular mechanism implicated early in the development and progression of the disease. During the past few decades, research progress has been made in investigating the pathophysiology of the disease; however, due to nonavailability of human retinal samples at different stages of the disease and also due to lack of a proper animal model of DR, the exact molecular mechanism has not been elucidated, making therapeutic a difficult task. In this review article, we have discussed a number of diabetes-induced metabolites such as glucose, lipids, amino acids, and other related factors and molecules that are implicated in the pathophysiology of the DR. Furthermore, we have highlighted neurodegeneration and regulation of neurotrophic factors, being recognized as early events that may be involved in the pathology of the disease in the course of DR. An understanding of the biochemical and molecular changes especially early in the diabetic retina may lead to new and effective therapies towards prevention and amelioration of DR, which is important for the millions of individuals who already have or are likely to develop the disease before a cure becomes available.     

Biomarkers of Diabetic Retinopathy

Diabetic retinopathy (DR), a leading cause of acquired vision loss, is a microvascular complication of diabetes. While traditional risk factors for diabetic retinopathy including longer duration of diabetes, poor blood glucose control, and dyslipidemia are helpful in stratifying patient’s risk for developing retinopathy, many patients without these traditional risk factors develop DR; furthermore, there are persons with long diabetes duration who do not develop DR. Thus, identifying biomarkers to predict DR or to determine therapeutic response is important. A biomarker can be defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Incorporation of biomarkers into risk stratification of persons with diabetes would likely aid in early diagnosis and guide treatment methods for those with DR or with worsening DR. Systemic biomarkers of DR include serum measures including genomic, proteomic, and metabolomics biomarkers. Ocular biomarkers including tears and vitreous and retinal vascular structural changes have also been studied extensively to prognosticate the risk of DR development. The current studies on biomarkers are limited by the need for larger sample sizes, cross-validation in different populations and ethnic groups, and time-efficient and cost-effective analytical techniques. Future research is important to explore novel DR biomarkers that are non-invasive, rapid, economical, and accurate to help reduce the incidence and progression of DR in people with diabetes.     

MTHFR gene polymorphism and diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of catastrophic loss of vision. Each year, DR darkens the lives of 12,000 to 24,000 diabetic patients in the United States, and more than 4,000 patients in Japan. Clinically, hyperglycemia induces proliferative changes in DR synergistically with other risk factors for vascular diseases. Methyl- enetetrahydrofolate reductase (MTHFR) is an enzyme involved in remethylation of homocysteine to methionine. A polymorphic mutation (C677T) in the MTHFR gene leads to impaired enzyme activity, resulting in hyper- homocysteinemia as an independent risk factor for macroangiopathy. Recently, more and more attention has been paid to the involvement of hyperhomocysteinemia in the progression of DR, a serious microangiopathic complication of diabetes. Clinical studies have demonstrated that MTHFR gene polymorphism can contribute to the progression of DR, especially in the patients with blood glucose poorly controlled. Furthermore, accumulating evidence suggests that homocysteine activates vascular inflammation through inflammatory cytokines, including VEGF. These data imply that the decrease in plasma homocysteine could prevent the development and progression of DR. We also propose the possibility of personalized medicine for diabetes mellitus based on a better understanding of MTHFR gene polymorphism and its ramifications, which might cast new light on diabetic retinopathy.     

Low cumulative incidence of proliferative retinopathy in childhood-onset type 1 diabetes: a 24-year follow-up study

Aims/hypothesis We estimated cumulative incidence of proliferative diabetic retinopathy (PDR) and risk factors for developing diabetic retinopathy (DR) in childhood-onset type 1 diabetes. Materials and methods A sample of 294 patients with childhood-onset type 1 diabetes (<15 years) diagnosed in Norway between 1973 and 1982 was examined for retinopathy at baseline between 1989 and 1990 and at follow-up from 2002 to 2003. At follow-up, mean age was 33 years (range: 21–44), mean diabetes duration 24 years (19–30) and total person-time contributed 7,152 person-years. Retinal photographs were taken at baseline and follow-up. Associations between baseline factors and PDR were estimated using Cox regression models. Results Overall, 262 of 294 (89.1%) developed DR from diabetes onset, of whom 31 developed PDR. The 25-year cumulative incidence of PDR was 10.9% (95% CI 7.3–14.5). Among 194 without retinopathy at baseline, 163 (84%) developed DR and nine (5%) progressed to PDR. Among 97 patients with non-proliferative DR at baseline, 19 (20%) progressed to PDR. Significant predictors for developing PDR were retinopathy at baseline (relative risk [RR]=3.71, 95% CI 1.59–8.68), HbA_1c (RR=2.05, 1.44–2.93), and triglycerides (RR=1.55, 1.06–1.95). Conclusions/interpretation Nine out of every ten patients diagnosed with type 1 diabetes developed DR, but only one out of ten developed PDR within their first 25 years of diabetes duration. The cumulative incidence of PDR is lower than previously reported from other countries. Potentially modifiable risk factors predict the development of DR and PDR.     

Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes

AimHypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR).MethodsIn this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined.ResultsOf 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98–9.56; P < 0.01) and, for progression of DR, 2.29 (95% CI: 0.45–11.78; P = 0.32) with severe hypoglycaemia.ConclusionHaving a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes.     

Metabolic memory: mechanisms and implications for diabetic retinopathy

Chronic hyperglycemia of diabetes leads to microvascular complications that severely impact quality of life. Diabetic retinopathy (DR) may be the most common of these and is a leading cause of visual impairment and blindness among working age adults in developed nations. Many large-scale type 1 and type 2 diabetes clinical trials have demonstrated that early intensive glycemic control can reduce the incidence and progression of micro and macrovascular complications. On the other hand, epidemiological and prospective data have revealed that the stressors of diabetic vasculature persist beyond the point when glycemic control has been achieved. These kinds of persistent adverse effects of hyperglycemia on the development and progression of complications has been defined as "metabolic memory", and oxidative stress, advanced glycation end products and epigenetic changes have been implicated in the process. Recent studies have indicated that such "hyperglycemic memory" may also influence DR, suggesting that manipulation of hyperglycemic memory may prove a beneficial approach to prevention and treatment. This review summarizes the evidence from DR-related clinical trials and mechanistic studies to investigate the significance of metabolic memory in DR and understand its potential as a target of molecular therapeutics aimed at reversing hyperglycemic memory.