Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies

ABSTRACT

Introduction: Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina.

This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors. Further, preclinical research suggests that gene therapy treatment for DR could provide significant benefits over existing treatments options.

Areas covered: Here we review the pathophysiology of DR and provide an overview of currently available treatments. We then outline recent advances made towards improved patient outcomes and highlight the potential of the gene therapy paradigm to revolutionize DR management.

Expert opinion: Whilst significant progress has been made towards our understanding of DR, further research is required to enable the development of a detailed spatiotemporal model of the disease. In addition, we hope that improvements in our knowledge of the condition facilitate therapeutic innovations that continue to address unmet medical need and improve patient outcomes, with a focus on the development of targeted medicines.     

Fenofibrate: treatment of hyperlipidemia and beyond

Fenofibrate is a PPAR-α agonist indicated for the treatment of hypertriglyceridemia and mixed dyslipidemia, and is approved for the treatment of hypercholesterolemia, lipid abnormalities commonly observed in patients at high risk of cardiovascular disease, including Type 2 diabetes and/or metabolic syndromes. Treatment with fenofibrate lowers triglycerides, raises HDL-cholesterol and decreases concentrations of small LDL-cholesterol particles and apolipoprotein B. Fenofibrate is particularly effective for reducing postprandial VLDL and LDL particle concentrations, and the increased oxidative stress and inflammatory response that occurs after a fatty meal. In addition, nonlipid pleiotropic effects mediated by PPAR-α are likely to contribute to the reduction in atherosclerosis progression and cardiovascular events, and have beneficial effects on diabetes-related microvascular diseases. While current approaches to treating dyslipidemia to prevent cardiovascular diseases focus on statin therapy, it is increasingly clear that substantial residual risk persists. The clinical significance of combination therapy with fenofibrate and a statin to macrovascular and microvascular risk is being evaluated in a large outcomes study.     

Glycogen synthase kinase-3: a key kinase in retinal neuron apoptosis in early diabetic retinopathy

Background Diabetes-related pathogenic factors can cause retinal ganglion cell （RGC） apoptosis, but the specific mechanism is not very clear. The aim of this study is to investigate the correlation between glycogen synthase kinase-3 （GSK-3） activation and retinal neuron apoptosis. Methods In an in vitro experiment, the number of apoptotic RGC-5 cells differentiated by staurosporine was evaluated via flow cytometry and nuclei staining using Hoechst 33258. GSK-3 phosphorylation and caspase-3 activation in RGC-5 cells after serum deprivation were determined using Western blotting. Mitochondrial membrane potential was detected using the dye 5,5＇,6,6＇-tetrachloro-l,l＇,3,3＇-tetrethyl benzimidalyl carbocyanine iodide, and reactive oxygen species （ROS） levels were measured with dihydroethidium. In an in vivo experiment, the number of apoptotic retinal neurons was evaluated via terminal transferase dUTP nick-end labeling （TUNEL）, and GSK-3 phosphorylation was determined using Western blotting, in the retinal nerve epithelial tissue of rats in which diabetes was induced by intravenous tail-vein injection of streptozotocin for 4 weeks. Results The levels of phosphorylated Ser21/9 in GSK-3α/13 and p-T308/S473-AKT were lower and the cleaved caspase-3 levels were higher in the serum-deprived model （P 〈0.05）. Lithium chloride treatment was associated with a slower rate of apoptosis, increased mitochondrial membrane potential, and decreased ROS levels in differentiated RGC-5 cells （P 〈0.05）. The level of blood glucose and the number of TUNEL-positive cells in the whole-mounted retinas were higher （P 〈0.01）, and the levels of phosphorylated Ser21/9 in GSK-3α/13 and body weight were lower （P 〈0.05）. However, the thickness of the retinal nerve epithelial layer was not significantly less in diabetic rats compared with control group. Lithium chloride intravitreal injection increased the levels of phosphorylated Ser21/9 in GSK-3α/13 and decreased TUNEL-positive cells in the whole-moun     

Ectopic orbital meningioma: report of two cases and literature review

Ectopic orbital meningioma is a rare tumor usually affecting the medial orbit. We present two cases that occurred in a 56-year-old woman and a 28-year-old man. The tumors in both patients were subtotally excised via orbitotomy surgery and were located in the superior quadrant in one of our patients and in the temporal quadrant in the other. Following histopathologic diagnosis, external beam radiotherapy (EBRT) was administered to one patient and intensity modulated radiotherapy to the other. We identified 12 other well-documented cases of ectopic orbital meningioma previously reported. Ectopic meningioma should be considered in the differential diagnosis of medial as well as lateral and superior orbital tumors. The tumor is usually well circumscribed but can be ill defined in imaging studies. There are intralesional calcifications and sclerosis of adjacent bone in some cases. Ectopic orbital meningioma can recur after incomplete excision. Based on the efficacy of EBRT in optic nerve sheath meningioma, we used this treatment to decrease the risk of recurrence in our two patients and found no tumor recurrence at follow-ups of 24 and 74 months, but one patient had severe vision loss from radiation retinopathy.     

Sight-threatening Diabetic Retinopathy at Presentation to Screening Services in Fiji

Purpose: To report the spectrum of retinopathy at first presentation to photoscreening services, to determine the proportion of patients that present with sight-threatening diabetic retinopathy (STDR), and to raise awareness of the burden of diabetic eye disease in Fiji.

Methods: This retrospective observational cohort study used data from the initial visit of all new patients presenting to the diabetes retinal screening service at the Pacific Eye Institute in Fiji over the 3-month period between July and September 2012. Patients were assessed using a detailed questionnaire regarding diabetes type, duration of disease, medications, complications and co-morbidities, and blood sugar control. Patients subsequently underwent non-mydriatic fundus photography according to Pacific diabetes retinal screening guidelines. Images were graded at the time of acquisition, and data were entered onto a computerized database. For the purposes of this study, information regarding retinopathy grading, visual acuity and patient demographics was used.

Results: A total of 522 new patients were screened over the 3-month period. STDR was observed in 27% of patients, with 15% observed to have bilateral STDR. Diabetes control was generally poor. Blindness and visual impairment were observed in 2.7% and 6.7% of the cohort, respectively.

Conclusion: Severe and advanced diabetic retinopathy was present in this population presenting to screening. This was observed 4 years after the formal expansion of the screening services and reflects the high prevalence of diabetes in the population. The need for increased public awareness and greater resource allocation into diabetes and its complications is emphasized.     

Female Reproductive Factors and Major Eye Diseases in Asian Women –The Singapore Malay Eye Study

Abstract

Purpose: To examine the association of reproductive factors and major eye diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy and cataract, in Asian women.

Methods: The Singapore Malay Eye Study is a population-based cross-sectional epidemiological study which examined 3280 persons (78.7% response) of Malay ethnicity aged 40–80 years; 1704 were female. Information on reproductive factors and use of hormone replacement therapy (HRT) was collected using an interviewer-administered questionnaire. Glaucoma was defined according to the International Society for Geographical and Epidemiological Ophthalmology criteria. Retinal photographs were graded for AMD following the Wisconsin grading system, and diabetic retinopathy according to the modified Airlie House classification system. Cataract was graded according to the Lens Opacity Classification System III.

Results: A total of 1176 women reported having experienced menopause by the time of the study with 1073 (91%) having a natural menopause, 88 (7.5%) a hysterectomy and 9 (0.8%) due to other reasons; HRT was used by 70 (6%) women. Women whose age at menopause was ≤52 years were 3.5 times more likely to have glaucoma (95% confidence interval, CI, 1.23–9.98, p value?=?0.02) than those whose age at menopause was ≥53 years. Age of menopause was not associated with AMD (age-adjusted odds ratio, OR, 1.22, 95% CI 0.65–2.31), diabetic retinopathy (age-adjusted OR 1.01, 95% CI 0.66–1.54) or cataract (age-adjusted OR 1.38, 95% CI 0.95–2.00). Use of HRT was not associated with any of these eye diseases.

Conclusion: Women who had menopause at a younger age were more likely to have glaucoma. This association needs to be confirmed in other studies.     

Prevalence of Diabetes and Diabetic Retinopathy in a Brazilian Population

Purpose: To evaluate the prevalence of type 2 diabetes mellitus and diabetic retinopathy (DR) in a Brazilian population.

Methods: Population-based, cross-sectional study conducted in 9 cities located in the Midwest region of the state of São Paulo, Brazil, between 2006 and 2007, including 4690 individuals aged ≥30 years. Diabetes was self-reported and DR was assessed by indirect ophthalmoscopy.

Results: The prevalence of type 2 diabetes was 8.68% (95% confidence interval, CI, 7.87–9.48%), and DR was present in 7.62% (95% CI 5.02–10.20%) of participants with self-reported type 2 diabetes. Approximately 35.4% of individuals diagnosed with DR did not know they had diabetes prior to DR diagnosis. Prevalences of low vision and blindness were higher among those with diabetes and DR. Cataract was still a major cause of blindness in this population.

Conclusion: This is the first large population-based study on DR in Brazil. High rates of visual impairment were found in persons with type 2 diabetes, but cataract is still one of the main causes of blindness. Large surveys are necessary for public health policy advocacy in developing countries.     

广东省东莞市横沥镇居民2型糖尿病患者糖尿病视网膜病变危险因素分析

背景国外研究表明,随着糖尿病发病率的升高,糖尿病视网膜病变（DR）已成为青壮年患者首要的致盲因素,而加强中国对DR发病危险因素的分析对于DR的防治具有重要意义。目的调查广东省东莞市横沥镇40岁及以上居民2型糖尿病患者发生DR的危险因素。方法采用横断面研究设计及整群抽样法,对广东省东莞市横沥镇40岁及以上居民进行糖尿病和DR发生率的现场流行病学调查。首先根据2010年美国糖尿病协会（ADA）制定的糖尿病诊断标准对糖尿病患者进行筛查,然后根据2002年悉尼国际DR分期标准对糖尿病患者进行DR筛查。所有受检者均接受一般资料调查、问卷调查、体格检查和实验室检查,专科检查包括裸眼视力、矫正视力、日常生活视力、验光检查以及眼压测量（非接触眼压计）、裂隙灯显微镜检查、眼底检查和眼底照相。分别采用,检验、独立样本t检验和单因素方差分析对DR患者与非DR者（NDR）的各项调查和检测结果进行比较,采用Logistic相关回归模型对DR危险因素进行分析。结果Logistic逐步回归分析结果显示,男性、糖尿病病程、收缩压、空腹血糖（FPG）和糖化血红蛋白（HBA1c）是影响2型糖尿病患者发生DR的独立危险因素,其中男性糖尿病患者发生DR的风险明显高于女性患者（OR=1．914,95％CI：1．382～2．651）;糖尿病病程为1—4年、5～9年和≥10年的患者发生DR的风险明显高于新诊断糖尿病患者,分别为新诊断患者的3．336倍（95％CI：2．322～4．880）、3．890倍（95％CI：2．327～6．503）和12．499倍（95％CI：6．607～23．647）;相对于收缩压≤120mmHg（1mmHg=0．133kPa）的糖尿病患者,收缩压为120～139mmHg、≥140mmHg的糖尿病患者发生DR的风险分别为1．953倍（95％CI：1．081～3．528）和1．950倍（95％CI：1．076～3．532）;与FPG≤5．6mmol／L的糖尿病患者比较,FPG为5．6—6．9mmol／L、≥7．0mmol／L的糖尿病患者发生DR风险分别增加1．567倍（95％CI：0．889～2．732）和2．170倍（95％CI：1．252～3．761）;此外,HBA1c≥6．5％的糖尿病患者DR发生风险明显高于HBA1c〈6．5％的糖尿病患者（OR=1．577,95％CI：1．105～2．253）。结论男性、糖尿病病程、平均收缩压、FPG和HBA1c是2型糖尿病患者发生DR的独立危险因素。早期诊断、控制高血糖、高血压等相关危险因素可以减少DR的患病率,并控制其进展。     

后Tenon囊下注射曲安奈德对激光光凝后糖尿病大鼠视网膜炎症相关细胞因子表达的影响

目的 观察后Tenon囊下注射曲安奈德（TA）对激光光凝后糖尿病大鼠视网膜炎症相关细胞因子表达的影响。方法 雄性Brown Norway健康大鼠48只,通过腹腔注射链脲佐菌素建立糖尿病大鼠模型。将大鼠随机分成实验组、对照组和空白组,分别为20、20、8只大鼠。实验组、对照组大鼠行激光光凝后,给予后Tenon囊下注射TA或生理盐水50 μl。空白组不作任何处理。激光光凝后1、3、7 d,采用荧光定量聚合酶链反应和酶联免疫吸附试验检测大鼠视网膜中血管内皮生长因子（VEGF）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的mRNA和蛋白表达。结果 激光光凝后1、3、7 d,实验组和对照组分别与空白组比较,其VEGF、IL-6、TNF-α mRNA和蛋白表达均明显升高,差异均有统计学意义（P＜0.05）。实验组VEGF、IL-6、TNF-α mRNA和蛋白表达均较对照组明显下降。实验组与对照组比较,激光光凝后1 d,VEGF mRNA表达间差异无统计学意义（P＞0.05）;其余各时间点VEGF、IL-6、TNF-α mRNA和蛋白表达间差异均有统计学意义（P＜0.05）。结论 后Tenon囊下注射TA可有效降低激光光凝导致的糖尿病大鼠VEGF、IL-6、TNF-α表达水平的升高。