Evidence Suggesting the Role of Gut Dysbiosis in Diabetic Retinopathy

PurposeGut dysbiosis has been identified and tested in human trials for its role in diabetes mellitus (DM). The gut–retina axis could be a potential target for retardation of diabetic retinopathy (DR), a known complication of DM. This study reviews the evidence suggesting gut dysbiosis in DR.MethodsThe published literature in the past 5 years was reviewed using predetermined keywords and articles. The review intended to determine changes in gut microbiome in DR, the hypothesized mechanisms linking to the gut–retina axis, its predictive potential for progression of DR, and the possible therapeutic targets.ResultsThe gut microbiota of people with DM differ from those without it, and the gut microbiota of people with DR differ from those without it. The difference is more significant in the former (DM versus no DM) and less significant in the latter (DM without DR versus DM with DR). Early research has suggested mechanisms of the gut–retina axis, but these are not different from known changes in the gut microbiome of people with DM. The current evidence on the predictive value of the gut microbiome in the occurrence and progression of DR is low. Therapeutic avenues targeting the gut–retina axis include lifestyle changes, pharmacologic inhibitors, probiotics, and fecal microbiota transplantation.ConclusionsInvestigating the therapeutic utility of the gut ecosystem for DM and its complications like DR is an emerging area of research. The gut–retina axis could be a target for retardation of DR but needs longitudinal regional studies adjusting for dietary habits.     

Diabetic Retinopathy Risk Factors: Plasma Erythropoietin as a Risk Factor for Proliferative Diabetic Retinopathy

Purpose

The purpose of this study was to evaluate whether any stage of diabetic retinopathy (DR) is associated with levels of plasma erythropoietin and other plasma parameters.

Methods

It was examined a representative sample of 180 type 2 diabetes patients aged 40 to 79 years. Ophthalmic examination including a funduscopic examination, performed by an experienced ophthalmologist and the retinal finding were classified according to the grading system for diabetic retinopathy of ETDRS (Early Treatment Diabetic Retinopathy Study). It was measured the levels of plasma erythropoietin, cholesterol, triglyceride, apolipoproteins A and B, C-reactive protein, fasting blood glucose and hemoglobin A1C (HbA1C) in 88 DR patients and 92 controls without DR. Risk factors correlated with DR were compared between groups.

Results

The study group of 180 patients included 72 males and 108 females. The mean age of the patients with and without DR was 57.36 ± 8.87 years and 55.33 ± 8.28 years, respectively. Of the 88 patients with DR, only 9 (10%) had proliferative DR and the rest suffered from non-proliferative DR. The mean plasma levels of erythropoietin in proliferative DR group showed a significant difference in comparison to other groups. The mean plasma levels of cholesterol, triglyceride, apolipoproteins A and B, C-reactive protein, and fasting blood glucose were not significantly different in the three groups except for HbA1C. The absolute relative risk (ARR) also showed that erythropoietin was an increasing risk for proliferative DR (ARR, 1.17; 95% confidence interval, 1.060 to 1.420; odds ratio,1.060).

Conclusions

Of the factors studied, erythropoietin level showed significant increase in proliferative DR group. The stepwise raised in mean plasma erythropoietin level which demonstrates significant correlation with proliferative DR versus remaining two groups, will be an indication of its role in proliferative DR.     

Relation Between Plasma Nitric Oxide Levels and Diabetic Retinopathy

Purpose Nitric oxide (NO) plays an important role in homeostatic vasodilation and the regulation of blood flow. On the other hand, excess release of NO causes various vascular complications. There are only a few reports on the relationship between plasma NO levels and microvascular complications, especially diabetic retinopathy (DR) in patients with type 2 diabetes. The purpose of this study was to determine the relationship between plasma NO levels and DR. Methods In a prospective study, blood samples were obtained from 36 patients with diabetes and no diabetic retinopathy (NDR), 43 patients with nonproliferative diabetic retinopathy (NPDR), 18 patients with proliferative diabetic retinopathy (PDR), and 40 subjects without diabetes mellitus, who served as controls. The levels of plasma NO_x (nitrite and nitrate), the stable metabolites of NO, were measured by high-performance liquid chromatography with the Griess method. Results The plasma NO_x levels were 92.8 ± 16.0, 70.2 ± 6.8, 90.3 ± 9.1, and 53.8 ± 6.1 μmol/l in patients with NDR, NPDR, or PDR, and in the controls, respectively. The plasma NO_x levels in the three diabetic groups were significantly higher than those in the control group (P < 0.05 in each case). Conclusion The increased plasma NO levels in patients with type 2 diabetes indicate that NO may be associated with the pathogenesis of DR. Jpn J Ophthalmol 2006;50:465–468 ? Japanese Ophthalmological Society 2006     

Association Analysis of Polymorphisms in Genes Related to Oxidative Stress in South Indian Type 2 Diabetic Patients with Retinopathy

Background: Diabetic Retinopathy (DR) is one of the most common microvascular complications of type 2 diabetes mellitus (T2DM) and is polygenic with a multitude of genes contributing to disease susceptibility. The present study aimed at exploring the association between DR and seven polymorphisms in oxidative stress-related genes, i.e. ACE, eNOS, p22phox subunit of NAD(P)H oxidase, PARP-1 and XRCC1 in South Indian T2DM subjects.

Materials and methods: The study included 149 T2DM subjects with DR (diagnosed through funduscopic examination) and 162 T2DM patients with no evidence of DR. The selected polymorphisms were genotyped by polymerase chain reaction (PCR) and Taqman allele discrimination assay.

Results: There was no significant difference in the genotype and allele distribution of ACE ins/del, eNOS-786T>C, 894G>T, 4a4b and p22phox 242C>T polymorphisms between T2DM groups with and without DR. Contrastingly, there appeared to be a significant association of PARP-1 Val762Ala and XRCC1 Arg399Gln polymorphisms with DR, wherein 762Ala allele seemed to confer significant protection against DR (p?=?0.01; OR?=?0.51 [0.3–0.86]), while the presence of 399Gln allele was associated with an enhanced risk for DR (p?=?0.02; OR?=?1.52 [1.07–2.15]). Multiple logistic regression analysis revealed a significant and independent association of Val762Ala and Arg399Gln polymorphisms and other putative risk factors with DR in T2DM individuals.

Conclusions: The polymorphisms in the DNA repair genes PARP-1 and XRCC1 tended to associate significantly with DR. While Val762Ala polymorphism was associated with reduced susceptibility to DR, the Arg399Gln polymorphism contributed an elevated to risk for DR in South-Indian T2DM individuals.     

二十二碳六烯酸与糖尿病视网膜病变的关联性

目的：探讨二十二碳六烯酸（DHA）与糖尿病视网膜病变（DR）的关联性,为DR人群筛查及其二级预防提供依据。方法：多中心病例对照研究。纳入温州医科大学和安徽医科大学的2个附属医院年 龄≥35岁的2型糖尿病患者197例,由专业医师根据其眼底检查结果诊断为DR 83例（病例组）和单 纯糖尿病114例（对照组）,采用倾向性评分匹配（1∶1）以控制主要混杂因素的影响。DHA检测使用 超高液相色谱质谱联用系统,局部加权回归和多元条件Logistic回归模型分析DHA与DR的关联性, 森林图显示各亚组间的异质性检验及与DHA交互作用的结果。结果：最终入选69对研究对象,其 中DR患者的DHA水平显著低于对照组（t=3.68,P<0.001）,DHA每增加一个四分位数间距,DR患病 风险平均降低53%（OR：0.47;95%CI：0.30,0.73）,提示DHA与DR患病风险间存在明显的负相关关系,亚组分析结果显示,年龄、性别、体质量指数、糖尿病病程、血压、吸烟及饮酒均不会明显改变 DHA与DR间的关联性（P>0.05）。结论：DHA与DR的发生密切相关,是DR的独立保护因素,并有可能可以用于DR的大规模人群筛查并指导其二级预防工作。     

Diabetic Retinopathy,Present and Future: Conclusion of Diabetic Retinopathy Symposium

The preceding reports of the Diabetic Retinopathy Symposium are reviewed. Diabetic retinopathy progresses with the duration of disease and often results in proliferative retinopathy in the juvenile onset patient and macular edema in the older onset patient. Periodic ophthalmoscopic examinations are essential in detecting the progression of retinopathy and development of disease characteristics which indicate a need for treatment. Laboratory and clinical experience stress the importance of rigid glucose control in preventing diabetic retinopathy. Ischemia of the midperipheral retina stimulates the development of high risk factors for which panretinal photocoagulation is indicated despite side effects such as decreased dark adaptation. Pars plana vitrectomy results in substantial visual improvement in eyes with nonclearing vitreous hemorrhage and/or traction retinal detachments involving the macula. Future advances in our knowledge of diabetic retinopathy should come from the National Eye Institute's Collaborative Diabetic Retinopathy Vitrectomy Study and Early Treatment Diabetic Retinopathy Study, and the analysis of vasoformative factors.     

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: IV. Diabetic Macular Edema

The prevalence of macular edema and its relationship to a number of risk factors were examined in a population-based study in southern Wisconsin. Macular edema was determined from its presence on stereoscopic fundus photographs or from past history as recorded and documented in clinic records and photographs. For participants whose age at diagnosis of diabetes was less than 30 years and who were taking insulin (n = 919), prevalence rates of macular edema varied from 0% in those who had diabetes less than 5 years to 29% in those whose duration of diabetes was 20 or more years. In these persons, macular edema was associated with longer duration of diabetes, presence of proteinuria, diuretic use, male gender and higher glycosylated hemoglobin. For those whose age at diagnosis was 30 years or older (n = 1121), prevalence rates of macular edema varied from 3% in those who had diabetes less than 5 years to 28% in those whose duration of diabetes was 20 or more years. In these persons, presence of macular edema was associated with longer duration of diabetes, higher systolic blood pressure, insulin use, higher glycosylated hemoglobin, and presence of proteinuria.     

Mini Review: Changes in the Incidence of and Progression to Proliferative and Sight-Threatening Diabetic Retinopathy Over the Last 30 Years

Purpose: Diabetic retinopathy is a leading cause of blindness worldwide. The last 3 decades have seen major improvements in glycemic and blood pressure control as well as the introduction of national screening programs, and we sought to determine if rates of proliferative diabetic retinopathy have changed as a result.

Methods: We conducted a systematic review to determine whether the incidence and progression rates of proliferative diabetic retinopathy and sight-threatening retinopathy have changed, focusing on large population-based studies with objective assessment of diabetic retinopathy.

Results: Comparisons across different studies is problematic due to different baseline retinopathy severity, different reported outcomes and different follow-up periods, but within these constraints certain trends could be identified. This review provides evidence that the incidence and progression of these conditions has reduced by approximately 2–3 fold over the last 3 decades.

Conclusion: These results have implications for current diabetic retinopathy screening guidelines and has identified future areas where research could be improved.     

近视与糖尿病视网膜病变的相关性

目的：利用双眼糖尿病视网膜病变（DR）程度的不对称性探讨近视与DR的相关性。方法：横断面研 究。根据糖尿病早期治疗研究（ETDRS）标准,将抚顺糖尿病视网膜病变队列研究的患者进行DR与 糖尿病性黄斑水肿（DME）分级。DR分级包括无DR、轻度非增殖性DR（NPDR）、中度NPDR、重度 NPDR与增殖性DR（PDR）。纳入双眼DR程度至少相差1级（314例,628眼）或仅单眼DME（74例, 148眼）的患者共388例（776眼）。近视与高度近视分别定义为等效球镜度（SE）<-1 D与<-5 D。采 用配对t检验比较较好眼与较差眼间SE的差异,采用McNemar配对检验比较较好眼与较差眼间近视 及高度近视比例的差异。结果：388例患者年龄（60.6±8.5）岁,其中男147例（37.9%）。双眼DR程 度大多数相差1级（297例,76.5%）。较好眼的SE较对侧眼偏负[（-0.22±2.24）D与（0.00±1.95）D, t=3.01,P=0.003],较好眼高度近视比例高于对侧眼（4.4%与2.1%,χ2 =6.23,P=0.01）。按较好眼 DR程度分组后,NPDR患者较好眼的SE较对侧眼偏负[（-0.37±2.76）D与（0.14±1.89）D,t=2.57, P=0.01],高度近视比例高于对侧眼（7.8%与1.1%,χ2 =6.00,P=0.01）。无DR患者以及DME患者中, 较好眼与较差眼间各屈光参数差异均无统计学意义。结论：本研究利用双眼DR程度的不对称性,证 实了高度近视与DR的负相关关系。     

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.     

新型炎症因子IL-17表达水平与糖尿病视网膜病变的相关性

目的：探讨新型炎症因子白介素-17（IL-17）与糖尿病视网膜病变（DR）的相关性。方法：病例对照研究。选取625 例2 型糖尿病患者,依据是否发生DR将其分为DR组和无糖尿病视网膜病变（NDR）组。比较2 组一般资料及生化指标。组间计量资料比较采用独立样本t检验,计数资料比较采用χ2 检验,并对DR的危险因素进行多因素Logistic回归分析。结果：625 例2 型糖尿病患者中,DR 251 例（40.2%）,NDR 374例（59.8%）;与NDR组相比较,DR组年龄（t=3.012）、糖尿病病程（t=3.873）、动脉硬化发生率（x2=23.791）、空腹血糖（t=2.659）、尿微量白蛋白/尿肌酐（A/C）值（t=5.917）及血清IL-17水平（t=5.242）均较高,差异有统计学意义 （P＜0.05）;2 组间性别构成、体质量指数、高血压、吸烟、舒张压、收缩压、糖化血红蛋白、总胆固醇、甘油三酯及高密度脂蛋白比较差异均无统计学意义;Logistic回归分析结果显示,糖尿病病程（OR=1.120,P=0.003）、A/C值（OR=1.014,P=0.028）及IL-17（OR=0.854,P=0.002）是DR的危险因素。结论：IL-17 与DR密切相关,检测血清IL-17 水平对DR的预测具有一定临床意义。     

Ocular Telemedicine for Diabetic Retinopathy and the Joslin Vision Network

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. The Joslin Vision Network Diabetes Eye Care Program (JVN) is a validated ocular telemedicine program developed at the Joslin Diabetes Center that has provided diabetes eye care to over 70,000 persons. The JVN allows accurate assessment of level of DR severity, detects the presence of nondiabetic eye disease, and allows determination of appropriate treatment recommendations. The JVN integrates eye care in a comprehensive diabetes program, extends access to evidence-based diabetes eye care, and offers alternative means of diabetes eye care in appropriate settings, ultimately preserving vision and preventing visual loss.     

Prevalence and Associated Factors of Diabetic Retinopathy among Type 2 Diabetes Mellitus Patients in Brunei Darussalam: A Cross-sectional Study

PurposeTo determine the prevalence of diabetic retinopathy (DR) and the factors associated with retinopathy among type 2 diabetes mellitus (DM) patients in Brunei Darussalam.MethodsCross-sectional study of all type 2 DM patients who attended diabetic eye screening over a 3-month period at one of four government hospitals. We assessed association between DR with the following variables: age, sex, glycated hemoglobin (HbA1c), duration of DM, hypertension, hyperlipidemia, and microalbuminuria.ResultsThere were 341 patients (female, 58.9%; mean age, 55.3 ± 11.9 years) with a mean duration of DM of 9.4 ± 7.4 years and mean serum HbA1c of 8.4% ± 1.9%. The overall prevalence of any DR was 22.6% (95% confidence interval, 18.8–27.1) with prevalence rates of 4.1% (95% confidence interval, 2.1–6.4) for proliferative DR and 9.7% (95% confidence interval, 6.8–13.2) for vision-threatening DR. Multivariate analysis showed that DR was significantly associated with certain age groups (reduced in older age groups), longer duration of DM (11 years or more), poor control (HbA1c >9.0%) and presence of any microalbuminuria.ConclusionsDR affects one in five patients with DM in Brunei Darussalam, comparable to rates reported for other Asian populations. It is especially worrying that one in ten patients with DM had vision-threatening DR. DR was significantly associated with longer duration of DM, poor control and presence of microalbuminuria but reduced in older age groups. It is important to advocate good control right from the time of diagnosis of DM and institute timely and effective management of retinopathy. DR was significantly associated with longer duration of DM, poor control of diabetes, and presence of microalbuminuria but reduced in older age groups.     

Dysbiosis in the Gut Microbiome in Streptozotocin-Induced Diabetes Rats and Follow-Up During Retinal Changes

PurposeTo analyze the gut bacterial microbiome of streptozotocin-induced diabetic rats and rats with retinal changes.MethodsInduction of diabetes was confirmed by an increase in blood sugar (>150 mg/dL), and the progression of diabetes with retinal changes was assessed by histology and immunohistochemistry of retinal sections. Microbiomes were generated using fecal DNA, and the V3–V4 amplicons were sequenced and analyzed by QIIME and R.ResultsDysbiosis in the gut microbiome of diabetic rats and diabetic rats with retinal changes was observed at the phylum and genus levels compared with the control rats. Heat-map analysis based on the differentially abundant genera indicated that the microbiomes of controls and diabetic rats separated into two distinct clusters. The majority of the microbiomes in diabetic rats with retinal changes also formed a distinct cluster from the control rats. β-diversity analysis separated the microbiome of control rats from the microbiome of diabetic rats and diabetic rats with retinal changes, but the microbiomes of diabetic rats and diabetic rats with retinal changes showed an overlap. Functional analysis indicated that the enhanced inflammation in diabetic rats showing retinal changes could be ascribed to a decrease in anti-inflammatory bacteria and an increase in pathogenic and proinflammatory bacteria.ConclusionsThis study showed that the gut bacterial microbiome in diabetic rats with retinal changes was different compared with control rats. The results could help develop novel therapeutics for diabetics and diabetic individuals with retinal changes.     

Associations Between Peripapillary Retinal Nerve Fiber Layer and Choroidal Thickness With the Development and Progression of Diabetic Retinopathy

PurposeTo evaluate the role of the peripapillary retinal nerve fiber layer (pRNFL) and peripapillary choroidal thickness (pCT) in the development and progression of diabetic retinopathy (DR).MethodsThis is a cohort study based on the baseline and 2-year follow-up data of the Guangzhou Diabetic Eye Study. Patients with type 2 diabetes mellitus between the ages of 30 and 80 years were recruited from communities in Guangzhou. DR was graded by seven-field fundus photography after dilation of the pupil. pRNFL and pCT were measured via swept-source optical coherence tomography.ResultsA total of 895 patients were included in the study; of these, 748 did not have DR at baseline and 147 had DR at baseline. During the 2-year follow-up, 80 developed DR (10.7%), and 11 experienced DR progression (7.5%). After adjusting for confounding factors, a higher risk of incident DR was strongly associated with a lower average thickness of the pRNFL (risk ratio [RR] per 1 SD, 0.55; 95% confidence interval [CI], 0.42–0.72; P < 0.001) and average pCT (RR per 1 SD, 0.49; 95% CI, 0.34–0.70; P < 0.001). Adding both metrics to the DR prediction model significantly improved the discriminant ability of the model for incidences of DR (area under the curve increased by 15.38% from 0.673 to 0.777; P < 0.001).ConclusionsNeurodegeneration shown by the thinning of pRNFL and impaired choroidal circulation shown by the thinning of pCT are independently associated with DR onset, and assessing both metrics can improve the risk assessment for DR incidences.     

糖尿病视网膜病变的药物治疗

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病(diabetes mellitus,DM)最为常见和严重的微血管并发症之一,已成为四大主要致盲病因之一,传统的DR治疗方法包括激光光凝和玻璃体手术等。虽然这些方法大大降低了DR的致盲率。然而其提高视力的可能性很小。因此,治疗效果并不理想。随着对DR发病机制认识的提高,药物治疗可以阻断DR发病机制的各个途径,已经成为DR治疗研究的热点,是目前一个重要的研究方向。我们对蛋白激酶C抑制剂、抗血小板聚集药、抗氧化剂、糖皮质激素、醛糖还原酶抑制剂、3-羟基-3甲基-戊二酰辅酶A抑制剂、免疫相关因子IL-1β以及中药等治疗进展作一综述。     

Population-Based Study of Nonproliferative Diabetic Retinopathy Among Type 2 Diabetic Patients in Kinmen, Taiwan

Purpose

This study was conducted to assess the prevalence and associated factors of nonproliferative diabetic retinopathy among type 2 diabetic patients in Kinmen, Taiwan.

Methods

From 1991 to 1993, 971 type 2 diabetic patients in Kinmen underwent diabetic retinopathy screening performed by a panel of ophthalmologists using indirect ophthalmoscopy and 45° color fundus retinal photographs.

Results

Of the 971 patients screened in 1991–1993, 578 (59.5%) were examined for this study. Diabetic retinopathy was diagnosed in 127 patients (22.0%), including nonproliferative diabetic retinopathy in 13.3%, proliferative diabetic retinopathy in 1.4%, legal blindness in 1.4%, and ungradable diabetic retinopathy in 5.9%. Significant associated factors of nonproliferative diabetic retinopathy based on multiple logistic regression analysis were fasting plasma glucose (FPG) at baseline [≥126?mg/dl vs. <126?mg/dl; odds ratio (OR) = 2.89; 95% confidence interval (CI), 1.01–9.09], 2-h postload at baseline (≥200 vs. <200?mg/dl; OR = 1.48; 95% CI, 1.09–2.07); HbA_1c at follow-up (≥7% vs. <7%; OR = 6.54; 95% CI, 3.01–14.20), duration of diabetes (≥15 years vs. <10 years; OR = 6.72; 95% CI, 2.13–21.18), and incremental systolic blood pressure between baseline and follow-up (OR = 1.02; 95% CI, 1.00–1.04).

Conclusions

In addition to the longer duration of type 2 diabetes, FPG at baseline, poorly controlled glucose concentration, and altered blood pressure may increase the risk of nonproliferative diabetic retinopathy in type 2 diabetic patients. Jpn J Ophthalmol 2006;50:44–52 © Japanese Ophthalmological Society 2006     

Vitreous Proteomics and Diabetic Retinopathy

Diabetic retinopathy is the major cause of acquired blindness in working-age adults. Studies of the vitreous proteome have provided insights into the etiology of diabetic retinopathy and suggested potential molecular targets for treatments. Further characterization of the protein changes associated with the progression of this disease may suggest additional therapeutic approaches as well as reveal novel factors that may be useful in predicting risk and functional outcomes of interventional therapies. This article provides an overview of the various techniques used for proteomic analysis of the vitreous and details results from various studies evaluating vitreous of diabetic patients using the proteomic approach.