Risk Factors for Proliferative Diabetic Retinopathy in African Americans with Type 2 Diabetes

Purpose: To assess personal and demographic risk factors for proliferative diabetic retinopathy in African Americans with type 2 diabetes.

Methods: In this prospective, non-interventional, cross-sectional case-control study, 380 African Americans with type 2 diabetes were enrolled. Participants were recruited prospectively and had to have either: (1) absence of diabetic retinopathy after ≥10 years of type 2 diabetes, or (2) presence of proliferative diabetic retinopathy when enrolled. Dilated, 7-field fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study scale. Covariates including hemoglobin A_1C (HbA_1C), blood pressure, height, weight and waist circumference were collected prospectively. Multivariate regression models adjusted for age, sex and site were constructed to assess associations between risk factors and proliferative diabetic retinopathy.

Results: Proliferative diabetic retinopathy was associated with longer duration of diabetes (odds ratio, OR, 1.62, p < 0.001), higher systolic blood pressure (OR 1.65, p < 0.001) and insulin use (OR 6.65, p < 0.001) in the multivariate regression analysis. HbA_1C was associated with proliferative diabetic retinopathy in the univariate analysis (OR 1.31, p = 0.002) but was no longer significant in the multivariate analysis.

Conclusions: In this case-control study of African Americans with type 2 diabetes, duration of diabetes, systolic hypertension and insulin use were strong risk factors for the development of proliferative diabetic retinopathy. Interestingly, HbA_1C did not confer additional risk in this cohort.     

Two-year Course of Visual Acuity in Severe Proliferative Diabetic Retinopathy with Conventional Management: Diabetic Retinopathy Vitrectomy Study (DRVS) Report #1

Seven hundred forty-four eyes with very severe proliferative diabetic retinopathy (PDR) were followed with conventional management over a two-year period. Decreases in visual acuity were more frequent during the first year of follow-up than during the second, and were related to baseline visual acuity level and retinopathy severity. After two years, visual acuity was less than 5/200 in 45% of eyes with more than four disc areas of new vessels and visual acuity of 10/30 to 10/50 at baseline, but in only 14% of eyes with traction retinal detachment not involving the center of the macula and without active new vessels or fresh vitreous hemorrhage at baseline. Vitrectomy, which was undertaken only if retinal detachment involving the center of the macula occurred or if severe vitreous hemorrhage failed to clear after a one-year waiting period, had been carried out in 25% of eyes after two years of follow-up.     

Detection of Glutamate and -y-aminobutvric Acid in Vitreous of Patients with Proliferative Diabetic Retinopathy

Purpose:To study the levels of glutamate and γ-aminobutyric acid (GABA) in vitreous of patients with proliferative diabetic retinopathy(PDR) and to investigate their roles in retinal ischemia.Method: Vitreous samples were collected from 25 patients (27 eyes) with PDR and 14 patients (14 eyes) with idiopathic macular hole. Glutamate and GAB A detection were performed by high-performance liquid chromatography (HPLC).Results: Patients with PDR had significantly higher concentrations of glutamate and GA-BA than the control group. The glutamate level has a significantly positive correlation with GABA level.Conclusion: Detection of glutamate and GABA in vitreous provides biochemical support for the mechanism and treatment of ischemic retinal damage in patients with PDR. Eye Science 2000; 16: 199-202.     

Macrophage-Like Cell Density Is Increased in Proliferative Diabetic Retinopathy Characterized by Optical Coherence Tomography Angiography

PurposeTo quantitatively characterize macrophage-like cells (MLCs) at the vitreoretinal interface in different severity stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA).MethodsThe study included 72 eyes of 72 subjects: 18 healthy controls, 22 diabetes mellitus (DM) without DR, 17 nonproliferative DR (NPDR), and 15 proliferative DR (PDR). We obtained repeated (average, 6.5; range, 3–10) macular OCTA scans for each eye. We registered and averaged the 3-µm OCT slab above the vitreoretinal interface to visualize MLCs. Using a semiautomated method, we binarized and quantified MLCs and compared MLC densities among groups. We also evaluated MLC distribution relative to underlying superficial capillary plexus vasculature and quantified MLCs overlying blood vessels within the perivascular 30-µm watershed region and within ischemic zones (defined as >30 µm from the nearest vessel).ResultsMLC density was 2.8- to 3.8-fold higher in PDR compared with all other groups (P < 0.05 for all). MLC density in PDR was most increased in perivascular areas (3.3- to 4.2-fold; P < 0.05 vs. all) and on blood vessels (3.0- to 4.0-fold; P < 0.05 vs. all), and elevated to a lesser extent in ischemic areas (2.3- to 3.4-fold; P < 0.05 vs. all). MLCs were more likely to localize on blood vessels in DM without DR, NPDR, and PDR (P < 0.05 for all), but not healthy eyes.ConclusionsMLC density was significantly increased in PDR. MLCs clustered on blood vessels in diabetic but not in healthy eyes. Further studies are needed to confirm the origin, identity, and function of MLCs during DR.     

Levels of Interleukin 27 and Interleukin 35 in the Serum and Vitreous of Patients with Proliferative Diabetic Retinopathy

Purpose: To examine the role of interleukin 27(IL-27) and interleukin 35 (IL-35) in diabetic retinopathy (DR).

Methods: Patients with diabetes mellitus were divided into three groups: diabetes without retinopathy (DWR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). Patients with idiopathic macular epiretinal membrane (IMEM) were included as a control group. The serum and vitreous levels of IL-27 and IL-35 were measured using ELISA.

Results: The serum levels of IL-27 (median 240.900 pg/mL, range 42.224 – 617.810 pg/mL; p < 0.001) and IL-35 (median 11.875 ng/mL, range 8.640 – 19.340 ng/mL; p < 0.001) were significantly decreased in PDR patients compared to controls (median 2712.310 pg/mL, range 1005.375–5786.877 pg/mL and median 25.185 ng/mL, range 22.845 – 29.590 ng/mL, respectively). The vitreous levels of IL-35 were significantly decreased in PDR patients (16.32 ± 3.24 ng/mL) compared to controls (24.54 ± 5.86 ng/mL, p < 0.001).

Conclusions: Serum and vitreous levels of IL-35 and serum level of IL-27 may be associated with the pathogenesis of PDR.     

玻璃体联合手术治疗并发白内障的增生性糖尿病视网膜病变

目的：探讨伴有严重晶状体混浊的增生性糖尿病视网膜病变的玻璃体手术联合白内障吸除及人工晶状体植入的疗效及并发症。方法：需行玻璃体手术且伴有白内障的增生性糖尿病视网膜病变38例(41只眼)，行超声乳化白内障吸除联合玻璃体切割、膜剥离、眼内激光、或长效气体填充、及人工晶状体植入。观察病人手术前后视力变化，裂隙灯下检查眼前段情况，眼底荧光造影检查病人视网膜情况及分析并发症。结果：平均随访9个月。术后36只眼视力提高，占87．8％。眼前节反应轻，并发症少。主要并发症有：高眼压1只眼，角膜水肿1只眼，虹膜红变1只眼。视网膜脱离1只眼。结论：玻璃体联合手术治疗并发白内障的增生性糖尿病视网膜病变是一种方便、安全、有效的手术。     

激活T淋巴细胞与增生性糖尿病性视网膜病变关系的研究

目的:研究免疫介导过程对增生性糖尿病性视网膜病变(proliferative diabetic retinopathy PDR)的发生发展的潜在作用。方法:应用特异性的抗辅助T淋巴细胞(CD4)、抗白细胞介素-2(interleukin-2 IL-2)及其受体的单克隆抗体(interleukin-2 receptor IL-2R),对经扁平部玻璃体切割术获得的15例PDR视网膜前膜标本进行了研究。结果:在15例标本中,12例(80%)呈CD4阳性;12例(80%)发现有IL-2,且其中11例也呈CD4阳性;10例(67%)发现有IL-2R,其中9例呈CD4阳性并有释放的IL-2。大多数IL-2R阳性的前膜都来自Ⅰ型糖尿病患者,其中40%的患者小于40岁。结论:研究证实了半数以上的糖尿病视网膜前膜中有激活的免疫细胞和释放的淋巴因子,揭示了免疫反应过程和淋巴因子的生物效应对PDR视网膜前膜的形成起重要作用,尤其在青年患者和Ⅰ型糖尿病患者。眼科学报1999;15:229-232。     

CD146/Soluble CD146 Pathway Is a Novel Biomarker of Angiogenesis and Inflammation in Proliferative Diabetic Retinopathy

PurposeInflammation, angiogenesis and fibrosis are pathological hallmarks of proliferative diabetic retinopathy (PDR). The CD146/sCD146 pathway displays proinflammatory and proangiogenic properties. We investigated the role of this pathway in the pathophysiology of PDR.MethodsVitreous samples from 41 PDR and 27 nondiabetic patients, epiretinal fibrovascular membranes from 18 PDR patients, rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy analysis. Blood-retinal barrier breakdown was assessed with fluorescein isothiocyanate-conjugated dextran.ResultssCD146 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic patients. In epiretinal membranes, immunohistochemical analysis revealed CD146 expression in leukocytes, vascular endothelial cells and myofibroblasts. Significant positive correlations were detected between numbers of blood vessels expressing CD31, reflecting angiogenic activity of PDR, and numbers of blood vessels and stromal cells expressing CD146. Western blot analysis showed significant increase of CD146 in diabetic rat retinas. sCD146 induced upregulation of phospho-ERK1/2, NF-κB, VEGF and MMP-9 in Müller cells. The hypoxia mimetic agent cobalt chloride, VEGF and TNF-α induced upregulation of sCD146 in HRMECs. The MMP inhibitor ONO-4817 attenuated TNF-α-induced upregulation of sCD146 in HRMECs. Intravitreal administration of sCD146 in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, intercellular adhesion molecule-1 and VEGF in the retina. sCD146 induced migration of HRMECs.ConclusionsThese results suggest that the CD146/sCD146 pathway is involved in the initiation and progression of PDR.     

Myeloid-Related Protein-14/MRP-14/S100A9/Calgranulin B is Associated with Inflammation in Proliferative Diabetic Retinopathy

Purpose: To investigate the expression of the leukocyte proteins myeloid-related protein (MRP)-8 and MRP-14 in proliferative diabetic retinopathy (PDR) and the effect of MRP-8/MRP-14 (calprotectin) heterodimer on induction of proinflammatory factors in human retinal microvascular endothelial cells (HRMEC).

Methods: Epiretinal membranes from 20 patients with PDR and 10 patients with proliferative vitreoretinopathy (PVR), vitreous fluid samples from PDR and non-diabetic subjects and HRMEC were studied by immunohistochemistry and Western blot analysis.

Results: MRP-14 expression was localized in endothelial cells, leukocytes and myofibroblasts in all PDR membranes. MRP-8 expression was limited to intravascular leukocytes in 42% of the studied membranes. In PVR membranes, MRP-14 was expressed in leukocytes and myofibroblasts, whereas MRP-8 immunoreactivity was limited to leukocytes. MRP-14 was significantly upregulated in vitreous from PDR patients. MRP-8/MRP-14 (calprotectin) increased expression of intercellular adhesion molecule-1, but attenuated vascular cell adhesion molecule-1 expression in HRMEC.

Conclusions: Increased MRP-14 levels are associated with inflammation in PDR.     

Expression of Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor in Fibrovascular Membranes from Patients with Proliferative Diabetic Retinopathy

Purpose

The expression of pigment epithelium-derived factor (PEDF), a strong inhibitor of angiogenesis, has not been examined in human ocular fibrovascular membranes, to the best of our knowledge. The purpose of this study was to determine whether PEDF is expressed in the fibrovascular membranes in eyes of patients with proliferative diabetic retinopathy (PDR), and to compare the expression of PEDF with that of vascular endothelial growth factor (VEGF).

Methods

The expression of PEDF and VEGF in the fibrovascular membranes excised during vitreous surgery in eight cases of PDR was determined by immunohistochemistry.

Results

VEGF was strongly expressed in the endothelial cells of newly formed vessels in the fibrovascular membranes. In contrast, PEDF was weakly expressed in the endothelial cells and was prominently expressed in the extracellular matrix and fibrous tissue surrounding the new vessels.

Conclusions

Our results suggest that PEDF, along with VEGF, may modulate the formation of fibrovascular membranes in patients with PDR.?Jpn J Ophthalmol 2006;50:116–120 © Japanese Ophthalmological Society 2006     

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.     

Soluble IL-6 Receptor in Vitreous Fluid of Patients with Proliferative Diabetic Retinopathy

Purpose

To identify the biological reaction of soluble interleukin-6 receptor (sIL-6R) in the vitreous of patients with proliferative diabetic retinopathy (PDR).

Methods

The subjects were 45 patients (45 eyes) with vitreoretinal diseases. The patients were divided into three groups: the PDR group comprised 28 patients (28 eyes) with PDR; the pre-proliferative diabetic retinopathy (PPDR) group comprised seven patients (seven eyes) with PPDR combined with diabetic macular edema; and the nondiabetic group comprised ten patients (ten eyes) with idiopathic macular hole or idiopathic epiretinal membrane. Vitreous samples were obtained at vitrectomy. sIL-6R, vascular endothelial growth factor (VEGF), and protein concentration in vitreous samples were determined by enzyme-linked immunosorbent assay (ELISA). sIL-6R levels in serum were also determined by ELISA in nine of the 28 patients with PDR and in six healthy volunteers as controls.

Results

In vitreous fluid, the levels of sIL-6R in the PDR group, PPDR group, and nondiabetic group were 612.7 ± 233.8 (mean ± SD), 746.3 ± 523.1, and 215.4 ± 98.3?pg/ml, respectively. Vitreous levels of sIL-6R in the PDR and PPDR groups were significantly higher than those in the nondiabetic group (PDR group, P < 0.0001; PPDR group, P < 0.01). In serum, the levels of sIL-6R were 39.38 ± 9.43?ng/ml in the PDR group and 22.84 ± 5.32?ng/ml in the control group. sIL-6R levels in serum in the PDR group were significantly higher than those in the control group (P < 0.01). A partial correlation analysis showed a significant correlation between the levels of sL-6R and VEGF in the vitreous in the PDR group (r = 0.34, P < 0.05).

Conclusions

We conclude that the level of sIL-6R in vitreous fluid can be considered as a biomarker of PDR.?Jpn J Ophthalmol 2007;51:100–104 © Japanese Ophthalmological Society 2007

     

Serum Antibody Responses to Bovine Retinal S-Antigen and Rod Outer Segments in Proliferative Diabetic Retinopathy before and after Argon Laser Photocoagulation

Using the enzyme-linked immunosorbent assay, the serum antibody titers to bovine retinal S-antigen and rod outer segments in preand post-argon laser treated diabetic retinopathy patients were compared to each other and to the titers of age- and sex-matched normal controls. The increase in anti-S titer following the initial laser treatment gave a P < 0.01 using the two-tailed paired Student’s t-analysis as compared to the prelaser anti-S titer. Both pre- and post-laser anti-S titers were elevated over normal controls with P values of <0.02 and <0.001, respectively. Eight weeks after the initial laser treatment, anti-S titers began to decline approaching control levels 12 weeks later. No significant change was found between pre- and post-laser titers when rod outer segments were used as antigen although the pre- and postlaser titers were increased over normal controls with P values of <0.05 and <0.001, respectively. The release and possible alteration of retinal components following photocoagulation may account for the rise in anti-S titers, while the prephotocoagulation titers may be due to retinopathy-related photoreceptor cell alteration.     

Unbalanced Vitreous Levels of Osteoprotegerin,RANKL, RANK,and TRAIL in Proliferative Diabetic Retinopathy

Purpose: We investigated the expression of the proinflammatory and proangiogenic factor osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the receptor RANK in proliferative diabetic retinopathy (PDR).

Materials and methods: Vitreous samples from PDR and nondiabetic control patients and epiretinal membranes from PDR patients were studied by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis.

Results: Vascular endothelial growth factor, OPG, and soluble RANK levels in vitreous samples from PDR patients were significantly higher than that in nondiabetic controls. Soluble TRAIL levels were significantly lower in PDR patients than that in nondiabetic control, whereas soluble RANKL levels did not differ significantly. RANKL, RANK, and TRAIL were expressed in vascular endothelial cells, myofibroblasts, and CD45-expressing leukocytes in PDR epiretinal membranes.

Conclusions: Dysregulated expression of OPG/RANKL/RANK pathway and TRAIL might be related to inflammation and angiogenesis in PDR.     

糖尿病视网膜病变肿瘤坏死因子-α水平测定及临床意义

目的 探讨肿瘤坏死因子-α与糖尿病及糖尿病视网膜病变的关系.方法 采用放射免疫分析法测定68例2型糖尿病视网膜病变肿瘤坏死因子-α的水平,经常规眼底检查及眼底荧光造影检查,凡有微血管瘤、点片状出血、渗出、新生血管形成,继发性视网膜脱离、玻璃体积血者,诊断为糖尿病视网膜病变(DR组)32例.其余36例无糖尿病视网膜病变者为DM组.正常对照组24例,排除高血压、糖尿病等全身性疾病,经询问病史及眼底检查排除眼病疾患.结果 DR组及DM组血清TNF-α明显高于对照组,(1.09±0.60)ng/ml对(0.71±0.27)ng/ml,P<0.01;(0.911±0.40)ng/ml对(0.71±0.27)ng/ml,P<0.05.DR组测定值高于DM组,差异无统计学意义,(1.09±0.60)ng/ml对(0.91±0.40)ng/ml,P>0.05.结论 TNF-α在DR的发生发展中有重要的病理意义.     

Rationale and Methodology for a Community-Based Study of Diabetic Retinopathy in an Indonesian Population with Type 2 Diabetes Mellitus: The Jogjakarta Eye Diabetic Study in the Community

Purpose: There are no available data about diabetic retinopathy (DR) in the Indonesian population. This report summarizes the rationale and study design of the Jogjakarta Eye Diabetic Study in the Community (JOGED.COM), a community-based study to estimate the prevalence and risk factors of DR in persons with type 2 diabetes in Jogjakarta, Indonesia.

Methods: The JOGED.COM aimed to examine a cross-sectional sample of 1200 persons with type 2 diabetes aged 30 years and older residing in the study area. We identified 121 community health centers (CHCs) in Jogjakarta and listed 35 CHCs with non-communicable diseases facilities. Multi-stage, clustered random sampling was used to select 22 CHCs randomly. We included CHCs with coverage population >30,000, and excluded those classified as 100% rural. Lists of persons with diabetes confirmed by their family physician were provided from each CHC. Examinations procedures included detailed interviews, general and eye examinations, anthropometry and body composition scan, and dilated fundus photography.

Results: We collaborated with local health authorities, family physicians, and local health practitioners in the recruitment phase. A total of 1435 invitations were distributed, and 1184 people (82.5%) with type 2 diabetes participated in this study, of whom 1138 (79.3%) had completed data with gradable retinal images.

Conclusions: JOGED.COM is the first epidemiologic study of DR in an Indonesian population. This study will provide key information about the prevalence and risk factors of DR in the community. These data are very important for future health promotion programs to reduce the burden of DR in the population.     

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.