2型糖尿病眼底增殖改变与冠状动脉病变关系的研究

目的:探讨2型糖尿病眼底增殖改变与冠状动脉病变的关系.方法:对330例2型糖尿病合并冠心痛患者进行眼底检测及冠状动脉造影,根据眼底是否具有增殖性改变进行对比分析,并应用多因素分析方法探讨与眼底增殖改变相关的危险因素.结果:2型糖尿病伴眼底增殖改变者,年龄较大,病程较长,尿微量白蛋白阳性检出率增加,TG、TC及HbA1c显著性升高;多支血管病变及钙化病变受累比例增高;Logistic回归分析显示,经调整糖尿病病程、HbA1c、微量白蛋白尿后,2型糖尿病眼底增殖改变仍与冠状动脉钙化相关.结论:2型糖尿病眼底增殖改变与冠状动脉钙化相关.     

Relationship between Vitreous Levels of Matrix Metalloproteinases and Vascular Endothelial Growth Factor in Proliferative Diabetic Retinopathy

To investigate which matrix metalloproteinases (MMPs) are more likely to be involved in the angiogenic process in proliferative diabetic retinopathy (PDR), we measured the levels of MMPs in the vitreous fluid from patients with PDR and controls and correlated these levels with the levels of vascular endothelial growth factor (VEGF). Vitreous samples from 32 PDR and 24 nondiabetic patients were studied by mosaic multiplex MMPs enzyme-linked immunosorbent assay (ELISA), single ELISA, Western blot and zymography analysis. Epiretinal membranes from 11 patients with PDR were studied by immunohistochemistry. MMP-8 and MMP-13 were not detected. ELISA, Western blot and gelatin ymography assays revealed significant increases in the expression levels of MMP-1, MMP-7, MMP-9 and VEGF in vitreous samples from PDR patients compared to nondiabetic controls, whereas MMP-2 and MMP-3 were not upregulated in vitreous samples from PDR patients. Significant correlations existed between ELISA and zymography assays for the quantitation of MMP-2 (r=0.407; p=0.039) and MMP-9 (r=0.711; p<0.001). Significant correlations were observed between levels of VEGF and levels of MMP-1 (r=0.845; P<0.001) and MMP-9 (r=0.775; p<0.001), and between levels of MMP-1 and MMP-9 (r=0.857; p<0.001). In epiretinal membranes, cytoplasmic immunoreactivity for MMP-9 was present in vascular endothelial cells and stromal monocytes/macrophages and neutrophils. Our findings suggest that among the MMPs measured, MMP-1 and MMP-9 may contribute to the angiogenic switch in PDR.     

Growth Factors in Proliferative Diabetic Retinopathy

Many growth factors are implicated in the pathogenesis of proliferative diabetic retinopathy. Alteration of growth factors and their receptors in diabetes has been shown in both experimental and clinical studies. Sustained hyperglycemia resulting from long-standing diabetes leads to several biochemical abnormalities that consequently result in retinal hypoxia. Retinal oxygenation state regulates various growth factors that promote angiogenesis in order to meet the oxygen demands of the tissue. However, unregulated expression of these growth factors and induction of complex cascades leading to augmentation of other proangiogenic factors, which may not be regulated by tissue oxygenation, leads to uncontrolled retinal neovascularization and blindness in diabetic patients.     

Vitreous and Plasma VEGF Levels as Predictive Factors in the Progression of Proliferative Diabetic Retinopathy after Vitrectomy

Purpose

To investigate the vitreous and plasma levels of vascular endothelial growth factor (VEGF) in patients with proliferative diabetic retinopathy (PDR) and to determine whether they predict a disease prognosis after primary vitrectomy.

Methods

Fifty patients (50 eyes) with PDR who underwent pars plana vitrectomy (PPV) and 56 healthy controls (56 eyes) were enrolled in this retrospective study. Clinical data were collected and analyzed. Vitreous and plasma VEGF concentrations were measured using enzyme-linked immunosorbent assays. VEGF levels and clinical data were compared and analyzed to see if they provide a prognosis of PDR progression after primary vitrectomy at more than 6 months follow-up. Correlation of VEGF concentrations between vitreous fluid and plasma was analyzed.

Results

The average BCVA was significantly improved after surgery (P<0.001). Vitreous and plasma VEGF levels were significantly elevated in PDR patients than those in healthy controls (P _vitreous<0.001; P _plasma<0.001). Both vitreous and plasma VEGF levels were significantly higher in PDR progression group than in stable group (P _vitreous<0.001; P _plasma = 0.004). Multivariate logistic regression analyses showed that the increased vitreous VEGF level was associated with the progression of PDR after primary PPV (OR = 1.539; P = 0.036). Vitreous VEGF level was positively associated with plasma VEGF level in PDR patients (P<0.001).

Conclusion

The increased VEGF level in vitreous fluid may be identified as a significant predictive factor for the outcome of vitrectomy in patients with PDR.     

High Prevalence of Lower Extremity Peripheral Artery Disease in Type 2 Diabetes Patients with Proliferative Diabetic Retinopathy

Little is known about the relationship between lower extremity peripheral arterial disease (PAD) and proliferative diabetic retinopathy (PDR) in type 2 diabetes (T2D). Here, we explored the relationship between sight-threatening PDR and PAD. We screened for diabetic retinopathy (DR) and PAD in hospitalized patients with T2D. Patients with a diabetic duration of more than 10 years, HbA1c ≥7.5%, eGFR ≥60mL/min/1.73m2 and with PDR or with no diabetic retinopathy (NDR) were eligible for this cross-sectional study. Severities of DR were graded by digital retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. We assessed PAD by measuring Ankle Brachial Index (ABI), Toe Brachial Index (TBI) and Doppler ultrasound. Statistical analyses were performed using SPSS 17.0 software. Of the 1544 patients, 169 patients with extreme eye (57 PDR and 112 NDR) phenotypes met the inclusion criteria. Patients with PDR had a significantly higher proportion of low ABI (≤0.99) and high ABI (≥1.3) than patients with NDR (28.1% and 15.8% vs. 14.3% and 6.2% respectively, P<0.05). PDR patients also had lower TBI than NDR patients (0.56±0.09 vs. 0.61±0.08, P<0.01). The proportion of patients with abnormal duplex ultrasound was higher in PDR than in NDR (21.1% vs. 9.8%, P<0.001). This showed that PDR associated with PAD could be defined in multiple ways: abnormal ABI (≤0.9) (OR = 3.61, 95% CI: 1.15–11.26), abnormal TBI (OR = 2.84, 95% CI: 1.19–6.64), abnormal duplex (OR = 3.28, 95% CI: 1.00–10.71), and critical limb ischemia (OR = 5.52, 95% CI: 2.14–14.26). Moreover, PDR was a stronger independent correlation factor for PAD than a diabetic duration of 10 years. In conclusion, PAD is more common in PDR than in NDR. It implies that PDR and PAD are mostly concomitant in T2D. We should focus on screening PAD in patients with PDR in clinical practice.     

Neurotrophins and Neurotrophin Receptors in Proliferative Diabetic Retinopathy

Neurotrophins (NTs) are emerging as important mediators of angiogenesis and fibrosis. We investigated the expression of the NTs nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) and their receptors TrkA, TrkB, and TrkC in proliferative diabetic retinopathy (PDR). As a comparison, we examined the expression of NTs and their receptors in the retinas of diabetic rats. Vitreous samples from 16 PDR and 15 nondiabetic patients were studied by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Epiretinal membranes from 17 patients with PDR were studied by immunohistochemistry. Rats were made diabetic with a single high dose of streptozotocin and retinas of rats were examined by Western blot analysis. Western blot analysis revealed a significant increase in the expression of NT-3 and NT-4 and the shedding of receptors TrkA and TrkB in vitreous samples from PDR patients compared to nondiabetic controls, whereas NGF and BDNF and the receptor TrkC were not detected with the use of Western blot analysis and ELISA. In epiretinal membranes, vascular endothelial cells and myofibroblasts expressed NT-3 and the receptors TrkA, TrkB and TrkC in situ, whereas NT-4 was not detected. The expression levels of NT-3 and NT-4 and the receptors TrkA and TrkB, both in intact and solubilized forms, were upregulated in the retinas of diabetic rats, whereas the receptor TrkC was not detected. Co-immunoprecipitation studies revealed binding between NT-3 and the receptors TrkA and TrkB in the retinas of diabetic rats. Our findings in diabetic eyes from humans and rats suggest that the increased expression levels within the NT-3 and NT-4/Trk axis are associated with the progression of PDR.     

The Effects of Pleiotrophin in Proliferative Diabetic Retinopathy

Pleiotrophin (PTN), a secreted, multifunctional cytokine, is involved in angiogenic, fibrotic and neurodegenerative diseases. However, little is known about its effects on diabetic retinopathy, a neurovascular disease. To investigate the role of PTN in proliferative diabetic retinopathy (PDR), PTN concentration in the vitreous was evaluated in PDR patients and non-diabetic controls. PTN expression was observed in epiretinal membranes from patients. PTN knockdown was performed using small interfering (si)RNA, and the effects on retinal pigment epithelium (RPE) cells and human umbilical vascular endothelia cells (HUVECs) were observed in vitro under hyperglycemic and hypoxic conditions. Cell attachment, proliferation, migration, tube formation, cell cycle, apoptosis, extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation, and VEGF levels were studied. The vitreous PTN concentration in PDR patients was higher than that in non-diabetic controls, and PTN was highly expressed in the fibrovascular membranes of PDR patients. Under hyperglycemic and hypoxic conditions, PTN knockdown reduced cell attachment, proliferation, migration, and tube formation and induced cell cycle arrest and apoptosis in vitro. Mechanically, PTN depletion decreased ERK 1/2 phosphorylation. Recombinant PTN up regulated the concentration of VEGF in vitro, which can be attenuated by the ERK 1/2 inhibitor. Taken together, our results implied that elevated PTN in PDR patients might participate in the critical processes of the development of PDR, most likely playing roles in angiogenesis and proliferation, possibly by activating the ERK 1/2 pathway and regulating VEGF secretion. These findings provide new insight into the roles of PTN in PDR and suggest that PTN may become a new target for therapeutic intervention in PDR.     

玻璃体切割联合硅油注入治疗增殖型糖尿病视网膜病变的术后护理

目的:玻璃体切割联合硅油注入治疗增殖型糖尿病视网膜病变的术后护理的临床效应。方法:对88例增殖型糖尿病视网膜病变患者采用玻璃体切割联合硅油注入术后的护理,针对糖尿病病人的特点及硅油注入的特殊要求提出术后严密观察眼部情况,控制血糖、保持特殊体位、预防眼压升高等并发症。结果:手术后患者视力均有不同程度提高,对玻璃体切割联合硅油注入术使许多糖尿病病人加强术后护理,有助于恢复患者的有用视力、提高手术效果的临床效应,提高生存质量。结论:针对糖尿病病人的特点,在围手术期做好周密的护理,对于提高手术疗效是十分重要的。     

玻璃体切割联合硅油注入治疗增殖型糖尿病视网膜病变的术后护理

目的：玻璃体切割联合硅油注入治疗增殖型糖尿病视网膜病变的术后护理的临床效应。方法：对88例增殖型糖尿病视网膜病变患者采用玻璃体切割联合硅油注入术后的护理,针对糖尿病病人的特点及硅油注入的特殊要求提出术后严密观察眼部情况,控制血糖、保持特殊体位、预防眼压升高等并发症。结果：手术后患者视力均有不同程度提高,对玻璃体切割联合硅油注入术使许多糖尿病病人加强术后护理,有助于恢复患者的有用视力、提高手术效果的临床效应,提高生存质量。结论：针对糖尿病病人的特点,在围手术期做好周密的护理,对于提高手术疗效是十分重要的。     

Chronic Kidney Disease and Diabetic Retinopathy in Patients with Type 2 Diabetes

Purpose

To explore the relationship between chronic kidney disease (CKD) and diabetic retinopathy (DR) in a representative population of type 2 diabetes mellitus (DM2) patients in Catalonia (Spain).

Methods

This was a population-based, cross-sectional study. A total of 28,344 patients diagnosed with DM2 who had recorded ophthalmologic and renal functional examinations were evaluated. Data were obtained from a primary healthcare electronic database of medical records. CKD was defined as an estimated glomerular filtration ratio (eGFR) of <60 ml/min/1.73m² and/or urine albumin to creatinine ratio (UACR) ≥30 mg/g. DR was categorized as non-vision threatening diabetic retinopathy and vision threatening diabetic retinopathy.

Results

CKD was associated with a higher rate of DR [OR], 95% confidence interval [CI], 1.5 (1.4–1.7). When we analyzed the association between different levels of UACR and DR prevalence observed that DR prevalence rose with the increase of UACR levels, and this association was significant from UACR values ≥10 mg/g, and increased considerably with UACR values ≥300mg/g (Odds ratio [OR], 95% confidence interval [CI], 2.0 (1.6–2.5). This association was lower in patients with eGFR levels 44 to 30 mL/min/1.73m² [OR], 95% confidence interval [CI], 1.3 (1.1–1.6).

Conclusions

These results show that CKD, high UACR and/or low eGFR, appear to be associated with DR in this DM2 population.     

Comparison of Combined and Sequential Surgery for Proliferative Diabetic Retinopathy: A Single Surgeon Study

Purpose

To compare the results of combined and consecutive surgeries to treat proliferative diabetic retinopathy and cataract.

Methods

Retrospective comparative study. Forty-one patients with proliferative diabetic retinopathy (PDR) were enrolled. Twenty-nine eyes for the combined surgery group and twelve eyes for the sequential group were included. All surgeries were performed by one surgeon. Phacoemulsification was performed using a clear cornea incision. The vitrectomy was performed using a 20-gauge vitreous cutter.

Results

The best corrected visual acuity (BCVA) and intra- and post-operative complications were the main outcome measures. In the combined surgery group, the BCVA increased in 18 (62.1%) eyes, while eight (27.6%) eyes remained stable and three (10.3%) eyes decreased. Postoperative complications included fibrinous exudation in nine eyes, macular edema in three eyes and vitreous hemorrhage in three eyes. In the sequential surgery group, the BCVA increased in seven (58.3%) eyes, remained the same in four (33.3%) eyes and was reduced in one (8.3%) eye. Postoperative complications included macular edema in two eyes, neovascular glaucoma in two eyes and vitreous hemorrhage in one eye.

Conclusions

Both combined and sequential surgeries are safe and effective for treating PDR and cataracts. The combined surgery had a higher incidence of fibrinous exudation.     

High Prevalence of Diabetic Retinopathy in Diabetic Patients Concomitant with Metabolic Syndrome

Objective

To evaluate the relationship between metabolic syndrome (MetS) and the prevalence of diabetic retinopathy (DR).

Research Design and Methods

We conducted a case-controlled study, with data obtained from 2,551 Chinese participants between 18–79 years of age (representing a population of 1,660,500 in a district of Beijing). 74 cases of DR were found following data assessment by two 45° digital retinal images. Subjects without DR (NDR group) selected from the remaining 2,477 subjects were matched 1:1 to the DR group by HbA1c. MetS was defined by incorporating diagnostic criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) and the International Diabetes Federation (IDF).

Results

There were no statistical differences between the DR group and NDR group in a number of biological or laboratory tests. However, the percentage of patients with DR increased vs. patients without DR with the number of MetS components from 1 to 5 (14.3% vs. 85.7%, 38.9% vs. 61.1%, 49.1% vs. 50.9%, 61.4% vs. 38.6% and 83.3% vs. 16.7%, respectively) (Pearson χ² = 9.938, P = 0.037). The trend to develop DR with MetS was significantly higher than that without MetS (NMetS) (χ² = 5.540, P = 0.019). MetS was an independent statistical indicator of the presence of DR after adjusting for age and sex [odds ratio (95% CI): 2.701(1.248–5.849), P = 0.012], which is still the case with an additional adjustment for WC, SBP, TC, HbA1c and duration of diabetes [odds ratio (95% CI): 2.948(1.134–7.664), P = 0.027].

Conclusion

DR is one of the diabetic microvascular complications. Apart from poor glycemic control, the concomitance of other metabolic factors can also influence DR. MetS, defined as a cluster of metabolic risk factors, is a strong and independent indicator of DR, even to the same extent as glycemic control.     

Diabetic Retinopathy,Classified Using the Lesion-Aware Deep Learning System,Predicts Diabetic End-Stage Renal Disease in Chinese Patients

Objective: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD).Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study severity scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD.Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval 1.05 to 4.53, P = .04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% of patients with mild retinopathy and severe glomerular lesions had higher low-density lipo-protein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions.Conclusion: Although the severity of DR predicted diabetic ESRD in patients with type 2 diabetes mellitus and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria.Abbreviations: CI = confidence interval; DM = diabetic mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = hemoglobin A1c; HR = hazard ratio; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; VEGF = vascular endothelial growth factor     

Potential Role of Endoplasmic Reticulum Stress in Pathogenesis of Diabetic Retinopathy

Diabetes mellitus is a metabolic disease that leads to several complications which include retinopathy. Multiple biochemical abnormalities have been proposed to explain the development of retinopathy, including oxidative stress. Although the existence of oxidative stress has been established in the retina from long standing diabetic animals, pathogenesis and progression of retinopathy remain unclear. In order to gain insight into the pathogenesis of diabetic retinopathy, we analyzed the levels of different oxidative stress biomarkers in the retina at early stages during the progress of streptozotocin-induced diabetes. No significant changes in glutathione content, expression of NADPH-oxidase, levels of lipid peroxidation, nor production of free radicals were observed in the retina up to 45 days of diabetes induction. Likewise, a transient decrease in aconitase activity, parallel to an increase in the superoxide dismutase activity was observed at 20 days of hyperglycemia, suggesting a high capacity of retina to maintain its redox homeostasis, at least at early stages of diabetes. Nonetheless, we found an early and time-dependent increase in the levels of oxidized proteins, which was not affected by the administration of the antioxidant quercetin. Also, positive immunoreactivity to the reticulum stress protein CHOP was found in glial Müller cells of diabetic rat retinas. These findings suggest the occurrence of endoplasmic reticulum stress as a primary event in retina pathogenesis in diabetes.     

Retinitis Pigmentosa Reduces the Risk of Proliferative Diabetic Retinopathy: A Nationwide Population-Based Cohort Study

Purpose

To study the association between retinitis pigmentosa (RP) and the progression of diabetic retinopathy (DR).

Methods

Using the Longitudinal Health Insurance Database 2000 of Taiwan, we identified individuals with an initial diagnosis for RP during the period of 1997–2008. A non-RP comparison group, 10-fold frequency matched by sex, age, index year and the year of diabetes diagnosed, were randomly selected from the same database. The occurrence of DR was observed for all subjects until the end of 2009. The Kaplan-Meier curves were used to illustrate the cumulative probability of developing DR for the RP group and comparison groups. The hazard ratio (HR) of DR for the RP group relative to the comparison group was estimated using Cox proportional hazards model after adjusting for potential confounders.

Results

The Kaplan-Meier curves were not statistically significant different between the RP group and the comparison group. However, the RP group had a higher cumulative probability of developing DR during the first six to seven years. The cumulative probability kept increasing and became higher in the comparison group but remained unchanged in the RP group. The HR for the RP patients comparing with the comparison group was 0.96 (95% confidence interval (CI) = 0.43–2.14). Stratified by severity, RP was associated with a non-statistically significant reduced risk of proliferative DR (PDR) (HR = 0.70, 95% CI = 0.16–3.14). The HR for non-proliferative DR (NPDR) was 1.08 (95% CI = 0.40–2.86).

Conclusion

In this study, RP was not statistically significant associated with the incidence of DR.     

Regenerative Therapeutic Potential of Adipose Stromal Cells in Early Stage Diabetic Retinopathy

Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Early stage DR involves inflammation, vascular leakage, apoptosis of vascular cells and neurodegeneration. In this study, we hypothesized that cells derived from the stromal fraction of adipose tissue (ASC) could therapeutically rescue early stage DR features. Streptozotocin (STZ) induced diabetic athymic nude rats received single intravitreal injection of human ASC into one eye and saline into the other eye. Two months post onset of diabetes, administration of ASC significantly improved “b” wave amplitude (as measured by electroretinogram) within 1–3 weeks of injection compared to saline treated diabetic eyes. Subsequently, retinal histopathological evaluation revealed a significant decrease in vascular leakage and apoptotic cells around the retinal vessels in the diabetic eyes that received ASC compared to the eyes that received saline injection. In addition, molecular analyses have shown down-regulation in inflammatory gene expression in diabetic retina that received ASC compared to eyes that received saline. Interestingly, ASC were found to be localized near retinal vessels at higher densities than seen in age matched non-diabetic retina that received ASC. In vitro, ASC displayed sustained proliferation and decreased apoptosis under hyperglycemic stress. In addition, ASC in co-culture with retinal endothelial cells enhance endothelial survival and collaborate to form vascular networks. Taken together, our findings suggest that ASC are able to rescue the neural retina from hyperglycemia-induced degeneration, resulting in importantly improved visual function. Our pre-clinical studies support the translational development of adipose stem cell-based therapy for DR to address both retinal capillary and neurodegeneration.