Role of endocannabinoids in the progression of diabetic retinopathy

In the past decades, the role of numerous factors in the pathophysiology of diabetic retinopathy has been explored, following which marked progress has been made in developing several novel therapeutic options, such as anti‐vascular endothelial growth factor, anti‐tumor necrosis factor‐alpha and various other anti‐inflammatory and anti‐angiogenic agents, for the treatment of diabetic retinopathy. However, the involvement of endocannabinoid system in its pathogenesis has not been much explored. This review aims at unveiling every aspect of association of the endocannabinoid system and its interactions with various physiological and pathological pathways to induce disease progression. The various alterations induced by endocannabinoids, such as anandamide and 2‐arachidonylglycerol, in retina during hyperglycaemia clearly demonstrate and verify their involvement in aggravating the pathological conditions, hence leading to the progression of diabetic retinopathy. Exploring this involvement furthermore, in greater depths, might be beneficial in acknowledging and understanding the hidden aspects of the pathogenesis of this complication even better and might provide a therapeutically beneficial alternative target to combat and restrict its progression amongst diabetic patients. Copyright © 2015 John Wiley & Sons, Ltd.     

Screening for diabetic retinopathy: the utility of nonmydriatic retinal photography in Egyptian adults

Although regular screening for diabetic retinopathy with ophthalmoscopy or retinal photography is widely recommended in the United States and Europe, few reports of its use in developing countries are available. We compared the performance of screening by retinal photography with that of indirect ophthalmoscopy by using data from a population-based survey of diabetes and its complications in Egypt. During that project, 427 persons with diabetes underwent an eye examination and fundus photography with a non-mydriatic camera through a dilated pupil. Data from the examinations of the right eye of each patient are presented. Ninety-two (22 %) of the 427 retinal photographs were ungradable; in 58 eyes (63 %), this was due to media opacity (42 eyes with cataract, 3 with corneal opacity, and 13 with both). Agreement between retinal photography and indirect ophthalmoscopy was poor (kappa = 0.33; 95 % CI = 0.27–0.39) and primarily due to the large number of eyes (n = 79) with ungradable photographs that could be graded by ophthalmoscopy. None of these eyes was judged by ophthalmoscopy to have sight-threatening retinopathy. Fifty-four photographs were diagnosed with greater retinopathy than found on ophthalmoscopy. Retinal photography with the nonmydriatic camera through a dilated pupil is a useful method to screen for diabetic retinopathy in most adults in Egypt. However, such screening strategies have limited use in older persons and in persons with corneal disease or cataract. © 1998 John Wiley & Sons, Ltd.     

Netzhautkomplikationen bei Diabetes

In September 2015 a revised version of the guideline “Prevention and therapy of diabetes-induced retinal complications” was released in Germany. It summarizes current recommendations for diagnosis and therapy of diabetic retinopathy with a special focus on practicability in daily routine. Newly included were the use of optical coherence tomography (OCT) for the diagnosis of diabetic macular edema and the evaluation of the therapeutic effect of anti-VEGF drugs (VEGF: vascular endothelial growth factor) or corticosteroids after intravitreal drug delivery. Screening intervals for diabetic retinopathy were extended to every 2 years for all diabetic patients with no retinopathy and limited systemic risk factors. Patients with known risk factors should be screened annually or in case of retinopathy, followed-up as recommended by the ophthalmologist.     

Surgery for Diabetic Eye Complications

New modalities for the treatment of diabetic eye complications have emerged in the past decade. Nevertheless, many severe diabetic retinopathy complications can only be treated with vitreoretinal surgery. Technological advances in pars plana vitrectomy have expanded the gamut of pathologies that can be successfully treated with surgery. The most common pathologies managed surgically include vitreous opacities and traction retinal detachment. The indications, surgical objectives, adjunctive pharmacotherapy, microincisional surgical techniques, and outcomes of diabetic vitrectomy for proliferative diabetic retinopathy and diabetic tractional retinal detachment will be discussed. With the availability of new microincisional vitrectomy technology, wide angle microscope viewing systems, and pharmacologic agents, vitrectomy can improve visual acuity and achieve long-term anatomic stability in eyes with severe complications from proliferative diabetic retinopathy.     

Fenofibrate and Diabetic Retinopathy

Diabetic retinopathy, a common and sight-threatening microvascular complication of diabetes mellitus, is a leading cause of blindness among working-aged adults. Medical therapies including intensive control of hyperglycemia and hypertension have been shown to reduce the incidence and progression of diabetic retinopathy. The association of dyslipidemia and treatment with statins with diabetic retinopathy is inconsistent in epidemiologic studies. However, two recent randomized clinical trials have demonstrated beneficial effects of systemic fenofibrate therapy in reducing the progression of diabetic retinopathy independently of serum lipid levels. These findings suggest that fenofibrate may be an effective strategy for reducing the progression of diabetic retinopathy, thus reducing the large and growing public health burden of treating the sight-threatening complications of diabetic retinopathy.     

A Protocol for Screening for Diabetic Retinopathy in Europe

Diabetic eye complications, and particularly diabetic retinopathy, are the major cause of blindness in the working age groups of industrialized countries. Laser photocoagulation has been proven to reduce blindness due to retinopathy by at least 60 % but even more patients would benefit if treatment were delivered at an early enough stage. High-risk retinopathy, though, may not cause visual symptoms, and when the latter occur it is often too late to reverse them. Hence, a screening programme for diabetic retinopathy should aim at detecting patients at risk when they can still be effectively treated. This can be achieved by regularly checking the patients' eyes. The screening programme's target, as defined by the joint World Health Organization/International Diabetes Federation Saint Vincent Declaration Working Group, is to reduce diabetes-related blindness by one-third or more in the next 5 years. The number of individuals to be screened is high, 30000 per million total population per year, but available data indicate that this is feasible and that the initial investments in professional and material resources are more than justified by the reduction of preventable blindness and of the financial burdens that go with it. Indeed, prevention of the major cause of blindness in the working age group should rate the same priority as other widely deployed programmes, such as those to screen for cancer, neonatal hypothyroidism, and phenylketonuria. The concerted action of government health departments, patients' and professional associations will be vital for the successful implementation of this programme. The texts of this document (a protocol for the screening of diabetic retinopathy and cataract), Appendix 1 (information leaflet for the patients), and Appendix 2 (data collection card) were approved by 57 specialists, representing 30 diabetic and ophthalmic societies from 21 European countries, and endorsed for translation into all European languages and distribution at the appropriate levels.     

Smoking and diabetes

The frequency of smoking in diabetic patients is not appreciably different from that in the general population. As in non-diabetic subjects, smoking is a major cardiovascular risk factor in diabetic patients. For young diabetic patients, smoking has been identified as a risk for macroproteinuric nephropathy. In respect of retinopathy, study results are more controversial. Recent studies also suggest smoking as a risk indicator for extra-articular connective tissue changes and neuropathy. Patients who already present with vascular complications, pregnant women, and women who use oral contraceptive drugs appear to run a particularly high risk by smoking. Stopping smoking reduces the risk of vascular morbidity and mortality in non-diabetic subjects. Although no comparable studies are available for diabetic populations, it should be assumed that the beneficial effects of stopping smoking are applicable to diabetic patients as well. Programmes to encourage diabetic patients to stop smoking are scarce and have not been successful.     

Detection of diabetic retinopathy in the community using a non-mydriatic camera.

The role of the non-mydriatic fundus camera in detection of diabetic retinopathy was evaluated as part of a comprehensive screening programme for diabetic complications offered to all diabetic patients in a rural town. Retinopathy was demonstrated in 124/358 (35%) of patients screened. Forty-eight patients (13%) were judged to have sight-threatening retinopathy, of whom 29 patients (8% of the total) were not already under the care of an ophthalmologist. However, in only 66% of patients were photographs of both eyes of adequate quality to assess for retinopathy. The percentage of poor quality photographs increased with age in those aged greater than 50 years. It is concluded that the non-mydriatic camera can increase the detection of sight-threatening retinopathy in the community. Although this method of screening is not perfect, because of the number of poor quality photographs, it may be as good as or better than existing screening practices in unselected diabetic populations.     

A lethal tetrad in diabetes: hyperglycemia, dyslipidemia, oxidative stress, and endothelial dysfunction

This paper addresses the consequences of diabetes and obesity, diseases that have become epidemic in our society, particularly in the past 20 years. Specifically, it summarizes current knowledge about some of the risk factors and mechanisms for the vascular complications of diabetes. These complications can be broadly divided into microvascular disease, such as diabetic retinopathy and diabetic nephropathy, and macrovascular disease, such as accelerated atherosclerosis, and they are the main cause for morbidity and premature mortality among diabetic patients. The roles of hyperglycemia, dyslipidemia and dyslipoproteinemia, oxidative stress, and endothelial dysfunction will be considered. Finally, the "treatment gap" will be addressed. This gap refers to our failure to achieve currently accepted goals to reduce established risk factors for complications in the clinical management of diabetic patients.     

Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy.

AIMS: To investigate the relationship of aqueous macrophage migration inhibitory factor (MIF) and monocyte chemotactic protein-1 (MCP-1) levels with the clinical stage of diabetic retinopathy. METHODS: We assayed MIF and MCP-1 levels in aqueous humour samples obtained from 40 diabetic patients (49 eyes) and 24 non-diabetic patients (31 eyes) using enzyme-linked immunosorbent assay. According to the clinical stage of diabetic retinopathy, the diabetic patients were classified into non-diabetic retinopathy (11 eyes), non-proliferative diabetic retinopathy (14 eyes) and proliferative diabetic retinopathy (24 eyes). RESULTS: The aqueous levels of MIF (mean +/- sd) were 6.34 +/- 4.53 ng/ml in proliferative diabetic retinopathy, 3.22 +/- 1.71 ng/ml in non proliferative diabetic retinopathy, 1.25 +/- 0.96 ng/ml in non-diabetic retinopathy and 1.07 +/- 0.94 ng/ml in non-diabetic patients. Significant differences were found among these four groups (P < 0.0001). Aqueous MCP-1 levels were 1668.6 +/- 1442.3 pg/ml in proliferative diabetic retinopathy, 1528.6 +/- 1994.6 pg/ml in non-proliferative diabetic retinopathy, 690.2 +/- 402.1 pg/ml in non-diabetic retinopathy and 622.7 +/- 245.3 pg/ml in non-diabetic patients. Significant differences were also found among these four groups (P < 0.0001). After correcting for total aqueous protein, the ratios of MIF and MCP-1 to total protein remained significantly correlated with the clinical stage of diabetic retinopathy (P < 0.0001, P = 0.0004, respectively). The ratios of MIF to total protein significantly correlated with the ratios of MCP-1 to total protein in diabetic patients (r = 0.680, P < 0.0001). CONCLUSIONS: Aqueous MIF levels significantly correlated with aqueous MCP-1 levels and the clinical stage of diabetic retinopathy. The results suggest that MIF has a co-operative role with MCP-1 in the progression of diabetic retinopathy.     

Progression of diabetic nephropathy enhances the plasma osteopontin level in type 2 diabetic patients

Osteopontin (OPN) is thought to play multiple roles in the progression of atherosclerotic plaque including diabetic vascular complications. However, it still remains unclear whether the level of OPN in vivo is indeed clinically associated with the progression of diabetic complications. This study evaluated whether the levels of OPN in plasma and urine are correlated with the progression of diabetic complications, such as retinopathy, neuropathy, and nephropathy in patients with type 2 diabetes. In 229 patients with type 2 diabetes, OPN level in plasma and urine was evaluated by both the severity of diabetic complications, such as retinopathy, neuropathy, and nephropathy, and the clinical characteristics and the substantial laboratory findings. Plasma OPN level increased significantly with aging and the progression of diabetic nephropathy, especially at the stage of renal failure (p<0.05). However, the level was not related to the progression of retinopathy or neuropathy, or to laboratory findings, such as HbA1c or serum lipids. In contrast, urinary OPN level was not associated with diabetic complications in any of the subjects. There was no correlation between the plasma and urinary values of OPN. The results established that the plasma OPN was elevated in proportion to the progression of diabetic nephropathy, indicating that the plasma concentration may be a potential diagnostic predictor of diabetic end-stage renal disease.     

Recent advances in diabetic retinopathy

Despite the fact that we still do not understand what causes the development of retinopathy in diabetic subjects, major advances in its treatment have taken place. Photocoagulation clearly reduces the development of severe visual loss in eyes with proliferative diabetic retinopathy although how early treatment should be initiated has not been clearly defined. Vitrectomy is capable of restoring vision in many already blind eyes but at some risk. We are inching closer to an understanding of the pathophysiology of retinopathy with development of retinal endothelial and pericyte cell-culture techniques, studies of vascular permeability, flow and angiogenesis. Diabetic retinopathy is more common at early durations of diabetes than previously realized. This may allow for prospective intervention studies, using development of retinopathy as an endpoint. Diabetic retinopathy may be a reasonable index of short-term survival.     

The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy

Diabetic retinopathy is one of the most common complications of diabetes and is a major cause of new blindness in the working-age population of developed countries. While the exact pathogenic basis of this condition remains ill defined, it is clear that hyperglycaemia is a critical factor in its aetiology. Protein kinase C (PKC) activation is one of the sequelae of hyperglycaemia and it is thought to play an important role in the development of diabetic complications. This review questions the currently held dogma that PKC stimulation in diabetes is solely mediated through the overproduction of palmitate and oleate enriched diacylglycerols. Blood glucose concentrations are closely tracked by changes in the levels of free fatty acids and these, in addition to oxidative stress, may account for the aberrant activation of PKCs in diabetes. Little is known about why PKCs fail to downregulate in diabetes and efforts should be directed towards acquiring such information. Considerable evidence implicates the PKCbeta isoform in the pathogenesis of diabetic retinopathy, but other isoforms may also be of relevance. In addition to PKCs, it is evident that novel diacyglycerol-activated non-kinase receptors could also play a role in the development of diabetic complications. Therapeutic agents have been developed to inhibit specific PKC isoforms and PKCbeta antagonists are currently undergoing clinical trials to test their toxicity and efficacy in suppressing diabetic complications. The likely impact of these drugs in the treatment of diabetic patients is considered.     

彩超检查对糖尿病视网膜病变的临床诊断价值

目的探讨彩超检查对糖尿病性视网膜病变的诊断价值。方法彩色多普勒超声对68例2型糖尿病（DM）病人进行检查，观察并记录视网膜、玻璃体各种病理改变的位置、形态、程度、范围、活动度及视网膜中央动脉（CRA）、中央静脉（CRV）血流动力学变化情况，根据其改变的程度对观同腹埔变进行分期，许对严重增殖期手术病人进行术后结果对照证实。结果对尊尿病视网膜病变早期、增殖前期、增殖期能作出正确的分期判断。68例病人中38例（48只眼）严重增殖型视网膜病变（玻翟体登血、玻璃体机化物形成、视网膜脱离），行玻璃体视网膜切割手术，术后结果证实诊断符合率达98％。结论彩超检查糖屎病视网膜病变诊断率高，无创伤，无痛苦，可对病变进行兮期，对预后进行估测，为临床医生早期药物治疗和手术治疗的筛选提供可靠的诊断依据．     

Oxidative stress: A cause and therapeutic target of diabetic complications

Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti‐oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end‐products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8‐hydroxydeoxyguanosine (8‐OHdG), which reflects mitochondrial oxidative damage, and further reported that 8‐OHdG was elevated in subjects with diabetic micro‐ and macro‐ vascular complications. We recently created vascular endothelial cell‐specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia‐induced mtROS production by the induction of PPARγ coactivator‐1α (PGC‐1α) and MnSOD and/or activation of adenosine monophosphate (AMP)‐activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK–PGC‐1α pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00013.x, 2010)     

Prospects for angiotensin receptor blockers in diabetic retinopathy

Retinopathy is the most common microvascular complication of diabetes mellitus, and is an important cause of blindness worldwide. Clinical trials have demonstrated that tight metabolic control inhibits the progression of retinopathy. Good blood pressure control has been shown to be protective in type 2 diabetes, and it may also reduce proliferative retinopathy in type 1 diabetes. However, such control is often difficult to achieve in clinical practice, and may be associated with problems such as hypoglycaemia. New therapies are therefore needed to reduce the risk of retinopathy. There is growing evidence that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of diabetic retinopathy, and this has led to interest in RAS inhibitors as agents to prevent retinopathy. Several trials have suggested that ACE inhibitor therapy can inhibit progression of retinopathy. The Diabetic Retinopathy Candesartan Trials (DIRECT) Programme is currently investigating the effects of the angiotensin II receptor blocker candesartan on the incidence of retinopathy in type 1 diabetes and its progression in type 1 and type 2 diabetes. It is hoped that the results from such large-scale clinical trials will provide more specific information about the medical treatment of diabetic retinopathy.     

Use of Thrombolysis for Acute Myocardial Infarction in the Presence of Diabetic Retinopathy in the UK,and Associated Ocular Haemorrhagic Complications

Diabetic retinopathy is still regarded as a relative contraindication to the use of thrombolysis for myocardial infarction because of a perceived risk of intraocular haemorrhage. However, this complication has rarely been reported and the risk may be too small to justify withholding thrombolysis. A questionnaire survey was therefore conducted of members of the Medical and Scientific Section of the British Diabetic Association (BDA), to ascertain the exclusion criteria applied to the use of thrombolysis in patients with diabetic retinopathy in the UK and to identify any related ocular haemorrhagic complications. Replies were received from 128 physicians in 107 centres. Exclusion criteria applied were: any retinopathy 7 (5 %), proliferative retinopathy and recent vitreous or pre-retinal haemorrhage 74 (58 %), recent vitreous haemorrhage only 25 (20 %), thrombolysis given regardless of retinopathy 22 (17 %). No cases of intraocular haemorrhage following thrombolysis in diabetic myocardial infarction patients were identified. The risks of this complication appear to be very small and probably do not justify withholding thrombolytic therapy from diabetic patients with most forms of retinopathy, including proliferative.     

Lipids, lipid-lowering therapy and diabetes complications

Cardiovascular disease (CVD) remains the primary cause of morbidity and mortality in patients with diabetes. Lipid-lowering therapy (LLT) is often required, and statin drugs are usually the first-line therapy. However, even when LDL-cholesterol values are within the target range, a substantial residual risk persists. Fibrates may help to lower this risk, especially in patients with high triglyceride and low HDL-cholesterol levels, as suggested by the lipid ACCORD trial. Furthermore, they may even have beneficial effects on the development of microvascular complications such as nephropathy and especially retinopathy, as suggested by the results of the FIELD study. Data suggest benefit with fenofibrate on diabetic retinopathy, with significant effects on the requirement for first laser treatment and macular oedema. Fibrates, like statins, may act directly to decrease the progression of diabetic complications through their lipid-lowering effects, but may also go beyond that via pleiotropic effects. Recent data and the possible underlying mechanisms are analyzed in this review.     

Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy

Vascular endothelial growth factor (VEGF) plays a key role in the development of both proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DMO). In recent years, anti-VEGF agents have emerged as new approaches to the treatment of these devastating diabetic complications. Although Phase III studies in the diabetic population are needed, intravitreal anti-VEGF therapy is currently being used in clinical practice. Intravitreal injection is an effective means of delivering anti-VEGF drugs to the retina. However, this is an invasive procedure associated with potentially serious complications, such as endophthalmitis or retinal detachment, which may be significant for patients requiring serial treatment over many years. In addition, although delivered within the vitreous, anti-VEGF drugs could pass into the systemic circulation, which could potentially result in hypertension, proteinuria, increased cardiovascular events and impaired wound healing. Pegaptanib, ranibizumab and bevacizumab are the currently available anti-VEGF agents. Ranibizumab and bevacizumab block all VEGF isoforms, thus impairing both physiological and pathological neovascularisation. Pegaptanib only blocks the VEGF₁₆₅ isoform, and would therefore seem the best option for avoiding systemic adverse effects in diabetic patients, although this remains to be demonstrated in clinical trials. In this regard, head-to-head studies designed to evaluate not only the efficacy, but also the systemic adverse effects of these drugs in a high-risk population such as diabetic patients are warranted.