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Pathophysiology of Diabetic Retinopathy  [PDF]
Joanna M. Tarr,Kirti Kaul,Mohit Chopra,Eva M. Kohner,Rakesh Chibber
ISRN Ophthalmology , 2013, DOI: 10.1155/2013/343560
Abstract: Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids. Although landmark cross-sectional studies have confirmed the strong relationship between chronic hyperglycaemia and the development and progression of diabetic retinopathy, the underlying mechanism of how hyperglycaemia causes retinal microvascular damage remains unclear. Continued research worldwide has focussed on understanding the pathogenic mechanisms with the ultimate goal to prevent DR. The aim of this paper is to introduce the multiple interconnecting biochemical pathways that have been proposed and tested as key contributors in the development of DR, namely, increased polyol pathway, activation of protein kinase C (PKC), increased expression of growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), haemodynamic changes, accelerated formation of advanced glycation endproducts (AGEs), oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and subclinical inflammation and capillary occlusion. New pharmacological therapies based on some of these underlying pathogenic mechanisms are also discussed. 1. Introduction With diabetes now recognised as a global epidemic, the incidence of retinopathy, a common microvascular complication of diabetes, is expected to rise to alarming levels. Diabetic retinopathy is classified into nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), characterised by the growth of new blood vessels (retinal neovascularization). NPDR is further divided into mild, moderate, and severe stages that may or may not involve the development of a macula diabetic macular oedema (DMO) [1]. The major causes of severe visual impairment are PDR and DMO. Nearly all patients with Type 1 diabetes and >60% of patients with Type 2 diabetes are expected to have some form of retinopathy by the first decade of incidence of diabetes [2, 3]. The risk of developing diabetic retinopathy can be reduced by early detection, timely tight control of blood glucose, blood pressure, and possibly lipids; however, clinically this is difficult to achieve. Laser photocoagulation
Therapeutic Interventions against Inflammatory and Angiogenic Mediators in Proliferative Diabetic Retinopathy  [PDF]
Daniel Gologorsky,Aristomenis Thanos,Demetrios Vavvas
Mediators of Inflammation , 2012, DOI: 10.1155/2012/629452
Abstract: The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy. 1. Introduction The global prevalence of diabetes is estimated to be 336 million people, and this number is projected to nearly double by 2030 [1, 2]. In addition to the primary disease itself, diabetic complications are expected to have profound implications for the future of patient management. Diabetes is a disease of hyperglycemia, and diabetic retinopathy (DR) results from cumulative microvascular damage to the retina. According to the World Health Organization, DR accounts for approximately 5% of global blindness [3]. Inflammation is a critical driver of the pathophysiology of DR [4]. This paper highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of DR and features specific and targeted therapeutic modalities to combat retinopathy. 2. Pathways to Damage Two major studies, the Diabetes Control and Complications Trial (DCCT) of 1993 and the United Kingdom Prospective Diabetes Study (UKPDS) of 1998, have demonstrated that hyperglycemia is the causative etiology for DR [5, 6]. Hyperglycemia causes microvascular changes, that in turn results in retinopathy. At least four distinct biochemical pathways have been suggested for the mechanism leading to retinopathy. These include increased polyol pathway flux, increased advanced glycation end product (AGE) formation, activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway flux. Taken together, these pathways result in oxidative stresses and inflammation that attenuate vascular wall integrity and result in increased vascular permeability, occlusion, and ischemia [7, 8]. These types of microvascular insults manifest in increased vascular leakage, as in nonproliferative retinopathy (NPDR), and retinal neovascularization secondary to ischemia, as in proliferative retinopathy (PDR) [9, 10]. There is increasing evidence that inflammation has a central role in the
Oxidative Stress and Diabetic Retinopathy  [PDF]
Renu A. Kowluru,Pooi-See Chan
Experimental Diabetes Research , 2007, DOI: 10.1155/2007/43603
Abstract: Oxygen metabolism is essential for sustaining aerobic life, and normal cellular homeostasis works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system, is implicated in the development of many diseases, including Alzheimer's disease, and diabetes and its complications. Retinopathy, a debilitating microvascular complication of diabetes, is the leading cause of acquired blindness in developed countries. Many diabetes-induced metabolic abnormalities are implicated in its development, and appear to be influenced by elevated oxidative stress; however the exact mechanism of its development remains elusive. Increased superoxide concentration is considered as a causal link between elevated glucose and the other metabolic abnormalities important in the pathogenesis of diabetic complications. Animal studies have shown that antioxidants have beneficial effects on the development of retinopathy, but the results from very limited clinical trials are somewhat ambiguous. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.
Cellular Signaling and Potential New Treatment Targets in Diabetic Retinopathy  [PDF]
Zia A. Khan,Subrata Chakrabarti
Experimental Diabetes Research , 2007, DOI: 10.1155/2007/31867
Abstract: Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-κB and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.
Management of diabetic retinopathy
Saxena Sandeep,Jalali Subhadra,Meredith Travis,Holekamp Nancy
Indian Journal of Ophthalmology , 2000,
Abstract: Diabetic retinopathy remains a major cause of blindness despite increased understanding of this disease and identification of successful treatments. The Diabetic Retinopathy Study identified risk factors associated with a high risk of blindness and confirmed the benefits of panretinal photocoagulation. The Early Treatment Diabetic Retinopathy Study defined the retinal characteristics, indications of treatment and results of laser treatment of clinically significant macular oedema. The Diabetic Retinopathy Vitrectomy study established the benefits and timing of vitrectomy for non-clearing vitreous haemorrhage and severe proliferative diabetic retinopathy. The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have also demonstrated the value of tight control of blood sugar and blood pressure in diabetic retinopathy. These studies developed specific recommendations for the management of diabetic retinopathy. Optimum use of this information can minimize visual loss due to diabetic retinopathy.
Effects of curcumin on retinal oxidative stress and inflammation in diabetes
Renu A Kowluru, Mamta Kanwar
Nutrition & Metabolism , 2007, DOI: 10.1186/1743-7075-4-8
Abstract: A group of streptozotocin-induced diabetic rats received powdered diet supplemented with 0.05% curcumin (w/w), and another group received diet without curcumin. The diets were initiated soon after induction of diabetes, and the rats were sacrificed 6 weeks after induction of diabetes. The retina was used to quantify oxidative stress and pro-inflammatory markers.Antioxidant capacity and the levels of intracellular antioxidant, GSH (reduced form of glutathione) levels were decreased by about 30–35%, and oxidatively modified DNA (8-OHdG) and nitrotyrosine were increased by 60–70% in the retina of diabetic rats. The levels of interleukin-1β (IL-1β) and vascular endothelial growth factor (VEGF) were elevated by 30% and 110% respectively, and the nuclear transcription factor (NF-kB) was activated by 2 fold. Curcumin administration prevented diabetes-induced decrease in the antioxidant capacity, and increase in 8-OHdG and nitrotyrosine; however, it had only partial beneficial effect on retinal GSH. Curcumin also inhibited diabetes-induced elevation in the levels of IL-1β, VEGF and NF-kB. The effects of curcumin were achieved without amelioration of the severity of hyperglycemia.Thus, the beneficial effects of curcumin on the metabolic abnormalities postulated to be important in the development of diabetic retinopathy suggest that curcumin could have potential benefits in inhibiting the development of retinopathy in diabetic patients.Diabetic retinopathy is the main cause of acquired blindness in working adults. Abnormalities in retinal metabolism, including elevated polyol pathway activity, increased nonenzymatic glycation and advanced glycation end products, oxidative stress, protein kinase C (PKC) activity [1-5], evidently contribute to the development of retinopathy, but the exact mechanism is still elusive. In diabetes the retina experiences increased oxidative stress [4,6-8], and reactive oxygen species (ROS) are considered as a causal link between elevated glucose an
Genes and diabetic retinopathy.  [cached]
Radha Venkatesan,Rema Mohan,Mohan Viswanathan
Indian Journal of Ophthalmology , 2002,
Abstract: Several recent studies have provided evidence that good diabetes control is important to prevent diabetic retinopathy. However, some groups of patients develop diabetic retinopathy despite good control and others escape retinopathy despite poor control. This suggests the role of genetic factors in susceptibility to retinopathy. This article reviews the role of genetic factors in determining diabetic retinopathy.
Plasma prostaglandin and diabetic retinopathy  [cached]
Maurya OPS,Singh R,Bhattacharya S,Agarwal J
Indian Journal of Ophthalmology , 1987,
Abstract: Estimation of prostaglandin El (PGE) levels by bioassay technique (Ritcher Crossland) was carried out in 15 normal persons, 15 diabetic patients without Retinopathy, and 30 diabetic patients with Retinopathy. Plasma PGE 1 values were higher in diabetic patients with or without retinopathy than in normal subjects Plasma PGE 1 levels were significantly higher in diabetic with retinopathy than in the control group (p < 0.001), whereas in diabetics without retinopathy the PGE levels did not show a statistically significant difference from controls In diabetic patients with retinopathy, the mean value of PGE 1 was higher in proliferative retinopathy than in background retinopathy, but on statistical analysis, it was not of much significane (P> 0.8).
Risk factors and diabetic retinopathy  [PDF]
Admira Dizdarevi?,Amila Alikadi?-Husovi?,Vahid Jusufovi?
Medicinski Glasnik , 2012,
Abstract: The aim of the study was to determine the correlation between risk factors and diabetic retinopathy, which is the leading cause of blindness in developed countries for patients aged 20 to 65.We compared risk factors between patients without retinopathy, with non-proliferate and with proliferate retinopathy (p< 0.05). Duration of diabetes is most important for the development of retinopathy. Hyperglycaemia and high blood pressure are important for progression. Better control of blood sugar and elevated blood pressure can reduce progression of retinopathy and riskof vision loss.
Iron Overload in Diabetic Retinopathy: A Cause or a Consequence of Impaired Mechanisms?  [PDF]
Andreea Ciudin,Cristina Hernández,Rafael Simó
Journal of Diabetes Research , 2010, DOI: 10.1155/2010/714108
Abstract: Iron is an essential ion for life, playing a central role in many metabolic processes. The most important property of free iron is its capacity to be reversibly oxidized and reduced, but at same time this make it highly pro-oxidant molecule. In this regard, iron is able to generate powerful reactive oxygen species (ROS). For this reason, careful control on iron availability is central to the maintenance of normal cell function in the retina. In the diabetic eye there is an impairment of iron homeostasis, thus leading to iron overload. The mechanisms involved in this process include: (1) Destruction of heme molecules induced by hyperglycemia (2) Intraretinal and vitreal hemorrhages (3) Overexpression of the renin-angiotensin system. The main consequences of iron overload are the following: (1) Retinal neurodegeneration due to the increase of oxidative stress (2) Increase of AGE-RAGE binding (3) Defective phagocytosis of retinal pigment epithelium, which generates the accumulation of autoantigens and the synthesis of proinflammatory cytokines. Further studies addressed to explore not only the role of iron in the pathogenesis of diabetic retinopathy, but also to design novel therapeutic strategies based on the regulation of iron homeostasis are needed. 1. Introduction Diabetic retinopathy (DR) is the leading cause of blindness in working-age individuals in developed countries [1]. DR classically has been considered as a microcirculatory disease of the retina due to the deletereous metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia on retinal capillaries [2]. In recent years, evidence has emerged showing that retinal neurodegeneration is an early event in DR and is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination [3–7]. However, this subject is still controversial, since not all of the studies evidence retinal neurodegeneration in the diabetic retina [8]. Alterations contributing to oxidative stress and downregulation of antioxidative enzymes play an important role in the pathogenesis of DR [9, 10]. Oxidative stress is considered to be one of the crucial contributors to the pathogenesis of DR and it is highly interrelated with other biochemical imbalances (i.e., increase in the polyol, PKC, hexosamine, and advanced glycation end-products [AGEs] pathways), that lead to structural and functional changes such as accelerated loss of capillary cells in the retinal microvasculature, increased vascular permeability, and increased VEGF formation [9–13]. Iron is an
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