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Diabetic retinopathy pathology

Diabetic retinopathy pathology

The Diwbetic of thromboxane and prostacylin Diabetid platelet hyperactivity. Pathklogy mitochondrial superoxide overproduction activates the hexosamine pathway and induces Fat loss workouts activator inhibitor-1 expression by increasing Diabetic retinopathy pathology glycosylation. Artichoke weight loss tips BM Daibetic a diameter of affected vessels and facilitates capillary obliteration. One should look carefully for the presence of abnormal blood vessels on the iris [neovascularization of the iris NVI or rubeosis], cataract associated with diabetes and vitreous cells blood in the vitreous or pigmented cells if there is a retinal detachment with hole formation. Klein R Klein BE Moss SE Cruickshanks KJ. Chen YF, Oparil S. Diabetic retinopathy pathology

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Diabetes 20, Diabetic Retinopathy

Diabetic retinopathy pathology -

Diabetic retinopathy. Reducing your risks of diabetic macular edema. The risk of developing the eye condition can increase as a result of: Having diabetes for a long time Poor control of your blood sugar level High blood pressure High cholesterol Pregnancy Tobacco use Being Black, Hispanic or Native American.

Complications can lead to serious vision problems: Vitreous hemorrhage. Retinal detachment. The abnormal blood vessels associated with diabetic retinopathy stimulate the growth of scar tissue, which can pull the retina away from the back of the eye.

This can cause spots floating in your vision, flashes of light or severe vision loss. New blood vessels can grow in the front part of your eye iris and interfere with the normal flow of fluid out of the eye, causing pressure in the eye to build.

This pressure can damage the nerve that carries images from your eye to your brain optic nerve. Diabetic retinopathy, macular edema, glaucoma or a combination of these conditions can lead to complete vision loss, especially if the conditions are poorly managed.

If you have diabetes, reduce your risk of getting diabetic retinopathy by doing the following: Manage your diabetes. Make healthy eating and physical activity part of your daily routine. Try to get at least minutes of moderate aerobic activity, such as walking, each week.

Take oral diabetes medications or insulin as directed. Monitor your blood sugar level. You might need to check and record your blood sugar level several times a day — or more frequently if you're ill or under stress. Ask your doctor how often you need to test your blood sugar. Ask your doctor about a glycosylated hemoglobin test.

The glycosylated hemoglobin test, or hemoglobin A1C test, reflects your average blood sugar level for the two- to three-month period before the test. Keep your blood pressure and cholesterol under control.

Eating healthy foods, exercising regularly and losing excess weight can help. Sometimes medication is needed, too. If you smoke or use other types of tobacco, ask your doctor to help you quit. Smoking increases your risk of various diabetes complications, including diabetic retinopathy.

Pay attention to vision changes. Contact your eye doctor right away if your vision suddenly changes or becomes blurry, spotty or hazy. Does keeping a proper blood sugar level prevent diabetic macular edema and other eye problems?

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Norrin restores blood-retinal barrier properties after vascular endothelial growth factor-induced permeability. Simo-Servat, O. Usefulness of the vitreous fluid analysis in the translational research of diabetic retinopathy.

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Demircan, N. Determination of vitreous interleukin-1 IL-1 and tumour necrosis factor TNF levels in proliferative diabetic retinopathy. Eye 20 , — Koleva-Georgieva, D. Serum inflammatory cytokines IL-1β, IL-6, TNF-α and VEGF have influence on the development of diabetic retinopathy.

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PLoS ONE 4 , e Ogata, N. Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment. Aveleira, C. Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction.

Lin, C. Inhibition of atypical protein kinase C reduces inflammation-induced retinal vascular permeability. A proposal for early and personalized treatment of diabetic retinopathy based on clinical pathophysiology and molecular phenotyping. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin Year Medalist Study.

Diabetes Care 34 , — Praidou, A. Angiogenic growth factors and their inhibitors in diabetic retinopathy.

Diabetes Rev. Yokomizo, H. Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy. Garcia-Ramirez, M. Interphotoreceptor retinoid-binding protein IRBP is downregulated at early stages of diabetic retinopathy.

Diabetologia 52 , — Gao, B. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Clermont, A. Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats.

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Hypoxic retinal Muller cells promote vascular permeability by HIFdependent up-regulation of angiopoietin-like 4. USA , E—E Bouleti, C. Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke. Heart J. Cho, D. Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair.

JCI Insight 4 , e Cerani, A. Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin Cell Metab. Wang, X. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Kallenberg, D. A humanized antibody against LRG1 that inhibits angiogenesis and reduces retinal vascular leakage.

Article Google Scholar. Duraisamy, A. Epigenetics and regulation of oxidative stress in diabetic retinopathy. Kowluru, R. Diabetic retinopathy, metabolic memory and epigenetic modifications. Barber, A. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin.

Sohn, E. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. An integrated approach to diabetic retinopathy research. Lynch, S. Diabetic retinopathy is a neurodegenerative disorder. Miller, W.

Bogdanov, P. Topical administration of bosentan prevents retinal neurodegeneration in experimental diabetes. Santos, A. Biessels, G. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. Kopf, D. Alzheimers Dis. Cheung, C. Imaging retina to study dementia and stroke.

Sundstrom, J. Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases. Stitt, A. The progress in understanding and treatment of diabetic retinopathy.

Wei, Y. Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. Xu, Z. NRF2 plays a protective role in diabetic retinopathy in mice. Diabetologia 57 , — Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion. Abcouwer, S.

Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury. Muthusamy, A. Blood Flow. Hui, Q. Inhibition of the Keap1-Nrf2 protein-protein interaction protects retinal cells and ameliorates retinal ischemia-reperfusion injury.

Free Radic. Vascular stem cells and ischaemic retinopathies. Mohan, R. Retinal revascularisation in diabetic retinopathy.

Takahashi, K. Reperfusion of occluded capillary beds in diabetic retinopathy. Abaci, A. Effect of diabetes mellitus on formation of coronary collateral vessels.

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Altabas, V. Diabetes, endothelial dysfunction, and vascular repair: what should a diabetologist keep his eye on? Patel, J. Functional definition of progenitors versus mature endothelial cells reveals key SoxF-dependent differentiation process.

Circulation , — Naito, H. Endothelial side population cells contribute to tumor angiogenesis and antiangiogenic drug resistance. Cancer Res. Iba, T. Isolation of tissue-resident endothelial stem cells and their use in regenerative medicine. Ingram, D.

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Stem Cell Res. Wakabayashi, T. CD marks tissue-resident endothelial stem cells with homeostatic and regenerative properties. Cell Stem Cell 22 , — Sekiguchi, H. The relative potency and safety of endothelial progenitor cells and unselected mononuclear cells for recovery from myocardial infarction and ischemia.

Cell Physiol. Grant, M. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Otani, A. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells.

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Endothelial cell-derived pentraxin 3 limits the vasoreparative therapeutic potential of circulating angiogenic cells. Medina, R. Endothelial progenitors: a consensus statement on nomenclature. Stem Cell Transl. Park, S. CAS PubMed Central Google Scholar.

Chambers, S. The vasoreparative function of myeloid angiogenic cells is impaired in diabetes through the induction of IL1β. Stem Cells 36 , — Medina, M. Outgrowth endothelial cells characterisation and their potential for reversing ischemic retinopathy.

Ex-vivo expansion of human endothelial progenitors leads to ILmediated replicative senescence and impaired vasoreparative function.

Stem Cells 31 , — Yoder, M. Defining human endothelial progenitor cells. Heo, S. WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells.

Stem Cells 32 , — CONFLICT OF INTERESTS: No potential conflict of interest relevant to this article was reported. DR, diabetic retinopathy; NPDR, non-proliferative DR; IRMA, intra-retinal microvascular abnormality; PDR, proliferative DR; PRP, panretinal photocoagulation; DME, diabetic macular edema; VEGF, vascular endothelial growth factor.

a Intravitreal ranibizumab is approved by the U. Food and Drug Administration to treat all forms of DR, with or without DME. Skip Navigation Skip to contents Search Home Current Current issue Ahead-of print Browse All issues Article by category Article by topic Article by Category Best paper of the year Most view Most cited Funded articles Diabetes Metab J Search Author index Collections Guidelines in DMJ Fact sheets in DMJ COVID in DMJ For contributors For Authors Instructions to authors Article processing charge e-submission For Reviewers Instructions for reviewers How to become a reviewer Best reviewers For Readers Readership Subscription Permission guidelines About Aims and scope About the journal Editorial board Management team Best practice Metrics Contact us Editorial policy Research and publication ethics Peer review policy Copyright and open access policy Article sharing author self-archiving policy Archiving policy Data sharing policy Preprint policy Advertising policy E-Submission.

mobile menu button. Author information Article notes Copyright and License information 1 Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. Corresponding author: Akiyoshi Uemura. Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya , Japan.

uemura med. ABSTRACT Vision loss in diabetic retinopathy DR is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells.

Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR.

Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions.

In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

Keywords : Angiopoietins ; Blood-retina barrier ; Diabetic retinopathy ; Endothelial cells ; Macular edema ; Pericytes ; Retinal neovascularization ; Vascular endothelial growth factors. A Pseudo-colored fundus left and fluorescein angiography right images from ultra-widefield ophthalmoscopy.

Note the elevated leakage of fluorescein dye in the macular area in non-proliferative DR NPDR and from aberrant neovascularization NV in proliferative DR PDR. Dark areas in fluorescein angiography represent vascular non-perfusion NP.

Diabetes mellitus as a disease was identified as patgology back as BC Quench water filtration Diabetic retinopathy pathology characterized by the sweet properties Diabetix urine. In Mering and Artichoke weight loss tips discovered the relevance of the pancreas in this disease process after Diahetic a severe and reginopathy Diabetic retinopathy pathology of diabetes in a dog following removal of the pancreas. Since then, advancements in medicine have led to multiple new medication therapies and approaches to treat diabetes mellitus. Despite this, diabetes remains one of the top ten most prevalent and important non-infectious causes of morbidity and mortality worldwide. An estimated adults, had diabetes in This prevalence, in concert with the associated diseases that usually coincide with and result from diabetes should solidify the importance of being familiar with this disease process.

Diabetic retinopathy pathology -

For example, hyperglycemia-mediated oxidative damage 15 impaired function of key transcription factors 16 , and changes to enzymes controlling the electron transport chain are sustained in the retinas of animals even following several months normoglycemia. Many of these pathways can become dysregulated following DNA and histone methylation, and there is now convincing preclinical evidence that such epigenetic modifications are associated with the metabolic memory phenomenon for not only retinopathy, but also other complications Interestingly, a recent transcriptomics study in the retinas of diabetic mice receiving insulin-producing islet cell transplants has suggested that gene changes relating to metabolic memory may be particularly associated with the neurovascular unit Dyslipidemia and hypertension may also influence DR 19 , although in the context of individual patients, the associations between plasma lipids, lipoproteins, and DR are not sufficiently strong to define retinopathy risk.

Likewise, hypertension has been linked to increased risk of DR 20 , and some data indicate that patients may benefit from the use of antihypertensive agents However, recent studies have demonstrated that more intensive blood pressure control does not confer additional benefits on retinopathy progression compared with standard control Such data strongly suggest that additional unidentified factors also play critical roles in DR initiation and progression.

The hallmark microvascular features of NPDR Figure 1 include intraretinal hemorrhages, microaneurysms, venous caliber abnormalities, formation of IRMA, lipid exudates from the damaged vasculature, capillary nonperfusion with accompanying neuronal infarcts represented as cotton-wool spots, and retinal neovascularization.

Several retinal vascular pathologic processes in DR have a direct impact on vision. In NPDR, gradual nonperfusion of the retinal vascular bed, characterized by loss of vessel integrity, ultimately leads to occlusion or degeneration of capillaries 3.

Localized capillary nonperfusion results in regions of ischemia and impaired oxygenation of the metabolically demanding retinal neurons. Progressive capillary nonperfusion and resultant ischemia underpin progression to PDR, which is driven by hypoxia and expression of proangiogenic growth factors, which stimulate the aberrant formation of new blood vessels in the retina that protrude into the preretinal space.

Retinal neovascularization can result in severe vision loss when it leads to vitreous hemorrhage or tractional retinal detachment 3. Another major pathologic process is DME, which is characterized by overt breakdown of the BRB that leads to macular edema and swelling of the neuropile, which frequently leads to vision loss.

A long-standing mystery in DR and other ischemic retinopathies is the striking lack of revascularization of ischemic retina, despite the strong hypoxia stimulus and enhanced production of proangiogenic growth factors.

Indeed, the diabetic milieu within the retina seems to be unfavorable for reparative angiogenesis, possibly due to pathogenic factors such as AGEs 3. More recently, evidence has emerged supporting a possible role for semaphorins, a class of proteins originally implicated in axonal growth cone guidance.

Some semaphorin molecules regulate angiogenesis, and several semaphorins — including semaphorin 3A 31 , semaphorin 3F 32 , and semaphorin 6A 33 — are specifically implicated in suppressing the revascularization response in the ischemic retina, redirecting neo-vessels toward the vitreous instead.

As the proangiogenic factors in DR lead almost exclusively to pathologic preretinal neovascularization rather than beneficial revascularization, extensive efforts have been made over decades to identify the major proangiogenic growth factors in PDR, such as VEGF As a result, anti-VEGF treatments have emerged as an effective approach for treatment of this condition 35 , 36 , although many additional proangiogenic pathways will likely also serve as therapeutic targets, including placental growth factor 37 , stromal-derived factor-1 38 , and erythropoietin Improvements in understanding the molecular basis of both pathologic retinal neovascularization and deficient revascularization may produce new therapeutic targets that can suppress aberrant angiogenesis in favor of revascularization.

Although 7-standard field color fundus photography based on the Early Treatment Diabetic Retinopathy Study ETDRS protocol 40 has been the validated standard for evaluation of DR for decades, substantial advances in ocular imaging over the last 2 decades have provided new insights into diabetic vascular and neuroretinal pathology.

Indeed, the presence and severity of peripheral DR lesions is predictive of future rates of DR worsening Retinal photographs that utilize adaptive optics technology to compensate for wavefront aberrations in individual eyes allow imaging with a theoretical resolution limit down to 2 μm and have greatly expanded the ability to visualize the retina on a cellular level.

Adaptive optics studies demonstrate changes in the cone photoreceptor mosaic in the diabetic eye 42 and allow visualization of early vascular changes that cannot be identified on standard photographs Optical coherence tomography OCT is a widely utilized option for imaging the diabetic neural retina that uses light interferometry to create cross-sectional images of the retina in which individual retinal layers can be distinguished.

OCT allows quantitative measurements of retinal thickness, as well as evaluation of morphologic changes in eyes with DR and DME. Potential neuroretinal biomarkers of visual acuity in eyes with DME based on OCT imaging have been suggested, including ganglion cell layer thinning, disorganization of the retinal inner layers, and photoreceptor disruption, although further validation is needed 44 — Recently, the technique of OCT angiography has also been utilized to create high-resolution perfusion maps of the central retinal vasculature Both full-field and multifocal electroretinography ERG demonstrate abnormalities in retinal electrical signaling in the diabetic eye.

Local changes in multifocal ERG implicit time appear to precede the development of DR lesions such as microaneurysms Assessments of visual function demonstrate abnormalities in contrast sensitivity, color testing, frequency-doubling perimetry, and microperimetry in the diabetic eye with varying levels of DR severity; however, these functional tests are not sensitive or specific enough to serve as a reliable surrogate or predictive marker of DR or DME.

Future efforts in DR imaging may be geared toward multimodal evaluation of the retina. The use of simultaneous or near-simultaneous imaging methods that focus on specific components of neural or vascular retina may improve understanding of which pathologies develop first in the diabetic eye and may provide predictive biomarkers of future visual function outcomes in DR.

Intraocular treatment modalities for diabetic eye disease include laser photocoagulation, intravitreous injections of anti-VEGF and steroid agents, and vitreoretinal surgery. Current therapeutic paradigms focus on treatment of advanced disease, once PDR or DME has developed. Panretinal photocoagulation PRP for PDR was first proposed in the s.

Despite initial skepticism that the creation of thermal burns throughout the retinal periphery could promote regression of retinal neovascularization, the efficacy of PRP in reducing rates of severe vision loss in eyes with PDR was quickly and incontrovertibly demonstrated by the nationwide, multicenter Diabetic Retinopathy Study In the modern era, multiple phase 3 clinical trials have demonstrated the superiority of intravitreous anti-VEGF injections to laser monotherapy in reducing vision loss and improving rates of vision gain in eyes with DME 52 — A recent comparative efficacy study of the 3 most commonly utilized anti-VEGF agents showed that all 3 agents — aflibercept, bevacizumab, and ranibizumab — were effective at improving vision over 1 and 2 years of treatment for DME 55 , However, on average, treatment with aflibercept provided superior visual gains at 1 year as compared with bevacizumab and ranibizumab.

Aflibercept remained superior to bevacizumab, but not ranibizumab, based on mean visual acuity outcomes after 2 years of therapy. Although first-line therapy for most eyes with central-involved DME consists of anti-VEGF, intravitreous injections of steroid can also be effective for DME treatment 57 , However, intravitreous steroid use is limited by more frequent ocular side effects, such as cataract and glaucoma.

Anti-VEGF therapy is highly effective in regressing retinal neovascularization in eyes with PDR Recent data suggest that anti-VEGF is a viable treatment alternative to PRP in eyes with PDR, especially for individuals with coexisting DME that already necessitates anti-VEGF therapy. Eyes treated with anti-VEGF for PDR have equivalent visual acuity outcomes at the 2-year endpoint of the study, compared with those treated with PRP.

In addition, eyes treated with anti-VEGF exhibited better average visual acuity over the entire course of the 2-year study period Additional benefits of anti-VEGF as compared with PRP include significantly less peripheral visual field loss, decreased rates of DME onset, and fewer vitrectomies over 2 years.

Despite these benefits, anti-VEGF therapy may not be optimal for patients who cannot comply with the near-monthly follow-up and injection regimen required for adequate treatment and prevention of PDR recurrences.

Vitreoretinal surgery is utilized for cases of nonclearing vitreous hemorrhage from PDR or cases of PDR with tractional retinal detachment to relieve fibrous attachments that may be distorting the retina and causing vision loss or metamorphopsia Vitrectomy with or without peeling of the internal limiting membrane can also be performed to treat DME, particularly when there is an epiretinal membrane or element of vitreoretinal traction leading to retinal thickening.

Although current therapies are effective at preventing vision loss and frequently result in visual gain for patients with both PDR and DME, unmet treatment needs still exist. For both PDR and DME, noninvasive, nondestructive, and longer-duration treatment options are also needed.

Advances in understanding early cellular changes in the diabetic retina combined with improved retinal imaging have led to a conceptualization that DR can be viewed as a disease of the retinal neurovascular unit Figure 2 , which refers to the functional coupling and interdependency of neurons, glia, and vasculature 4 that integrate to regulate normal retinal function An important facet of this integration is the coordination of local blood flow changes with fluctuations in metabolic demands.

Retinal capillaries are composed of endothelial cells and pericytes but also have intimate associations with glial endfeet, neural processes, and professional immune cells such as microglia. Retinal arterioles have smooth muscle cells and, depending on the order of vessel, may also have significant pericyte coverage.

These contractile cells respond dynamically to complex circulatory and neural cues to control blood flow These cellular interactions are best recognized in the processes of neurovascular coupling, whereby neural, glial, and vascular cell interactions in both large and small vessels regulate blood flow to meet the metabolic demands of the retinal neuropile.

This response is dysregulated in the diabetic retina prior to appearance of observable vascular lesions, although it regulates the changes in blood flow that occur in animal models of DR 63 and in diabetic patients Retinal vascular responses to diffuse illuminance flicker reflects impaired neurovascular coupling and abnormal endothelial-glia associations 65 , resulting in attenuated arteriolar and venular dilatory responses 66 that may have early predictive value 67 in early-stage DR.

The neurovascular unit and its disruption by diabetes. In normal, healthy retina shown in the center , there is functional coupling and interdependency of neurons, glial elements including Müller cells, and vascular cells, with associated immune cells such as microglia. The insets show pathological changes associated with diabetic retinopathy in multiple components of the neurovascular unit and interacting immune cells, including compromise of endothelial-mural cell interactions, vascular basement membrane damage, Müller cell gliosis, and immune cell activation.

Together, these changes result in impairment of neurovascular coupling, with consequences including blood-retinal barrier breakdown and dysregulation of retinal blood flow. The conceptualization of DR as a disease of the neurovascular unit broadens our appreciation of the cell types that contribute to the development and progression of DR.

A greater understanding of the interactions of these various cellular elements and their pathogenic contributions could greatly expand the possibilities for new therapeutic strategies.

Pathology in the neural retina during DR. Vascular dysfunction and capillary loss are critical features of DR, as evidenced by the impact on visual function stemming from treatments including anti-VEGF aimed at ameliorating retinal vascular changes.

However, a growing body of evidence suggests that a neuropathy also exists in diabetic retina, perhaps even before overt nonperfusion of the neuropile. This broadening perspective has heightened the understanding of neuronal dysfunction and neurodegeneration and their corresponding clinical features, such as loss of color vision 68 and contrast sensitivity 69 and reduced electrical responses on electroretinographic testing 70 , 71 that can occur before overt microvascular changes.

Apoptotic death of retinal ganglion cells RGC and amacrine cells occurs in diabetic animal models 72 and has also been observed clinically in postmortem diabetic eyes 73 , Further evidence for structural changes include OCT imaging studies that demonstrate a reduction in thickness of the inner retinal layers in type 1 diabetics with minimal diabetic retinopathy 75 , Diabetes-induced alterations in the neurosensory retina could have major consequences, as neuronal dysfunction may contribute to the progression of vascular DR pathology.

Retinal neurons, including photoreceptors, may be an important source of oxidative stress that help drive the proinflammatory environment in DR In addition, retinal neuronal elements may secrete molecules, such as semaphorin 3A, that promote BRB dysfunction, contributing to macular edema The notion that neuronal dysfunction and damage can promote clinical diabetic retinopathy, including microangiopathy, is supported by observational studies indicating that regional neuronal dysfunction ascertained by multifocal ERG predicts corresponding retinal locations that will develop retinopathy within 1—3 years 79 , Subscribe Sign in.

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All rights reserved. Topic Feedback. Schematic diagram of the pathogenesis of diabetic retinopathy Relation between diabetic retinopathy and glycemic control Role of sorbitol in diabetic microvascular disease Formation of advanced glycation end products Strict glycemic control slows progression of retinopathy.

Schematic diagram of the pathogenesis of diabetic retinopathy. Relation between diabetic retinopathy and glycemic control. Diabetic retinopathy DR is a microvascular disorder caused by vision-threatening damage to the retina, a long-term sequela of diabetes mellitus.

DR is the most common microvascular complication in diabetic patients and the leading global cause of vision loss in working middle-aged adults. For more information on the disease entity, etiology, risk factors, diagnosis, and management, see Diabetic Retinopathy.

DR can be classified clinically into non-proliferative NPDR and proliferative PDR forms, according to the presence or absence of retinal neovascularization, and it can present with or without macular edema DME. NPDR represents the early stage of DR, with increased vascular permeability and capillary occlusion being the two main observations in retinal vasculature.

Based on the severity of retinal vascular lesions, NPDR is categorized into mild, moderate, and severe forms. Lesions vary from microaneurysms, dot and blot hemorrhages, hard exudates, and cotton wool spots to venous beading and intra-retinal microvascular abnormalities IRMAs.

The new abnormal vessels may bleed into the vitreous or cause a tractional retinal detachment, severely impairing vision.

However, the most common cause of vision loss in type II diabetes patients is DME. Hyperglycemia results in damage to retinal capillaries through the formation of advanced glycation endproducts AGEs. The resulting endothelial damage compromises capillary walls and results in microaneurysms.

Microaneurysms consequently rupture to form hemorrhages deep in the retina, appearing as "dots" on retinal examination, more commonly known as dot and blot hemorrhages. Inflammatory cytokines are significantly up-regulated in diabetes, and as a result, chronic inflammation and endothelial damage lead to increased vascular permeability of blood vessels.

Sediment left behind from this edema leads to waxy, yellow lipid byproducts referred to as hard exudates. Continued ischemia stimulates retinal cells to release pro-angiogenic factors such as VEGF.

Such factors stimulate neovascularization to bypass damaged retinal blood vessels. The formation of new blood vessels occurs from existing capillaries as a result of angiogenesis. These blood vessels usually arise in the interface between perfused and non-perfused areas of the retina in retinal neovascularization.

These new vessels are extremely immature, fragile, permeable and bleed very easily, originating severe complications such as vitreous hemorrhage or tractional retinal detachment. Chronic hyperglycemia is the key promotor for the development and progression of DR due to its tissue-damaging effects, as described in the UKPDS [12] and DCCT [13] trials.

However, genetic factors may play a role in individual susceptibility to those effects and other clinical factors like hypertension, dyslipidemia and pregnancy have also been implicated. Hyperglycemia leads to the activation of alternative pathways of glucose metabolism [1] such as the polyol pathway, advanced glycation endproducts AGEs formation, protein kinase C PKC activation, hexosamine pathway flux and Poly ADP-ribose polymerase activation.

Excess glucose is metabolized via the polyol pathway to sorbitol. Due to the high availability of glucose, AGEs formation is markedly increased in diabetic patients.

Moreover, AGEs receptors activation induces prooxidant and pro-inflammatory cascades, thus exacerbating oxidative stress and leukocyte adhesion. An increase in glycolysis activity also occurs during hyperglycemic episodes, elevating the synthesis of diacylglycerol DAG which in turn activates the PKC pathway.

In the hexosamine pathway, fructosephosphate F6P is converted into uridinediphospho-N-acetylgalactosamine UDP-GlcNAc. Hyperglycemia-induced oxidative stress correlates to increased poly ADP-ribose polymerase PARP activation.

In conjunction, these molecular mechanisms contribute to DNA damage and endothelial cell dysfunction in diabetic blood vessels. Several signaling pathways can be altered by having hyperglycemia in different tissues, which produces oxidative stress. Hyperglycemia activates a particular pathway involving diacylglycerol DAG , the activation of protein kinase C PKC , and the NADPH-oxidase system.

This particular signaling pathway is involved in the control of angiogenesis, oxidative stress, and cell death. Increasing evidence points to inflammation as a key factor in the pathogenesis of DR, although the exact molecular mechanisms are not well understood.

The simultaneous course of multiple metabolic pathways, such as oxidative stress, AGEs, and increased VEGF expression all likely contribute to the inflammatory response. Inflammatory cytokines such as tumor necrosis factor alpha TNF-α , interleukin 6 IL-6 , IL-8 and IL-1 were significantly up-regulated in diabetic patients, and their expression level is correlated with the severity of DR.

Retinal glial cell dysfunction is also presumed to be involved in inflammation in DR. Under hyperglycemic stress, microglia activation increases secretion of TNF-α, IL-6, MCP-1 and VEGF. Hyperglycemia causes pericyte loss, apoptosis of endothelial cells and thickening of the basement membrane, which collectively contribute to the impairment of the BRB.

Neural retina cells are also affected in DR pathophysiology. In fact, retinal neurodegeneration is an early event during the progression of DR that may even precede vascular apoptosis. Upregulation of pro-apoptotic molecules has been detected in retinal neurons in diabetic animals and humans.

Therefore, neuroprotective agents may play a role in preventing retinal neurodegeneration in early stages of DR. New evidence shows that this interaction is uncoupled in DR.

The pathophysiology of DR is fascinating and complex, with many mechanisms that need further study. DR treatment is an economic burden due to the number of patients affected and the cost of anti-VEGF therapies.

Therefore, filling the gaps in the landscape of DR pathophysiology is of the utmost importance for a better understanding of the disease.

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Review Diabetic retinopathy pathology access Address psthology to: Elia Retinppathy, Department of Ophthalmology, Wilmer Ophthalmologic Institute, Johns Hopkins University School of Medicine, N. Broadway, RoomBaltimore, MarylandUSA. Phone: stitt qub. Find articles by Duh, E. in: JCI PubMed Google Scholar. The pathogenesis Diabetic retinopathy pathology Muscle building techniques is retinopathj here. Issues related to screening and treatment retinopaty discussed separately. See Artichoke weight loss tips retinopathy: Screening" and "Diabetic retinopathy: Classification and clinical features" and "Diabetic retinopathy: Prevention and treatment". Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you.

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