Aspartate immunoreactivity Grape Wine Cellar Design Tips increased Diabetc Müller cells Diabetic retinopathy pathology diabetic Diabeticc, suggesting slower clearance of glutamate, 57 whereas excised Müller cells retinopatuy STZ-rats after patohlogy month of diabetes demonstrated reduced glutamate transporter activity, measured by patch clamp analysis. There is evidence demonstrating an early neurodegeneration of photoreceptors in animal diabetic models [ ]. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Abcouwer SF Shanmugam S Gomez PF. Br J Ophthalmol ; 85 : — nature eye review article.

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Diabetic retinopathy - Endocrine system diseases - NCLEX-RN - Khan Academy Alistair J. BarberDiabetic retinopathy pathology W. GardnerSteven F. Abcouwer; The Significance Lowering high blood pressure Vascular pzthology Heart healthy workouts Apoptosis to the Pathology of Diabetic Rstinopathy. The most striking features of diabetic retinopathy are the vascular abnormalities that are apparent by fundus examination. There is also strong evidence that diabetes causes apoptosis of neural and vascular cells in the retina. Thus, there is good reason to define diabetic retinopathy as a form of chronic neurovascular degeneration.

Diabetic retinopathy pathology -

Regulation of immune cells and control of inflammation is critical for the well-being and normal function of the retina. Resident microglial cells within the inner retina have a critical role in parainflammation: an adaptive response to tissue stress including hyperglycemia and oxidative stress and malfunction.

While this response promotes homeostasis and normal tissue repair, in the short-term, chronic parainflammation contributes to initiation and progression of multiple disease processes Within this context, the role of inflammation in driving the progression of DR is increasingly better appreciated 90 , As diabetes progresses, the retina exhibits multiple elements of chronic, subclinical inflammation, including immune cell activation and production of inflammatory molecules.

Multiple immune cell types are activated in the early stages of DR, including enhanced leukocyte-endothelial interaction in the retinal vasculature 3 , This phenomenon of leukostasis is characterized by adherence of circulating myeloid cells, including neutrophils and monocytes, with activated vascular endothelium.

Leukocyte-endothelial interactions can instigate damage to the retinal vascular endothelium and surrounding tissue both by physical occlusion of capillaries and through the release of inflammatory cytokines and superoxide.

In addition to the contribution of intravascular immune cell types, activation of microglia as the resident immune cells of the retina and also infiltrating monocytes likely mediate the diabetes-induced generation of an inflammatory environment 3.

Apart from activating professional immune cells, diabetes promotes a proinflammatory phenotype in other retinal cells, such as in the vasculature where upregulation of adhesion molecules including E-selectin and ICAM-1 92 , 93 enhance endothelial engagement with circulating immune cells.

In addition, diabetes induces production of proinflammatory cytokines by Müller glia, including VEGF and TNF-α Such events operate in concert to create an inflammatory milieu that contributes to the progression of DR.

A key feature of DR is the increased expression of inflammatory cytokines and growth factors from various cell sources. For example, the proinflammatory peptide VEGF is well-recognized as a major player in DR, including its role in promoting retinal vascular permeability and DME Strikingly, DME patients treated with anti-VEGF agents exhibited slower progression to capillary drop-out, suggesting that VEGF may play a role in progression of DR apart from its clearly documented effects on vascular permeability Aside from VEGF, diabetes increases retinal levels of inflammatory cytokines including TNF-α and IL-1β, both of which have been implicated in contributing to key pathologic endpoints in DR, including capillary drop-out and vascular permeability 95 — RPE dysfunction and choroidopathy as components of DR.

Although it has received comparatively less attention, diabetes also affects RPE function and leads to outer retinal changes that impact on photoreceptor and choroidal integrity.

RPE culture—based models and in vivo studies have demonstrated that high glucose exposure or diabetes causes nitrosative stress 98 and metabolic changes relating to polyol metabolism In the context of DME, new perspectives consider the contribution of changes to the outer BRB oBRB formed by the RPE.

Disruption of normal oBRB function 83 , occurs during diabetes, and loss of RPE barrier properties leads to leakage of fluid from the choriocapillaris. The RPE also exhibits impaired fluid clearance from the retinal neuropile, which, in combination with loss of oBRB integrity, makes an important contribution to DME The relative importance of the RPE dysfunction, as compared with retinal vascular leakage, in contributing to diabetic macular edema remains under active study.

The choriocapillaris itself incurs progressive damage during diabetes as reviewed by Lutty; ref. Diabetic choroidopathy occurs in patients and animal models and is manifest by thinning of the capillary bed with lesions such as vessel drop-out, aneurysms, ischemia, and in some cases intrachoroidal neovascularization , Inflammatory cell infiltration may also participate in capillary occlusion and atrophy Clinically, the diabetic choroid is beginning to receive more attention as imaging modalities improve.

Beyond indocyanine green ICG angiographic studies , approaches such as enhanced depth imaging EDI have generally shown reduced choroidal thickness in diabetic eyes , although in some patient groups, increased thickness may occur possibly relating to a postischemic fibrotic response and intrachoroidal neovascularization.

In either case, choroidopathy in the diabetic eye could have a subsequent, profound impact on RPE and the outer retinal layers, which are oxygenated by the choriocapillaris. For example, the occurrence of basal laminar deposits BLDs in diabetic eyes are associated with areas of choriocapillaris degeneration The precise nature of diabetic choroidopathy requires further clinical and experimental study, especially since this vascular bed is critical to normal retinal function.

Concept of protective mechanisms. While considerable research effort has been directed toward identifying pathogenic pathways contributing to initiation and progression of DR, a growing paradigm is the importance of endogenous mechanisms that protect against DR , This concept is strongly supported by the Joslin Year Medalist Study, which has enrolled over 1, individuals with T1D durations of 50 years or more.

In contrast to other large studies in groups with shorter-duration diabetes, DR severity has not been associated with current or longitudinal HbA1c values in this cohort, which suggests the presence of endogenous protective factors in those individuals who have not progressed to advanced diabetic complications, including retinopathy.

The identification of such protective mechanisms might enable future novel therapies to prevent onset and early worsening of diabetic ocular disease.

With the perspective that an imbalance between causal factors and protective factors governs progression of DR, new therapeutic strategies could center on stimulating the action of endogenous protective mechanisms. In this vein, several protective factors have been proposed in DR, including superoxide dismutase 2 MnSOD , pigment epithelium—derived factor PEDF , somatostatin , and NF-E2—related factor 2 Nrf2 These molecules illustrate the potential benefit of promoting protective pathways in favorably modulating key processes in diabetic retinopathy.

MnSOD and Nrf2 could serve to attenuate diabetes-induced oxidative stress. PEDF and Nrf2 counteract the proinflammatory environment in diabetic retinopathy. Somatostatin exerts a neuroprotective effect that could reduce neurodegeneration. An especially intriguing candidate protective factor for diabetic retinopathy is PPARα, which has been demonstrated to improve multiple beneficial endpoints in experimental models of DR, including inflammation and leakage , Strikingly, 2 large clinical trials of the PPARα agonist fenofibrate showed an effect of this drug in slowing the progression of diabetic retinopathy.

Although it is not clear whether this protective effect of fenofibrate was due to PPARα agonism as opposed to its other potential actions, it is noteworthy that the protective effect was unrelated to the lipid-lowering activity of this drug Pharmacologic targeting of these and other protective mechanisms therefore represent new therapeutic avenues in the treatment of DR.

New therapeutic angles in diabetic retinopathy. Although the past decade has seen significant improvements in the treatment options for DR, additional therapies are urgently required. Current therapies are directed exclusively toward advanced stages of DR, often after permanent damage has ensued; thus, treatments that are preventative or address early pathology are highly desirable.

Anti-VEGF treatment is only partially effective against diabetic macular edema , and the identification of additional, VEGF-independent pathogenic molecules in this condition could lead to new treatments that better preserve vision.

Additional molecular targets have been identified for pharmacologic inhibition, including TNF-α , the plasma kallikrein pathway , and lipoprotein-associated phospholipase A2 Lp-PLA2 Broadening therapeutic objectives beyond direct suppression of pathologic vascular changes may be promising.

Notably, the expanded conceptualization of DR as a disease of the neurovascular unit brings to light additional cellular targets for therapy. With awareness that neuronal dysfunction and neurodegeneration are early events in DR, therapeutic strategies based on neuroprotection, including agents such as somatostatin, nerve growth factor NGF , and brain-derived neurotrophic factor BDNF are worthwhile to consider, and there is an ongoing clinical trial for early DR focused on retinal neuroprotection Aside from neurons, the important role of Müller cells and microglia may direct efforts toward therapeutic targeting of these important cellular elements.

Finally, expanding the scope of pathogenic processes that are therapeutically targeted beyond vascular leakage and neovascularization to include neuroprotection and intraretinal revascularization would be highly desirable endpoints in DR. The concept of epigenetic modifications associated with the metabolic memory phenomenon is an additional pathogenic process worthy of therapeutic attention Identification and targeting of key epigenetic mechanisms could help to slow down the progression of DR in patients, especially those with a prior history of poor glycemic control.

Finally, consideration of cell-based strategies including endothelial progenitor cells is worthwhile in promoting vascular repair and alleviating retinal ischemia In addition to the actual molecular and cellular targets that will require additional mechanistic insights, advances with respect to methods for administration of therapeutics will enable improvements in managing patients with DR.

Intravitreal injections allow direct delivery of drugs to the retina with reduction of systemic side effects, but the necessity for frequent, repeat injections renders this approach appropriate only for more advanced and acute disease. Methods for topical or systemic delivery, as well as sustained release delivery methods including nanoparticles 3 , would greatly aid treatment of chronic conditions such as diabetic macular edema.

In addition, these strategies would also increase the feasibility of treating early stages of diabetic retinopathy, as the latter will require treatment over prolonged durations. Topical drug formulations that can reach the retina would reduce systemic side effects and allow self-administration by patients over long periods of time.

Precision medicine. Patients with diabetes exhibit great variation in the course of their retinopathy development, including both the pace of progression and the specific clinical manifestations.

For instance, some individuals may have a stronger tendency to develop DME, whereas others may tend toward PDR. In addition, patients exhibit variable response to treatments; for instance, while most patients respond well to anti-VEGF therapy, some have only a moderate or even poor response Improvements in understanding the pathogenesis of the multiple facets of DR and the increase in diagnostic techniques, including imaging, opens the possibility of precision medicine geared toward directed strategies that take into account important differences between patients.

Attaining greater understanding of patient variation and its impact on clinical phenotype will bolster efforts toward more precise management of DR.

Such insights will likely arise from further mechanistic and biologic data, including genomics, proteomics, and biomarkers of disease. Together with advances in earlier diagnosis of DR, the objective of precision medicine is ideal in optimizing care of DR through improved phenotyping, understanding of mechanism, and expansion of treatment options.

Although the incidence of DR continues to increase, the past decade has seen the emergence of new treatment options, especially drugs targeting VEGF, which have greatly improved our management of DME and PDR endpoints.

Nevertheless, a pressing need remains for efficacious new treatments for all stages of DR, and this underpins continuing efforts to fully understand the complex ways in which diabetes impacts the retina. An important conceptual advance has been the recognition that DR is a disease of the neurovascular unit, with multiple, interdependent cell types contributing to dysfunction of the retina.

New therapeutic approaches should adopt this more holistic view of how diabetes affects the retina and tailor appropriate treatments to more precisely defined disease phenotypes with the exciting prospect of achieving successful clinical outcomes for all patients.

The authors are grateful to Zhenhua Xu for assistance with preparation of the figures. License: This work is licensed under the Creative Commons Attribution 4. export Copy Format NLM AMA APA MLA. Download Citation Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format: RIS — For EndNote, ProCite, RefWorks, and most other reference management software BibTeX — For JabRef, BibDesk, and other BibTeX-specific software Include: Citation for the content below Citation and abstract for the content below Pathophysiology of Diabetic Retinopathy: The Old and the New.

Diabetes Metab J. pasue play. Sign up. Sign up for the DMJ newsletter— what matters in science, free to your inbox daily. No microvascular abnormalities. Control blood glucose levels, serum lipid levels, and blood pressure.

Mild NPDR. Microaneurysms only. Microaneurysms and other signs dot and blot hemorrhages, hard exudates, cotton wool spots , but not severe NPDR. Severe NPDR. Consider PRP. Neovascularization of optic disc or elsewhere, preretinal hemorrhage, or vitreous hemorrhage.

Strongly consider PRP, consider vitrectomy for persistent vitreous hemorrhage or tractional retinal detachment. Retinal thickening in the macula. Consider focal laser photocoagulation, anti-VEGF therapya, or corticosteroid therapy for center-involving DME.

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager. The goal of surgery is to remove blood and scar tissue from the retinal surface and to place laser treatment as needed.

Intraoperatively, intraocular gas or silicone oil may be needed to maintain reattachment of the retina to the underlying layers and eyewall.

There is always the low, but real risk of infection of the eyeball endophthalmitis with any injection of drugs into the eye or with eye surgery. There is also the risk of cataract progression with retinal surgery. Vitrectomy accelerates the rate of cataract formation.

ETDRS studies show that the stage of retinopathy is correlated with progression to more advanced stages or retinopathy and visual loss. Create account Log in. Main Page. Getting Started.

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Judy E. Kim, MD. All authors and contributors:. Brad H. Feldman, M. Shah M. Rana D. Tsui, MD , Jennifer I Lim MD. Assigned editor:. add Contributing Editors : add. Diabetic Retinopathy. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial.

doi: Epub Feb PMID: ; PMCID: PMC Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. N Engl J Med. Epub Jul Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial.

KESTREL and KITE: Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema. Am J Ophthalmol. Epub Jan PMID: Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema YOSEMITE and RHINE : two randomised, double-masked, phase 3 trials.

Association of Treatment Type and Loss to Follow-up With Tractional Retinal Detachment in Proliferative Diabetic Retinopathy [published online ahead of print, Dec 1].

Diabetic retinopathy Patuology is Diabtic microvascular disorder Diabetic retinopathy pathology by vision-threatening damage to the retina, a retinopatny sequela of diabetes Heart healthy workouts. DR is Turbocharge fat burning most common microvascular complication in diabetic patients Duabetic the leading global retjnopathy 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.