Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO.
PurposeDiabetic retinopathy is the leading cause of preventable blindness in the working population and its prevalence continues to increase as the worldwide prevalence of diabetes grows. The main cause of visual loss in diabetic eye disease is diabetic macular oedema caused by an increase in microvascular endothelial permeability. Endothelial cell permeability is influenced by multiple factors which have not been fully elucidated, particularly in human models. Inflammation has been reported in the pathogenesis of diabetic retinopathy and the potential use of anti‐inflammatory agents such as the glucocorticoid dexamethasone is being extensively studied.MethodsThe effect of high glucose (25 mM) and dexamethasone on retinal endothelial cell proliferation and permeability were assessed using Cell‐8 proliferation reagent and passage of Evan's blue albumin, respectively. qPCR was used to quantify gene expression of selected tight junction molecules (Occludin, Claudin‐5, JAM‐A and JAM‐C) and adheren junction (VE‐Cadherin) molecules with high glucose and dexamethasone.ResultsHigh glucose decreased endothelial cell proliferation and this effect was reversed by dexamethasone. High glucose conditions significantly increased endothelial cell permeability and this effect was decreased with dexamethasone treatment for 24 and 72 hours. In retinal endothelial cell exposed to high glucose claudin‐5, occludin and JAM‐A gene expression were reduced and that of JAM‐C increased when evaluated with qPCR; dexamethasone was effective in partially reversing these changes.ConclusionsDexamethasone reverses high glucose induced alterations in retinal endothelial cell behaviour.
PurposeDiabetic retinopathy is the leading cause of preventable blindness in the working population and its prevalence continues to increase as the worldwide prevalence of diabetes grows. The main cause of visual loss in diabetic eye disease is diabetic macular oedema caused by an increase in microvascular endothelial permeability. Endothelial cell permeability is influenced by multiple factors which have not been fully elucidated, particularly in human models. Inflammation has been reported in the pathogenesis of diabetic retinopathy and the potential use of anti‐inflammatory agents such as the glucocorticoid dexamethasone is being extensively studied.MethodsThe effect of high glucose (25 mM) and dexamethasone on retinal endothelial cell proliferation and permeability were assessed using Cell‐8 proliferation reagent and passage of Evan's blue albumin, respectively. qPCR was used to quantify gene expression of selected tight junction molecules (Occludin, Claudin‐5, JAM‐A and JAM‐C) and adheren junction (VE‐Cadherin) molecules with high glucose and dexamethasone.ResultsHigh glucose decreased endothelial cell proliferation and this effect was reversed by dexamethasone. High glucose conditions significantly increased endothelial cell permeability and this effect was decreased with dexamethasone treatment for 24 and 72 hours. In retinal endothelial cell exposed to high glucose claudin‐5, occludin and JAM‐A gene expression were reduced and that of JAM‐C increased when evaluated with qPCR; dexamethasone was effective in partially reversing these changes.ConclusionsDexamethasone reverses high glucose induced alterations in retinal endothelial cell behaviour.
Purpose Diabetic retinopathy (DR) is the most common cause of visual loss in the working population and the incidence of diabetes is increasing. In addition, 80% of diabetic patients will show some form of retinopathy after 15 years, even with good glycaemic control. The mechanism of diabetic retinopathy is still not fully understood although hyperglycaemia is the main determinant. Diabetes appears to have contradictory effects on vasculature, causing reduced angiogenesis or increased angiogenesis at different vascular sites.
Methods The effect of high glucose (HG) on in vitro proliferation, apoptosis and angiogenesis of retinal endothelial cells was investigated using relevant assays. Real time PCR was used to quantify signalling responses to high glucose through gene expression of key signalling molecules such as HIF and expression of VEGF.
Results HG conditions reduced the proliferation of retinal endothelial cells but no increase in apoptosis was detected, and increased VEGF prevented this response. Gene expression of HIF was increased with HG and that of VEGF decreased dependent on glucose concentration and exposure time.
Conclusion Contrary to other research in this area we found that apoptosis may not play the major role in the early phase of DR, and that reduced endothelial cell proliferation precedes apoptosis. Angiogenic signalling induced by hyperglycaemia is complex and requires further elucidation.
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