Diabetic Retinopathy

Abstract

Diabetic retinopathy remains a frightening prospect to patients and frustrates physicians. Destruction of damaged retina by photocoagulation remains the primary treatment nearly 50 years after its introduction. The diabetes pandemic requires new approaches to understand the pathophysiology and improve the detection, prevention, and treatment of retinopathy. This perspective considers how the unique anatomy and physiology of the retina may predispose it to the metabolic stresses of diabetes. The roles of neural retinal alterations and impaired retinal insulin action in the pathogenesis of early retinopathy and the mechanisms of vision loss are emphasized. Potential means to overcome limitations of current animal models and diagnostic testing are also presented with the goal of accelerating therapies to manage retinopathy in the face of ongoing diabetes. Diabetes 55:2401-2411, 2006 D espite years of clinical and laboratory investigation, diabetic retinopathy remains the leading cause of vision impairment and blindness among working-age adults, yet the fundamental cause(s) remains uncertain. Retinal photocoagulation to reduce neovascularization and macular edema was developed in the 1950s and is still the standard of care (1). The number of people worldwide at risk of developing vision loss from diabetes is predicted to double over the next 30 years (2), so it is imperative to develop better means to identify, prevent, and treat retinopathy in its earliest stages rather than wait for the onset of vision-threatening lesions. Progress in these areas requires a new perspective on the problem that includes the roles of the neural retina, impaired insulin action, and inflammation. In this way, established neurobiological principles can inform us how diabetes impairs vision, and knowledge of metabolism, inflammation, and regenerative medicine may lead to new treatments.This perspective will discuss how the unique anatomy and physiology of the retina may render it vulnerable to the metabolic derangements of diabetes and lead to impaired vision. The intent of this unconventional approach is to encourage consideration of new opportunities for investigations that will advance the field. NORMAL RETINAL STRUCTURE AND PHYSIOLOGY Topographic and cellular organization of the retina.It is instructive to consider the functional organization of the retina (literally a network) to better understand the impact of diabetes (http://webvision.med.utah.edu). The retina is a transparent layer of neural tissue between the retinal pigmented epithelium and the vitreous body. Normal vision depends on intact cell-cell communication among the neuronal, glial, microglial, vascular, and pigmented epithelial cells of the retina. The fundamental functions of the retina are to capture photons, convert the photochemical energy into electrical energy, integrate the resulting action potentials, and transmit them to the occipital lobe of the brain, where they are deciphered and interpreted into recognizable images. The retina is partitioned from the syst...

Ischemia–Reperfusion Injury Induces Occludin Phosphorylation/Ubiquitination and Retinal Vascular Permeability in a VEGFR-2-Dependent Manner

“…4,31 Decreased protein contents of occludin (B30%) and claudin-5 (B25%) were observed in the cerebral cortex of sheep fetus after 4 hours of ischemia and were suggested to cause BBB permeability. 32,33 In the present study, no change in the content of claudins, VE-cadherin, or ZO-1 was observed in early or late reperfusion.…”

“…[1][2][3][4][5][6] The IR model has been widely used for studying retinal neuronal cell damage after ischemic insult 6 and consists of transient ischemia followed by natural reperfusion leading to an inflammatory and neurodegenerative response in the intact retina. 7 Histologic analysis demonstrated that the IR injury causes selective neuronal loss indicated by reduced thickness of retinal layers including the ganglion cell layer, inner nuclear layer, and inner plexiform layer.…”

“…18 Several studies have demonstrated that changes in occludin content and distribution are associated with endothelial cell barrier properties. 4,[19][20][21][22] Although cells do not require occludin for TJ formation, 23 occludin phosphorylation on specific sites regulates barrier properties. 19,24 Treatment of endothelial cells with VEGF increases occludin phosphorylation and alters its distribution from cell border to intracellular puncta.…”

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

“…Unraveling which are the most critical mechanisms is unlikely to be achieved in studies limited to the clinically observable retinal changes in human DR. Far more detailed and invasive studies are required, preferably in a readily available animal model. 4 The streptozotocin-induced diabetes in rats shows many of the retinal alterations associated with human DR. [5][6][7] Therefore, this model could be a useful tool for studying the pathogenic mechanisms involved in DR, as well as for developing new therapeutics.…”

Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

“…A similar approach could be applied to other retinal diseases, particularly those with known cell-based dysfunctions. There is accumulating evidence that diabetic retinopathy compromises distinct components of the neurovascular unit, such as astrocytes, pericytes, and cholinergic amacrine cells [54,56]; optogenetics could target these cells to supplement their health and function.…”