Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3

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...

Diabetic retinopathy is characterized by early onset of neuronal cell death. We previously showed that insulin mediates a prosurvival pathway in retinal neurons and that normal retina expresses a highly active basal insulin receptor/Akt signaling pathway that is stable throughout feeding and fasting. Using the streptozotocin-induced diabetic rat model, we tested the hypothesis that diabetes diminishes basal retinal insulin receptor signaling concomitantly with increased diabetes-induced retinal apoptosis. The expression, phosphorylation status, and/or kinase activity of the insulin receptor and downstream signaling proteins were investigated in retinas of age-matched control, diabetic, and insulin-treated diabetic rats. Four weeks of diabetes reduced basal insulin receptor kinase, insulin receptor substrate (IRS)-1/2-associated phosphatidylinositol 3-kinase, and Akt kinase activity without altering insulin receptor or IRS-1/2 expression or tyrosine phosphorylation. After 12 weeks of diabetes, constitutive insulin receptor autophosphorylation and IRS-2 expression were reduced, without changes in p42/p44 mitogen-activated protein kinase or IRS-1. Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity, and acute intravitreal insulin administration restored insulin receptor kinase activity. Insulin treatment restored insulin receptor-␤ autophosphorylation in rat retinas maintained ex vivo, demonstrating functional receptors and suggesting loss of ligand as a cause for reduced retinal insulin receptor/Akt pathway activity. These results demonstrate that diabetes progressively impairs the constitutive retinal insulin receptor signaling pathway through Akt and suggests that loss of this survival pathway may contribute to the initial stages of diabetic retinopathy.