From: Diabetic Retinopathy: Battling the Global Epidemic Invest. Ophthalmol. Vis. Sci.. 2016;57(15):6669-6682. doi:10.1167/iovs.16-21031 Figure Legend: Pathophysiology of diabetic macular edema (DME) and different therapeutic strategies. Hyperglycemia in diabetes activates different biochemical pathways that lead to increased hypoxia, reactive oxygen species (ROS) formation, and inflammation with production of cytokines and chemokines. These mediators then cause endothelial cell junction breakdown and leukostasis, resulting in alteration of the blood–retinal barrier (BRB), increased retinal vascular permeability, and DME. Hyperglycemia also causes thickening of the basement membrane (BM) and pericyte dropout. Hypertension and hyperlipidemia, which coexist commonly in diabetic persons, further damage the already altered BRB. Currently, control of systemic factors, focal/grid laser (for noncenter-involving DME), anti-vascular endothelial growth factor (VEGF) therapies (for center-involving DME), steroids, and vitrectomy (in cases of vitreomacular traction) are the mainstays of management of DME. However, the current anti-VEGF therapies have limitations because they target only VEGF rather than other inflammatory molecules (e.g., angiopoietin [Ang]-2, matrix metalloproteinase [MMP], tumor necrosis factor [TNF]α, interleukin [IL]-1β, kallikrein–kinin) present in the retina in diabetic persons. Many future therapies target these other mediators. AGE, advanced glycation end products; ICAM, intercellular adhesion molecule; MCP, monocyte chemoattractant protein; PKC, protein kinase C. Reprinted with permission from Das A, McGuire PG, Rangasamy S. Diabetic Macular Edema: Pathophysiology and Novel Therapeutic Targets. Ophthalmology. 2015;122:1375–1394. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier, Inc. All rights reserved. Date of download: 10/9/2017 The Association for Research in Vision and Ophthalmology Copyright © 2017. All rights reserved.