title: Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage.
abstract: Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.
authors.affiliation: Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Alecia
authors.initials: A
authors.lastname: Cutler
authors.forename: Bailey
authors.initials: B
authors.lastname: Shen
authors.forename: Scot E
authors.initials: SE
authors.lastname: Moss
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Bela
authors.initials: B
authors.lastname: Anand-Apte
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D066259:Betacellulin; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008269:Macular Edema / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012160:Retina; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000378:metabolism
chemical_list: C587851:BTC protein, human; D066259:Betacellulin; C587852:Btc protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse