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S. Dell, V. Poulaki, N. Mitsiades, N. Kociok, A.M. Joussen; Intensive insulin therapy–induced vascular leakage and leukostasis in diabetes are decreased by anti–IGF . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4111.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Intensive insulin therapy is an independent risk factor for progression of diabetic retinopathy. The molecular mechanisms underlying this phenomenon are still unknown. We have previously shown that acute intensive insulin therapy induces HIF–1a (hypoxia inducible factor) activation, which subsequently leads to VEGF (vascular endothelial growth factor) upregulation, followed by blood–retinal barrier breakdown. In the current study we investigated the role of IGF–I (insulin–like growth factor) in this mechanism. Methods: Control–released insulin implants were inserted into streptozotocin–induced diabetic rats (Long Evans). In addition mini osmotic pumps were implanted containing either IGF–I receptor–neutralizing or control antibody. Vascular leakage was determined with the Evans Blue method. Perfusion with FITC–conjugated lectin was employed for analysis of leukocyte adhesion. VEGF–concentration was measured by ELISA according to the manufacturers instruction. HIF–1a and akt kinase activity were analyzed using a modified ELISA protocol. Results: In vivo inhibition of IGF–IR reduced the insulin–induced akt kinase activity, the HIF–1a activation, and VEGF upregulation. Additionally, IGF–IR blockade reduced both the insulin–induced increase in leukocyte adhesion and the blood–retinal barrier breakdown. Conclusions: Intensive insulin treatment induces VEGF expression and subsequently leakage and leukocyte adhesion during diabetic retinopathy. Inhibition of IGF–1 reduces these effects and unveils a potential therapeutic tool to prevent the observed exacerbation of diabetic retinopathy.
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