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M. Sugimoto, A. Cutler, B. Anand-Apte; Insulin-Induced Betacellulin Cleavage Regulates the Blood-Retinal Barrier. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5626.
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While large-scale clinical trials have identified hyperglycemia as a risk factor for progression of diabetic retinopathy (DR), some studies have suggested a worsening of DR following insulin therapy. The exact molecular mechanisms underlying the initial exacerbation of microvascular complications in the first two years of intensive insulin therapy remains unknown. We have previously reported that betacellulin (BTC), a member of the epidermal growth factor family plays a critical role in the induction of increased vascular permeability in the diabetic retina. In the present study we tested the hypothesis that the effect of insulin on the blood-retinal barrier (BRB) is mediated via BTC.
The localization of BTC protein expression was evaluated by immunohistochemistry and western blot analysis using a retinal pigment epithelial cell line (ARPE-19), Müller cell line, retinal endothelial cell line and post-mortem human retina sections. The effect of increasing concentrations of insulin on the tight junction protein, zonula occludens-1 (ZO-1), BTC cleavage and activation as well as a disintegrin and metalloproteinase-10 (ADAM-10) in ARPE-19 was evaluated. The signaling pathways utilized by insulin in exacerbating retinal vascular permeability were also evaluated in vivo using streptozotocin-induced diabetic mice with and without insulin therapy.
Western blot analyses identified the presence of BTC protein in cultured human retinal endothelial cells, Müller cells and ARPE-19. Immunohistochemistry studies on human retina determined BTC to be predominantly localized to the RPE. Using ARPE-19, BTC was found to be co-localized with ZO-1 in tight junctions. Exposure of ARPE-19 to insulin resulted in the disruption of ZO-1 and cleavage/activation of BTC mediated by ADAM-10. Similar pathways were activated in the retinas of diabetic mice treated with insulin.
Insulin induces the activation of BTC through ADAM-10 and causes a disruption of the outer BRB. The transient worsening of DR in some diabetic patients following intensive insulin therapy may be a result of these mechanisms.
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