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Mariya Ali, Shiming Luo, Masahiko Sugimoto, Alecia Cutler, Bela Anand-Apte; Insulin-Mediated Breakdown of Outer Blood Retinal Barrier: Implications for Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4159.
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© ARVO (1962-2015); The Authors (2016-present)
The Wisconsin Epidemiological Study of Diabetic Retiniopathy demonstrated that patients with type 2 diabetes undergoing insulin treatment for ≥10 years had a significantly higher risk of macular edema compared to patients not given insulin within 6 months of the time of analysis. We have previously demonstrated that insulin leads to outer blood-retinal barrier (BRB) disruption, possibly mediated by betacellulin a member of the Epidermal Growth Factor (EGF) family. The purpose of this study was to identify the EGF receptors present on RPE cells and evaluate the signaling mechanisms by which insulin and betacellulin mediate BRB breakdown.
ARPE-19 cells were cultured on transwell filters in high glucose (4.5g/L) media with 1% FBS for at least 4 weeks. Western blot analysis was used to identify EGF receptors and downstream signaling pathways with appropriate antibodies and the Licor Odyssey CLx imaging system. Immunohistochemistry with antibodies to ZO-1 identified and displayed the integrity of tight junctions on RPE cells.
Human RPE cells express basal EGFR (ErbB1), ErbB2, ErbB3 and ErbB4 receptors at baseline conditions. Betacellulin phosphorylates ErbB1/3/4 and downstream Akt and GSK-3 a and b. Insulin treatment of RPE cells results in phosphorylation of ErbB1 and ErbB3 as well as downstream Akt and GSK-3 and upregulation of HIF1-a. Downregulation of Btc (siRNA) or inhibition with EGFR inhibitor prevents RPE tight junction disruption by insulin.
Insulin has the propensity to disrupt RPE tight junctions and mediates this effect via betacellulin and EGF receptor signaling. These data suggest that insulin may play a role in the development of DME in patients (particularly those with type-2 diabetes) on high doses of insulin.
This is a 2020 ARVO Annual Meeting abstract.
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