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Acute Intensive Insulin Therapy Exacerbates Diabetic Blood-Retinal Barrier Breakdown via HIF-1a and Vascular Endothelial Growth Factor

1Joussen A. M., 2Adamis A., 2Qin W., 1Kirchhof B., 2Poulaki V.,
1Universität zu Köln, Zentrum für Augenheilkunde, Abteilung für Netzhaut- und Glaskörperchirurgie (Köln)
2Harvard Medical School, Massachussets Eye and Ear Infirmary (Boston)

Acute intensive insulin therapy is an independent risk factor for diabetic retinopathy progression. The molecular mechanisms underlying this phenomenon remain unknown.
Methods: Diabetic Retinopathy was investigated in a rat model of STZ induced diabetes. VEGF protein and mRNA levels were investigated after intensive insulin therapy.
Results: Here we show that acute intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae of diabetic rats. Retinal nuclear extracts from insulin-treated rats contain higher HIF-1a levels and demonstrate an increased binding to radiolabeled probes corresponding to hypoxia-response elements (HRE) in the VEGF promoter. An antibody against HIF-1a induces a supershift, confirming the presence of HIF-1a-containing HRE complexes. Blood-retinal barrier breakdown is markedly increased with acute intensive insulin therapy and is reversed with a VEGF soluble receptor Flt/Fc chimera construct (VEGF TrapA40), but not with an inactive IL-6 receptor/Fc control (IL-6R Trap).
Conclusions: Taken together, these findings indicate that acute intensive insulin therapy produces a transient worsening of diabetic retinopathy via an HIF-1a -mediated increase in retinal VEGF gene expression. These data are the first to identify a specific mechanism for the transient worsening of diabetic retinopathy that follows the institution of intensive insulin therapy.