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Ming Lu, Shiro Amano, Kazuaki Miyamoto, Rebecca Garland, Karen Keough, Wenying Qin, Anthony P. Adamis; Insulin-Induced Vascular Endothelial Growth Factor Expression in Retina. Invest. Ophthalmol. Vis. Sci. 1999;40(13):3281-3286.
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purpose. Clinical studies have demonstrated that intensive insulin therapy
causes a transient worsening of retinopathy. The mechanisms underlying
the initial insulin-induced deterioration of retinal status in patients
with diabetes remain unknown. Vascular endothelial growth factor (VEGF)
is known to be operative in the pathogenesis of diabetic retinopathy.
The current study was conducted to characterize the effect of insulin
on retinal VEGF gene expression in vitro and in vivo.
methods. The effect of insulin on VEGF expression in vivo was examined by in
situ hybridization studies of rat retinal VEGF transcripts. To examine
the mechanisms by which insulin regulates VEGF expression, human
retinal pigment epithelial (RPE) cells were exposed to insulin, and
VEGF mRNA levels were quantified with RNase protection assays (RPAs).
Conditioned media from insulin-treated RPE cells were assayed for VEGF
protein and capillary endothelial cell proliferation. The capacity of
insulin to stimulate the VEGF promoter linked to a luciferase reporter
gene was characterized in transient transfection assays.
results. Insulin increased VEGF mRNA levels in the ganglion, inner nuclear, and
RPE cell layers. In vitro, insulin increased VEGF mRNA levels in human
RPE cells and enhanced VEGF promoter activity without affecting
transcript stability. Insulin treatment also increased VEGF protein
levels in conditioned RPE cell media in a dose-dependent manner with a
median effective concentration of 5 nM. The insulin-conditioned RPE
cell media stimulated capillary endothelial cell proliferation, an
effect that was completely blocked by anti-VEGF neutralizing antibody.
conclusions. Insulin increases VEGF mRNA and secreted protein levels in RPE cells
through enhanced transcription of the VEGF gene. Intensive insulin
therapy may cause a transient worsening of retinopathy in patients with
diabetes through increased retinal VEGF gene
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