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The interplay between insulin and hyperglycemia in modulating the angiogenic and inflammatory mediators may help explain the biphasic effects of insulin therapy on DR - early worsening followed by long-term risk reduction [4, 5]

The deletion of ATF4, an upstream factor of ChaC1, in embryonic fibroblasts, results in a ferric oxide-dependent death phenotype, emphasizing the role of ATF4 as a downstream molecule of the eIF2/ATF4 pathway (117)

However, incidence of developing NAION is still very low: in one study, only 0.2% of all studied patients developed NAION