FOXO3 and Hyperglycemia: In addition, it was found that the ROS overproduction (mediated by p66Shc following stimulation by hyperglycemia) activated AKT1/PKb kinases, resulting in phosphorylation and inactivation of the FOXO3a protein [18,38], and also inhibition of SOD expression by increased recruitment of repressive epigenetic markers (H4K20me (3)/SUV420H2) in its promoter [38].