IRS1 and Hyperglycemia: Hyperglycemia activates the hexosamine biosynthesis pathway and modifies proteins involved in insulin and NO signalling by the O-Glc-N-acylation of IRS-1, which impairs activation of PI3-K and reduces glucose uptake [31] and O-Glc-N-acylation of eNOS at the Akt phosphorylation residues, leading to its inactivation [32].