Interestingly, inhibitory serine residues of IRS1 can also be O-GlcNAcylated (Jahangir et al., 2014) leading to the possibility of hypoglycemia mediated reduced O-GlcNAcylation on inhibitory serine residues of IRS1 that may result in its increased phosphorylation and development of impaired insulin signaling in AD brain. Here, INS is linked to Alzheimer disease.