These results strongly indicate that hyperglycemia augments Notch signaling pathways through increase in O-GlcNAcylation of NOTCH1 and an increase in Notch ligands such as Dll3 and Dll4. Thus, hyperglycemia-induced Nrg1 overexpression in breast cancer cells may be partly mediated by Notch activation, leading to NICD-RBPJ assembly in the active Nrg1 enhanceosome. The gene discussed is DLL4; the disease is breast cancer.