Proposed model of changes in epigenetic status before and after establishing hiONs from hiPSCs and epigenetic silencing by hyperglycemia in orexin neurons. (A) Epigenetic status in HCRT expressing and non-expressing cells on HCRT gene locus. (B) Hexosamine biosynthetic pathway (HBP) and sialic acid synthetic pathway. Some glucose is metabolized by the HBP into UDP-GlcNAc, ManNAc, and sialic acid. UDP-GlcNAc is used to modify O-GlcNAc in cells, while sialic acid is essential for extracellular bioactivity. ManNAc is an intermediate of UDP-GlcNAc and is a precursor of sialic acid. ManNFAc, a potent ManNAc derivative, enters the sialic acid biosynthetic pathway, while 5S-ManNAc, another potent derivative, does not.