Elevated O-linked N-acetylglucosamin metabolism in pancreatic beta-cells

High intracellular glucose concentrations increase flux though the hexosami ne biosynthetic pathway, resulting in elevated UDP-N-acetylglucosamine (Glc NAc) concentrations. The nucleocytoplasmic enzyme O-linked N-acetylglucosam inyltransferase (OGT) uses UDP-GlcNAc as a donor to modify numerous critica l substrates, including nuclear pore proteins and transcription factors. He re, we document (a) the overwhelming enrichment of pancreatic OGT transcrip ts in the beta-cells of the islets of Langerhans, (b) the physiologically s ignificant increase in the level of O-GlcNAc residues present in beta-cells , and (c) the action of streptozotocin, a close analogue of GlcNAc, to sele ctively inhibit O-GlcNA-case, an enzyme involved in the removal of O-GlcNAc residues, Taken together, these findings suggest that pancreatic beta cell s maintain a highly elevated O-GlcNAc metabolism and that the diabetes indu cing drug streptozotocin inhibits O-GlcNAcase. (C) 1999 Academic Press.