Elevated O-LinkedN-Acetylglucosamine Metabolism in Pancreatic β-Cells

High intracellular glucose concentrations increase flux though the hexosamine biosynthetic pathway, resulting in elevated UDP–N-acetylglucosamine (GlcNAc) concentrations. The nucleocytoplasmic enzyme O-linkedN-acetylglucosaminyltransferase (OGT) uses UDP–GlcNAc as a donor to modify numerous critical substrates, including nuclear pore proteins and transcription factors. Here, we document (a) the overwhelming enrichment of pancreatic OGT transcripts in the β-cells of the islets of Langerhans, (b) the physiologically significant increase in the level of O-GlcNAc residues present in β-cells, and (c) the action of streptozotocin, a close analogue of GlcNAc, to selectively inhibit O-GlcNAcase, an enzyme involved in the removal of O-GlcNAc residues. Taken together, these findings suggest that pancreatic β cells maintain a highly elevated O-GlcNAc metabolism and that the diabetes inducing drug streptozotocin inhibits O-GlcNAcase.