STREPTOZOTOCIN, AN ANALOG OF N-ACETYLGLUCOSAMINE, BLOCKS THE REMOVAL OF O-GLCNAC FROM INTRACELLULAR PROTEINS

Streptozotocin (STZ), an analog of N-acetylglucosamine (GlcNAc), is a specific toxin for the pancreatic beta cell. We found that treatment o f rats with STZ results in an early beta-cell-specific increase in the level of intracellular protein modification by O-linked GlcNAc (O-Glc NAc). Using a model O-GlcNAc peptide based on the transcription factor Spl, we show that treatment of cultured cells with STZ during peptide biosynthesis results in hyperglycosylation of the peptide as a result of the ability of STZ to specifically inhibit the activity of O-GlcNA c-selective N-acetyl-beta-D-glucosaminidase. Although this inhibitory activity of STZ probably can occur in all cells, we found, using in si tu hybridization, that beta cells express very high levels of the mRNA encoding the enzyme responsible for cytoplasmic protein O-glycosylati on, O-GlcNAc transferase (OGT). These findings suggest that the pancre atic beta cell is particularly sensitive to the toxicity of STZ becaus e it expresses such high levels of OGT. When STZ blocks O-GlcNAc remov al from intracellular proteins, the cell with the most rapid on-rate f or O-GlcNAc, the beta cell, will experience the most rapid accumulatio n of this protein modification. Because we also show that the on-rate of O-GlcNAc is substrate driven in several cell types, we speculate th at the beta cell, with its high level of OGT, may also respond to elev ations of blood sugar with increased protein modification by O-GlcNAc. Thus, this proposed mechanism of STZ toxicity on the beta cell may re sult from an exaggeration of a heretofore unrecognized physiological r esponse to glucose mediated through the high level of OGT in these cel ls.