Streptozotocin-induced beta-cell death is independent of its inhibition ofO-GlcNAcase in pancreatic Min6 cells

Streptozotocin (STZ) injection into experimental animals selectively causes massive beta -cell death. The mechanism of this specific toxicity is not f ully understood. Recently, it has been discovered that O-linked N-acetylglu cosamine (O-GlcNAc) is enriched in the beta -cells, it has been proposed th at STZ toxicity may be due to its inhibition of neutral O-GlcNAcase activit y, the enzyme that removes O-GlcNAc from cytosolic proteins (K, Liu ct al., 2000, Proc. Natl Acad. Sci. USA 97, 2820-2825), To further ascertain the r ole of O-GlcNA-case in beta -cell death, we have used PUGNAc, a potent and specific O-GlcNAcase inhibitor, together with STZ in pancreatic Min6 cells. Both STZ and PUGNAc increased O-GlcNAc to similar levels on intracellular proteins. STZ, but not PUGNAc, decreased cellular protein synthesis by 66.0 % within 8 h, killed 80.9% of the cells within 18 h, and decreased insulin secretion. STZ, but not PUGNAc, also caused genomic DNA fragmentation, sugg esting that some of the cells were undergoing apoptosis. Prolonged treatmen t with PUGNAc (72 h) maintained high intracellular O-GlcNAc levels, but did not result in any apparent cell damage. Furthermore, the toxicity of STZ c an be largely reversed by 3-aminobenzamide, a poly(ADP-ribose) polymerase i nhibitor. These data strongly indicate that STZ-induced beta -cell death is not caused by elevated intracellular O-GlcNAc levels, but instead likely i nvolves poly(ADP-ribose) polymerase in the mechanism. (C) 2000 Academic Pre ss.