Streptozotocin-induced β-cell death is independent of its inhibition of O-GlcNAcase in pancreatic Min6 cells

Y. Gao, G. J. Parker, Gerald Warren Hart

Research output: Contribution to journalArticle

Abstract

Streptozotocin (STZ) injection into experimental animals selectively causes massive β-cell death. The mechanism of this specific toxicity is not fully understood. Recently, it has been discovered that O-linked N-acetylglucosamine (O-GlcNAc) is enriched in the β-cells. It has been proposed that STZ toxicity may be due to its inhibition of neutral O-GlcNAcase activity, the enzyme that removes O-GlcNAc from cytosolic proteins (K. Liu et al., 2000, Proc. Natl. Acad. Sci. USA 97, 2820-2825). To further ascertain the role of O-GlcNA-case in β-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, suggesting that some of the cells were undergoing apoptosis. Prolonged treatment with PUG-NAc (72 h) maintained high intracellular O-GlcNAc levels, but did not result in any apparent cell damage. Furthermore, the toxicity of STZ can be largely reversed by 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor. These data strongly indicate that STZ-induced β-cell death is not caused by elevated intracellular O-GlcNAc levels, but instead likely involves poly(ADP-ribose) polymerase in the mechanism. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)296-302
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume383
Issue number2
DOIs
StatePublished - Nov 15 2000

Keywords

  • β-cell death
  • Diabetes
  • Glucosamine
  • O-GlcNAc
  • O-GlcNAcase
  • PUGNAc
  • Streptozotocin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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