Activation of the Hexosamine Pathway Leads to Deterioration of Pancreatic β-Cell Function through the Induction of Oxidative Stress

Hideaki Kaneto, Gang XU, Ki Ho Song, Kiyoshi Suzuma, Susan Bonner-Weir, Arun Sharma, Gordon C. Weir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

239 Citations (Scopus)

Abstract

It is known well that activation of the hexosamine pathway causes insulin resistance, but how this activation influences pancreatic β-cell function remains unclear. In this study, we found that in isolated rat islets adenovirus-mediated overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the first and rate-limiting enzyme of the hexosamine pathway, leads to deterioration of β-cell function, which is similar to that found in diabetes. Overexpression of GFAT or treatment with glucosamine results in impaired glucose-stimulated insulin secretion and reduction in the expression levels of several β-cell specific genes (insulin, GLUT2, and glucokinase). Additionally, the DNA binding activity of PDX-1, an important transcription factor for these three genes, was markedly reduced. These phenomena were not mimicked by the induction of O-linked glycosylation with an inhibitor of O-GlcNAcase, PUG-NAc. It was also found that glucosamine increases hydrogen peroxide levels and that several hexosamine pathway-mediated changes were suppressed by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, activation of the hexosamine pathway leads to deterioration of β-cell function through the induction of oxidative stress rather than O-linked glycosylation. Thus, the hexosamine pathway may contribute to the deterioration of β-cell function found in diabetes.

Original languageEnglish
Pages (from-to)31099-31104
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number33
DOIs
Publication statusPublished - 17 Aug 2001

Scopus Subject Areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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