It is known well that activation of the hexosamine pathway causes insulin resistance, but how this activation influences pancreatic ␤-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 ␤-cell function, which is similar to that found in diabetes. Overexpression of GFAT or treatment

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... glucosamine results in impaired glucose-stimulated insulin secretion and reduction in the expression levels of several ␤-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 ␤-cell function through the induction of oxidative stress rather than O-linked glycosylation. Thus, the hexosamine pathway may contribute to the deterioration of ␤-cell function found in diabetes.