Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress

It is known well that activation of the hexosamine pathway causes insulin r esistance, but how this activation influences pancreatic beta -cell functio n remains unclear. In this study, we found that in isolated rat islets aden ovirus-mediated overexpression of glutamine:fructose-6-phosphate amidotrans ferase (GFAT), the first and rate-limiting enzyme of the hexosamine pathway , leads to deterioration of beta -cell function, which is similar to that f ound in diabetes. Overexpression of GFAT or treatment with glucosamine resu lts in impaired glucose-stimulated insulin secretion and reduction irk the expression levels of several beta -cell specific genes (insulin, GLUT2, and glucokinase). Additionally, the DNA binding activity of PDX-1, an importan t transcription factor for these three genes, was markedly reduced. These p henomena were not mimicked by the induction of O-linked glycosylation with an inhibitor of O-GlcNAcase, PUG-NAc. It was also found that glucosamine in creases hydrogen peroxide levels and that several hexosamine pathway-mediat ed changes were suppressed by treatment with the antioxidant N-acetyl-L-cys teine. In conclusion, activation of the hexosamine pathway leads to deterio ration of beta -cell function through the induction of oxidative stress rat her than O-linked glycosylation. Thus, the hexosamine pathway may contribut e to the deterioration of beta -cell function found in diabetes.