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 resistance, but how this activation influences pancreatic beta-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 beta-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 beta-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, PUGNAc. 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 beta-cell function through the induction of oxidative stress rather than O-linked glycosylation. Thus, the hexosamine pathway may contribute to the deterioration of beta-cell function found in diabetes.
Kaneto
H
H
Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Xu
G
G
Song
K H
KH
Suzuma
K
K
Bonner-Weir
S
S
Sharma
A
A
Weir
G C
GC
D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000503:physiopathology*; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000096:biosynthesis; D006031:Glycosylation; D006595:Hexosamines / Q000378:metabolism*; D006943:Hyperglycemia / Q000503:physiopathology; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D006595:Hexosamines; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)