| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
E-mail contact: sesti{at}unicz.it
Because adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP), we inquired whether HBP activation affects pancreatic β-cell survival. Exposure of human islets to high glucose resulted in increased apoptosis of β-cells upon serum deprivation that was reversed by azaserine. Also, glucosamine, a direct precursor of the downstream product of the HBP, increased human β-cells apoptosis upon serum deprivation, which was reversed by benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (BADGP), an inhibitor of protein O-glycosylation. These results were reproduced in RIN rat β-cells. Glucosamine treatment resulted in inhibition of tyrosine-phosphorylation of the insulin receptor (IR), IRS-1, and IRS-2, which was associated with increased O-glycosylation. These changes caused impaired activation of the PI 3-kinase/Akt survival signaling that resulted in reduced GSK-3 and FOXO1a inactivation. BADGP reversed the glucosamine-induced reduction in insulin-stimulated phosphorylation of IR, IRS-1, IRS-2, Akt, GSK-3, and FOXO1a. Impaired FOXO1a inactivation sustained expression of the pro-apoptotic protein Bim, without affecting Bad, Bcl-XL, or Bcl-2 expression. These results indicate that hyperglycemia may increase susceptibility to apoptosis of human and rat β-cell through activation of the HBP. Increased routing of glucose through this metabolic pathway results in impaired activation of the IR/IRSs/PI3-kinase/Akt survival pathway by induction of O-glycosylation of signaling molecules.
Key words: glucose toxicity • hexosamine pathway • diabetes mellitus
This article has been cited by other articles:
|
|
 |
|
  L. Shu, N. S. Sauter, F. T. Schulthess, A. V. Matveyenko, J. Oberholzer, and K. Maedler Transcription Factor 7-Like 2 Regulates {beta}-Cell Survival and Function in Human Pancreatic Islets Diabetes, March 1, 2008; 57(3): 645 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-C. Jang, S.-H. Sung, J.-G. Park, J.-W. Park, J. H. Bae, D. H. Shin, G.-Y. Park, S.-B. Han, and S.-I. Suh Glucosamine Hydrochloride Specifically Inhibits COX-2 by Preventing COX-2 N-Glycosylation and by Increasing COX-2 Protein Turnover in a Proteasome-dependent Manner J. Biol. Chem., September 21, 2007; 282(38): 27622 - 27632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Fulop, R. B. Marchase, and J. C. Chatham Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system Cardiovasc Res, January 15, 2007; 73(2): 288 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Cooksey, S. Pusuluri, M. Hazel, and D. A. McClain Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in {beta}-cells Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E334 - E340. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
