| Autor: |
Natalicchio, Annalisa, De Stefano, Francesca, Laviola, Luigi, Perrini, Sebastio, Orlando, Maura R., Cignarelli, Angelo, Melchiorre, Mariangela, Martemucci, Sabina, Caccioppoli, Cristina, Giorgino, Riccardo, Giorgino, Francesco |
| Předmět: |
|
| Zdroj: |
Diabetes; Jun2007 Supplement 1, Vol. 56, pA444-A444, 1/4p |
| Abstrakt: |
TNFα represents an important mediator of beta-cell dysfunction and death in diabetes. To evaluate the mechanisms of TNFα induced beta-cell damage, INS-1 beta-cells were stimulated with 20 ng/ml TNFα for several hours. Treatment with TNFα increased the phosphorylation levels of the serine-kinase INK 2-fold (p<0.05) and reduced Iκ-Bα protein content 50% (p<0.05). Furthermore, TNFα stimulation resulted in enhanced serine phosphorylation of IRS proteins (p<0.05), but did not change the total levels of IRS-1 or IRS-2. Sequential immunoprecipitation with anti-IRS-1 or anti-IRS-2 antibodies, followed by immunoblotting with phosphoserine antibodies, demonstrated that IRS-2 was the most important substrate affected by TNFα, whereas serine phosphorylation of IRS-1 could be barely detected. Moreover, TNFα reduced basal AM phosphorylation 30% and increased beta-cell apoptosis 7-fold (p<0.05). Since the incretin hormone GLP-1 has been shown to antagonize beta-cell damage induced by various cytokines, we next investigated potential protective effects of GLP-1 receptor agonists on TNFα-induced beta-cell damage. Pre-incubation of INS-1 cells with GLP-1 (10 nM) or Exenatide (Ex, 10 nM) for 18 h prevented TNFα-induced JNK phosphorylation and IRS-2 serine phosphorylation, and restored AM phosphorylation, without affecting p38 phosphorylation or protein content. In addition, Ex treatment resulted in a 3-fold increase in IRS-2 protein expression. Finally, both GLP-1 and Ex markedly inhibited TNFα-induced apoptosis by 50% (p<0.05). In conclusion, TNFα induces apoptosis in INS-1 beta-cells, and this likely occurs by induction of JNK phosphorylation and impairment of IRS-2 and AM signalling. GLP-1 and Ex prevent the signaling abnormalities and cell apoptosis induced by TNFα. Thus, GLP-1 and Exenatide may promote beta-cell survival by directly antagonizing cytokine-dependent signaling reactions mediating beta-cell death. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
