Tumor necrosis factor alpha pathways develops liver apoptosis in type 1 diabetes mellitus

We analyzed the contribution of TNF-alpha intracellular pathway in the development of apoptosis in the liver of streptozotocin-induced diabetic rats. In liver tissue, diabetes promoted a significant increase of INF-alpha/INF-R1, and led to the activation of caspase-8, of nuclear factor kappa B (NF kappa B), and JNK signaling pathways. The activation of NF kappa B led to an induction of iNOS and consequent increase in NO production. As a consequence of such changes a significant increase of caspase-3 activity and of apoptotic index were observed in the liver of diabetic animals. Importantly, the treatment in vivo of diabetic rats with etanercept (TNF-alpha blocking antibody) or aminoguanidine (selective iNOS inhibitor) significantly attenuated the induction of apoptosis by reduction of caspase-3 activity. Overall, we demonstrated that in the diabetes enhances TNF-alpha in the liver, which may be a fundamental key leading to apoptotic cell death, through activation of caspase-8, NF kappa B and JNK pathways. (C) 2011 Elsevier Ltd. All rights reserved.