Diabetes, an inflammatory process: Oxidative Stress and TNF-alpha involved in hepatic complication

Abstract

Diabetes\rmellitus (DM) is a serious and growing worldwide health problem and is\rassociated with severe acute and chronic complications that negatively\rinfluence both quality of life and survival of affected individuals. It is a\rheterogeneous deregulation of carbohydrate\rmetabolism. The liver is a central regulator of carbohydrate homeostasis\rand releases glucose according to metabolic demands. In the last years, the\rliver injury has been recognized as a major complication of DM. In fact, evidence\rsuggests that in diabetic patients, the mortality rate due to liver cirrhosis\ris even higher than that due to cardiovascular disease and it has been\rsuggested that there is a two-fold increased\rrisk of liver disease in diabetic patients. Among the different types of\rdiabetes, we analyze type 1 diabetes mellitus as a chronic disorder and an inflammatory process, which is also associated with increased risk of chronic liver\rinjury. Animal models have contributed extensively to the study of diabetes,\rand it is well established that administration of a unique dose of\rstreptozotocin (STZ) induces insulin-dependent type 1 diabetes mellitus. We\ranalyzed the contribution of Tumor Necrosis\rFactor alpha (TNF-α) intracellular\rpathway and oxidative stress in the development of apoptosis in the liver of streptozotocin-induced diabetic animals. In this review, we describe the role\rof upstream mediators of the interaction between TNF-α and its receptor, TNF-R1, by assessing the ability of the in vivo treatment with etanercept (TNF-α blocking antibody) to protect against\rTNF-α-induced apoptosis. Also, we\rstudied the role of iNOS-induction in the TNF-α-induced liver apoptosis by type 1 diabetes, by treatment of\rdiabetic rats with aminoguanidine (selective iNOS inhibitor), which blocked the\rinduction of apoptosis. Interestingly, iNOS inhibition significantly reduced\rTNF-α levels, evidencing an\rinteraction between TNF-α and iNOS\ractivity. On the other hand, we found that the administration of\rantioxidants/hydroxyl radical scavengers (Tempol and Desferal) prevented\roxidative stress by reducing the effects of hydroxyl radical production and\rboth lipid peroxidation (LPO) levels and apoptosis. Taken together, our studies support that, at least in\rpart, the hydroxyl radical acts as a reactive intermediate, which leads to\rliver apoptosis in a model of STZ-mediated hyperglycemia. Conclusion and Future:\rThe relevance of the present review is\rto provide further knowledge about the mechanisms which may contribute to the\rdisease process in the liver during the course of an inflammatory process as it\ris type 1 diabetes. Regulation of hepatic TNF-α levels and oxidative\rstress in the diabetic state could be\rof therapeutic relevance for the improvement or delay of the hepatic complications linked to chronic hyperglycemia.