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

Abstract

Diabetes mellitus (DM) is a serious and growing worldwide health problem and is associated with se- vere acute and chronic complications that negatively influence both quality of life and survival of affected individuals. It is a heterogeneous deregulation of car- bohydrate metabolism. The liver is a central regulator of carbohydrate homeostasis and releases glucose according to metabolic demands. In the last years, the liver injury has been recognized as a major complica- tion of DM. In fact, evidence suggests that in diabetic patients, the mortality rate due to liver cirrhosis is even higher than that due to cardiovascular disease and it has been suggested that there is a two-fold in- creased risk of liver disease in diabetic patients. Among the different types of diabetes, we analyze type 1 dia- betes mellitus as a chronic disorder and an inflam- matory process, which is also associated with in- creased risk of chronic liver injury. Animal models have contributed extensively to the study of diabetes, and it is well established that administration of a unique dose of streptozotocin (STZ) induces insulin- dependent type 1 diabetes mellitus. We analyzed the contribution of Tumor Necrosis Factor alpha (TNF-α) intracellular pathway and oxidative stress in the de- velopment of apoptosis in the liver of streptozotocin- induced diabetic animals. In this review, we describe the role of upstream mediators of the interaction be- tween 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 TNF-α- induced apoptosis. Also, we studied the role of iNOS- induction in the TNF-α-induced liver apoptosis by type 1 diabetes, by treatment of diabetic rats with aminoguanidine (selective iNOS inhibitor), which blocked the induction of apoptosis. Interestingly, iNOS inhibition significantly reduced TNF-α levels, evidencing an interaction between TNF-α and iNOS activity. On the other hand, we found that the ad- ministration of antioxidants/hydroxyl radical scaven- gers (Tempol and Desferal) prevented oxidative stress by reducing the effects of hydroxyl radical production and both lipid peroxidation (LPO) levels and apop- tosis. Taken together, our studies support that, at least in part, the hydroxyl radical acts as a reactive inter- mediate, which leads to liver apoptosis in a model of STZ-mediated hyperglycemia. Conclusion and Future: The relevance of the present review is to provide fur- ther knowledge about the mechanisms which may contribute to the disease process in the liver during the course of an inflammatory process as it is type 1 diabetes. Regulation of hepatic TNF-α levels and oxi- dative stress in the diabetic state could be of thera- peutic relevance for the improvement or delay of the hepatic complications linked to chronic hyperglycemia.