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

FRANCÉS D. E.; INGARAMO P. I.; RONCO M. T.; CARNOVALE C. E.

Journal of Biomedical Science and Engineering

Scientific Research Publishing

Año: 2013 vol. 6 p. 645 - 653

1937-6871

Diabetes mellitus (DM) is a serious and growing worldwide health problem and is associated with severe acute and chronic complications that negatively influence both quality of life and survival of affected individuals. It is a heterogeneous deregulation of carbohydrate 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 complication 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 twofold increased risk of liver disease in diabetic patients. Among the different types of diabetes, we analyze type 1 diabetes mellitus as a chronic disorder and an inflammatory process, which is also associated with increased 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-alpha) intracellular pathway and oxidative stress in the development 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-alpha and its receptor, TNF-R1, by assessing the ability of the in vivo treatment with etanercept (TNF-alpha blocking antibody) to protect against TNF-alpha induced apoptosis. Also, we studied the role of iNOS- induction in the TNF-alpha-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-alpha levels, evidencing an interaction between TNF-alpha and iNOS activity. On the other hand, we found that the ad- ministration of antioxidants/hydroxyl radical scavengers (Tempol and Desferal) prevented oxidative stress by reducing the effects of hydroxyl radical production and both lipid peroxidation (LPO) levels and apoptosis. Taken together, our studies support that, at least in part, the hydroxyl radical acts as a reactive intermediate, which leads to liver apoptosis in a model of STZ-mediated hyperglycemia. Conclusion and Future: The relevance of the present review is to provide further 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-alpha levels and oxidative stress in the diabetic state could be of therapeutic relevance for the improvement or delay of the hepatic complications linked to chronic hyperglycemia.