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

FRANCÉS, DANIEL E.; INGARAMO, PAOLA I.; RONCO, MARÍA T.; CARNOVALE, CRISTINA E.

Journal of Biomedical Science and Engineering

Scientific Research Publishing Inc

Año: 2013 vol. 06 p. 645 - 653

1937-6871

p { margin-bottom: 0.25cm; line-height: 120%; Diabetesmellitus (DM) is a serious and growing worldwide health problem andis associated with severe acute and chronic complications thatnegatively influence both quality of life and survival of affectedindividuals. It is a heterogeneous deregulation of carbohydratemetabolism. The liver is a central regulator of carbohydratehomeostasis and releases glucose according to metabolic demands. Inthe last years, the liver injury has been recognized as a majorcomplication of DM. In fact, evidence suggests that in diabeticpatients, the mortality rate due to liver cirrhosis is even higherthan that due to cardiovascular disease and it has been suggestedthat there is a two-fold increased risk of liver disease in diabeticpatients. Among the different types of diabetes, we analyze type 1diabetes 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 ofstreptozotocin (STZ) induces insulin-dependent type 1 diabetesmellitus. We analyzed the contribution of Tumor Necrosis Factor alpha(TNF-α) intracellular pathway and oxidative stress in thedevelopment of apoptosis in the liver of streptozotocin-induceddiabetic animals. In this review, we describe the role of upstreammediators 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 TNF-α-inducedapoptosis. Also, we studied the role of iNOS-induction in theTNF-α-induced liver apoptosis by type 1 diabetes, by treatment ofdiabetic rats with aminoguanidine (selective iNOS inhibitor), whichblocked the induction of apoptosis. Interestingly, iNOS inhibitionsignificantly reduced TNF-α levels, evidencing an interactionbetween TNF-α and iNOS activity. On the other hand, we found thatthe administration of antioxidants/hydroxyl radical scavengers(Tempol and Desferal) prevented oxidative stress by reducing theeffects 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 reactiveintermediate, which leads to liver apoptosis in a model ofSTZ-mediated hyperglycemia. Conclusion and Future: The relevance ofthe present review is to provide further knowledge about themechanisms which may contribute to the disease process in the liverduring the course of an inflammatory process as it is type 1diabetes. Regulation of hepatic TNF-α levels and oxidative stress inthe diabetic state could be of therapeutic relevance for theimprovement or delay of the hepatic complications linked to chronichyperglycemia.