TITLE:
Diabetes, an inflammatory process: Oxidative Stress and TNF-alpha involved in hepatic complication
AUTHORS:
Daniel E. Francés, Paola I. Ingaramo, María T. Ronco, Cristina E. Carnovale
KEYWORDS:
Diabetes Mellitus (DM); Liver; Apoptosis, Inflammation; TNF-α; iNOS; NO; Oxidative Stress; Hydroxyl Radical
JOURNAL NAME:
Journal of Biomedical Science and Engineering,
Vol.6 No.6,
June
26,
2013
ABSTRACT: 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 two-fold 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-α) 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 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-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 administration 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-α 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.