Diabetes and Its Hepatic Complication

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

Hot Topics in Endocrine and Endocrine-Related Diseases

Intech

Año: 2012; p. 129 - 144

Chapter content (Abstract) Diabetes mellitus (DM) is a serious and growing health problem worldwide and is associated with severe acute and chronic complications that negative influence both quality of life and survival of affected individuals. It is a heterogeneous dysregulation of carbohydrate metabolism. The liver is a central regulator of carbohydrate homeostasis and releases glucose according to metabolic demands. In the last years, it has recognized the liver injury as a major complication of DM. In fact, evidence suggests that in diabetic patients, the mortality rate due to liver cirrhosis is even greater than that due to cardiovascular disease and has been suggested that there is a twofold increased risk of liver disease in diabetic patients. Between the different types of diabetes we analyze the Diabetes mellitus type 1 as a chronic disorder considered as 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 is well established that administration of streptozotocin induced diabetes mellitus type 1 insulin-dependent. We analyzed the contribution of Tumor Necrosis Factor alpha (TNF-alpha) intracellular pathway in the development of apoptosis in the liver of streptozotocin- induced diabetic animals. We present the well-known pro-inflammatory mediator, TNF-alpha , as a factor that interacts with their receptor (TNF-R1) inducing the activation of caspase-8, the increase of nuclear factor kappa B (NFkB) free in cytosol, and augmentation of expression of proteins of signaling pathways of JNK , in the liver ofdiabetic rats. The activation of NFkB produces an induction of iNOS and the consistent increase in NO production. In this chapter, we described the role of upstream mediators of the interaction TNF-alpha/TNFR1 by the ability of in vivo treatment with etanercept (TNF-alpha blocking antibody) to protect against the TNF-alpha induced apoptosis. Also, we studied the role of iNOS-induction in the TNF-alpha liver apoptosis by diabetes type 1, with the aminoguanidine (selective iNOS inhibitor) treatment of diabetic rats, which blocked the induction of apoptosis. Interestingly, iNOS inhibition significantly reduced TNF-alpha levels, evidencing an interaction between TNF-alpha and iNOS activity. The relevance of the present chapter is to provide further knowledge about the mechanisms which may contribute to the disease process in the liver during an inflammatory process as type 1 diabetes. The regulation of hepatic TNF-alpha level and iNOS activity in the diabetic state could be of therapeutic relevance for improvement or delay of the hepatic complications linked to chronic hyperglycemia. Key words: Diabetes mellitus (DM), hyperglycemia, TNF-alpha, iNOS, NO, liver