Apoptosis in Liver Cells Due to Diabetes Induced Hyperglycemia By James Parra

Diabetes is a metabolic disorder that affects multiple systems of the body, resulting increased morbidity and mortality. Often the presence of diabetes is a contributing factor to the onset of other medical problems through direct or indirect pathways. These effects are the result of biochemical and functional irregularities particularly in the liver, such as changes in carbohydrate, lipid, and protein metabolism and changes in antioxidant status. However, even with insulin treatment, diabetics still show alterations in their tissue growth, affecting liver size in both juvenile and adult diabetic patients which can stem from a change in cell number mechanisms, cellular growth mechanisms, and/or the initiation of apoptosis. The experiment outlined in the article specifically addresses the concern of increased apoptotic activity in liver cells. This experiment stemmed from the an article published in 2000 by a colleague who showed that the damage in liver cells is oxidative in nature in both type 1 and type 2 diabetes, as well as showing deficits in antioxidant defense enzymes and vitamins in liver cells. This research suggests that oxygen, antioxidant defenses, and cellular redox status should be regarded key factors in diabetes. In 1996, it was experimentally shown that hyperglycemia induced by diabetes accelerated hydroxyl radical generation in liver cells. Other experiments showed that hyperglycemia increases mitochondrial reactive oxygen species (ROS) production which may be a key contributor to the development of complications due to diabetes. In the presence of high glucose concentrations in the blood, the cellular response is the generation of ROS which, in turn rapidly produces apoptotic cell death via the activation of the Bax-caspase proteases pathway. A family of intracellular cysteine proteases known as caspases are well known to be promoters of apoptosis. A feature of apoptisis in which caspases are used is altered mitochondrial function exhibited by reducing the proton gradient across the mitochondrial membrane and the release of mitochondrial cytochrome c to the cytoplasm which is inhibited by the Bcl-xL. Translocation of apoptosis promoting BAX proteins into the mitochondrial membrane is accompanied by significant increases in caspase-3 and caspase-9 activities.

Given the above background, the objective of the study outlined in the article was to explore whether hyperglycemia produces an increase in hydroxyl radicals. Such an increase would serve as a regulatory action of the cell on apoptosis in the liver through the Bax-caspase pathway. Also explored was the effect of insulin over this pathway. The subjects of the study were male adult Wistar rats, which were randomized into three groups: control which were administered a sodium citrate buffer, streptozotocin (STZ)-induced diabetic (SID), and insulin-treated SID (SID+I; 15 days post STZ injection, SID received insulin twice a day over 15 days). The rats were then autopsied on day 30. Examination of liver tissue showed that diabetes promoted a significant increase in hydroxyl radical production. Also, hyperglycemia significantly increased mitochondrial BAX protein expression, cytosolic cytochrome c levels, and caspase-3 activity suggesting an increase in apoptosis levels in those cells. Diabetic rats treated with desferoxamine or tempol, which are antioxidants and hydroxyl radical scavengers, significantly reduced the increase in both hydroxyl radical production. The effect of this was decreased levels of apoptosis by reduction of mitochoondrial BAX and cytosolic cytochrome c levels relative to diabetic rats which did not receive treatment. Insulin treatment received similar results, reducing apoptotic activity in liver cells. Also, co administration of antioxidants and hydroxyl radical scavengers with insulin did not provide any additional benefit when compared to using either of the inhibitors or insulin alone, suggesting that insulin prevents oxidative damage to cells by reducing the effects of hydroxyl radicals. Also significant was the finding that insulin increased apoptosis inhibitor protein expression by induction of its mRNA. The aggregate of these results suggests that, at least in part, the hydroxyl radical acts as a reactive intermediate, leading to liver apoptosis such as in the model created in the STZ-mediated hyperglycemic rats.

Works Cited Frances, Daniel, Maria Ronco, Juan Monti, Jose Pellegrino, Paola Ingaramo, Gerardo Pisani, Juan Parody, Paloma Sanz, Maria Carrillo, and Cristina Carnovale. "Hyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect." Journal of Endocrinology 205, no. 2 (2010): 187-200. http://joe.endocrinology-journals.org/cgi/content/full/205/2/187 (accessed April 20, 2010).