الفهرس 
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Abstract
Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, and action or both. The chronic hyperglycemia of diabetes is associated with long term damage, dysfunction and failure of various organs, especially the eyes, kidney, nerves, heart, and blood vessels.
Type I diabetes mellitus is an autoimmune disease in which mononuclear cells of the immune system (macrophages and lymphocytes) infiltrate the pancreatic islets of Langerhans (insulitis), leading to selective destruction of the islets ~-cells and to insulin dependent diabetes mellitus. Apoptosis has been identified as a mechanism of pancreatic islets l3-cell death in autoimmune diabetes.
Animal and human studies and in vitro experiments suggested a role for oxidative stress in the pathophysiology of diabetic complications. High glucose concentration is known to activate a number of enzymatic and non-enzymatic pathways of glucose metabolism that are implicated in ROS production. The resulting increased production ofROS interacts with several cellular targets and result in tissue injury.
Inactivation and removal of reactive oxygen species depend 011 reactions involving the anti oxidative defense system. The capacity is determined by a dynamic interaction between individual components. Central to this defense are the antioxidants of the blood which include vitamins E, C, n- lipoic acid, N-acetyl-cystiene, reduced glutathione (GSH), and several antioxidant enzymes as glutathione peroxidase (Gpx).
The present study was carried out to evaluate the potential usefulness of multiantioxidants (N-acetyl-cysteine (NAC), alpha-lipoic (LA), vitamin E and vitamin C) supplementation in the treatment of type 1 diabetes. The severity of diabetes in the different groups of albino rats were studied in relation to the level of cytokines released during the oxidative stress.
Male Sprague Dawely white albino rats, weighing 150-200 g were injected by a double interperitoneal injection of cyclophosphamide (100 mg / kg body weight) supplemented with a mixture of antioxidants by using a stainless-steal stomach tube daily for a period of two months. Afterwards, fasting blood glucose level of the animals was determined.
The rats were divided into three groups of eight animals each (n=8) as follows:
Group 1: Normal control rats were given distilled water (I ml/ 100 g body weight).
Group 2: Diabetic control rats were given distilled water (I ml/ 100 g body weight). Group 3: Diabetic rats were given mixture of the following antioxidants: NAC solution (500 mg / kg body weight), LA solution (30 mg / kg body weight), Vitamin E (100 IV / kg body weight) and Vitamin C (1 g / kg body weight).
After two months of dialy treatment with multiantioxidants, the rats were fasted overnight and sacrificed by cervical decapitation. Whole blood; plasma and serum were immediately collected for biochemical analysis. After animal dissection, the pancreas was obtained and stored in 10 % formaline solution for histopathological and immunocytochemical studies.
The results indicated that the supplementation of diabetic rats with the antioxidants induced highly significant decrease in fasting plasma glucose level, lipid peroxide and nitric oxide level, tumor necrosis factor-a and transcription factor-kappa beta (NF-KP) concentration and highly significant increase in glutathione level and glutathione peroxidase activity, when compared with the diabetic group.
Histological studies of the pancreas revealed that the antioxidants treatment maintained on the normal morphology of islets of pancreas, p-cell mass when compared with diabetic rats. The combination of these antioxidants was most effective in suppression ofapoptosis, which associated with the development of type I diabetes. Immunoflourescence studies indicated that antioxidants protect p- cell from cytokine induced dysfunction and death through inhibition specific nuclear factor-Kp activity, which was more visible in the nuclei of the islet cells in diabetic rats than treated rats.
from these results, it could be concluded that the combined antioxidants (NAC, LA, vitamine E and vitamine C) treatment could exert beneficial effects in diabetes, with maintainace of in vivo p-cell function. These finding suggests a potential usefulness of multiantioxidants for treating diabetes and provides further support for the implication of oxidative stress in p-cell dysfunction in diabetes by providing protection against glucose toxicity and inhibit stress-sensitive signaling pathways that lead to the development of diabetes. Moreover, identification of the basis for the protection afforded by a variety of antioxidants against oxidative-induced damage, might lead to the discovery of pharmacological targets for novel therapies to prevent, reverse, or delay the onset of the resultant pathologies.
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