Streptozotocin, lipid

It should be mentioned that the inhibition of superoxide overproduction and lipid peroxidation by lipoic acid has been recently shown in animal models of diabetes mellitus. The administration of LA to streptozotocin-diabetic rats suppressed the formation of lipid peroxidation products [213], In another study the supplementation of glucose-fed rats with lipoic acid suppressed aorta superoxide overproduction as well as an increase in blood pressure and insulin resistance [214]. 

Lipid peroxidation is another free radical-mediated process enhanced in diabetes mellitus. It should be noted that some data obtained in animal models of diabetes could be misleading and not related to real diabetic state. For example, the enhanced intracellular generation of hydroxyl radicals has been shown in widely applied streptozotocin-induced model of diabetes in rats [121]. However, Lubec et al. [122] later showed that streptozotocin itself and not the diabetic state is responsible for the formation of hydroxyl radicals in this model. 

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Quine SD, Raghu PS. (2005) Effects of (-)-epicatechin, a flavonoid on lipid peroxidation and antioxidants in streptozotocin-induced diabetic liver, kidney and heart. Pharmacol Rep 57 610-615. 

Numerous studies have indicated that pro-inflammatory mediators (cytokines) are involved in the destruction of the insulin-producing p-cells of the pancreas in the development of type I diabetes. Tabatabaie et al. introduced cytokines and PBN into the pancreas of rats. The analysis of pancreatic extracts revealed that the cytokines stimulate the formation of lipid radicals. Radical generation did not occur in rats treated with streptozotocin, which destroys the P-cells.33 Evidence for the role of radicals in diabetes has also been provided by spin trapping studies in pancreatic homogenates, showing that streptozotocin, which is often used to induce the condition in laboratory animals, stimulates OH production.332 Other workers, using EPR to observe the decay of a spin probe in the abdomen of mice (at 1.2 GHz), have demonstrated that strep-... 

In a related study, streptozotocin-induced diabetic rats were treated with pyridox-amine, vitamin E, and enalapril (7V-(l-[ethoxycarbonyl -3-phcny I propyl)-Ala-Pro), an AGE/ALE inhibitor, an antioxidant, and an ACE-inhibitor, respectively.598 Diabetic hyperglycaemia was accompanied by severe dyslipidaemia. Treatment with pyridoxamine was the most effective in reducing lipid abnormalities and in retarding nephropathy, retinopathy, and protein modification. Vitamin E was the next most effective treatment in retarding nephropathy, but did not affect retinopathy or AGE/ALE formation. Enalapril normalised blood pressure and retarded nephropathy and the accumulation of CML in the kidney, but did not affect dyslipidaemia and retinopathy. Thus pyridoxamine is the most effective therapy overall. 

T. Yokozawa, H. Y. Kim, and E. J. Cho, Erythritol attenuates the diabetic oxidative stress through modulating glucose metabolism and lipid peroxidation in streptozotocin-induced diabetic rats, J. Agric. Food Chem., 2002, 50, 5485-5489. 

Whiting, P.H., Palmano, K.P., and Hawthorne, J.N., 1979, Enzymes of myo-inositol and inositol lipid metabolism in rats with streptozotocin-induced diabetes. Biochem. J. 179 549-553. 

Faas FH. Carter WJ. Altered microsomal phospholipid composition in the streptozotocin diabetic rat. Lipids 1983 18 339-342. 

Related studies on the bioactivity of LJ have also been reported. Jin et al. (2004) investigated the preventive effects of LJ aqueous extract (LJE) on alterations in the activity of hepatic xanthine oxidase and oxidative stress in streptozotocin-induced experimental diabetes. Pretreatment with LJE at 100 mg/kg orally for 5 days significantly reduced blood glucose levels and hepatic lipid peroxidation in diabetic rats due to the antioxidant activity of the extract. 

The antioxidant role of pterostilbene in streptozotocin-nicotinamide-induced type 2 diabetes mellitus in Wistar rats was evaluated [113]. The activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione significantly decreased in liver and kidney of diabetic animals compared to normal control. The increased levels of lipid peroxidation measured as thiobarbi-turic acid reactive substances in liver and kidney of diabetic rats were also normalized by treatment with pterostilbene. Chronic treatment of pterostilbene remarkably reduced the pathological changes observed in the liver and the kidney of diabetic rats. 

The efficacy of capsaicin as a hypocholesterolemic agent has also been investigated in animals fed cholesterol in their diets. Sambaiah and Satyanarayana [104] have reported that the serum cholesterol levels in rats on a 1 % cholesterol -i- 5 % red pepper diet were lower than those not fed with red pepper. Liver cholesterol was lower in the red pepper- as well as capsaicin (an equivalent level of 15 mg%)-fed groups. Fecal excretion of free cholesterol and of bUe acids was enhanced in animals fed the spice and capsaicin. The anti-hypercholesterolemic efficacy of dietary capsaicin has been evidenced in rats fed an atherogenic high-cholesterol diet, and such an influence also resulted in countering of the changes in membrane lipid profile in the erythrocytes [105]. In streptozotocin-induced diabetic situation however, dietary capsaicin did not show any beneficial hypolipidemic property [106]. 

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of diabetes mellitus. There is evidence for increased levels of circulating ROS in diabetics, as inferred by the increased lipid peroxidation. Streptozotocin-induced diabetic rats maintained on a 0.5% curcumin diet for 8 weeks showed lowered lipid peroxidation in plasma and urine when compared to control diabetic group (Babu and Srinivasan 1995). The effect of chronic curcumin treatment (200 mg/kg) on the oxidative stress in streptozotocin-diabetic rats was studied at four weekly intervals up to 24 weeks (Majithiya and Balaraman 2005). Curcumin treatment significantly reduced lipid peroxidation. 

Sahin K, Onderci M, Tuzeu M, Ustundag B, Cikim G, Ozercan IH, Sriramoju V, Juturu V, Komorowski JR. Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus the fat-fed, streptozotocin-treated rat. Metabolism. 2007 56 1233 0. 

In compensation for this abnormal situation, fat is preferentially used as a sole energy source in the body. The metabolic shift to lipid utilization leads to hypertriglyceridemia accompanied by elevation of free fatty acid in blood and, in very advanced stages by elevation of ketone bodies including acetoacetate and 3-hydroxy-butyrate in blood. Increased level of CoA and acyl CoA in the diabetic rat liver was reported by Smith et al. [1]. This seems to be a metabolic response to increased utilization of fatty acid in diabetic state and suggests increased requirement for CoA in diabetic tissues. It is, therefore, interesting to study the effect of some precursors of CoA on diabetic hyperlipidemia. The present paper deals with a favorable effect of pantethine on lipid metabolism in streptozotocin diabetic rats. Pantethine treatment has been found to reduce increased levels of serum triglycerides,... 

Fig. 2. Effect of pantethine treatment on serum lipids in diabetic rats in vivo. The streptozotocin-induced diabetic rats were given pantethine ( group III, n=10 ) in diet for 4 weeks, being started at 2 weeks after streptozotocin injection. Serum lipid levels were compared with those in the normal ( grouo I, n=12 ) and the diabetic control rats ( group II, n=10 ) before and after pantethine treatment.

The induction of streptozotocin diabetes was associated with increased accumulation of lipid rich plaque in the arch, thoracic and abdominal aorta, as detected by staining for fat with Sudan IV. Treatment with the AGE-inhibitor, LR-90 had a modest but significant effect on plaque accumulation, especially in the thoracic and abdominal segments (Figure 3). No significant effect was observed in the arch, consistent with the known haemodynamic dependence of arch lesions... 

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