Diabetes, lipid peroxides

Simonelli, F., Nesti, A., Pensa, M. etal. (1989) Lipid peroxidation and human cataractegenesis in diabetes and severe myopia. Exp. Eye Res. 49, 181-187. 

Table 12.1 Studies of serum/plasma lipid peroxides in human diabetes modified from Lyons (1991)...

TBA, thiobarbituric acid reactivity DCs, diene conjugates MA, microangiopathy LP, lipid peroxides DM, diabetic patients C, controls HDL, high-density lipoprotein. 

Overall, and contrary to others (Lyons, 1991), we feel that the weight of scientific evidence indicates that lipid peroxidation is increased in diabetes irrespective of whether complications are present or not. The presence of microangiopathy or severe atheroma is likely to increase the degree of peroxidation even further. 

Further research is required to establish whether free-radical-induced damage is a primary event in diabetes. Tissue damage, which is associated with inactivation of antioxidants and release of metal ions that are potent catalysts of free radical reactions, can lead to lipid peroxidation. This raises the possibility that the diabetic process itself or other frctors may increase free-radical activity following direct tissue damage. 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

Several studies have demonstrated that treatment of diabetic patients with the sulphonylurea, gliclazide, is associated with a fall in lipid peroxidation, protein fluorescence and beneficial effects on platelet function (Florkowski et al., 1988 Jennings et al., 1992). These changes were seen to be independent of changes in giycaemic control. 

Nishigaki, 1., Hagjhara, M., Tsunekawa, H., Maseki, M. and Yagi, K. (1981). Lipid peroxide levels of serum lipoprotein fractions of diabetic patients. Biochem. Med. 25, 373-378. 

Parinandi, N.L., Thompson, E.W. and Schmid, H.H.O. (1990). Diabetic heart and kidney exhibit increased resistance to lipid peroxidation. Biochim. Biophys. Acta 1047, 63-69. 

Sato, Y., Hotta, N., Sakamoto, N., Matsuoka. S, Ohishi, N. and Yagj, K. (1979). Lipid peroxide level in plasma of diabetic patients. Biochem. Med. 21, 104-107. 

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]. 

Vitamin B6 (pyridoxine) and its derivative pyridoxamine are apparently able to inhibit superoxide production, reduce lipid peroxidation and glycosylation in high glucose-exposed erythrocytes [353], It was suggested that the suppression of oxidative stress in erythrocytes may be a new mechanism by which these natural compounds inhibit the development of complication in diabetes mellitus. 

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]. 

At present, antioxidants are extensively studied as supplements for the treatment diabetic patients. Several clinical trials have been carried out with vitamin E. In 1991, Ceriello et al. [136] showed that supplementation of vitamin E to insulin-requiring diabetic patients reduced protein glycosylation without changing plasma glucose, probably due to the inhibition of the Maillard reaction. Then, Paolisso et al. [137] found that vitamin E decreased glucose level and improved insulin action in noninsulin-dependent diabetic patients. Recently, Jain et al. [138] showed that vitamin E supplementation increased glutathione level and diminished lipid peroxidation and HbAi level in erythrocytes of type 1 diabetic children. Similarly, Skyrme-Jones et al. [139] demonstrated that vitamin E supplementation improved endothelial vasodilator function in type 1 diabetic children supposedly due to the suppression of LDL oxidation. Devaraj et al. [140] used the urinary F2-isoprostane test for the estimate of LDL oxidation in type 2 diabetics. They also found that LDL oxidation decreased after vitamin E supplementation to patients. 

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. 

Yilmaz HR, Uz E, Yucel N, Altuntas I, OzceUk N. (2004) Protective effect of caffeic acid phenethyl ester (CAPE) on lipid peroxidation and antioxidant enzymes in diabetic rat Uver. J Biochem Mol Toxicol 18 234-238. 

Figure 16.14 represents a summary of the most important studies performed in the field of free radical scavenging effects. G115 inhibits lipid peroxidation in rats. It protects the rabbit pulmonary artery from free radical injury and the rat heart from ischemia reperfusion injury. Figure 16.15 illustrates the various diseases that are due to an excessive production of free radicals, such as atheroclerosis, diabetes, rheumatoid arthritis, and aging. 

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