Inhibitors of AGE Production

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The production of AGE, as a result of prolonged exposure of proteins to chronic hyperglycemia, can result in direct quenching of NO and increasing the oxidative stress.

Fig. 6. Forearm blood flow (FBF) dose-response curves to intra-arterial methacholine chloride infusion before and during coinfusion of vitamin C in noninsulin-dependent diabetic subjects. The concomitant infusion of methacholine and vitamin C resulted in an improved endothelium-depen-dent vasodilation compared with methacholine alone (p = 0.002 by ANOVA). Comparisons of FBF at each methacholine dose before and during vitamin C administration were performed by paired i-tests adjusted with a Bonferoni correction for multiple comparison. *p < 0.05; **p < 0.01. (From ref. 63a.)

Fig. 6. Forearm blood flow (FBF) dose-response curves to intra-arterial methacholine chloride infusion before and during coinfusion of vitamin C in noninsulin-dependent diabetic subjects. The concomitant infusion of methacholine and vitamin C resulted in an improved endothelium-depen-dent vasodilation compared with methacholine alone (p = 0.002 by ANOVA). Comparisons of FBF at each methacholine dose before and during vitamin C administration were performed by paired i-tests adjusted with a Bonferoni correction for multiple comparison. *p < 0.05; **p < 0.01. (From ref. 63a.)

An inhibitor of AGE production, aminoguanidine, has been shown both to reduce AGE and to improve endothelial function (88,171) in animal models.

Vitamins C and E

As discussed earlier, one possible mechanism of endothelial dysfunction in both type 1 and type 2 DM is the inactivation of NO by oxygen-derived free radicals. There is also a decrease in levels of endogenous antioxidants including superoxide dismutase and catalase in animal models of diabetes (172). Furthermore, several clinical studies have reported a decrease in endogenous vitamin C (173,174) and E (173,175) levels in both type 2 and type 1 DM. Any means of decreasing the oxidative stress has the potential to improve endothelium-dependent vasodilation. Timimi et al. (176) and Ting and coworkers (177) (Fig. 6) found that intra-arterial infusion of vitamin C improved endothelium-depen-dent (but not endothelium-independent) relaxation in patients with type 1 and type 2 diabetes, respectively. Furthermore, the intra-artrial infusion of ascorbic acid restored the impaired endothelial vasodilation in healthy subjects exposed to hyperglycemic clamp (178).

Tetrahydrobiopterin

Conversely, hyperglycemia, which increases oxidative stress, can convert even elevated levels of NO to peroxynitrite, which is deleterious to vascular function (179). A decrease in oxidative stress can restore vascular function rather than increase the NO supply. Prolonged hyperglycemia and hypercholesterolemia both cause a depletion of tetrahydrobiopterin (BH4), an essential cofactor for NOS, resulting in an uncoupling of eNOS and lowered production of NO (180). Studies using both diabetic animal models (113) and hypercholesterolemic patients (112) have demonstrated that tetrahydrobiopterin supplementation restored endothelium-dependent vasodilation. This has yet to be confirmed in studies involving diabetic patients.

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