Alteration in Oxidative Stress

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Increases of oxidative stress by metabolic derangement has long been reported in diabetic states and proposed to cause vascular complications (44,59,63,64). In diabetic states, induction of oxidative stress could be as a result of the increased production of superoxide anion via the induction of NADPH oxidase and mitochondrial pathway; decreases of superoxide clearance; lipid and protein modification; and the reduction of endogenous antioxidants such as ascorbic acid, vitamin E, and glutathione.

Several lines of evidence support a role of increased oxidative stress in the pathogenesis of diabetic vascular complications. Reactive oxygen species, an index of oxidative stress, has been reported to be increased and in diabetic patients with retinopathy (65) and other cardiovascular complications in the Framingham Heart Study (66) and correlate with the severity of these diseases. Furthermore, these results have been recapitulated in diabetic animals or even in vascular cells cultured in media containing high levels of D-glucose (59,64).

Induction of oxidative stress has been suggested to induce vascular dysfunctions via multiple approaches including cellular DNA damage by activating the poly(ADP-ribose) polymerase (67,68); reduction of NO bioavailability (59), and the activation of other mechanisms known to induce vascular cell damage such as AGE formation, PKC activation, and induction of polyol pathway (69). Additionally, evidence has shown that reactive oxygen species can cause severe disturbances in the regulation of coronary flow and cellular homeostasis, leading to the severe macrovascular lesions typically observed in diabetic patients after more than 10 years of disease (70,71). Inhibition of reactive oxygen species also prevent the generation of AGE products and the activation of PKC in cultured endothelial cells (69), suggesting that the auto-oxidative process plays an important role in the complex reaction cascade leading to AGE formation.

Several pathways in diabetic states, such as activation of PKC pathway, especially the P2 isoform (72,73); AGE formation (54), oxidized lipids (64,66), and altered polyol activity (59) can lead to the activation of NADPH oxidase or flux through the mitochondrial respiratory chain (69) to generate reactive oxygen species that further increases tissue oxidative stress. On the other hand, oxidative stress can precedes formation of some AGE, such as pentosidine and CML, and activation of the DAG-PKC pathway (74).

Although multiple studies using vascular cell in culture or diabetic animals have all supported that oxidative stress play an important role in vascular complications of diabetes. However, clinical studies have not yet provided conclusive results. The Heart Outcomes Prevention Evaluation Study (HOPE) has shown that treatment with vitamin E at a dose of 400 IU per day for a mean of 4.5 years has no apparent effect on cardiovascular outcomes in patients who had CVD or diabetes in addition to one other risk factor (75). Similarly, the MICRO-HOPE study also yielded negative results showing

Table 4

Summary of DAG Levels and PKC Activities in Cultured Cells Exposed High Glucose Condition and Tissues Isolated From Diabetic Animals

Diacylglycerol Protein kinase C

Cultured cells

Retinal endothelial cells î î

Aortic endothelial cells î î

Aortic smooth muscle cells î î

Renal mesangial cells î î Tissues

Renal glomeruli (diabetic rats) î î

that400 IU per day of vitamin E failed to show difference in cardiovascular outcomes and diabetic nephropathy (76). However, we have reported that oral vitamin E treatment at a dose as high as 1800 IU per day appears to be effective in normalizing retinal hemodynamic abnormalities and improving renal function in type 1 diabetic patients of short disease duration without inducing a significant changes in glycemic control (77). At this dose, vitamin E is capable of inhibiting PKC activity (74). These results suggest that highdose vitamin E supplementation may reduce the risks of diabetic vascular complications by antioxidant-dependent and -independent pathways. These largely inconclusive clinical results have suggested that oxidative stress play a supporting rather than central role in the pathogenesis of diabetic vascular complications.

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