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Regeneration-Recycling bv Adding Vitamin C

ss ss

Semiascorbyl Radical (AscH»-)

When added vitamin C becomes oxidized (Asc?-) The vitamin E radical reappears

Figure 2 Vitamin E radical reactions during lipid peroxidation.

through regenerating vitamin E as described above or through directly substituting for vitamin E as an antioxidant, or some combination of both.

The vitamin E radical slowly decomposes as a result of reacting with itself or with other radicals. When ascorbic acid is added to a system in which vitamin E radical is being generated, the vitamin E radical disappears as it is reduced back to vitamin E by reaction with ascorbate and the semiascorbyl radical appears. But the vitamin E radical eventually returns as the the semiascorbyl radical disappears. From this experiment, the time that it takes for the vitamin E radical to reappear, or the lag period, can be determined. The time of the lag period is directly related to the vitamin C concentration. However, if dihydrolipoic acid is added to the reaction mixture, as well as vitamin C, and the same experiment is performed, one now observes that it takes a much longer time for the vitamin E radical to return. In this experiment, the lag period time is directly related to the concentration of the reduced lipoic acid. Reduced lipoic acid recycles the vitamin C radical (13). There are other ways in which lipoic acid can react with, and thus recycle, other antioxidants. After lipoic acid is reduced, it can regenerate oxidized thioredoxin, glutathione disulfide, or dehydroascorbate. Also, reduced lipoic acid has been reported to regenerate the semiquinone of ubiquinone (coenzyme Q10) in membranes (H.

Nohl Laboratory, Vienna). Thus, the entire antioxidant defense system can be affected by the presence of reduced lipoic acid.

III. OXIDATIVE STRESS, THE ANTIOXIDANT NETWORK, AND DIABETES

Why are oxidative stress, antioxidants, and the antioxidant network important in diabetes? Hyperglycemia causes, as a result of stimulation of the sorbitol dehydrogenase pathway, accumulation of NADH and an increase in the lactate/pyruvate ratio. This is accompanied by decreased glycolysis, increased reactive oxygen species formation, increased protein kinase C activity, and decreased Na+/K+ ATPase, among other effects, as shown in Figure 3. It is reasoned that the reductive imbalance that occurs in hyperglycemia, and which may also occur in ischemia/hypoxia injury (20-22), might be reversed by

Figure 3 Proposed mechanism of lipoate-mediated reversal of the reductive imbalance in hyperglycemia.

lipoic acid. Roy et al. (19) performed experiments to study if lipoic acid could affect the metabolic situation in hyperglycemia.

If R-lipoic acid is added to cells, it should, as a result of its reduction by mitochondrial dihydrolipoamide dehydrogenase activity, reverse the reductive imbalance in hyperglycemia and perhaps normalize the imbalance of overproduction of NADH and change the NADH/NAD+ ratio toward normal. Using human T lymphocytes as a model system, we performed experiments to determine if this was the case (19). Indeed, treating these human T cells with R-lipoic acid (but not S-lipoic acid) normalized the redox status (Fig. 4).

Lipoate treatment caused the NADH/NAD+ ratio to be reversed in hyperglycemia; the ATP/ADP ratio, which had fallen, was increased, and the imbalance of the pyruvate/lactate ratio was also reversed. Furthermore, the uptake of glucose by these cells was stimulated. With lipoic acid treatment, even at 100-|iM concentrations, significant increases in the uptake of glucose by these cells were observed (19).

Of course, one may wish to know how relevant these observations from a cellular system are to diabetes. We have proposed two models to link the ideas presented above and the possible therapeutic effects of lipoic acid in diabetes:

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