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2 Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615-1625.

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5 Horani MH, Haas MJ, Mooradian AD: Rapid adaptive down regulation of oxidative burst induced by high dextrose in human umbilical vein endothelial cells. Diabetes Res Clin Pract 2004;66:7-12.

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7 Horani MH, Haas MJ, Mooradian AD: Suppression of hyperglycemia-induced superoxide formation and endothelin-1 gene expression by carvedilol. Am J Ther 2006;213:2-7.

8 Jaiswal AK: Regulation of genes encoding NAD(P)H: quinone oxidoreductases. Free Radic Biol Med 2000;29:254-262.

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39 The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035.

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Dr. Schiffrin: You have mentioned different antioxidants such as vitamin C and vitamin E. What about the status of other intracellular antioxidants such as glu-tathione? Is it possible that giving glutathione precursors, such as cysteine or proteins rich in cysteine, can improve the glutathione cellular status? This is my first question. What about the administration of arginine? In fact arginine as a substrate of endothe-lial nitric oxide synthase and a precursor of nitric oxide may well modify the endothelial status. My last question is whether the redox status in diabetes in addition to altering endothelial function could also have an influence on the immune system such as the level of macrophage activation that in turn may increase the inflammatory stress in this type of patient. Is the glutathione status of these patients known?

Dr. Mooradian: Glutathione is a very important antioxidant and indeed there are some studies showing that glutathione stores might be reduced in diabetes, especially in uncontrolled diabetes, but these are small studies. There are no studies showing that interventions or replacement with glutathione or its substrates, precursors, would have an impact on any long-term outcome. But the clinicians in the room would know that those intermediates have been used to protect the kidney from other damage during the administration of contrast agents and drug-related hepatic disease, which is another disease entity that involves oxidative stress. So at the moment the short answer is that glutathione precursors are not involved or have not been used in interventional trials to show any outcome measures. Your second question about argi-nine and endothelial nitric oxide synthase is interesting because it does have some beneficial effects on endothelial cell function, but also remember that one of the sources of oxidative stress is nitric oxide and proteins are modified with nitric oxide. So there is a fine balance whether you are going to achieve a favorable effect with supplementation or not. By the way arginine and a lot of biochemical molecules, including simple molecules such as creatinine or uric acid, all have very important antioxidant activity. In that sense it may have some additional effect as an antioxidant. Again, there are actually no interventional trials on the immune system and macrophage activation, but there are experimental data on the role of macrophages in promoting atherosclerosis, and obviously that is highlighted by the story on myeloperoxidase as a key enzyme in promoting atherosclerosis. I am not aware of any interventional trial targeting myeloperoxidase to prevent premature atherosclerosis. But probably that will come eventually because it is a very hot area of investigation.

Dr. Halimi: Could you say some words regarding the zinc status, the tissue contents of zinc in human diabetic patients? With my group I did some studies on this topic in rats with insulin resistance induced by a high fructose diet. Zinc plasma and tissue concentrations were found to be very low, furthermore zinc supplementation was able to normalize insulin sensitivity in these animals. What is your opinion about the loss of zinc in diabetic patients, perhaps in urine partly due to glycosuria, diuretics?

Dr. Mooradian: There is a lot of literature on the issue of zinc and as Dr. Halimi mentioned, diabetic individuals, especially those with uncontrolled hyperglycemia and those on diuretic therapy, tend to have excessive excretion of zinc in the urine. But when the zinc stores are measured, be it in plasma or intracellularly as in white or red cells, it is highly variable; sometimes it is normal, sometimes it is high, sometimes it is low, so there is really no consistent effect. One of the reasons is that zinc metabolism is a good example of what I mentioned in terms of the organism protecting itself against micronutrient deficiency. Once there are losses of zinc in the urine, the gut absorption of zinc is multiplied, it increases several fold. Zinc absorption in diabetic individuals is actually quite high for various reasons. One is that the transporters are upregulated, and also the intestinal mucosal area in diabetes, especially in uncontrolled diabetes, is vastly expanded. They tend to absorb zinc much more efficiently than an average individual; so even though they are losing zinc they are also absorbing zinc quite a bit, and therefore they may not have any zinc deficiency. The problem with zinc deficiency or the determination of zinc deficiency is that we really don't have reliable methods of measuring zinc. Certainly measuring the elemental zinc in plasma or intracellular zinc may not be the best indicator. There are some new methods now that enable estimation of zinc status by measuring certain gene products that are modulated by zinc, but again they have not really caught on in clinical practice. Zinc is an important element in terms of diabetes management, but it doesn't seem that easy to produce zinc deficiency.

Dr. Eshki: Do you believe that controlling for upper levels or recommended allowances on both macro- and micronutrients is essential before looking at specific oxidants and their effect on diabetes?

Dr. Mooradian: Are you asking about daily recommended intakes (DRIs) and the variety of nomenclatures in that regard, whether it is recommended dietary allowances or dietary guidelines and dietary recommended ranges? Your point was to first look at the dietary intakes and then see if supplementation on top is useful?

Dr. Eshki: The reason I am asking is because normally when dealing with trauma patients under stress, some physicians ask me why I don't use zinc because they heard that zinc is good at this point. What I tell them is that for me the optimal is to reach the DRI for the patient, and then look at other factors. But when we say, alright, start this way, it is going to become more confusing because we are going to end up with a bag of supplements.

Dr. Mooradian: Yes, I understand what you are saying and I fully subscribe to that. In terms of limiting supplementation or intake to the DRIs rather than trying large amounts of micronutrients and supplements. I think at the moment that would be the most rationale thing to recommend.

Dr. Tong: I noticed that a lot of dietary recommendations do suggest that patients with cardiovascular disease increase their intake of vegetables and fruits. One of the reasons is because it has been claimed that they can get antioxidant products from vegetables and fruits. Are you aware of any study that has looked at the antioxidative capacity in patients taking different proportions of vegetables or different amounts of fruits?

Dr. Mooradian: Again the optimal way of getting antioxidants is to consume good looking and good tasting food, that would be vegetables and fruits, and I agree with that recommendation. But in terms of evidence in interventional trials, we have the same problems we were discussing this morning and yesterday that it is very hard to implement an interventional trial with a dietary change and sustain that dietary change over a prolonged period of time in a large number of individuals to be able to show that a particular dietary intervention is effective. At the moment I suspect that it should remain a commonsense approach, a consensus approach. I think people have to emphasize the importance of acquiring antioxidants through dietary means and healthy food choices. But it doesn't mean that we should not be continuing to look for effective antioxidants in pill form, and if it has any health protective effect that will obviously be a welcome addition to the diet.

Dr. Tong: Vitamin E, e.g. some antioxidants from vegetables or natural products, are they going to be different in terms of the isoforms compared to pharmaceutical preparations of vitamin E?

Dr. Mooradian: I suspect that it is probably true that the antioxidants in food are different from the more purified elements that are available in pill form from the pharmaceutical industry. The antioxidants in food are very complex since a whole series of compounds has variable degrees of antioxidant activities but is a very rich mixture of compounds. When you select one compound as the candidate element to introduce as a supplement, you are at risk of either choosing the one that may not have as much efficacy as the others when they are all in conjunction, or the one that may end up having some toxicity as well. I don't want to discourage people from pursuing and looking into specific components of the diet that have important antioxidant activities that may be useful pharmaceutically.

Dr. Hill: The large epidemiological studies provide one way to look at this issue, but is anyone doing the clinical trials with fewer numbers of subjects and with more control, where the oxidative state is measured with interventions such as with increased fruit and vegetable consumption or supplements?

Dr. Mooradian: It should be done, but as yet it has not been done and that is the major problem in the field. We have been doing study after study with very primitive tools and the results are not always reliable, so we need to have better clinical trials designed.

Dr. Chiasson: All these interventional trials are definitely very disappointing and as a matter of fact there is only the CHAOS study, which is questionable as you mentioned. You did mention that one of the problems is that the antioxidant capacity of the subjects was not measured. But do you really think that that is the problem? Why do you think that all these interventional studies are totally negative?

Dr. Mooradian: I suspect that there are various potential reasons: one is that the right antioxidants are not being used, but conventional antioxidants are. As I mentioned these are interceptors or scavengers rather than real agents that reduce oxida-tive stress. It is possible that perhaps the dosing is inadequate, as we have no idea what the appropriate dose will be for these conventional agents to have an effect on oxidative stress. The third potential limitation is that this is a process that takes years and years to develop, and these studies, usually in the range of 4, 5, 6 years, may not be long enough to show the benefit of antioxidant supplementation. What really is needed are studies that go on for 15, 20 years to see an effect. So that is a very difficult point to prove or disprove.

Dr. Jianqin Sun: I have three questions. What is the role of the phytochemical substances in antioxidative stress? There are many supplements in either a natural or an artificial form. Which do you think is better; is one better than the other? And the third question, it is quite common that many people take supplements. Should supplements be taken for a long time or for a short time?

Dr. Mooradian: The first question is about phenols and naturally occurring antioxidants which are extremely important, there is no question about that, and there are a lot of them. The question is are they effective in the long run: I really don't know. People have been promoting the use of phenol-containing products, and obviously one of my favorite sources of that would be red wine. Again, there is no clear evidence though that it really makes a big difference. There is a lot of evidence in experimental models in cell cultures preventing oxidation. The other issue of whether the antioxidant should come from natural sources or from pharmaceutical sources: I really don't know the answer. My naive thinking is that it should not make a difference. If you have an effective compound, whether it is packaged in the food or packaged in a pill, it should not make a difference. The problem is we don't know what that effective compound is, so that is where the problem arises. The third question about the duration of treatment is even more difficult. One of the criticism of these interven-tional trials is that they have not been long enough. So if I see people who are taking supplements, what I do is to ask them to try to limit the supplements to within what I consider to be a reasonably safe margin. In other words if they are taking 1,000mg vitamin E, I ask them to cut it back to less than 400mg/day and negotiate a happy medium. The same with carotene and certainly with the retinol. Retinol certainly should not exceed 10,000 or even 8,000 units/day. This is especially an issue for women of reproductive age because retinol in high concentrations is associated with significant teratogenicity. Those women who are taking supplements and planning a pregnancy have to be careful to avoid that. They should be on folate and calcium supplements, possibly a little bit of iron supplementation, but not high concentrations of retinol.

Dr. Bantle: In North America the most commonly taken antioxidant supplement is vitamin E, As a participant in a physician's health study, there is one chance in two I personally am taking it. So I would like to ask what your thoughts are about the recent meta-analysis suggesting that vitamin E may actually increase mortality rates.

Dr. Mooradian: You have raised a very important issue that mortality appears to be increased with vitamin E use in this recent meta-analysis. Having said that, I have a very negative bias against meta-analyses in general. I have always said that meta-analysis is to analysis as metaphysics is to physics, and it is really very difficult to compile the data. I understand there are ways of improving your analysis if you are careful and take all the factors into consideration. But nevertheless meta-analyses are like observational trials, they are very good in terms of generating hypotheses. Again it raises the spectra that perhaps indiscriminate use of antioxidants is not the wisest thing to do, and it brings to the forefront the potential that there might be some toxi-city involved with the use of very large doses of antioxidants. But I would not drop out of the study because of that meta-analysis; just continue taking your vitamin E, I guess, if you are taking it already.

Bantle JP, Slama G (eds): Nutritional Management of Diabetes Mellitus and Dysmetabolic Syndrome. Nestlé Nutr Workshop Ser Clin Perform Program, vol 11, pp 127-137, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2006.

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