Tuesday, May 26, 2009

On Antioxidants

For a long time, many people have suggested that one reason we age is that we basically "rust" with time.

Rust is formed when oxygen reacts with iron, and the "aging as rusting" idea is that reactive oxygen compounds in our bodies, called
free radicals or reactive oxygen species (ROS), react with important compounds in our body and destroy their effectiveness.

Hence a lot of people have been taking huge doses of antioxidants in the hopes that this will make them healthier.

But recently, a news article that was ricocheting around the Internet said that when you take high doses of antioxidants (the researchers studied vitamins C [1000 mg] and E [400 mg] taken for 4 weeks), the beneficial effects of exercise are eliminated. This study was performed in nondiabetic healthy young men.

On the basis of this news report, some people probably decided to throw their antioxidants away.

But wait a minute! There are a lot of studies out there suggesting that antioxidants can help people with diabetes. What's going on here? Are antioxidants good or bad?

ROS are formed in our cells when we metabolize our food to produce the energy we need to live (or when we metabolize the glucose or fatty acids stored in the body to be used when we're not eating). The process of producing energy is not 100% efficient, and the ROS are the result of this inefficiency.

ROS are extremely reactive, and if not neutralized, they can cause damage to our cells. Our body knows this, so it produces antioxidants to neutralize the ROS. The more ROS we produce, the more endogenous antioxidants we make. This is called mitohormesis.

Beta cells, however, produce fewer antioxidants than other cells, and for this reason, they're much more susceptible to cell damage from ROS. When the damage is severe, the beta cells commit suicide, a process called
apoptosis. Chemicals used to make rodents diabetic (streptozotocin and alloxan) use ROS to kill the beta cells.

Why do beta cells produce fewer antioxidants than other cells? Is this just an accident of nature, or is there a good reason? I'd tend to vote for the latter, as the body usually has reasons for doing things, even when we don't always understand those reasons.

People with diabetes have even lower levels of endogenous antioxidants than nondiabetics, so researchers have suggested that antioxidants might be a good idea for people with diabetes. In fact, entire books have been written on this topic.

It has been suggested that people who develop complications may be especially deficient in endogenous antioxidant production, and those who do not despite poor control may be more fortunate in their natural production of these natural antioxidants.

Although in vitro and animal studies (e.g., here) have shown benefits of adding antioxidants, so far no major studies have shown major benefits in humans with diabetes. One question is how we define benefits. Do we mean A1c levels? Lipid levels? Diabetes prevention? Less insulin resistance? Decrease in cardiovascular disease rates? Increased longevity? Nicer hair?

In fact, sometimes the addition of antioxidants has been shown to be deleterious.
One study even suggested that taking one common antioxidant (N-acetylcysteine, or NAC) might cause pulmonary hypertension (high blood pressure in the arteries that take blood to the lungs).

Nothing is ever black and white when it comes to diabetes, and this is certainly true of antioxidants. Although ROS can have deleterious effects on a cell, they can also have positive effects.

For example, scavenger cells use ROS to destroy bacteria and damaged cells, including cancer cells. Using
too much of an antioxidant might lessen the effectiveness of this beneficial effect. You could think of ROS as rifles. When you use the rifles to kill bad guys like rabid panthers, that's positive (for us, that is; not for the panthers). When you use the rifles to kill good guys like innocent people, that's negative.

Some chemotherapy to treat cancer works by producing ROS that destroy the cancer cells. So some people say you shouldn't take antioxidants if you're undergoing chemotherapy. Others say that taking antioxidants helps prevent side effects from the therapy. This issue has not yet been resolved.

And recently it has been discovered that ROS are not just harmful byproducts of reactions in cells. They can also act as signaling molecules.

In fact, ROS can increase the production of insulin
in the beta cell. The ROS alone won't stimulate insulin production, but it will augment the response triggered by glucose. Perhaps this is one reason beta cells don't produce as many antioxidants as other cells. The increase in insulin sensitivity seen after exercise also seems to be triggered by ROS, which explains why antioxidants might abolish the benefit.

Insulin secretion itself seems to increase the production of ROS. Studies have shown
that compounds such as diazoxide and calcium channel blockers, which inhibit insulin secretion, improve beta cell function in humans.

This would argue for limiting anything that causes high insulin secretion, for example, high-carbohydrate diets.

When you have insulin resistance, you produce even more insulin than normal until you wear your beta cells out. Perhaps it's the ROS that are causing the damage.

This is all fascinating (well, at least I think so). But what does it mean for us?

In healthy people, the production of ROS and the production of antioxidants to neutralize unwanted ROS should be in balance. When the system becomes unbalanced, it's called
oxidative stress. But if we have type 2 diabetes, we know that something in our bodies is out of balance and we probably have less antioxidants than normal, so perhaps we need to help the cells restore the balance by taking some antioxidants.

The cited exercise study was performed on nondiabetic men. It's possible that because they were already producing sufficient antioxidants, further antioxidants were harmful. In people with diabetes who were deficient in antioxidants, the results might have been different.

Ideally, we'd be able to take just enough antioxidants to keep the beta cells from committing suicide, but not so much that the ROS wouldn't be able to augment the insulin response to glucose and protect us from cancer and infections. Needless to say, no one knows how much antioxidant this would be.

The timing and location of the antioxidants are also important. We may need antioxidants in one part of a cell but not in another. When functioning properly, our endogenous antioxidant systems would be able to control this. Taking antioxidants in pills probably can't.

Cells use short bursts of ROS to stimulate insulin production, but chronic production of ROS is harmful. This is analogous to the situation with glucose and fatty acids. Short-term increases in fatty acids or glucose will increase insulin production. But chronically high levels of fatty acids or glucose will cause insulin resistance.

In fact, when you have chronic oxidative stress (chronic production of ROS), your body starts producing more endogenous antioxidants, and this can be sufficient to reduce the secretion of insulin.

So how can we decrease the chronic production of ROS?
Preventing the formation of ROS in the first place would be likely to work better than trying to destroy just the right amount after they're formed.

The most important factor is to keep our blood glucose levels as close to normal as we can. Beta cells (and also endothelial cells) don't need insulin to take up glucose, so the more glucose there is in the blood, the higher the levels will be in these cells. The higher the levels of glucose in the cells, the more glucose they burn and the more ROS they produce.

ROS are formed when we metabolize our food. So the less food we eat, the fewer ROS we produce. Perhaps this is one reason why when overweight people (being overweight is one of several contributors to insulin resistance; about 50% is genetic) are put on a very low calorie diet, their BGs improve even before they've lost any weight.

However, we need to eat in order to live. Fasting is not a long-term solution.

I think taking a few antioxidant supplements might be a good idea, but overdoing it might not. It might also be wise to think about stopping the antioxidants if one were on chemotherapy.

Of course, it's always better to get your vitamins and other beneficial compounds in food. This is how we evolved to get them, so we're probably designed to absorb small amounts of antioxidants as we slowly digest our food rather than getting huge amounts from a pill all at once.

Sometimes, taking a lot of a substance shuts off the body's endogenous production of that substance. It probably thinks, "Gosh, I'm getting all this antioxidant from that pill. Why should I bother to make it myself?"

Furthermore, many vitamins and supplements these days come from China, which lacks the strict qualtity control we would like to see.

Whole, unprocessed foods also contain fiber and other beneficial substances in addition to the antioxidants. They may also contain antioxidant precursors, giving the body the raw materials to make antioxidants when and where they are needed.

But when we have diabetes and we're trying to eat less food, and perhaps omit some foods like sweet fruits that are full of antioxidants, this becomes more difficult. This is especially true as we get older and need less food to keep us going.

Some drugs some of us may be taking are reported to have antioxidant properties. These include metformin, ACE inhibitors, TZDs, statins, and calcium channel blockers. Some foods
with high levels of antioxidants include spinach, cumin, fennel, basil, and black pepper.

I myself take vitamin C (500 mg, not a huge amount). I stopped taking vitamin E because I had an uneasy feeling about it. There are many different forms of vitamin E, and I worried that taking the form found most commonly in standard vitamin E pills would shut off the production of the other, more beneficial, forms of the vitamin. You can buy vitamin E mixtures, but they're much more expensive, and who knows if they contain all the forms that we need.

I've also started taking coenzyme-Q10, which is a powerful antioxidant. I take it because I'm taking a statin, and I found my legs were getting weaker and weaker. When I tried the Q10, my muscles seemed to regain some strength. However, the effect seemed to be greatest in the first week, and now I'm wondering if taking it exogenously is shutting of my own production of this vital compound.

I also take metformin, a statin, and an ACE inhibitor, which have some antioxidant properties, and I love green vegetables, berries, and coffee, all of which contain antioxidants.

Another common antioxidant is alpha-lipoic acid. It's supposed to be especially beneificial when you have neuropathy. It also reduces insulin resistance, but the half-life in serum is so low that it can't do much unless you take an extended-release form.

I tried taking it and saw no effect on my blood glucose levels. Other people do.

Of course, I have no idea whether my own antioxidant regimen is really the best one for me, and I'm not recommending it for everyone else. There are so many unknowns in this business, and we have to make decisions on the basis of incomplete evidence.

Antioxidants are good when they are in the part of the cell that needs them, when it needs them. But when we eat antioxidants in pill form, they have to be taken up by the digestive system and then transported to the cells and taken up by those cells. Then they have to get into the particular part of the cell that needs them.

Some parts of the cell might get more than it needed (for example, the antioxidant might reduce the secretion of insulin), and other parts might not get enough, so the cell would commit suicide. We don't yet have the technology to make sure the antioxidants we ingest get where they're needed.

So helping our deficient systems along with a few antioxidants is probably a good thing. However, knowing that ROS can also have some beneficial effects, I think we should think carefully before gulping down huge amounts.

One author came to pretty much the same conclusion, although he prefers bigger words: ". . . it is now plausible that such entities have an evolutionarily orchestrated capacity to self-regulate that may be pathologically disturbed by overzealous use of antioxidants, particularly in the healthy."


  1. Dear God, Why are you taking a statin? There is no evidence they help women at all.
    Please do some research in this area.

    Jeanne Shepard

  2. 1. The fact that there's no evidence of something doesn't mean that it's not true. There are no studies showing that that aspirin reduces pain, for example. Just annecdotal evidence.

    2. If my cholesterol were something like 230, I wouldn't take a statin. Without drugs, my cholesterol is in the 400s, and there's evidence that reducing superhigh levels does help.

  3. I assume you know the breakdowns, HDL, LDL, (and the kinds of LDL, small particle, vs. larger, benign particle) and triglycerides.
    Those all play a role too.
    It's none of my business what people choose to take, however I am watching a brother in law lose his memory slowly, and I think its a side effect of Lipitor. It's hard not to say anything.


  4. Yup I'm aware of potential problems.

    All drugs have side effects, and one is constantly weighing risks vs benefits. Your BIL might want to taper the Lipitor and see if his memory improves. When memory loss is caused by the statins, it seems to reverse pretty quickly.

    If there's no change, then he could start the statin again. I think the water-soluble statins are less risky than Lipitor.

    The University of California at San Diego has published an extensive article about statin side effects.