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."

Tuesday, May 12, 2009

Bromocriptine and Hibernation

The Food and Drug Administration recently approved the drug bromocriptine mesylate for use in treating diabetes.

The drug works on dopamine receptors in the brain to produce the same effects as dopamine would produce. For this reason, it's been used in dopamine-deficiency diseases like Parkinson's disease for some time.

In other words, it's not a new drug. It's a new use of an old drug.

But why, you might wonder, would a drug that works on dopamine receptors in the brain do anything for diabetes, which is a disease that causes blood glucose (BG) levels to be too high?

This is because there is some evidence that insulin resistance and obesity are regulated in part by the brain.

One example of this is the phenomenon of hibernation or, in some species, what is called torpor, a shorter period of reduced temperature and slower metabolism. Animals that hibernate typically put on a lot of weight in the late summer and fall. They also have increased insulin resistance.

People who believe that obesity is simply a case of eating too much and not exercising enough, causing obesity that in turn causes insulin resistance, would say this is what is happening in hibernating animals. There's a lot of food in the late summer and fall so the animals pig out and get fat, and the fat causes the insulin resistance, they'd argue.

But here's the interesting part. Ground squirrels normally put on a lot of weight in the fall. They also eat a lot more. But if you keep the squirrels in the laboratory and don't let them eat any more than normal, they'll put on weight anyway, mostly fat.

In other words something, most likely hormonal signals triggered by changes in daylength, are telling the squirrels to store fat. Because they're storing the fat instead of letting it hang around in the blood to be burned for energy, they have an energy deficit, and this makes them hungry.

This is consistent with the theory of weight gain described by Gary Taubes in his book Good Calories, Bad Calories. He says the "energy balance" equation so beloved of dieticians who use it to say that the only thing that matters is calories in and calories out is true, but the cause and effect have been reversed. This equation says:

Change in weight = energy in - energy out.

The dieticians would say if you change the right hand side of the equation, reducing energy in or increasing energy out, your weight will change. To some degree, this is true in extremes or for the short term, when an animal or person has no access to enough food, as in starvation, or has super willpower because of a belief that the latest diet will really work. But when food is available, the drive to eat becomes overpowering and any lost weight will be regained.

Taubes and other argue that some external force, mostly likely hormones or nervous system signals (Taubes argues that it's insulin) affects the left-hand side of the equation. This causes extreme hunger or lethargy, or both, as the body tries to balance the equation.

In other words, the net energy change is not causing the weight change, but the weight change makes the body try to balance the equation by creating an overwhelming desire to eat and aversion to exercise.

When food is available, the animal or person will thus eat more than normal and exercise less. But if you don't let them eat more than normal, they'll still store the fat. They'll just be very hungry and lethargic.

Furthermore, animals are not machines. Energy in from the same food can differ depending on the efficiency of digestion, and energy out can vary with the efficiency of transforming food into forms of energy the body can use. Some people turn excess calories into heat instead of turning them into fat.

So where does bromocriptine come into all this?

Syrian hamsters normally become insulin resistant and gain a lot of weight before they hibernate; these effects are blocked by bromocriptine. Similar effects were seen in obese women: glucose and insulin levels decreased and energy expenditure and fat burning both increased, although body weight did not change in this 8-day experiment. And other researchers
found that bromocriptine helped people with type 2 diabetes.

Some authors see hibernation as a model for insulin resistance, and the more we learn about what triggers the weight gain in hibernating animals, the more we'll know about what triggers insulin resistance and weight gain in obese humans.

They suggest that hibernators have a sliding set point. The con
cept of a set point is that the body has a certain weight that it wants to be, and if you go over or under that weight, you will have a strong urge to eat more if you're under the set point or eat less if you're over the set point. Instead of having one set point, hibernators have different set points depending on the time of year.

There are reasons to believe that bromocriptine might help people who have serious problems with obesity and insulin resistance. The drug has been around for a long time to treat other diseases, so we have a better idea of side effects than we do with brand-new drugs. And there are side effects.

The Mayo Clinic has a good outline of some of these side effects. They note that they're more apt to occur in older people, and can include confusion and hallucinations (the drug is an ergot alkaloid). This is a powerful drug, and I doubt that many physicians would prescribe it as the first choice when someone is diagnosed.

But for a person with a serious weight problem that isn't helped by other measures as well as uncontrolled BG levels, the drug might be worth a try, keeping a close watch to make sure no serious side effects occurred.

Friday, May 8, 2009

Spinning the News

Earlier this year, the Web science news site Science Daily ran a story headlined "Mice Stay Lean with High-Carb Diet."

Reading the head, I assumed the story would be about a study showing that mice who followed a high-carb, low-fat diet stayed lean while their littermates who were allowed more fat became obese.


In fact, the story reported a study showing that mice lacking a particular gene were able to stay lean despite being fed a high-carb diet. Researchers said the gene might play a role "in the prevention of obesity related to the over-consumption of high-carbohydrate foods, such as pasta, rice, soda, and sugary snacks."

In other words, the headline said the exact opposite of what the story said. And busy people who only read headlines would come away with the impression that high-carb diets kept mice (and they'd probably assume it also related to people) lean.

Four days later, Science Daily reran the exact same story. But this time the head was accurate: "Mice With Disabled Gene That Helps Turn Carbs Into Fat Stay Lean Despite Feasting on High-Carb Diet." Apparently I wasn't the only one who noticed the bad headline. Perhaps the researchers complained.

This story illustrates the problem that faces anyone who supports a concept that isn't the dogma of the day. Many people, especially reporters in the popular press, buy into the idea that only low-fat, high-carbohydrate diets are healthy. So they interpret everything through those biased glasses.

This means that when science reporters see a research study that supports something they believe in (let's say that red meat is bad for you) they'll read it, write about it, and write a headline that supports the thesis they believe in.

An example of this is the "red meat is bad for you" hypothesis. People do studies in which they lump red meat along with luncheon meats and hot dogs, both of the latter usually packed with carbohydrate fillers, sugar, and chemicals to keep them fresh. They find people who eat any of these three things don't do well on some outcome, let's say heart disease, so they then write stories with headlines that say, "Red meat causes heart disease."

But what if the luncheon meats and hot dogs cause heart disease -- or, more accurately are related to heart disease, as many of the studies only show a relation between two factors, not causation -- and red meat does not? By lumping foods together in groups, one has no idea which of these foods is actually responsible for the effect they found.

Anyone actually taking the trouble to read the original research paper should be able to figure this out. But how many people do that? Very few. Most will rely on the science reporters to do an unbiased job.

But they don't. They choose the outcome they believe in and trumpet that.

To be fair to the reporters, I'll add that I suspect they're under a great deal of time pressure. I worked at a newspaper for 8 years, and I know what it's like to try to write a complex news story when the clock is ticking. The science reporters in this case are trying to digest extremely complex research reports and translate them into terms the general public can understand.

The scientists, on the other hand, and especially the public relations officers at the institutions where the scientists work, are trying to put a "sensational" spin on the results to make them sound more important than they really are, hoping that this will help them get more funding to do more research.

What we as patients have to do is to try to extract the truth from all this spin. It's sometimes difficult and takes a lot of time.

The physicians who treat us are also very busy people, and they too -- even those who can remember the statistics they studied years ago, if at all -- don’t have time to pour through science magazines checking to make sure the statistics are accurate.

Sometimes they’re not.

I copy edit articles for a science journal and I’m constantly amazed at the number of careless errors I find in the manuscripts that authors with advanced degrees have submitted for publication. One author using advanced statistics wasn’t distinguishing between
average and median, a very basic difference that every statistics newbie should be familiar with. Other papers give different numbers in the text and in the tables they supply to support the text. I'm sure many of these problems get through the editors and appear in print.

So our physicians also have to rely on headlines that they see in the medical magazines they read, and these headlines too may be misleading.

Just remember that you can't trust the headlines. TV sound bites and newspaper headlines are the least reliable. TV news has to be short and interesting. Newspaper headlines have to give a message in a limited amount of space. But even science news stories and journal article can have misleading titles.

If you see a headline that sounds interesting, read the story carefully. If it seems like something that will be important for you, see if you can get access to the original journal article. The abstracts of such articles are usually free. You may have to pay or wait 6 months or a year to read the full text. Or you can see if the article is at a local hospital or academic library.

You can also look around on the Internet, putting the title of the article into your favorite search engine. Perhaps someone else has read the whole thing and written a commentary on it. Or maybe some site has posted a link to the full text.

Put the names of the authors into your search engine. Sometimes scientists write very similar articles for different journals, and some slightly earlier publications may now be available without charge and will give a good indication of the methods that these researchers use in their work.

Otherwise, take any short summary with a grain of salt. It may be true. Or it may not be. Reader beware.