Wildly Fluctuating

The Glucagon Connection

2011-12-21T13:27:00.001-08:00

Most of us understand the importance of insulin in controlling our blood glucose (BG) levels. When our BG levels get too high, we can bring them down by injecting insulin. Insulin is made in and secreted by the beta cells in the pancreas.

Many of us are also aware that another hormone, glucagon, helps bring BG levels up when they get too low. Glucagon is made in and secreted by the alpha cells in the pancreas.

In nondiabetics and people with type 2 diabetes or early type 1 diabetes, glucagon automatically gets secreted when BG levels get too low. But people with longstanding type 1 diabetes often stop producing much glucagon and need glucagon shots to bring up a serious low.

Insulin and glucagon are like the accelerator and brake on your car. And it's the ratio of the two, rather than the absolute amount, that is important. If you have almost no insulin, you might be able to have normal BG levels if you also had almost no glucagon.

In fact, a study done in 1981 in a man who had no pancreas, showed that BG levels could be maintained at about 100 without insulin as long as they didn't give the man glucagon.

The problem is that when the beta cells give out, the alpha cells don't give out as well. In fact, they often secrete even more glucagon than they would in a nondiabetic. Glucagon tells the liver to produce and secrete glucose, so the BG levels stay high even when you don't eat.

Most diabetes researchers focus on beta cells and insulin production, but some are studying the alpha cells and glucagon production as well. A recent study found that hyperglucagonemia (too much glucagon in the blood) actually precedes the decline in insulin secretion seen in diabetes.

These researchers infused rats with a lot of glucose for 10 days. After initial high BG levels, the rats adapted and maintained normal BG levels for 4 days. But then their BG levels started to go up, and by 10 days 89% of the rats had high BG levels.

This isn't surprising. The traditional view is that coping with a lot of glucose and producing a lot of insulin can "exhaust" the beta cells; this is called glucotoxicity.

But the researchers found that the rats weren't producing any more insulin than normal. Instead, their glucagon levels increased fivefold. Thus endogenous glucose production, production of glucose by the liver, was what was making the BG levels go up. And infusing them with anti-glucagon antibodies made their BG levels return to normal.

That is surprising.

The authors conclude that glucotoxicity may first manifest as alpha cell malfunction, before any deficit in beta cells and insulin secretion is seen. This is a new way of looking at how diabetes procedes.

A few months earlier, another paper showed that glutamate (or glutamic acid), an important neurotransmitter in brain and pancreas, is secreted from alpha cells along with glucagon. The glutamate contributes to beta cell destruction; it doesn't affect the alpha cells.

Hence, if you're secreting more glucagon, you'd also be secreting more glutamate, thus accelerating beta cell loss and insulin production when you needed more to oppose the extra glucagon.

The authors also found that the protein GLT1 (glial glutamate transporter 1) could protect the beta cells, and they are working on finding other beta-cell-protective compounds.

Neither of these discoveries will result in an instant cure for type 2 diabetes. The first was done in rodents, and the second was done in isolated human cells. Before they can be translated into actual diabetes treatments, they'd have to be replicated in humans, not isolated cells or rats, and treatments that turned down the alpha cells would have to be developed.

However, for decades, researchers have been studying how type 2 diabetes evolves, and they're still not sure. Of course it's all terribly complex. But is it possible people are looking in the wrong places? Maybe it's time for some new ways of looking at an old problem.

Focusing on the alpha cells is one such approach. Let's hope this work continues.

Closed Minds

2011-12-20T10:03:00.000-08:00

I follow a low-carb (LC) diet to help control my type 2 diabetes. I can understand that this approach is very difficult for some people, and some with relatively mild type 2 can control despite eating more carbs.

But I'm always amazed at the closed-minded comments I often see in blogs of anti-low-carbers. Here's one, commenting on a photograph of a LC breakfast posted with a blog:

"There's nothing on the plate that I consider breakfast food."

The photograph seems to show bacon, ham, eggs, sausage, tomato, and mushroom.

I wonder why the poster feels that he needs special foods for breakfast. And apparently that special "breakfast food" should have a lot of carbohydrate, and little protein. That makes no sense. Most people are more insulin resistant at breakfast, and many studies have shown that blood glucose levels rise more after breakfast than after other meals. So if you feel a need for a daily allotment of orange juice, skim milk, toast, jam, and cereal, it would make more sense to eat it for supper, not breakfast.

Of course, this poster is not alone. Many people have irrational prejudices about "breakfast food." For instance, most Americans think bacon and ham are OK for breakfast. But if you say you had chicken or lamb chops, they'll think you're odd. Most Americans would consider Danish pastry or toast and jam to be suitable breakfast food. But if you say you had cheesecake or blueberry pie, they'll think you're odd.

What's the difference? Bacon, ham, chicken, and lamb are all meats. Danish, toast and jam, cheesecake, and blueberry pie are all sweetened starches.

It was the Kellogg brothers at the turn of the 20th century who pushed dry "breakfast cereals," at first primarily corn flakes, on the American public. At that time, rich people tended to eat meat and eggs for breakfast. Poor people ate starches, often boiled into porridge. Farm breakfasts tended to include a little of everything: meat, eggs, milk, pancakes, potatoes, breads, and pies. The farmers needed a lot of energy when facing long hours of backbreaking work and tended to eat the lighter meals like cereal in the evening.

By now, several generations of Americans have grown up thinking that breakfast has to include a dry cereal, often sweetened, and milk. But why do we have to mindlessly accept that there should be special "breakfast food"? We're smarter than that, aren't we?

In the rural area where I live, most people still conform to older patterns of eating. But in urban areas, it seems people are getting more creative with their meals, as described here. (The trend toward daylong snacking does not sound healthy, however, as commercial snacks are usually highly processed.) Nevertheless, the reporter reveals his underlying bias when he refers to eating nontraditional meals as "weird."

When we have diabetes, we need to eat the foods that keep our blood glucose levels down, whether they're considered "breakfast food" or "lunch food" or "dinner food." We can't let old patterns get in the way.

Lamb chops and broccoli for breakfast anyone?

Those Lab Mice

2011-11-25T17:34:00.000-08:00

Derek Lowe, a chemist who has done research in the pharmaceutical industry, recently had an interesting blogpost on the problems with research done on lab mice.

Because Lowe has done research with Big Pharma (including diabetes research), he provides a different point of view from the common "Big Pharma is evil and doesn't want to cure diseases" point of view found in many patient blogs. I think it's important to look at both sides of any issue, and Lowe often points out the difficulties of various chemical approaches to solving some drug problem. Most of them are over my head, but this one was interesting.

He links to another blog that has a series on mouse models, for those who are interested.

Many of the comments on Lowe's post are from other researchers, and it's interesting to see that unlike the popular press, the researchers are cautious about using mouse results. Even different strains of mice can show different results with the same drug.

One interesting comment was that when you put a human tumor into a mouse and some drug cures the tumor in that mouse it's possible that the drug simply kills human cells and hence would be dangerous in humans.

I think most of us understand that mouse studies often don't pan out to be human treatments. They are only suggestive. If only the popular press could show some restraint, patients wouldn't be told over and over again that some new cure was on the way, only to be disappointed when they never hear about it again.

Association and Causation

2011-11-25T17:03:00.000-08:00

I recently read a great cat annecdote in Temple Grandin's book Animals Make Us Human.

According to Grandin, someone's cat loved watching the water swirl around when a toilet was flushed. The cat couldn't figure out how to flush itself, but it had noticed that when there was paper in the toilet, it was more apt to be flushed.

So the cat tore up toilet paper and threw it in the toilet and waited expectantly.

This is a perfect example of the difference between association and cause. The cat correctly noted that toilet paper was associated with toilet flushing. But the cat incorrectly decided that toilet paper caused toilet flushing.

Of course, flushing didn't cause toilet paper any more than toilet paper caused flushing. It was a third factor, pulling the handle on the toilet, that caused the flushing.

Many of our scientific interpretations are like the cat's. If we see a fat person eating more than a thin person, most people conclude that overeating causes obesity. But perhaps obesity causes increased appetite, or perhaps a third factor that no one has discovered yet causes both obesity and increased appetite.

Whenever we see research that shows that two factors are associated, we should think of this cat story. Does the research provide any evidence that one factor caused the other, or is the researcher simply thinking like the cat because of a preconceived notion?

Gary Taubes is challenging the catlike assumption that because fat people tend to eat a lot and not exercise much, it's their behavior that is causing their obesity. Instead, he says it's insulin that is making the body store fat instead of burning it, and the resulting energy deficit makes the person want to eat more and exercise less.

The blogosphere is filled with people debating this theory. I won't go through it all here.

My point here is simply that we should keep this graphic cat story in mind as we evaluate evidence. Surely we humans can be smarter than a cat!

Is DPP-4 an Adipokine?

2011-08-02T11:49:00.000-07:00

DPP-4, or dipeptidyl peptidase 4, is an enzyme that breaks down certain proteins, including GLP-1, or glucagon-like peptide.

GLP-1 has positive effects on insulin secretion, and the drug exenatide (Byetta) works by mimicking natural GLP-1. Because GLP-1 can help people with diabetes, it was thought that drugs that inhibit DPP-4, which would keep GLP-1 in the circulation longer, would also help people with diabetes.

Several DPP-4 inhibitors, the "gliptins" have been developed and include Januvia (sitagliptin) and Trajenta (linagliptin). They do reduce A1c levels somewhat, although they don't appear to be as effective as the GLP1-mimetics.

And one problem with such drugs is that DPP-4 affects many different proteins, and the inhibitors seem to reduce the effectiveness of the immune system, which could be deleterious.

DPP-4 exists as a membrane-bound protein and also free in solution. Both forms break down GLP-1.

But now European researchers report that DPP-4 is an adipokine that impairs insulin sensitivity.

An adipokine is a cytokine secreted by adipose tissue. A cytokine is similar to a hormone; it is a signalling molecule. Many of these substances have been discovered only recently and not everyone agrees about which should be called hormones and which cytokines. The important thing is that they're secreted by one type of cell and can affect others.

The European researchers found that the levels of DPP-4 were higher in persons with more fat cells, and in those with larger fat cells. Also, the production of DPP-4 in obese persons was fivefold higher in visceral adipose tissue (the tissue around organs that is associated with metabolic syndrome) than it was in subcutaneous fat. There were no regional differences in lean subjects.

After weight loss, the release of DPP-4 reverted to levels similar to those of lean subjects.

If DPP-4 is an adipokine that impairs insulin sensitivity, then it makes sense that the DPP-4 inhibitors would improve insulin sensitivity and lower BG levels. It's not clear at this time which of the DPP-4 effects would be more important.

But this could be the link between obesity and insulin resistance, or it could simply be one of many links between the two conditions. Perhaps this report will stimulate more research in this area.

Spinning Science News

2011-07-28T21:45:00.000-07:00

Science Daily recently (well, sort of recently) had two stories about the same research, one put out by the PR department at Johns Hopkins and the other distributed by the PR department at the University of East Anglia, in the UK. See if you can tell which is which.

1. ScienceDaily (June 14, 2011) — People who use a mist inhaler to deliver a drug widely prescribed in more than 55 countries to treat chronic obstructive pulmonary disease (COPD) may be 52 percent more likely to die, new Johns Hopkins-led research suggests.

2. ScienceDaily (June 13, 2011) — An inhaler designed to help chronic bronchitis and emphysema sufferers breathe could be significantly increasing their risk of dying, according to new research by the University of East Anglia (UEA) and three US universities.

Right you are! The Hopkins PR department didn't even mention the UK university and the UK university dismissed Hopkins as just one of three US universities.

These press releases that get published by Science Daily and then picked up by newspapers are released not only when some research group has a real breakthrough, not only when some research group has something slightly new to say, but often whenever a clever PR person at the research center can figure out how to put a positive spin on something that might or might not be confirmed with future research.

The lead invariably mentions the institution. The next few paragraphs often describe the researchers and give all their titles. I usually skip reading all this. Then there are a few paragraphs giving background, for example, giving the differences between type 1 and type 2 or once again describing the "obesity epidemic."

The real news is often far down in the article, sometimes only a sentence or two. Then come quotes from the researchers saying how important this work is and how it either suggests the need for more research (the researchers want more grants) or suggests the need for the development of new drugs on the basis of the work (the researchers want to patent something).

[These two articles did have more meat than some others, and the safety concerns are, in fact, newsworthy. It was the leads that were so obviously PR-department generated.]

When science news is spun just like political news or "sold" by PR departments like a new type of plastic kitchenware, how can we trust anything we read on these news sources? There are zillions of scientific journals out there today, and no one can read even the tables of contents of them all. We have to trust science journalists to notice the important stuff and let us know about it.

But if all they do is reprint press releases from PR departments, is there any point? I suppose these press releases are better than nothing. They do alert us to the possibility there's something new there, and they usually give links to the source, so we can check it out ourselves.

But wouldn't it be wonderful if we could read real science news without having to scrutinize it for spin?

War on Fruits

2011-07-28T17:34:00.001-07:00

How many times have you read recently that you should eat more fruits and vegetables?

It's today's fad mantra. Want to lose weight? Eat more fruits and vegetables. Feeling sad? Eat more fruits and vegetables. Credit card maxed out? Eat more fruits and vegetables.

Sometimes I think we should just make it one word: fruitsandvegetables.

When I read one article that claimed that people in previous centuries ate lots of fruitsandvegetables my tolerance limit was reached.

That's idiotic!

Sure, there wasn't as much junk food in past centuries. But then, as now, poor people couldn't afford expensive fruits, or even vegetables unless they grew their own. Oranges were considered a rare luxury. Then, as now, poor people had to eat a lot of starches like bread and potatoes to get sufficient calories.

Even rich people didn't feast on lots of fruitsandvegetables. Here's a menu from Queen Victoria's household on her 80th birthday. I don't see a lot of fruits there. A few vegetables, but mostly meat and fish and eggs.

Here's an article describing what people ate in Boston restaurants in the 19th century. Like Queen Victoria's household menu, the restaurants seemed heavy on lots of meat courses, thick sauces, and pastry. Certainly not what today's nutritionists would recommend. Not a lot of emphasis on salads. Fruit was offered at the end, but only after a pastry course.

Here's another 19th century menu so heavy on meats that it makes me slightly nauseous to read it . . . and I'm on a low-carb diet! They do offer some fruit at the end, but by that time you'd probably be so stuffed with meat, game birds, lobster, and fish that you wouldn't have much room to stuff yourself with fruit.

I have nothing against eating more vegetables, limiting them to the low-carb ones like greens and other above-ground vegetables except peas and corn if you have diabetes. But fruits are full of sugar. If you have diabetes, it's not a good idea to eat a lot of fruit.

It's time we came to our senses and got rid of the fruitsandvegetables mantra. It's time we stopped thinking of some past Golden Age when everyone ate lots of lean meat (people in the 19th century would have guffawed at the idea of lean meat; they added bacon or lard to meat to make it juicier) and fruitsandvegetables and low-fat dairy and had glowing skin and never got fat.

Let's separate fruits from vegetables and eat less of the former and more of the latter. Let's focus on the carb counts of foods rather than whether they're fruitsandvegetables or other things.

Let's control our diabetes by finding out what foods make our blood glucose levels go up instead of listening to idiotic fad mantras.

We're smarter than fruitsandvegetables, right?

Warped Logic

2011-07-02T07:31:00.000-07:00

In science, it's good to have an open mind, because we're always discovering new things that change the "facts" we were once so certain of.

But too many scientists get stuck in a groove, and they can't be budged from the current dogma, even when the evidence doesn't support their beliefs.

This is apparent in the eternal debate about the best diet. One problem is that people are different, they interpret diets differently, they keep track of what they're actually eating differently, they have different exercise patterns, they take different drugs, and so on and so on. But focus on "evidence-based medicine" means physicians won't believe anything unless it's been proved in a double-blinded controlled randomized trial.

And because such trials involve large groups of people, some of them usually respond one way and others respond in another way, and only statistical analysis will show whether the intervention worked on average. It says nothing about how the intervention will work on any individual patient in the future.

Nevertheless, what bothers me is the tendency of the scientists doing these trials to interpret the results in the light of their own biases. One such ploy when your intervention didn't work is to suggest that you didn't intervene hard enough.

For example, when a study of l0w-fat diets resulted in no benefit, the researchers said maybe the fat content wasn't low enough, that the study should be repeated with even less fat in the diet. It didn't seem to occur to them that perhaps lowering the fat content of the diet wasn't helpful.

A recent study shows the same type of reasoning. This study showed that adding moderate exercise (walking) to diet in people with type 2 diabetes resulted in no benefit for hemoglobin A1c. The first explanation by the lead author of the study was that "the activity chosen, walking, was suboptimal."

In other words, if the exercise you used shows no benefit, maybe more exercise will help.

A lot of studies have shown that exercise doesn't contribute to weight loss. Just Google "exercise, weight loss, doesn't help" for a smorgasbord of articles. Often, exercise just makes you hungrier. Other studies have shown that diet and exercise do work better for overall fitness than either diet or exercise alone.

Exercise helps the cardiovascular system and is certainly a good thing to get. (So why am I sitting here typing instead of finishing the wood stacking I started this morning? Answer: I'm human, just like you.)

I'm not suggesting that exercise is bad. What bothers me is the knee-jerk reaction of some science investigators. "My study doesn't support my hypothesis, so maybe the study wasn't done right" instead of "My study doesn't support my hypothesis, so maybe the hypothesis is wrong."

If everyone thought like this, we'd never make any progress.

Luckily, there are always a few brave souls who dare to defy the current dogma. They're usually laughed at when they start, and some of them give up. Some persist. And they're the ones who end up with the Nobel Prizes.

Stupid quotes: Blood glucose and complications

2011-06-26T14:39:00.000-07:00

From a story on statins in the New York Times discussing the fact that statins increase risk of diabetes:

"Exactly how statins may increase diabetes risk isn’t entirely clear, though animal studies suggest that statins can increase muscle resistance to insulin, resulting in higher levels of circulating blood sugar. Dr. Kausik notes that the patients in the studies were diagnosed with diabetes because of elevated blood sugar levels, but that the long-term consequences of higher blood sugar levels triggered by statin use aren’t known.

" 'Diabetes is defined by blood glucose levels, but none of us are absolutely certain if this is going to carry the same risk as if you traditionally developed diabetes,' Dr. Kausik said.

["Dr. Kausik" is Dr. Kausik Ray, professor of cardiovascular disease prevention at St. George’s University of London and senior author on the paper. Apparently the reporter couldn't even get the name right, so perhaps she also misquoted the doctor. Or maybe she refers to doctors as "Dr. Bob" or "Dr. Mary."]

A high blood glucose level is a high blood glucose level. It doesn't matter what caused it. The good doctor's statement makes as much sense as saying that high blood pressure caused by some drug has different consequences from high blood pressure caused by stress or genetics. It's the high blood pressure, or the high blood glucose, that causes the complications.

One could argue that high blood glucose levels caused by insulin resistance were riskier than high blood glucose levels caused by autoimmunity if you think it's the insulin resistance rather than the high blood glucose levels that are harmful in type 2.

But Dr. Ray said statins increase insulin resistance, so the diabetes they cause is like type 2.

With stupid reasoning like this, it's a miracle any of us survive our doctors' treatments! Remind me to avoid St. George's University of London.

I found it interesting that Dr. Steven Nissen, the one who pressed to have Avandia removed from the market because it increases heart disease risks, is arguing that people shouldn't stop taking statins even though they increase diabetes risks, and diabetes increases heart disease risks.

Leisure Time or Forced Labor? [humor]

2011-06-16T05:57:00.000-07:00

I just read a shocking statistic provided by the University of California, Los Angeles, in an article about rural elders having high risks of obesity, diabetes, and heart disease.

"One in five rural elders do not participate in either moderate or vigorous physical activity in their leisure time."

Gasp! No vigorous physical activity in leisure time. I was shocked.

So I called my friend Hortensia Supergranny, who spent a lifetime working in a factory and now, at 94, is retired and spends a lot of time baking cakes and pies for local fund-raising events. When she's not baking, she's knitting winter clothing for low-income children or helping neighbors who can't do chores themselves. Every afternoon at 4, she sits down for a cup of tea.

"Hortensia," I asked, "How many minutes of vigorous physical activity did you get yesterday? For instance, did you go to Senior Lacrosse or play Touch Football or anything? The University of California seems to think that's how you should spend your leisure time if you want to be healthy."

"Well, gosh," she answered. "I'd hate to be unhealthy. But after I fisished the Times crossword early yesterday morning, I baked 10 pies and 3 cakes and then motored over to Fritzie's house, cooked dinner for him and did a few loads of laundry. I don't know when I'd have time for the lacrosse."

"Well, you could cut out the cup of tea," I suggested. "The University of California thinks we need to use our leisure time wisely, with lots of vigorous physical activity."

"Vigorous physical activity in our leisure time?" Hortensia responded. "Have you looked up the term leisure lately?"

"Well, no," I had to admit. "I always thought it had something to do with vigorous physical activity. But I suppose with your experience with crosswords, you probably consult the dictionary more often than I do."

"I did have to look up a new word in 1976," she admitted. "Not since then. But sorry, I've got to go. The cakes are coming out of the oven and I'm in charge at the school fund-raiser in a few minutes. Gotta go."

She hung up, and I found a dictionary and looked up the work leisure. According to Webster, it means "freedom provided by the cessation of activities." I guess the University of California doesn't know that. Maybe they don't have time to consult dictionaries because they're spending so much time in vigorous physical activity. Or maybe they sold all their dictionaries at yard sales when the state had so many budget problems.

Maybe we should change the name of when we're not employed from leisure time to forced labor. Or we could have Leisure Police going around making sure rural elders were getting enough vigorous physical activity when they weren't working.

In the meantime, now that we know how important it is, everyone should urge Granny to get out on the football field every day instead of lounging around drinking tea!

Insulin Receptor Downregulation

2011-06-14T08:48:00.000-07:00

A recent study at the Mayo Clinic in Florida has shown that removing the enzyme that degrades insulin in mice improves their glucose tolerance when they're young. But when they get older, the same treatment causes them to become diabetic.

The enzyme in question is called, not very creatively, insulin-degrading enzyme, or IDE. When you secrete insulin after eating carbohydrate (or protein), if there were no way to remove insulin from your system, you'd end up with more insulin than you needed after the blood glucose (BG) levels had returned to normal. So in healthy people, there's a delicate balance between the amount of insulin being put into the system and the amount that is removed.

IDE isn't the only way insulin levels can be lowered, but it's an important one. And because genetic manipulation is difficult in humans and has potentially damaging consequences, the researchers are developing drugs that inhibit IDE either totally or partially and are planning human trials of such drugs.

The researchers showed that mice who lacked IDE through genetic manipulation had higher insulin levels and were "more efficient" at controlling their BG levels.

But as these mice aged, they became insulin resistant, gained weight, and lost control of their BG levels. In other words, they developed classic type 2 diabetes.

The focus of news reports of the Mayo research is on the possibility of developing drugs that would inhibit IDE, a new approach to controlling type 2 diabetes. But I think the research is interesting for another reason: It suggests that anything that increases insulin levels in the short term may result in insulin resistance and type 2 diabetes in the long term.

Chronic high insulin levels in these mice made them become diabetic. You can also produce higher insulin levels by injecting insulin or by taking sulfonylurea drugs that cause your pancreas to secrete more insulin. Could long-term use of sulfonylureas or insulin cause a loss of effectiveness for the same reason?

Another thing that increases insulin levels is eating carbohydrate foods. And for the past 40 years or so, Americans have been bombarded by messages urging them to eat less fat and more carbohydrate. Many have. And diabetes rates are skyrocketing.

Someone with a healthy pancreas that is able to cope with huge carbohydrate overloads can tolerate them, at least in the short run. But as we age, everything tends to wear out. And that's when type 2 diabetes becomes even more prevalent.

The elderly mice were found to have fewer insulin receptors on their cells. With fewer receptors, they needed more insulin to do the same job. In other words, they had insulin resistance.

This downregulation of a receptor when the substance it binds is present in excess is not unusual. Nor is the opposite, upregulation of a receptor when the substance is present at low levels. The cells are constantly trying to maintain the status quo, avoiding being overwhelmed by a sudden influx of something or not getting enough of something that is rare.

A classic example of this is the adaptation to caffeine. Caffeine normally binds to receptors called adenosine receptors. When the adenosine receptors bind adenosine, you tend to get sleepy. Caffeine can also bind to the adenosine receptors and block the binding of adenosine. But the caffeine-receptor complex doesn't make you sleepy. So by keeping adenosine from binding, the coffee makes you feel more alert.

There's just one problem with this. When you ingest caffeine regularly, the body starts making even more adenosine receptors, hoping it can bind the usual amount of adenosine. This means that if you drink caffeinated beverages chronically, you'll need even more caffeine to block the sleep-inducing receptors. Then the body makes more receptors. So then you have to ingest even more caffeine to feel more alert. Eventually, you have to ingest caffeine just to stay awake. You're addicted.

A similar phenomenon could be occurring with insulin. When insulin levels are always high, the body may produce fewer insulin receptors, causing insulin resistance, meaning you need those high insulin levels in order to have normal responses. This theory was proposed in the past, but most evidence suggested that insulin resistance is caused by postreceptor effects, meaning effects that occur after insulin binds to the receptor.

But what if short-term hyperinsulinemia causes insulin resistance via postreceptor effects but very long term hyperinsulinemia causes insulin resistance via downregulation of the receptors? The mice who developed diabetes were 6 months old, but this is fairly elderly for a mouse. Mice generally live only 1 or 2 years, sometimes a little more, depending on the breed.

If so, then eating a high-carbohydrate diet for years and years might cause diabetes, especially if carbs were eaten pretty constantly throughout the day. People eating traditional high-starch diets and maintaining traditional lifestyles, with lots of exercise, don't all develop diabetes. But they don't usually snack all day, and their active lifestyles burn a lot of glucose, so their BG levels don't stay high for very long. And when BG levels aren't high, insulin secretion isn't stimulated.

Many Americans, on the other hand, seem to be constantly snacking. That means constant higher-than-fasting BG levels, even when those levels are not diabetic. Higher BG levels stimulate the secretion of insulin. And constant hyperinsulinemia could cause downregulation of the receptors.

When you're fasting, insulin is normally secreted in pulses, about every 15 minutes. Some researchers have found that pulsatile insulin secretion doesn't increase insulin resistance, but constant infusion of insulin does. Normally the body is in fasting condition overnight and before the next meal. But if one snacks constantly, the insulin levels might be constantly high, with less pulsatility.

A substance losing its effectiveness with time is not limited to insulin. High doses of niacin, much larger than those needed for its vitamin effects, are very effective in reducing lipid levels, especially free fatty acids. Niacin also increases levels of HDL.

A continuous infusion of niacin for more than 5 hours lowered free fatty acids. But when the infusion was increased to 24 hours, there was a "rebound" effect, in which the free fatty acids increased to the level of the controls. In this case, the rebound was not caused by downregulation, but by an increase in lipolysis, the hydrolysis of fats to produce free fatty acids. The researchers showed that this was caused by changes in gene expression.

But the result was the same. Constant high levels of a substance cause the body to try to reduce those levels. In this case, free fatty acids. In the case of insulin resistance, the increased glucose uptake that results from insulin action.

In the case of niacin, researchers found that during the niacin infusion, glucose metabolism was improved. But when they stopped the infusion and the free fatty acid levels rebounded to much higher than normal, insulin resistance resulted.

So many things can cause insulin resistance it's very difficult to tease out the most important causes. But every clue helps. Sometime someone will figure it all out. In the meantime, even if you're not ready to try a low-carbohydrate diet, limiting snacks and limiting the amount of carbohydrate you eat would be a good idea.

"Sticky" LDL

2011-05-30T12:01:00.000-07:00

The Internet is awash with stories announcing the discovery of a new "sticky" LDL (low-density lipoprotein) molecule that is much more deadly than the regular LDL. This new LDL is called MGmin-LDL.

Most of the stories simply reprint the press release used by Science Daily and EurekAlert and other popular science-news alerting services. These tell you that the new form of LDL is glycated and it turns LDL into small, dense LDL, the kind that is more easily taken up by the arterial wall to form plaque.

Interestingly, metformin seems to block the formation of MGmin-LDL.

But what exactly is MGmin-LDL?

The MG stands for methylglyoxal, which is a highly reactive side product of glycolysis (the aerobic metabolism of glucose). MG reacts with proteins and is one way cells produce AGEs, or advanced glycation end products, which are glycated proteins that cause a lot of the side effects associated with diabetes.

MG is known to cause AGEs in a lot of proteins, including enzymes and DNA transcription factors, and has even been implicated as a cause of insulin resistance. MG has also been used as a marker of oxidative stress. We know that glycated proteins are not effective. Glycation of serum albumin (not necessarily by MG) seems to decrease insulin secretion. Glycation of LDL reduces its uptake by the LDL receptor. And so forth.

The higher your blood glucose (BG) levels, the more MG you make and the more glycation of protein occurs. One study showed that MG levels reflected the level of postprandial BG levels and suggested that high postprandial levels are as important as hemoglobin A1c levels when it comes to causing complications.

In fact, the idea that MG reacts with LDL is not new. It was shown in 1998, and possible even earlier, that MG reacts with LDL. However, each new research project adds new information, and the current one emphasized the atherogenicity of the MG-LDL complex.

The min in the MGmin-LDL stands for minimally modified, meaning that they didn't carry out the reactions to such an extent that the product was not physiological. They modified it so that it was present in concentrations they thought would actually occur in a human.

It's interesting that the popular, and generic, drug metformin reduces the level of MGmin-LDL. It may do this by blocking the formation of MG.

Because MG is formed as a byproduct of glycolysis, the more glucose that goes through the glycolytic pathway, the more MG you'll be apt to make. But glucose not only source of MG. Other compounds, including ketones, can also be broken down into MG.

Hence, just to be on the safe side, the best way to reduce the levels of MG might be simply to eat less food of all kinds. But we have to eat something, so eating less of the glucose-forming foods would most likely be the most effective in reducing the levels of MG. We know that high BG levels increase glycation of all kinds of proteins, as illustrated above, whether through MG or other mechanisms. Some of these proteins are needed to keep our bodies in top working order. Glycating them means they can't do their job.

It's hard to give up the carby foods we love. But to me, it doesn't make sense to risk getting complications just for the temporary pleasure of eating rice or toast and jam.

Low-Carb Diets and Logic

2011-04-26T12:38:00.000-07:00

Sometimes my mind is boggled by the idiotic logic used by people who are telling patients how to live their lives. For example, a physician writing about low-carb diets recently wrote:

"People do lose weight, but not for the reasons put forth by those who champion such plans. The weight loss comes partly from eating fewer calories and partly because in this day and age, eliminating carbohydrates means eliminating calorie dense, highly processed foods (most of which contain high fructose corn syrup (HFCS)."

Huh? You mean eating fewer calories and eliminating highly processed foods full of HFCS is a bad thing? Maybe I don't understand this because I never went to medical school, but I thought when you wanted to lose weight, eating fewer calories was your goal, and everyone is saying today that we should eliminate highly processed foods.

Then this sage goes on to say, "I can't imagine why anyone would follow a diet -- any diet -- that takes entire food groups away from you. There's no reason to give up great foods like pasta, potatoes, beans and corn to lose weight or to be healthier. Giving up these foods is one of the main reasons that the Atkins diet is not a diet that can be sustained for the long term."

One could also say, "There's no reason to give up great foods like whole-fat milk and yogurt, steaks, and heavy cream to lose weight or to be healthier. Giving up these foods is one of the main reasons that low-saturated-fat diets cannot be sustained for the long term."

Because people like this author think that low-carb diets consist of nothing but rib roasts and cream cheese with no vegetables, they're prejudiced about them, label them "fad diets," and then use ridiculous logic to support their preconceptions.

Another stupid argument warns people with diabetes not to go on low-carb diets because their blood sugar might go down, as if that were a terrible thing. Of course people should be warned to keep track of their blood sugar and if it goes down too much to consult their doctors about reducing their medications. But for someone with a disease that causes high blood sugar to avoid a diet because it would make blood sugar go down is ridiculous.

One can only hope that physicians like this use better logic with the non-nutritional aspects of their practices. Would they say, "I don't want you to use chemotherapy because it might make your cancer cells shrink too much"? Or would they tell people who were gluten-intolerant, "There's no reason to give up great foods like bread and cereal to be healthier. Giving up these foods is one of the main reasons that gluten-free diets are not diets that can be sustained for the long term."

No one really wants to give up "great foods" like potatoes, bread, corn, and peas. But sometimes when you have a chronic disease like diabetes, you have to make difficult choices. Would you rather eat "great foods" or would you rather have your eyesight?

Caffeine and Diabetes

2011-04-15T13:25:00.000-07:00

Does caffeine make our blood glucose (BG) levels go up?

The popular news stories about caffeine and BGs can be confusing. Some say that caffeine is bad for BG control. Others say it's good. For example, heavy coffee drinkers are at lower risk of developing diabetes than light users or coffee abstainers.

What's going on here?

James D. Lane's recent review in a new science journal, the Journal of Caffeine Research, attempted to bring some order to these conflicting views by doing a meta-analysis of the various studies of caffeine and insulin resistance and BG control.

There does seem to be good evidence that high caffeine doses cause an increase in insulin resistance (IR) in healthy, nondiabetic adults. In a healthy, nondiabetic person, however, an increase in insulin resistance wouldn't necessarily mean higher BG levels. They'd just secrete more insulin to cover the increased IR.

When you have diabetes, however, and you can't just secrete more insulin, then an increase in IR usually results in an increase in BG levels. And, indeed, research has shown higher BG levels in people with type 2 diabetes after drinking coffee.

According to Lane, more than 17 studies in nondiabetic adults from 1968 through 2010 have demonstrated transient increases in IR with moderate caffeine doses (equivalent to 2 or 3 cups of brewed coffee) in both habitual caffeine consumers and abstainers. Different studies used different methods, but the results were consistent. Thirteen of 14 studies measuring the glucose response after a carbohydrate challenge found an increase in insulin resistance with caffeine. (Those who want more details can consult the references in the Lane paper, which is free full text online.)

Many studies used pure caffeine in amounts designed to replicate the amounts in coffee, and some of the caffeine doses were infused intravenously, hardly a physiological situation, although I've sometimes thought mainlining my coffee would get me going faster in the morning.

So Terry Graham and colleagues at the University of Guelph, Ontario, studied the effects of drinking coffee, to try to mimic the real-world effect of caffeine. They also studied the effect of fat. As reported here, they found that both fat and caffeine independently increased insulin resistance and glucose levels in the 10 young healthy men in the study. The caffeinated coffee had the greatest effect alone. Both together had an even greater effect than either one alone.

Both caffeinated and decaffeinated coffee increased levels of glucagon-like peptide-1 (GLP-1).

Graham explained that coffee alone won't raise BG levels. It only increases BG levels when you eat carbs. And even drinking the coffee at the same time you eat the carbs won't have much effect. But when you drink coffee, wait a bit, and then eat carbs, your BGs will go higher. The researchers had previously shown that this effect persists through a second meal and occurs with low-glycemic-index as well as high-glycemic-index carbohydrates.

Lane concluded from the meta-analysis that "Caffeine in coffee, tea, or soft drinks causes transient insulin resistance that can produce exaggerated glucose and insulin responses when carbohydrate is consumed" [italics mine].

This qualifier made me wonder what the effect would be in people on low-carb diets. The Graham group used 75 grams of carbohydrate in their test meals. Many people on low-carb diets eat only 30 to 50 carbohydrate grams a day. Would the caffeine be important in them?

To test this question in myself I adopted the following procedure.

1. Drink my usual 2 cups of strong espresso (or decaf another day) on arising.
2. Measure BG every hour until 2 hours after lunch.
3. Wait an hour after the coffee. Then eat 26 home roasted almonds.
4. Eat a poached egg with butter an hour after the almonds (so I'd have some protein to keep me until lunch) and take oral meds, including extended-release metformin.
5. Have lunch. I had 3 oz beef, 6 spears of asparagus with 1 tsp olive oil and a few slivers of red pepper, cracker-sized wedge of LC wrap with butter, half cup of plain kefir with a few nuts.

An hour after eating lunch and measuring, I took my standard walk, about 1.4 miles.

Here are the results:

Time__CAF__DECAF
0_____87____ 89
1_____85_____81___almonds
2_____104____86___ egg and ER metformin
3_____105___104
4_____*_____101
5_____88____108___lunch
6_____133____130___walk
7_____104____119

*I was absorbed in something else and forgot to test here.

At hour 2 (1 hour after eating nuts), I thought maybe the coffee was having an effect, but at hour 3 the readings were almost identical. Graham said that research has shown that caffeine doesn't affect gastric emptying, so this could be random variation.

Because my BG was higher before lunch on the decaf day than it was on the caffeine day, although the 1-hour postlunch BGs were similar, the rise was almost twice as much on the caffeine day.

Finally, perhaps the real peak might have occurred at 1.5 hours after eating the almonds and might have been higher with the caffeine (I'd planned to measure every 30 minutes, but then I got lazy).

But if so, it came down fast enough, so I concluded that for me and my diet, the effect of the caffeine was not large enough to persuade me to give up the pleasure I get from drinking black coffee.

Because we're all slightly different physiologically, with different sensitivities to chemicals and different diets, anyone who is concerned about the effects of caffeine should try a similar test themselves. If you want, you could let us know what you found.

The effect in someone on a low-fat high-carb diet might be quite different. And the effect on most Americans, who eat a lot of carbohydrate and fat as well as a lot of caffeine, especially in today's world where coffee houses are so popular, might be more significant.

The mechanism of the increased IR from caffeine is not known. There are two major hypotheses. The first is that it's because of interference with adenosine receptors on cells. Adenosine is involved in insulin-mediated glucose transport as well as playing a role in sleepiness.

One reason coffee keeps us awake is that blocking the adenosine receptors means adenosine can't bind to the receptors and make us sleepy. Blocking the receptors also seems to reduce inflammation and affect IR. Some research has shown that blocking the receptors decreases IR. Other research shows the opposite. And a study cited by Lane suggested that adenosine receptors had no effect.

The picture is further complicated by the fact that there are different subtypes of adenosine receptors on different cells, and the caffeine may have different effects in different tissues.

The other hypothesis is that caffeine increases the release of stress hormones like cortisol and epinephrine (adrenaline), counterregulatory hormones known to increase BG levels. There is some evidence for this effect, but more research needs to be done.

Finally, there's the paradoxical evidence that heavy coffee users are at much lower risk of getting type 2 diabetes. Those who drink 7 cups a day have half the risk of those who drink 2 or less.

Perhaps there's something in coffee other than caffeine that is causing this protection. In some studies, decaffeinated coffee reduced risk as much as caffeinated.

Common sense suggests that people who drink a lot of coffee probably drink fewer sodas.

But now a study at the University of California at Los Angeles, reported in January, suggests that a hormone-binding protein called SHBG (sex-hormone binding globulin) may be involved. The levels of SHBG in postmenopausal women were increased by caffeine; decaffeinated coffee and tea had no effect.

So far, this is just a hypothesis, but it's one more clue in this complex picture. When it comes to diet and type 2 diabetes control, nothing seems to be simple.

Metformin and Thyroid Tests

2011-03-17T16:20:00.000-07:00

Every drug we take has many effects. The main effects are usually known by patients as well as physicians. For example, most people know that the drug metformin often causes gastric distress, which can be reduced by starting with a small dose and gradually working up to a therapeutic dose.

But most drugs also have minor effects. Sometimes your doctor is aware of these but doesn't tell you because the incidence of these effects is low and the doctor doesn't want to worry you. This is often true of the muscle weakness and memory problems that statins can cause.

Sometimes even your doctor isn't aware of the minor side effects.

Sometimes no one has yet discovered some side effects. This can be because you have to be on a drug for a certain amount of time before these side effects show up. It can be because no one has noticed the link between a particular drug and some side effect.

Or it can be because drugs can interact with other drugs, and when you're taking a lot of different drugs -- say a diabetes drug, a blood pressure drug, a lipid-lowering drug, an anti-reflux drug, an antidepressant, a beta blocker, an antihistamine, an osteoporosis drug, and an asthma drug -- and you complain of fatigue, it's not immediately clear which one of these drugs or which combination is causing that problem.

One relatively unknown drug-hormone interaction was first reported in 2006.

It seems that metformin suppresses thyroid-stimulating hormone (TSH; also called thyrotropin), the hormone that is generally tested to ascertain your thyroid function.

When your thyroid hormones (called T4 and T3) are too low, your pituitary gland secretes TSH. The TSH then tells the thyroid gland to secrete more T4 and T3.

Thus a high TSH level suggests low thyroid, and a low TSH level suggests high thyroid.

Your doctor often tests the T4 and T3 levels too, but often not. If the TSH is in the normal range, your doctor may assume your thyroid levels are fine and refuse to do more testing.

The normal ranges are controversial. The usual range is said to be about 0.4 to 5 microunits per milliliter. But some people say the cutoff on the high end should be lower, about 2.5. And graphs in endocrinology books show that the average TSH level in people considered to have healthy thyroid control is only 1.1, with very few in the upper ranges.

The new research shows that metformin therapy suppresses TSH levels. Two studies showed that it did this without affecting T4 and T3 levels. A third found that free T4 levels increased as TSH went down.

Most of the T4 and T3 in your blood is bound to proteins. The free (unbound) levels of the hormones are the active hormones, and that's what the free T4 (fT4) and free T3 (fT3) measure.

No one yet understands the mechanism of the TSH reduction by metformin. It's especially puzzling because it doesn't seem to be linked with the thyroid hormone level. And the metformin has no effect on TSH in people who have no thyroid problems.

But what it does mean for you is that if you're on metformin you should be aware of this link. Let's say you're on thyroid medication and then you start taking metformin. Your TSH goes down, and your doctor may worry that your thyroid is now too high and might reduce your dose.

But what if it's just a result of the metformin? Then you'd end up with a thyroid level that was too low.

So if you're on metformin and your TSH test doesn't seem to agree with how you're feeling, discuss this interaction with your doctor and have your T4 and T3 levels tested as well as the TSH. It could be that the lower TSH is caused by the metformin and notw higher thyroid levels.

Does this mean that metformin could interact with other lab tests? It's possible. The metformin-TSH interaction was only noticed in 2006, more than 10 years after the drug first became available.

Does this mean that other drugs could interact with the TSH test? It's possible.

We need to be vigilant about all the drugs we take, and if something seems wrong, we need to try to figure it out. Sometimes the published science reports can't tell us.

Trust your body. You know it better than anyone else. And don't let some doctor tell you that your symptoms are all in your head because there's no evidence for what you're saying. Maybe you're right and the current literature is wrong.

A1c and Iron

2011-02-26T13:46:00.000-08:00

Sigh. It's happened again. I set up an experiment and then something beyond my control made the results meaningless.

That often seems to happen. I'm doing a test that requires measuring blood glucose (BG) at a specific time, and just as I'm about to do so, the phone rings, and it's an important call I can't ignore. Or I want to compare BG control on two consecutive days, do a whole slew of tests on day 1 and then on day 2 come down with the flu, which makes any BG measurements useless.

I've always had A1c levels that seem to be higher than what I'd expect on the basis of my BG readings. Because of this, I even spent more than $500 on continuous glucose monitor sensors (a kind friend gave me the meter) to make sure I wasn't going high at some unexpected time when I wasn't measuring.

I wasn't. The results were what I'd expect. Fastings were 70 to 90, and going over 130 was rare. But my A1c was always around 6, which calculates to an average BG of 130, which means I'd be going way over 130 a lot of the time to balance the lower fastings.

I tested my two different meters (Ultra and Freestyle), and they agreed quite well with each other and with my hospital lab.

I know there's some individual variation in red blood cell (RBC) lifetimes, and an increased lifetime could raise A1c, because the longer a RBC has been in your body, the more likely it is to be glycated.

So when I read, as reported here, that low iron can make your A1c higher than it should be, I decided to try taking iron-containing multivitamins a couple of weeks before my next A1c. I usually use iron-free vitamins, because iron can contribute to cardiac problems, and people with diabetes are at increased risk of that.

The theory is that if you're iron-deficient, you won't produce reticulocytes, or new RBCs, as fast as you should, so your body will let the older, more-glycated RBCs live longer. If you take iron, you'll produce more new, glycation-free RBCs, so your A1c will be lower.

I did the test, and the results seemed to confirm the theory. My A1c dropped to 5.3, which is about what I'd expect.

But then I read the fine print. Apparently the A1c machine at the local hospital had broken, so they sent all the samples to the Mayo Clinic. So was the lower A1c because of the iron? Or was it because Mayo was using a different type of test that gave different results. I didn't know.

So I did the test again. Two weeks before I gave blood, I switched to the iron-containing vitamins. This time the A1c, done at my local hospital, was 5.4.

I called the hospital lab to make sure they were still using the high-performance liquid chromatography method they'd used before. This is supposed to be the best method because it's the one used in the famous DCCT trials.

They weren't. They'd changed methods to an immunoassay. So was the result this time because of the iron? Or was it because of a different method?

I don't know. I'll have to do it all over again. I don't get labwork every three months, more like six, because it's a pain and the results are usually pretty much the same. So maybe by the time I get this resolved I'll be living in a nursing home. Who knows.

It's just one of the many frustrations of having diabetes.

On the other hand, being able to test things is one of the fun things about having diabetes. With so many other diseases, we have to let the medical people do all kinds of arcane tests and procedures. I don't know of a home MRI machine, or a home "put in your own coronary stent" kit, for example.

If I ever resolve this issue, I'll post here about it.

Escaping Old Ideas

2011-02-16T14:51:00.000-08:00

I wonder if we could supply these to all (well most) nutritionists.

The article cites the economist John Maynard Keynes, who said, "“The difficulty lies, not in the new ideas, but in escaping from the old ones, which ramify . . . into every corner of our mind.”

And this is just what is true today. Many nutritionists just can't escape the idea that dietary fat is the cause of all our problems.

Diagnosing Diabetes

2011-02-02T20:30:00.000-08:00

Diagnosing diabetes is a lot like trying to sculpt warm Jell-O.

At the extremes, it's pretty easy to decide if someone has diabetes or not. For example, when I was diagnosed, I was having symptoms (constant thirst and urinating a lot), my random blood glucose (BG) level was over 300 mg/dL (to convert to mmol/L divide by 18) hours after my last meal, and my next-day fasting was 269. The glucose level in my urine was so high that the hospital recalibrated its machine to make sure the result was correct.

Clearly, I was diabetic.

At the other extreme, someone with a fasting BG level of 65 who goes up to 80 after drinking a huge glucose drink and has a hemoglobin A1c level of 4.2 obviously doesn't have diabetes.

In between the extremes, there are a lot of patterns that could or could not be considered to be diabetes.

The official guidelines for diagnosing diabetes are that you should be considered diabetic if

Your fasting BG level is 126 or greater on at least two occasions (less than 100 is considered normal) or

Your BG level is 200 or greater 2 hours after starting an oral glucose tolerance test (OGTT) with 75 grams of glucose (less than 140 is considered normal) or

A random BG level is greater than 200 and you're having symptoms.

Recently, some official diabetes groups are suggesting using the hemoglobin A1c test for diagnosis, with any result of 6.5 or greater confirmed by a second test considered diagnostic.

Some years ago, the diagnostic fasting levels were even higher, as some diabetes experts felt that a diagnosis of diabetes would cause harm because of the stigma against "diabetics" and because insurance companies would refuse to insure them. More recently, people have realized that diabetic complications occur even at BG levels below these diagnostic values, and the earlier people are diagnosed, the greater their chance of preventing complications.

However, regardless of where the cutoff points are set, none of these criteria are perfect. Anyone with diabetes knows that fasting BG levels can vary from day to day, and even testing fasting levels on two different days doesn't ensure that they represent a true value.

The same may be true of the OGTT. We all know that we can eat exactly the same thing on two different days at exactly the same time and get exactly the same amount of exercise, yet one day our postprandial BG levels will be higher than the other. Furthermore, because this test is time consuming, very few physicians use it for diagnosis.

And the A1c test is affected by a lot of things, including red blood cell lifetime, which can be genetic and is also affected by various hemolytic anemias, spleen damage, or major blood loss; and abnormal hemoglobin types. Furthermore, although most labs now claim to have standardized their A1c tests, in practice there's still variation from one lab to the other.

Hence one person might have normal BG levels all day long but have an abnormal A1c result, and another person might have elevated BG levels yet have a low A1c. I know someone who had fasting BG levels above 130 but an A1c in the 4s so her doctor refused to diagnose her until things got much worse.

To further complicate things, there are various different patterns of BG abnormalities. Some people may have normal fasting BG levels but go high after meals (this was formerly called impaired glucose tolerance). Others may have high fasting levels but not go very high after meals (this was formerly called impaired fasting glucose).

Some years ago official diabetes groups decided to merge both groups into a new category called prediabetes even though some people think their risks and outcomes differ.

These aren't the only patterns one can get. Some people may have a little impaired glucose tolerance and a little impaired fasting glucose.

Some may have normal fasting BG levels, go very high after meals, but come down again quickly, so they wouldn't satisfy the official requirement for high BG levels at 2 hours after an OGTT. This and this show the variation in BG levels after a high-carb breakfast in people considered nondiabetic.

But no one knows if such wide variations in BG levels might cause complications. Some people think wide variation is worse than sustained high BG levels. Yet the people shown in the cited graphs are considered nondiabetic. Their A1c levels are in normal ranges.

Other people may have temporary increases in BG levels because of some stress, such as surgery or emotional stress, and then revert to normal BG levels.

Diet can also affect your BG levels. Someone following a low-carb diet for weight loss might have normal fasting and postprandial BG levels and normal A1c levels as long as he or she followed the LC diet. An OGTT would show the underlying diabetic defect, but most doctors don't use that test these days, especially in someone with normal fasting BG levels. And these people would be grouped with the nondiabetics if they were included in any clinical trials.

Just fasting can affect your BG levels. Fasting is the ultimate low-carb diet, and after a long fast you'll test diabetic even if you're not on a standard carbohydrate-containing diet because when you don't need them, your body stops producing carbohydrate-processing enzymes. This is called starvation diabetes.

If you've been on a very low carb diet and you're given an OGTT, you'll probably test diabetic even if you're not, for the same reason.

Some people may have abnormal BG levels because of very high insulin resistance, which can sometimes be reversed with weight loss and exercise. They also have defective beta cells that aren't able to cope with the excess demand. But if they can reduce the insulin resistance, their beta cells can cope. Many overweight couch potatoes don't have diabetes because their beta cell mass simply expands to cover the increased need.

The same situation occurs during pregnancy. In most people, the beta cell mass expands during pregnancy to cover the increased need in late pregnancy. Some people have beta cells that are unable to do this, so they are diagnosed with gestational diabetes. After the baby is born and the demand is lowered, their BG levels revert to normal.

Others may have abnormal BG levels with a lot less insulin resistance and but even wimpier beta cells. And of course there can be all kinds of combinations of these two factors.

If diagnosing diabetes is difficult, diagnosing prediabetes is even more difficult because someone with full-blown diabetes like I had when I was diagnosed is unlikely to revert to normal no matter what they do. At that point we've lost so many beta cells that unless we figure out how to get them to regenerate, we're always going to have to be careful about our diet.

But in the prediabetes range, the probability of reverting to normal BG control is greater, especially if you're very overweight and hence are still producing a lot of insulin when you're diagnosed. Thus a diagnosis may be more vague. One month you'd qualify as prediabetic and then you'd lose some weight and you wouldn't. Then you'd regain the weight and you would.

Because of all this diagnostic vagueness, arbitrary cutoff points, and changing standards, any studies that purport to show that "diabetics" are at increased risk or decreased risk or should be taking X drug or avoiding Y practice are somewhat questionable. The older the study, the less relevant it's likely to be. In the old days they didn't even differentiate between type 1 (autoimmune; insulin requiring) and type 2.

I personally don't put a lot of trust into studies that rely on complex statistics to show some effect. You can study 10,000 patients with type 2 and show that there's a slightly better, statistically significant benefit from some treatment (usually a drug). If you're a physician interested in prescribing that drug, that suggests that the odds of success are greater if you prescribe it. (Not taking into account the biases caused by the fact that most drug studies are sponsored by drug companies that know how to manipulate data.)

But it says nothing about whether the drug will help or harm any individual patient. And as patients, that's what we want to know.

Does that mean we should simply ignore all these massive trials? I don't think so. They do tell us something; they suggest that some treatment could help or harm.

But if your doctor tells you that all "diabetics" should be taking some drug or avoiding some drug or following some other regimen and you don't think it sounds "right for you" as the TV ads are so enamored of saying, then research it carefully.

Find out if the patients in the study sound similar to you. If they were mostly elderly white men on low-fat diets and you're a young Asian woman on a low-carb diet, you might respond differently than those patients.

Diabetes comes in many flavors. Diagnosis can be arbitrary. Statements like "All diabetics should be on aspirin" are unlikely to be true, even if supported by references to some big clinical trial.

Cholesterol, CVD Risk, and Type 2

2011-01-23T07:54:00.001-08:00

Deciding whether or not to use a statin to reduce cholesterol levels can be confusing.

On one hand is the medical profession, which in general thinks statins are good things and that LDL cholesterol levels above normal ranges should be treated with statins. Recently, some have been recommending statins even for people with normal cholesterol levels but elevated levels of C-reactive protein (CRP), an indication of inflammation.

In some populations, lowering cholesterol with statins has been shown to result in lower rates of cardiovascular "events" and deaths. But some people think this isn't because of lower cholesterol levels. They suggest that the statins have some other effect as well and the lower cholesterol levels are simply a "side effect" of the drug.

At the other extreme are people who think statins are poisons. Some think no one should take a statin. Others agree they're warranted in specific populations, for example middle-aged men with previous heart attacks, but they say there's no evidence that statins help women or elderly men.

A recent Cochrane Systematic Review concluded that risks of statins are greater than benefits for those at low risk of heart disease. However, when you have diabetes, you're not considered to be at low risk.

An earlier study concluded that statins don't benefit women who have not had a heart attack and in fact may increase cardiovascular risk in this population. They say CRP levels are better predictors of heart attacks in women.

Most people agree that statins do have side effects, most commonly muscle weakness or pain, which can cause permanent damage if it's serious (rhabdomyolysis). In mild cases, taking coenzyme Q10 can sometimes help with the muscle weakness. Tendons can also be weakened by statin treatment (and treatment with other drugs like niacin that reduce cholesterol).

Beatrice Golomb of the University of California at San Diego has been studying side effects of statins and has published a comprehensive review on the topic. She says the two most common side effects are muscle weakness or pain and memory impairment.

She agrees that statin benefits outweigh risks in middle-aged men with high cholesterol and existing heart disease who tolerate the drugs, and that statins probably benefit middle-aged men with high cholesterol and "significant other risk factors for heart disease."

But she says that although those without significant risk factors for heart disease do have fewer cardiovascular deaths, there is not even a trend for lower overall death rates. In other words, fewer heart attacks and strokes but more deaths from other diseases.

Golomb says that statin benefits are not clear in middle-aged men who have heart disease or significant risks but who get side effects from statins. There is some evidence that the benefits of statins don't occur in people who get side effects.

Golomb says there is currently no evidence that statins benefit women or men over 70. They do reduce heart attacks, she says, but not overall mortality.

One problem when reading about all these studies is that different studies use different patient populations and different end points, but the news media tend to report the results without emphasizing that point.

So a drug-company-sponsored trial might be headlined as "Drug X Reduces Heart Attacks by 40%" when in fact the study showed that the drug reduced heart attacks in middle-aged men who had already had several heart attacks, had high blood pressure and high blood sugar, and smoked, and the deaths from some other disease increased with the drug. But what the public, and some physicians, will remember is "Drug X prevents heart disease."

And the confusing thing for those of us with diabetes is knowing whether or not simply having diabetes constitutes a "significant other risk factor."

Most people consider simply having diabetes to give you the same risk of cardiovascular events as people who have already had a heart attack. Is that true?

A recent Spanish research group says no, at least in the Spanish patient population they studied: 4410 patients aged 30 to 74 years, 2260 with type 2 diabetes and 2150 who had already had an acute myocardial infarction but no diabetes.

They found that the 10-year hazard ratios for the type 2 patients were significantly lower than those of the MI patients.

That's encouraging. So should we stop worrying about heart disease?

Definitely NO!

For one thing, other studies have had conflicting results. Some show that people with diabetes have heart disease death risks similar to those of nondiabetics who have had heart attacks; others show the opposite. Another study showed that prior heart attacks resulted in higher risks than diabetes among men 45 to 54 years old, but in older men, the risk was reversed.

As noted by the Spanish researchers, "Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies."

The cited studies also noted differences according to the age and sex of the patients. Furthermore, the results may depend on how you define diabetes.

Someone with type 2 diabetes who was diagnosed 5 years ago, controls blood glucose levels well, eats healthy foods, gets a lot of exercise, doesn't smoke, and makes sure to keep blood pressure and lipid levels in good ranges would be different from someone who is unfortunately probably more typical: a patient who just takes a pill or two, doesn't measure blood glucose levels, continues to smoke and spend most of the evening watching TV, eats mostly fast food or convenience foods, and has high blood pressure.

And the recent Spanish study was comparing diabetic patients with patients who had already had an acute MI, not with healthy people.

When we have type 2 diabetes, we're still at increased risk of heart disease, and we should do whatever we can to reduce that risk: Keep blood glucose levels down, monitor lipid levels and treat if necessary, monitor blood pressure and treat that if necessary, get regular exercise, and eat a healthy diet, although definitions of "healthy diet" of course depend on who you're talking to.

But all these studies illustrate the need to be vigilant when reading a popular press article stating that some study has shown something or other. First, see if you can read the journal article that the popular press story refers to. Even if you can't see the full text, you can usually see the abstract for free.

Find out what populations were studied, how various parameters were measured, and how the researchers define diabetes.

This takes a lot of time, and a firm grasp of statistics helps. So it can be frustrating when you're trying to earn a living or spend time on other projects and don't have time to pour through confusing research reports all day.

Sometimes the authors of drug-company-sponsored studies have used statistics to spin the results to make their drugs look more favorable. You sometimes need to comb through the methods and the statistics to see how the results have been biased. This takes a lot of time.

When you can't track all this down, don't ignore the health news, but take the health news you hear on TV or read in your local paper with a grain of salt. If your LDL cholesterol level is high, you might want to try a statin. Some people can take them without getting side effects. But be vigilant. If you get muscle weakness, try some coenzyme Q10, which Golomb says helps about 70% who have that problem. Some people recommend taking the coenzyme Q10 even if you don't have muscle problems.

But if the muscle pain or weakness persists, talk with y0ur doctor about other alternatives, like niacin. Muscle pain that progresses to rhabdomyolysis is serious.

Hepatokines

2010-12-22T14:21:00.000-08:00

Most of us have heard of cytokines, signaling molecules secreted by cells that affect other cells. Examples are the various interleukins, some of which stimulate inflammation and others of which reduce inflammation. They are like text messages between cells.

When some cellular stress occurs, let's say an infection in your finger, certain cytokines are the distress signals, telling other types of cells to rush to the site and fix it. Then when things seem to be OK, different cytokines tell the cells to cool it, to stop trying to fix things (fixing involves inflammation) and let the site get back to normal.

Fat cells used to be considered boring blobs of stored calories, with no interesting functions. Then they discovered that fat cells also secreted signaling molecules, which they termed adipokines. One of the most widely known adipokine is leptin.

Hormones are also signaling molecules, and some people debate about which signaling molecules should be called cytokines or adipokines and which should be called hormones. Traditionally, hormones were considered to be molecules secreted by one organ that affected other organs. For example, beta cells secrete insulin, which has effects all over the body.

Cytokines were considered to be hormonelike molecules secreted by numerous cells throughout the body that affected immune system cells. Adipokines were considered to be hormonelike molecules secreted by fat cells. In both cases, a certain type of cell rather than a certain organ secretes the signaling molecules. And unlike hormones, which are usually synthesized and then stored within the cell for rapid release when needed, cytokines tend to be synthesized only when needed.

But there's a lot of overlap between cytokines and hormones, and some people think it's time to stop trying to classify the numerous new signaling molecules that seem to be discovered every week. The important thing is what they do.

Recently a new type of cellular "kine" has been proposed: the hepatokine.

A protein called selenoprotein P is produced in the liver and transports the trace mineral selenium from the liver to the cells that need it. These researchers found that selenoprotein P concentrations are higher in people with type 2 diabetes than they are in healthy people, and they proposed that overproduction of selenoprotein P in the liver causes insulin resistance and type 2 diabetes. Their research results were consistent with this hypothesis.

Interestingly, their results suggested that selenoprotein P works via AMPK, which is also affected by the diabetes drug metformin.

They said their research "raises the possibility that the liver functions as an endocrine organ by producing a variety of hepatokines and that the dysregulation or impairment of hepatokine production might contribute to the development of various diseases."

Whether or not selenoprotein P turns out to be vital in causing type 2 diabetes, I find this paper fascinating because it gives us a new way of approaching diabetes: looking for important modulators in a new place. Sometimes takes a shakeup of traditional ideas in order to make breakthroughs.

If there are adipokines and hepatokines, might there not also be musculokines or myokines? Skelatokines or osteokines? Or other "kines" in places no one has thought to look?

Maybe the tongue produces signaling molecules when it tastes different kinds of foods. We know that the sight, smell, and even thought of food can trigger nervous signals that affect gastric and insulin secretion (the cephalic phase of digestion). Why not small molecules as well?

Progress in genetic research is proceeding rapidly, but we still don't know what really causes type 2 diabetes. Perhaps these new ideas will stimulate new research that will come up with something that will help us prevent this epidemic disease.

Preconceptions . . . Again

2010-11-24T14:39:00.000-08:00

Maybe it's a waste of time to point out the biased preconceptions one sees in various science journals; most of the intelligent people I assume are the primary readers of this blog can spot them for themselves. But they annoy me so much I can't not point them out.

The latest one occurred in an article titled "Overweight Primarily a Problem Among Wealthier Women in Low To Middle-Income Countries" and published in the American Journal of Clinical Nutrition.

Researchers at the Harvard School of Public Health reported that in less affluent countries, being overweight is more common among women with higher incomes (they studied only women). In contrast, in more affluent countries like the United States, obesity is associated with poverty.

I think this is intuitively obvious. When it's difficult to get enough food, then only richer people will obtain enough calories to become fat. When food is plentiful but starchy and fatty food is cheaper than meat and vegetables, then the poorer you are, the more apt you are to be fat.

A famous photo of an emaciated boy holding out a bowl and begging for rice, while behind him a fat (by the standards of those days) merchant woman sits among huge bags of rice, illustrates this. The boy isn't counting calories; he's starving.

So initially, I found the study pretty ho-hum. Then I came on this attempt at an explanation:

"The researchers theorize that these findings could be due to a number of factors, including that women in higher income groups are more likely to have diets richer in animal fats than lower-income women."

In other words, they started with the assumption that obesity (and probably all the other ills of a "Western" diet) stem from too much animal fat. So that must surely be the explanation here too.

Couldn't it also be because the richer women were able to buy white bread and jam instead of fiber-filled vegetables the poorer people probably grew themselves?

They do make a couple of other suggestions:

"Also, cultural norms in developing countries may favor fatty body shapes among wealthier women. Richer women are also less likely than poor women to engage in regular physical labor."

I'm sure the difference in physical work does make a difference. But if cultural norms in developing countries favored fatty body shapes among wealthier women (as a sign that you could afford a lot of food), wouldn't you think the same would be true among poor people as well? Wouldn't poor people want to look as if they were rich?

Sometimes the logic in nutrition papers boggles my mind.

Free Full Text

2010-11-13T13:38:00.000-08:00

Mary Ann Liebert, Inc, publisher of many journals, is offering free full text of their diabetes-related journals through the end of November. The offer is in recognition of World Diabetes Day.

The three journals are Diabetes Technology & Therapeutics, Metabolic Syndrome and Related Disorders, and Childhood Obesity.

I've often seen abstracts in the first journal and wished I could read the full texts, but access was too expensive. So this is a good chance to download the articles that interest you, if any.

Are Parasites in Charge?

2010-10-22T12:57:00.000-07:00

Parasites can influence the behavior of the organisms they inhabit.

For example, mice infected with the protozoan Toxoplasma gondii, the organism that causes toxoplasmosis, become lethargic and lose their fear of cats, the primary host of the parasite

Clearly, in a cat-infested environment, such mice don't last very long. And the cats that eat the infected mice become infected themselves and then spread the eggs (oocysts) through their feces.

The behavior modification caused by other parasites in other organisms are even more bizarre.

So, could human behavior also be influenced by some of the parasites we all carry? Some people think yes.

Our guts are filled with bacteria. Many of these bacteria are beneficial. For example, gut bacteria produce most of the B vitamin biotin that we need. Other bacteria can cause obvious harm, for example, gut inflammation, pain, and diarrhea. The diarrhea benefits the bacteria because it increases the probability that other people will come in contact with the abundant fluid and become infected themselves.

Effects on behavior could be more subtle. We know that animals infected with rabies virus behave differently. They become more aggressive and tend to bite. Because the virus colonizes the salivary gland, such bites pass the infection on.

But why am I babbling about all this, interesting though it might be?

It's because I'm wondering if it's gut bacteria that program some people to eat more than normal, causing obesity. Why would the bacteria do that? Well, the more you eat, the more food there will be in the gut, which means the more the bacteria could grow.

There is some evidence that gut bacteria are related to obesity: overweight people tend to have different types of bacteria than normal-weight people. And some animal studies showed that transferring the gut bacteria from mice prone to metabolic syndrome into normal mice caused the normal ones to develop metabolic syndrome too.

So this idea that gut bacteria are associated with obesity is not new. Whether the bacterial population causes the obesity or the obesity provides a gut environment friendly to certain types of bacteria, or perhaps both in a vicious circle, has not yet been definitively proved.

A recent study reported at the Stockholm meeting of the European Association for the Study of Diabetes showed that transplanting fecal matter from thin people into obese people with prediabetes did not result in any weight loss. However, the recipients did see their insulin resistance decrease.

Clearly, obesity, type 2 diabetes, and gut populations are related somehow. One possibility is that certain bacteria are especially efficient converters of food and fiber into compounds that can easily be taken up in the gut, essentially adding calories to whatever we eat.

But I'm wondering if there's more than a metabolic effect. I wonder if the gut bacteria, like the parasites that change behavior in mice and spiders, are subtly changing the behavior of their hosts.

If the bacteria made the hosts feel sluggish, they wouldn't want to move around a lot and burn off calories. If the bacteria made the hosts hungry all the time, they would eat more than they needed to maintain their weight.

The bacteria could then happily munch on the extra calories, rapidly multiply, and infect other people.

Is this really true? No one knows. But the idea intrigues me.

Popular Press Spins

2010-10-15T17:57:00.000-07:00

When I was in graduate school, way back in the 1960s, almost every news report about some scientific finding ended by trying to explain why this finding would help to cure cancer. This was the era of the War on Cancer, and scientists hoped that relating their research to curing cancer would increase their chances of getting big research grants.

In the virus course I took with Jim Watson, the exams usually included a question in which we had to explain why some newspaper report of a scientific finding was wrong, that it actually would have nothing to do with cancer. They were fun questions.

Today, instead of trying to show how new studies can help to cure cancer, most popular press stories I see suggest that the findings provide a new target for new drugs, probably hoping to increase their chances of getting funding from drug companies.

Many of the stories appearing in popular science releases like Eurekalert and Science Daily are written by PR people at the institutions where the research is done. Their goal is to call attention to their institutions, professors, and funding sources as well as to the research itself. As a result, usually more than half of the articles is garbage.

When I was a newspaper editor, we'd get tons of press releases like this, and part of our job was to rewrite them without the self-promoting garbage. But these science news sites don't do this. Most of them simply print the press releases verbatim; you can read exactly the same stories on myriad sites.

An example from Science Daily:

"Researchers at the University of Edinburgh report a new experimental compound that can improve memory and cognitive function in aging mice. The compound is being investigated with a view to developing a drug that could slow the natural decline in memory associated with aging.

"With support from the Wellcome Trust Seeding Drug Discovery award, the team has identified a preclinical condition that they hope to take into human trials within a year."

Note that in the first two paragraphs they've mentioned the institution, the potential for drug development, and the funding source. They haven't mentioned what we all want to know: what this compound is. You have to slog through a lot of other boring stuff before they'll reveal that. Some stories even list all the researchers, their degrees, and their positions at the university before they'll tell you what the new finding actually was.

Here's another one:

"University of Michigan scientists have identified events inside insulin-producing pancreatic cells that set the stage for a neonatal form of non-autoimmune type 1 diabetes, and may play a role in type 2 diabetes as well. The results point to a potential target for drugs to protect normally functioning proteins essential for producing insulin."

In this case the PR people managed to make the institution the first word of the article.

You may say, "So what!" and that's partially true. We just have to learn to skim most of these articles to get to the crux of the story. And these popular press releases are important in alerting us to new journal articles that we'd probably never know of otherwise. Most of the press releases do have links to the original articles, although in many cases we can only read the abstracts unless we want to pay.

But I think the important thing is to remember that these articles are written by PR people whose goal is different from our goal. Their goal is to publicize their institution and overemphasize the importance of the research there. Our goal is to understand as completely as possible how good the evidence supporting the claims in the summary article is.

Whenever possible, I try to get the full text of an important article. I don't make the effort for what I consider less important ones. Time is not infinite. I once spent 2 days researching the science behind a story about using lettuce and some complex molecular biology to give people insulin by eating lettuce. Most of the popular press summaries didn't really understand what the research showed.

But if I spent 2 days researching every article I read, I wouldn't be able to read very many, and in the long run I'm hoping that having a surface acquaintance with a lot of research will be more useful than having an in-depth acquaintance with just a little.

I'm sure most of you are already aware of the way the press spins news about science research. But it never hurts to examine it again.

It's a reader-beware situation out there.

Lipids and Diet

2010-08-05T19:11:00.000-07:00

Low-carb and low-fat diets result in similar weight loss at 2 years when both are accompanied by comprehensive lifestyle counseling, according to a recent research project by Gary Foster and colleagues published in the Annals of Internal Medicine.

But people in the low-carb diet showed better lipid profiles after 2 years.

You have to pay to read the full text of the article, but low-carb advocate Jimmy Moore has an extensive discussion of the results including some graphs.

This study is important because it shows that various improvements in people following low-carb diets are not simply temporary. Although 2 years can't really be called long term, it's heading in the right direction.

What I find fascinating is the reaction to this article. I can't find it at all on either Science Daily or Eurekalert, both popular summaries of science news. They're always quick to report studies that say red meat is bad or low-carb diets cause problems. Why aren't they summarizing this study? Many other media outlets are, so it's not that the study is obscure.

Others have put a positive or a negative spin or a neutral spin on the study (not mentioning the better lipid profiles is actually a negative spin), some by the way they write their headlines. If you support low-carb diets, you can emphasize the fact that the lipid levels improved on that diet. If you don't, you can focus on the fact that weight loss was the same. Many people remember only the headlines; here are a few of them:

Positive:

Low-carb diets improve cholesterol long term (Medicinenet)
Low-carbohydrate diet beats low-fat diet in decreasing heart risk (Thaindian news)
Low-carb diet better for heart health than low-fat diet (The Money Times)

Neutral

Low-carb, low-fat diets tied for long term weight loss (uamshealth.com) (University of Arkansas for Medical Sciences)
Study disputes low-carb diet concerns (Philadelphia Inquirer)
Low-carb diet as good as low-fat one (Press TV)

When people do studies of "low-carb" diets that include 150 grams of carbs, low-carb supporters scream that such diets aren't really low carb (and I agree with this), that if they'd tested 50 g or 30 g or 20 g a day, they would have seen different results.

In this case, the low-fat supporters are screaming that a diet with <30% fat isn't really a low-fat diet, that if they'd limited fat to 10%, they would have seen different results.

I agree that this study would have been better if they'd tested 4 different diets: very low carb ketogenic diet (<50 g carbs), low-carb diet (50-130 g), low-fat diet (<30% fat), very low fat (<10%).

But I think the researchers were trying to compare a standard Atkins diet (the diet many people think about when they think low carb, even though there are other low-carb diets that I think are better) with "standard care," which still often means following the old Food Pyramid with 60% carbs and <30% fat.

They may also have worried that few of the study subjects would have been willing to stick to the stricter diets for 2 years or more. Even with the more moderate diets, attrition was high: 32% for the low-fat diet and 42% for the low-carb diet at the end of 2 years.

The low-fat diet was limited in calories; the low-carb diet was not.

Both groups lost weight, rapidly at first, reaching a nadir at 6 months, and then regained some of the weight, so that by the end of 2 years, they'd lost an average of 7% of their starting weight.

Interestingly, this was the goal in the Diabetes Prevention Program weight-loss study of people at high risk of developing diabetes. The DPP showed that modest weight loss (the goal of 7% was not actually reached) could reduce the risk of progressing to overt diabetes. The same phenomenon occurred in that study too: subjects initially lost weight fast, then leveled off and started regaining again.

I think we've all experienced this phenomenon. We try a new diet and are enthusiastic and follow it exactly. Then after some time we hit a plateau and we also get bored with the diet and gradually revert to our old habits.

It's also possible that the body wants to maintain a certain weight that is higher than the weight we want it to have (the set-point theory), and after some time the metabolism changes to encourage the regaining of the weight.

People will never agree on the best diet for weight loss, partly because different people do better on different diets: YMMV, or "Your mileage may vary." But the more we know about various diets and various groups of dieters, preferable for as long as possible, the better.

Like weight loss, lipid levels tend to be different in the short term than they are in the long term. For example, in this study, triglycerides rapidly decreased in the low-carb group but then went up again and by the end of 2 years were about the same as the levels in the low-fat group. LDL levels went up in the low-carb group but later went down again. Only HDL levels were consistently higher on the low-carb diet throughout the study.

It's not clear whether the fluctuating lipid levels were because after 12 weeks the people on the low-carb diet were instructed to slowly start adding back carbs until their weight stabilized. This is what Atkins told people to do. But in fact, the weights in the low-carb group continued to drop after 12 weeks and then instead of "stabilizing" started to climb.

So it's also possible that the body was adapting to a different diet and adjusting the lipid levels after a certain amount of time on the diet. Perhaps we have a "lipid set-point" as well as a weight set-point, and the body keeps trying to reach it.

Regardless of the reasons for these shifts, in order to really understand how diets affect various heart health risks, we need longer-term data. Foster and colleagues have made a valuable first step. Perhaps even longer studies will follow.

Is Avandia Safe?

2010-07-07T12:35:00.000-07:00

Stastics is not my strong suit, so I confess that I find reading about these massive human trials of drugs and other treatments to be more of a chore than a pleasure. Each study may use a different population group, a different drug dosage, a different end point, and a different time to the end point.

Furthermore, most of these trials are supported by drug companies, and I don't trust the results. There are many ways to manipulate the data to make small differences sound like large differences, or to explain away results that aren't what you wanted.

And you can't trust the headlines written by popular science news services like Science Daily or those in general medical magazines. They'll just restate the conclusions emphasized by the authors of a particular study and then reiterate the background of the topic. In many diabetes news stories, more space is devoted to explaining the difference between type 1 and type 2, giving the numbers now suffering from these conditions, and then describing the "obesity epidemic" than in describing what's new.

Three Science Daily headlines about Avandia (rosiglitazone from studies reported at the recent American Diabetes Association meeting in Orlando, Florida, illustrate how difficult it is for us to know what is really going on. They were as follows:

1. No Link Between Diabetes Drug Rosiglitazone and Increased Rate of Heart Attack, Study Finds.

2. Type 2 Diabetes Medication Rosiglitazone Associated With Increased Cardiovascular Risks and Death, Study Finds.

3. New Meta-Analysis Demonstrates Heart Risks Associated With Rosiglitazone.

What's going on here?

First note that the first headline mentions "heart attack," the second refers to "cardiovascular risks and death," and the third refers to "heart risks." None say what the risks are compared to, and cardiovascular risks or heart risks could refer to a lot of different things. I suspect most people wouldn't delve deeply into the details and would interpret these headlines simply as (1) Avandia good, (2) Avandia bad, and (3) Avandia bad.

Let's start with study number 3. This is a meta-analysis, and like many other people, I don't trust meta-analyses. What they do is try to take a lot of small studies in which the results weren't statistically significant and pool them all together so that the results become significant.

This is because the statistical significance depends on both the magnitude of an effect and the number of people in the study. So, for example, let's say you were testing a drug called SugarDown and found that among 300,000 people matched to controls not taking the drug, 200,000 saw their A1cs decrease by at least 1 point and only 100,000 of the control subjects reached this endpoint. That is, twice as many people taking the drug had a desired result.

But if you gave the drug to only 3 people matched to controls, 2 of those taking the drug reached the end point and only 1 not taking the drug reached the end point, this might suggest to you that this drug was worth trying in a larger trial, but even though twice as many taking the drug had a desired result, just as in the larger trial, the results would obviously not be significant. The result could have been the result of chance.

When the results are more extreme -- let's say all 3 people taking the drug dropped dead 15 minutes after taking it and none of the controls did, then there's less chance that the results would be from chance.

These are obviously extremes; most studies have more realistic numbers. But no trial is perfect. Too many study patients make the studies too expensive, and too few patients make the results unreliable.

A meta-analysis tries to overcome these limitations.

The problem is that unlike the studies themselves -- which are usually "double-blinded," meaning that neither the patient nor the researchers know which ones got the real drug and which one got the placebo -- the researchers doing the meta-analyses have the results of all the trials in front of them.

They are able to pick which ones to use. This can be difficult when each study has a different end point and different parameters. And even a researcher without an ulterior motive might have unconscious biases that would result in rejection of one study that had an undesired result and the use of another that had a desired result.

With those caveats, here's what this study, by Steven Nissen and Kathy Wolski, published in the Archives of Internal Medicine, concluded: "Eleven years after the introduction of rosiglitazone, the totality of randomized clinical trials continued to demonstrate increased risk for myocardial infarction [heart attack] although not for cardiovascular or all-cause mortality. The current findings suggest an unfavorable benefit to risk ratio for rosiglitazone."

In other words, in this meta-analysis of rosiglitazone (Avandia) studies, more patients had heart attacks when on rosiglitazone, but no more died.

Study number 2, published in JAMA, which was not a meta-analysis, concluded that "Compared with prescription of pioglitazone, prescription of rosiglitazone was associated with an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of acute myocardial infarction (heart attack), stroke, heart failure, or all-cause mortality in patients 65 years or older." [Italics mine}

So this study was limited to people over 65, and the results were compared with those of patients getting a similar drug, pioglitazone, not with those of patients not getting any of this type of drug. It's always possible that some drug might have a positive effect on some outcome compared with no drug, but it might have a less positive effect than another drug, so compared with the second drug the results would appear to be negative.

Their conclusions also refer to stroke, heart failure (not heart attack), and all-cause mortality. They found no increase in heart attack rates, but then they lump heart attacks together with the other end points and say there was an increase in this composite result!

That's like saying eating beans causes a lot of gas, and a composite consisting of people who ate beans, crackers, and chicken soup had more gas than people who ate none of these things. Many people reading that statement would avoid crackers and chicken soup before important meetings, even though the crackers and chicken soup had no effect on gas production.

The conclusion in the Abstract of the article doesn't specifically mention that the drug had no significant effect on heart attack rates. It just mentions the significant effect on stroke, heart failure, and all-cause mortality and the effect on the composite index.

Some busy physicians quickly reading this composite conclusion in the Abstract (and many people don't take the time to read an entire article, assuming the Abstract summarizes it correctly) might conclude that heart attack rates were increased as well as the other endpoints.

This article has other flaws. They mention in the Introduction that 7 previous studies showed that rosiglitazone increased heart attack rates, but they don't say 7 out of how many or increased compared with what. Seven studies out of 8 would be one thing; 7 studies out of 50 would be another.

The authors noted that most studies that showed an increase in heart attacks with rosiglitazone (again, they don't say increased compared to what) were done in younger patients (54 to 65 years old), whereas their study was in people older than 65 years.

This is another source of confusion for people trying to decide whether or not to use a drug. What helps or harms in one patient population might not do the same in another population.

Study number 1 seems to contradict the other two. It has not yet been published but was presented at the ADA meeting. According to this study, rosiglitazone had no effect on heart attack rates or mortality. Then they also used a composite outcome -- heart attack, mortality, and stroke -- and said rosiglitazone reduced this composite outcome.

But only stroke rates actually decreased, by 64%, whereas the "rates of heart attack and death on their own showed no significant difference between those who took rosiglitazone and those who did not." Once again, the composite outcome is confusing, and people may come to an erroneous conclusion.

This study was limited to patients with diabetes and existing cardiovascular disease. Some got revascularization for their cardiovascular disease. Some got insulin or metformin instead of rosiglitazone.

And the results reported at the ADA meeting were from a post-trial analysis of the results from the BARI-2D trial, which was not designed to test the safety of rosiglitazone. Hence the drug was not randomly assigned. Reanalysis of studies designed to test something else are somewhat questionable.

So is rosiglitazone safe to take? The evidence is not clear-cut. The FDA will soon meet to discuss the safety issue, presumably taking into account other studies in addition to the three discussed here.

But these three studies are a good example of the slippery slope we have to deal with when results of large clinical trials are published: confused statistics, biased authors with ties to drug companies, and different patient groups, comparisons, and end points.

I wonder how many bad drugs are on the market because of confusing clinical studies. So too, I wonder how many good drugs might have been dropped from the pipeline because of equally confusing clinical studies.

Evaluating risks vs benefits is not simple, and the best choice for a large population is not always the best choice for an individual patient. You might be allergic to a drug that helps most patients. Conversely, a drug that harms most patients might be wonderful for you.

All this is one reason that controlling with good food and exercise should always be the first choice. But this isn't always enough. Then we and our physicians have to evaluate which drugs will work best for us.

It is not a simple task.

Stupid Fat Study

2010-05-17T09:59:00.001-07:00

No this isn't about "stupid fats." It's a stupid study, in my opinion.

I try to give research scientists the benefit of the doubt, because I've done lab research myself, and I know how difficult it can be to get reliable results. It's even more complex today than it was when I was in graduate school.

Nevertheless, I think this study, reported in Science Daily, really takes the cake. The SD title is "High-Fat Meals a No-No for Asthma Patients, Researchers Find."

So what did the researchers do?

They fed two different meals to 40 people with asthma and measured any resulting inflammation. Diet 1 was 1000 calories, 52% fat, and consisted of fast-food burgers and hash brown potatoes. Diet 2 was 200 calories, 13% fat, and consisted of reduced-fat yogurt.

They found that people eating diet 1 had more inflammation. So they concluded that the inflammation was caused by fat!

How can you possibly assign blame when the diets differed in so many ways?

An equally valid headline might have been "High-calorie meals a no-no for asthma patients" or "Hash-brown potatoes a no-no for asthma patients" or "Dairy products good for asthma patients" or "Eating lots of fat in combination with lots of carbohyrate a no-no for asthma patients" or "Hamburger buns a no-no for asthma patients."

Instead, they focused on the one ingredient they probably started out believing would be bad and ignored the rest.

This study was presented at the American Thoracic Society 2o10 conference in New Orleans.

One of the researchers said, "This is the first study to show that a high fat meal increases airway inflammation." No it didn't. It showed that a high-fat, high-calorie, high-carbohydrate, commercial junk-food meal increased airway inflammation.

Unfortunately, headlines are all that many people read and remember. Keep in mind that headlines can be misleading. Before accepting the conclusions in any study you think might be important for you, read as much of the full text as you are able to and then make up your own mind.

We can't depend on other people to inform us correctly. We have to take control ourselves.

ACCORD again

2010-05-07T06:52:00.000-07:00

A couple of years ago, it was reported that intensive treatment of type 2 diabetes, aiming for a hemoglobin A1c level below 6, increased cardiovascular events compared with patients aiming for an A1c between 7 and 7.9. The study was called ACCORD, and the glucose arm of the study was stopped early because of the excess deaths in the intensive-treatment group.

On the basis of this one study, a lot of doctors told their diabetes patients who had A1c values in the normal ranges that they were too low and they should attempt to get them higher!

They seemed to apply this advice to everyone with type 2, even though the patients in the ACCORD study were older (between 40 and 79 years), had had diabetes for a median of 10 years, and already had signs of heart disease or had several risk factors for heart disease.

I've previously discussed the ACCORD trial here, here, and here.

A conservative interpretation of the study was that aiming for a normal A1c might be harmful in older people with longstanding type 2 and pre-existing signs of or risk factors for cardiovascular disese but it would be OK for younger people who had recently been diagnosed. The idea was that if damage from high blood glucose levels has already been done, it may be too late to help by getting those levels down.

Another interpretation was that these people had been put on traditional high-carbohydrate American Diabetes Association diets, so they needed a lot of drugs to get their A1cs in normal ranges, and it was the combination of so many drugs that caused the increased cardiac events.

Another interpretation was that they'd brought the A1cs down too quickly, and that was what caused the harm.

And another was that the intensive-control group had more serious incidents of hypoglycemia.

Now comes a new interpretation of this study that says that those who were actually able to reach the normal A1c goals had lower rates of cardiovascular events. It was the patients who were unable to reach the goals despite the intensive treatment who had increased rates of cardiovascular events.

Mortality was greater in the intensive-treatment group only when the A1c was above 7.

The new interpretation was published in the May 2010 issue of Diabetes Care.

None of the mainstream analyses of the ACCORD study have suggested that instead of intensive treatment with drugs, patients might benefit by using lower-carb diets to get their A1c levels down. We know that works. Why can't the cardiologists understand it?

I think one thing the back-and-forth recommendations resulting from the ACCORD trial tell us is that we shouldn't forget to use common sense. If we're discussing treatment of a mentally compromised relative who is 99 and unable to understand why he shouldn't eat huge dishes of ice cream and chocolate sauce, perhaps trying to enforce a low-carb diet so the poor man would have no enjoyment in life wouldn't make sense.

One vision that haunts me is the description of an old diabetic woman in a nursing home. Everyone else got ice cream for dessert, and the nurses said, "You can't have ice cream because you are diabetic." The old woman cried all during dessert because she wanted the ice cream so much. That's cruel. Especially because they were probably stuffing her with starches like bread and potatoes.

But if we're still pretty healthy and able to manage our diabetes diet ourselves, and if we understand how harmful high blood glucose levels can be, we should make an effort to get the best A1c levels we can manage, even if some study shows that this might be harmful to some people.

We shouldn't reverse our treatment plan on the basis of one study, which is what the doctors who told all their type 2 patients to get their A1cs higher did. One study doesn't prove much. The study might have been poorly designed. The population studied might not be representative of the population as a whole, or it might not match your own situation (a study of 80-year-old male veterans might not apply to a 40-year old woman). The statistics used might have been faulty. The treatment in the study might have been different from what you are using.

There are many reasons that one study might be misleading. It's only consistent results that are significant. We shouldn't totally ignore any study. But we need to take them with a grain of salt.

Saturated Fat and the Popular Press

2010-05-02T07:23:00.000-07:00

The May issue of the mainstream magazine Scientific American had an article saying that dietary carbohydrates are more important than fats in terms of heart disease risk.

Wow!

Many people thought the news would never reach the mainstream press. But it finally has. The article cites the recent meta-analysis by Krauss and colleagues that suggested that the amount of saturated fat in the diet is not related to heart disease.

I would note several caveats. First, although some of the studies in the meta-analysis used food diaries to assess intake, others used the ubiquitous "food frequency questionnaires," which may not be accurate, as discussed here.

Second, Krauss et al. suggested that the effect of saturated fat may depend on what people substitute for the saturated fat. (This assumes that no one would want to decrease calories by simply eating less saturated fat, which is what makes the most sense to me.) Eating more unsaturated fat may decrease heart disease rates, whereas eating more carbohydrates may increase heart disease rates. Not everyone agrees with this, however.

Finally, the Scientific American article says it's mostly highly processed carbohydrates that are the villains, and the author writes, "some high-fiber carbohydrates are unquestionably good for the body." Many people do, in fact, question that statement, especially in relation to people with diabetes.

The author of the Scientific American article is not urging people to pig out on saturated fats. She says that current studies "do not suggest that saturated fats are not so bad; they indicate that carbohydrates could be worse."

It takes a long time for generally accepted ideas to be thrown out. Further studies may convince people that the "healthy whole grains" that people (including those with diabetes) are currently being urged to make the focus of their diets are just as bad as white bread, pasta, and sodas.

But for now, every little nail hammered into the brittle saturated fat hypothesis of heart disease helps. Saying that high-glycemic-index carbohydrates may increase heart disease risk is a step toward accepting the idea that all carbohydrates may do the same, especially in people with a genetic propensity to insulin resistance.

Publicizing the evidence in a mainstream popular magazine will help to spread the news, because the popular press operates with a herd mentality. If one mainstream news outlet carries a story, everyone else has to report on it too.

In fact, just today I got in the mail a copy of the Harvard Medical School Focus, which included a brief comment titled "For Heart Health: More Polyunsaturated Fat, Fewer Refined Carbohydrates." This discusses both the Krauss paper cited above and another paper that supports the idea that substituting polyunsaturated fat for saturated fat instead of carbohydrate will reduce heart disease risks.

Perhaps the brittle saturated fat hypothesis of heart disease it will soon be shattered.

Is Dieting a Sport?

2010-04-03T15:41:00.000-07:00

One thing that annoys me (well, OK, a lot of things annoy me; I'm becoming a curmudgeon) is when people approach dieting like a team sport.

You pick your favorite diet, and then you defend that diet come heck or high water. When a scientific paper supporting your diet choice is published, you crow. When a scientific paper supporting some other diet is published, you ignore it.

A couple of recent papers concerning the impact of saturated fat on heart disease illustrate this unscientific approach by some people in the science-discussing community.

In January, a study titled Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease was published online ahead of print publication. The study concluded that "there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD."

The study was pretty much ignored by the mainstream science press, which tends to support the official American Heart Association low-fat approach to heart health. The New York Times didn't mention it. The various popular science summary services like Science Daily and EurekAlert also didn't report on it.

As diabetes blogger David Mendosa wrote, "I couldn't find any mainstream articles about it today. Not one of the four sources that I rely on heavily for leads to new studies has carried a word about this one."

But response in the low-carb community was immediate. People on low-carb diets tend to eat a lot of fat, often including a lot of saturated fat. Blog after blog reported on this study, and some of the bloggers made fun of the "low fatters" and patted each other on the back for following the "correct" diet.

More recently, another paper, titled Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials was published online. This paper concluded that replacing saturated fat with unsaturated fat could reduce the risk of having a coronary heart disease "event" almost 20%.

This study was picked up by the science reporting services like Science Daily, but to date, I haven't seen a single one of the sites or blogs that publicized the "no effect of saturated fat" study mention this other study, and I've been looking.

To be fair, I get the URLs of some lipid blogs from the links in other blogs, and because people tend to link to blogs that agree with them, they do tend to read each other's posts and come to similar conclusions. But I find this business of ignoring the studies you don't agree with sad.

This isn't science. This is religion, or politics . . . or sports. When I was a child, I was a big supporter of the Washington Senators, the team that ended up in the basement year after year. The big excitement was whether they'd end up last, as usual, or perhaps claw their way up to next-to-last. So I know what it's like to root for a loser. You grasp at straws.

For example, Dean Ornish, who advocates an extremely low fat diet to prevent heart disease, was once asked about the fact that when your fat intake is low, your HDL cholesterol, the "good" cholesterol, goes down as well as your LDL, the "bad" cholesterol, so the ratio remains the same or even gets worse.

He said well, maybe when you're not eating fat, you don't need HDL.

But finding the best diet for people with diabetes shouldn't be pursued like this. We need to look at all the evidence, whether it supports our preconceived notions or not.

In fact, these two studies are not that far apart in their conclusions. What the first study said was that there was no significant evidence for linking saturated fat with heart disease. But they hinted at the results of the second study: "More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat."

And the second study concluded that yes, it does matter what you replace the saturated fat with. Replace it with carbohydrate, and people's risk goes up. Replace it with unsaturated fat, and people's risk goes down.

Both studies were meta-analyses, and like many people, I'm not a big fan of meta-analyses, as I discussed here. Nevertheless, they hint at possible relationships.

And I don't think we should sit around throwing darts and this study or that study and maintaining the ideas we've had for decades. What we need to do is to look at all the evidence and try to interpret it in the best way we can given today's scientific and statistical tools. We need to try to find out why different studies seem to give different results and figure out how we can apply those findings to individual patients.

When I was in graduate school, forced to read a little in the history of biology, one thing that struck me was that often when there were two different schools of thought on some topic, it turned out they were both wrong. The answer turned out to be something else, which they couldn't have known because the technology for testing for that thing had not yet been developed.

So it's possible that a similar thing applies to research on dietary fats. Maybe it's not the saturation/unsaturation of the fats that is important but how fresh they are. Maybe it's the degree to which the fats are oxidized, or glycated because of high blood glucose, or modified in some other way that makes the most difference in heart disease.

Maybe the type of fat depends on what you're doing with that fat. Unsaturated fats, expecially the omega-3 fats found in fish, are easily oxidized when warm. This is what causes the "fishy" smell when fish sit around before you cook them. Using fish oil for frying would be a bad idea. The best fats for frying are the saturated fats. But most studies don't ask about how the various fats were used, or how fresh they were.

Maybe we can tolerate any kind of fat when it's not modified by food additives or the many chemical pollutants in our environment. Even organic food and bottled water are not free from contaminants, especially when the water is bottled in plastic.

Maybe we can tolerate almost any kind of fat in limited quantities, but when we overwhelm our metabolism with huge amounts of any kind of fat we'll see our heart health decline.

If it turns out that any type of food does, indeed, affect heart disease, we need to study why that food has that effect. We need to determine if it's eating any of the suspect food or eating a tremendous amount of that food that is important.

We need to abandon more studies designed to prove some preconceived notion (fat is bad, or fat is good) and instead encourage studies that show why different studies appear to give different results. Was it study design? Poor use of statistics? Poor choice of patient populations? Poor choice of endpoints?

You can look at short-term effects or long-term effects. You can lump together all cardiovascular events, including mortality, or you can study only mortality, or you can separate strokes from heart attacks, or you can try to study them all. In the latter case you need gargantuan overall sample sizes to have statistical significance in all the groups. And that means very expensive studies, especially if it's a long-term study.

You can study saturated fat from meat, butter, chicken, and coconut oil or you can study saturated fat from fast-food burgers, luncheon meats, hot dogs, french fries, potato chips, and southern fried chicken. The latter sources are apt to be associated with other behaviors such as eating a lot of processed convenience foods and drinking lots of sodas. So is it the effect of saturated fat that you're measuring or an overall unhealthy eating pattern?

So until we find the best possible diet, what do I think is the best diet for both preventing heart disease and controlling diabetes?

A l0w-carb diet. I've been following a low-carb diet for about 14 years.

But if you start out on a "standard American diet" that is high in both carbs and fats, I think the best approach is to drastically reduce the carbs and not replace them with anything. This way, your percentage of fat will increase; a typical low-carb diet includes about 60% fat. But your calories will go down.

In fact, studies have shown that when most people switch from a typical American diet to a low-carb diet, they reduce calories without thinking about it. This is because a low-carb diet tends to reduce hunger, so you don't want as much food.

Simply losing weight (not that the process itself is simple) improves blood pressure and blood glucose levels in most people. So if you reduce the carbs and don't replace them with a lot of other calories, you're apt to lose weight.

If not replacing the carbs with anything means that you're hungry, you can eat a little extra protein. Or even have a little extra fat. Just don't make a big effort to replace those 1000 calories a day you were eating in the form of bread, mashed potatoes, and doughnuts with something else.

I don't know why, when the press keeps blathering about the "obesity epidemic" the nutrition researchers hone in on replacing fat calories with something else. Do they want to keep people fat?

Come on, people. Let's stop bickering and use our brains and figure out how to make us all as healthy as we can be.

ADVANCE and NAVIGATOR

2010-03-15T15:19:00.001-07:00

The Internet is abuzz with the latest results from a couple of those massive trials that physicians who practice "evidence-based medicine" require before they'll believe in any treatment.

Although I understand why such studies are needed, I hate them, because they're studying a huge, diverse population of patients who may differ a lot in their baseline characteristics, even though the mean is usually all you can see.

Unless the outcome is black and white, for example, 100% of the patients who took the new drug dropped dead within 2 weeks, you need statistics to evaluate the study. Quite often, individual patients may be harmed or helped, but the published conclusion refers only to the average impact, as I noted here. Then physicians apply these average results to everyone.

A good example of this is the blood glucose (BG) arm of the ACCORD study, which was stopped early a couple of years ago because it appeared that the patients who used intensive treatment with a lot of drugs and lowered their A1cs to a mean of 6.5% had higher mortality than those who used standard treatment and had A1cs of about 7.3%.

This was despite the fact that patients in both groups had mortality rates lower than those of most people with diabetes.

In fact, the patients in the ACCORD study were older, had had type 2 for at least 10 years, had other risk factors for heart disease, and started with mean A1cs of 8.3. This means they had probably had poor control for years. Yet doctors are applying the conclusions to everyone.

Many patients are now reporting that their doctors tell them that their excellent A1c levels in the 5s are too low and they should increase them until they're over 7!

Furthermore, like most patients, the ACCORD patients were told to follow an ADA-type diet with less than 30% total fat and less than 10% saturated fat. This means they undoubtedly increased their consumption of carbohydrates, most likely the kind most Americans eat: potatoes, rice, white bread, processed fat-free foods. Yet a recent meta-analysis showed that there is no significant evidence to conclude that saturated fat causes heart disease. Some studies showed an increase when saturated fat was reduced, and others showed an increase. This averaged out to no effect.

The authors suggested that it might depend on what you substitute for the saturated fat, as studies with substitution of unsaturated fat tended to reduce heart disease and mortality and studies with substitution of carbohydrate tended to increase it, although no studies have been done that would actually prove this.

Yet replacing saturated fat with carbohydrate is undoubtedly what people in ACCORD were told to do, and those in the intensive treatment arm of the study got more intensive nutritional counseling and hence probably ate more carbohydrate.

Now the other two arms of the ACCORD study have been published. The blood pressure arm showed that reducing the systolic blood pressure below 120 resulted in no better cardiovascular outcomes than using fewer drugs to keep the systolic blood pressure below 140. The lower blood pressures did result in fewer strokes.

This is the same patient population as the BG arm of the study, and the same caveats apply: longstanding diabetes in an elderly population with coexisting medical problems (34% had already had a cardiovascular event), relatively high starting A1cs and fasting BG levels over 170, and multiple blood pressure drugs given to reach the goal. Also, twice as many of the intensively treated patients gained more than 10 kg during the study.

The final arm of the study was designed to see whether adding a fibrate drug to the treatment of patients already taking a statin would reduce cardiovascular events. The fibrates (they used fenofibrate) reduce triglycerides and increase HDL levels.

Again, they found no significant effect but a suggestion that the drug might help in patients who began with triglyceride levels over 204 and HDL levels under 34. Men appeared to do better and women appeared to do worse on the fibrate. Such studies can show differences that appear to be real but aren't statistically significant.

Again: same population and same caveats.

Another study, the NAVIGATOR study, was reported at the same time. This study started with patients who had prediabetes, with mean A1cs of 5.8 and also either preexisting heart disease or cardiovascular risk factors. They tested whether using valsartan (Diovan), an angiotensin-receptor inhibitor that lowers blood pressure, would reduce progression from prediabetes to diabetes. Similar drugs had been shown in the past to do so.

Again, all the patients were given "lifestyle modification" advice, although the papers don't specify exactly what that was other than the usual ADA line of reducing total and saturated fat and increasing exercise. You have to go to an Appendix, which most people won't read, and then to a reference to a Finnish study they cite to see what type of dietary advice was given.

It turns out to be the usual low fat with "lots of whole grains, fruits and vegetable." Many Americans told to eat lots of whole grains are apt to eat whole-wheat bread (which isn't whole grain) and to drink more orange juice and eat more apples and bananas, and maybe more peas and corn. Very few will up their intake of kale and broccoli and other low-carb veggies.

It turned out that the low-fat high-carb diet plus increased exercise plus the drug reduced the progression to type 2 diabetes from 36.8% to 33.1%, which they calculate is a 13% reduction in the "absolute hazard difference using an exponential model," but a pretty small absolute reduction. It didn't affect the rate of cardiovascular events.

The second arm of the NAVIGATOR trial involved the same patient population and the drug nateglinide (Starlix), which is a sulfonylurea-type drug that increases insulin secretion by the beta cells but for a shorter period than the traditional sulfs.

The rationale was that high postprandial BG levels are said to lead to beta cell deterioration, and higher A1cs are associated with increased heart disease. They tested whether or not this drug would reduce progression from prediabetes to diabetes and whether it would affect cardiovascular events.

They found it did neither.

Do these studies mean there's no point in trying to control our diabetes?

Not at all. What they really show is that you can't give people with longstanding diabetes or even a diabetic tendency and either preexisting heart disease or a lot of heart disease risk factors a low fat, and hence very high carbohydrate, diet, try to control the resulting high BG levels with a lot of drugs, and expect the heart disease to go away.

Furthermore, even though you tell people to eat lots of vegetables and whole grains, you know that in the general population, most of them -- if they modify their diet at all -- will eat high-glycemic foods, low-fat processed convenience foods, and sugary fruits. If they show the dietician that their fat consumption is down, the dietician will probably tell them they're doing great.

No one has tested whether or not trying to control diabetes with lower-carb diets and fewer drugs would reduce heart disease rates.

But I'm afraid that the results of these trials will make a lot of people simply throw up their hands and give up, figuring that heart attacks are inevitable, no matter what they do.

Even if the results from a lower-carb study showed fewer cardiovascular events, I'm afraid most Americans wouldn't make significant changes in their diets. An intelligent woman with type 2 once told me she had trouble eating just a couple of potato chips. I asked why she bought potato chips (she lived alone). She said, "Because I like potato chips."

Well, who doesn't. I also used to like blueberry pie (I probably wouldn't like it now, because it would seem overwhelmingly sweet with relatively little taste) and homemade bread slathered with butter and homemade jam. But I don't eat those things now.

What we need to learn to do is to become gourmets, seeking out foods with a lot of taste and not a lot of carbohydrate, like berries, or exotic fresh vegetables from a farmers market. This is a lot more fun and cheaper than paying $500 a month for a lot of pills to try to cover the damage from eating ho-hum potato chips and packaged snack cakes.

The intelligent people who read this blog will understand this. I worry about the other millions of people in the country who don't have access to good information. I worry about the overworked GPs who don't have time to slog through long statistical studies and try to figure out what an "absolute hazard difference using an exponential model" is.

Many of the details, like the actual dietary advice, in these papers are difficult, if not impossible, to find. If you make an effort to download the full study protocol of the ACCORD study, you find that patients were taught carb counting but it doesn't say how many carbs they were supposed to eat. They were taught self-monitoring of BG, and how to titrate their drugs according to the results. They were apparently not taught how to "titrate" their carb consumption according to the results.

And the authors are often sloppy. For example, sometimes they give both mean and median A1c. Sometimes they give only one. Sometimes they don't indicate which one they calculated.

I worry that the busy physicians will just read the headlines in medical magazines and the New York Times ("Diabetes Heart Treatments May Cause Harm") and conclude that they shouldn't try to treat diabetic patients with high blood pressure, high BG levels, or high lipid levels. Why bother, because they might be sued if they caused harm.

As studies become old, people who write about them tend to simplify, ignoring the many caveats that apply to the studies. For example, Gina Kolata wrote in the recent New York Times story, "It was discovered 2 years ago that rigorously controlling blood sugar did not prevent heart disease or deaths in people with type 2 diabetes." What that study actually showed was that "rigorously controlling blood sugar with a lot of drugs to cover a high-carb diet did not prevent heart disease or death in elderly patients with preexisting heart disease or at least two cardiovascular risk factors and long-standing poorly controlled diabetes."

But how many physicians have retained Kolata's interpretation? I suspect a lot. I've mentioned the many patients whose doctors told them that their diet-controlled A1cs of 5.6 were too low and they should try to get them up to 7!

I would agree that if someone had an A1c of 5.6 only because they were on 7 different expensive medications with a lot of potential side effects, it would make sense to stop several of the drugs and let the A1c go up a bit, especially if the patient was elderly with several other medical problems treated with even more drugs.

But if someone has an A1c of 4.8 because of strict diet control and a lot of exercise, and if that person doesn't go low (after all, nondiabetics don't go low when they have low A1cs), there's absolutely no reason to tell that person to increase the A1c.

Applying a "rule" for the wrong reasons is the type of faulty logic that has caused harm in a lot of diabetic patients. I know some who have been told by registered dieticians that they should put raisins in their oatmeal "to get the carb counts up."

The reason for the high-carb ADA diet is not to eat a lot of carbohydrate; it's to eat less fat. The idea is that when you eat more carbohydrate, you'll eat less fat. But adding carbohydrate to a meal instead of substituting carbohydrate for fat won't reach the ADA goals (which many people today don't agree with anyway). It will just add calories, increase insulin levels, and promote even more fat gain.

So will patients with type 2 diabetes soon be told to get their blood pressure up, not worry about lipid levels, and pay no attention to postprandial BG levels?

I certainly hope not.

The full texts of the New England Journal of Medicine articles cited are available free here.

Ancient Bacteria

2010-03-05T17:54:00.000-08:00

It's generally agreed that low-grade chronic inflammation is related to metabolic syndrome, cardiovascular disease, and type 2 diabetes. But no one knows what causes this generalized inflammation.

Acute, localized inflammation is a good thing. It's what walls off an infection, "eats" the offending organism, and then digests it with the help of heavy-duty oxidants. Then, when things are working right, the body repairs the damage, and the cells that have been doing all this leave the scene.

Chronic inflammation, on the other hand, is not a good thing, and the more scientists can find out about it, the better.

Hence I was intrigued by a recent paper in Nature that proposed a totally new idea and confirmed an old idea. You can read a popularized description here, or a link to the original paper here.

When we are invaded by pathogens, the body mounts what is called the innate immune response. This is a nonspecific response triggered by certain chemicals on the surface of many organisms that are unique to them and are not found on our own cells. The body sends out cells called macrophages to engulf the offending organisms and sends chemical signals to recruit other cell types to help rid the body of the organisms and then repair any damage that occurred.

This response is more primitive than the adaptive immune response that uses antibodies and is more specific than the innate immune response.

Usually, the cause of the response is clear, as bacteria or viruses or other pathogens can be found in the blood. But sometimes people seem to have such a response when no pathogens can be found. This puzzled scientists for a long time.

But Carl Hauser and colleagues, the authors of the Nature paper, came up with a fascinating hypothesis. It is generally accepted that mitochondria, known as the "powerhouses of the cell" because they are where most of the cell's energy is produced, were originally bacteria that invaded the cells of other organisms and adapted to the benefit of both.

Mitochondria have their own DNA, which comes only from the mother.

Hauser and colleagues wondered if perhaps trauma that destroys cells could release mitochondria from the damaged cells into the bloodstream. Then, because the mitochondria are descended from bacteria, they might have surface molecules that our bodies would interpret as foreign, so we would mount an innate immune response, just as we do to other bacteria.

His researched suggested that this does indeed happen.

It explains why severe trauma patients sometimes get reactions that look like severe infections when no signs of infecting organisms can be found.

And I wonder if less severe chronic trauma could cause just enough of an innate immune response to trigger chronic disease. For example, we know that chronic gum disease can increase blood glucose levels, along with various signs if inflammation. Could this be because the gum disease is causing gum cells to break down and release mitochondria?

Could other hidden infections be doing the same? By reducing various chronic infections, could we reduce people's chance of getting type 2 diabetes?

I find this research exciting, not because it offers an immediate chance for a cure of type 2 diabetes, but because it's a new idea and I find new paradigm-shifting ideas much more fascinating than huge studies of drugs that rely on statistics to prove anything. Even then, although the statistics can show that the drug worked on average, it can never show whether or not it will help you in particular, as I discussed here.

Creative new ideas can suggest new research paths that may some day lead to real cures.

.

Slow Progress

2010-03-01T07:04:00.000-08:00

One thing that annoys me is how long it takes for new ideas and new research results to filter down to practitioners. At this rate I will have died of old age before they figure out a better way to treat type 2 diabetes.

When I was first diagnosed in 1996, because I had been a biology major and had done some research in biochemistry, I wanted to learn more about the science of type 2 diabetes.

I was puzzled because the nurse practitioner who diagnosed me told me to follow the American Diabetes Association (ADA) diet, which was chock-a-block full of carbohydrates. I knew that diabetes was caused by an inability to process carbohydrates. So why were they telling me to eat more of them? It made no sense.

So I went to the library. Remember libraries? They were places with books and preceded Internet searches and Google and all that. The library didn't have much of interest, so I searched the interlibrary loan catalogs and found and ordered a book called Insulin, edited by F. M. and S. J. H. Ashcroft. It was published in 1992, which means it was probably written around 1990, as the publishing process does take time.

The book was very interesting. A chapter author named Erol Cerasi said he and others had done a study of a large group of obese and nonobese subects both with and without diabetes and studied insulin resistance (IR) and insulin secretion.

They found that only beta-cell responsiveness could distinguish the diabetic from nondiabetic subjects. The IR could only distinguish obese from nonobese subjects.

In other words, if you're obese, you'll have IR, but you won't necessarily have diabetes. If you have diabetes, your beta cells won't secrete enough insulin, whether or not you're overweight.

They concluded that "the diabetic state is much more closely related to a failure of the secretion of insulin than to diminished efficiency of the circulating hormone level," that is, beta cell defects are more important than IR in causing type 2.

Another group did a similar study and found that those who progressed from prediabetes to diabetes had decreased insulin responses to glucose at the beginning of the study.

Yet people with type 2 diabetes continued to be told that their obesity had caused IR and the IR had caused the diabetes.

Recently, 23 years after the research published by Cerasi and others, there was a report of a study of 13 new genes increasing the risk of type 2 diabetes. The authors of the study said they were "intrigued" by the finding that most of these genes affect beta cell secretion rather than insulin resistance.

"Beta cell impairment may play a larger role in type 2 diabetes than previously recognized," the authors said, as if this was a totally new idea.

It is true that there's so much diabetes research published that no researcher can have read all of it. One report or one person's opinion isn't considered proof of anything, but it should suggest something, so researchers shouldn't be stunned 23 years later to discover the same thing.

Why is it that an amateur researcher, a newly diagnosed patient, can find information a professional apparently cannot? I'm sure the Cerasi papers were not the only ones to come to the same conclusion, and the other researchers had 23 years in which to look.

Cerasi also recommended using insulin in type 2 patients right from the beginning, to normalize blood glucose levels and reduce glucotoxicity, which he felt contributed to the IR. "Present therapeutic approaches based on initial dietary restriction followed after a period of up to several months by oral diabetic agents, seem rather unsuited" for returning the patient to mild diabetes or prediabetes.

"I propose initial, short-term (one to a few weeks) intensified insulin treatment aimed at achieving euglycemia very rapidly, in order to block down-regulation of glucose transport and inprove beta-cell function." He showed in a pilot study that when patients in whom the oral drugs had stopped working were given insulin to maintain normal BG levels for two weeks, they could then maintain good control on oral agents alone after the insulin was stopped.

Again, a recent proposal suggests essentially the same thing. Ralph DeFronzo proposed starting newly diagnosed patients with type 2 on an intensive drug regimen of metformin, a TZD, and exenatide. And he and 15 other diabetes experts proposed the same at the 2008 ADA meeting.

The ADA's response: Prove it. They just now started a 3-year study to see if early normalization of BG levels with drugs helps. But what is taking them so long? And why use drugs instead of insulin?

Other research has shown that early intensive insulin treatment is more effective than drugs in maintenance of beta cell function. So why mess around with expensive drugs that can have serious side effects when a simpler, cheaper treatment has already been shown to work?

It boggles the mind.

Another example is a 2007 paper by Frank Q. Nuttall and Mary C. Gannon. They showed in 1996 that fasting caused normalization of BG levels in people with type 2 diabetes and wondered, "Could merely a reduction in carbohydrate mimic the effect of a reduced fuel-energy diet or short-term starvation on blood glucose in people with type 2 diabetes mellitus?"

They published the results of using l0w-carb diets (20 and 30% carbohydrate), showing that BG levels and HbA1c levels were much lower. However, their request for further funding was rejected by the National Institutes of Health, which said their sample sizes were too low to show anything and "it is difficult to conceive of the diet as producing larger improvements than metformin or rosiglitazone, for example, especially if the subjects are maintaining their body weight."

"So much for open mindedness," wrote Nuttall and Gannon. The health authorities cling to their old views even in the face of new evidence. They seem to have made up their minds, and there's no more room in their tiny minds to consider alternatives.

But wait a minute. For decades, Richard K. Bernstein has been proposing low-carbohydrate diets for both type 1 and type 2 patients. His first book was published in 1984. But almost no one in the professional world listened to him either. Why did Nuttall and Gannon have to "wonder" in 1996 if the idea of reducing carbohyrate would work?

Research has been done, and it has been published, but other researchers don't seem to pay a lot of attention.

Why must the patients be the ones to ferret out the facts?

Fuzzy Fats

2010-01-30T17:34:00.000-08:00

Fats have been in the news lately, with publication of a meta-analysis mentioned in a previous blogpost showing that there's no statistical evidence that saturated fat is associated with deaths from cardiovascular disease (CVD).

Well, let me qualify that statement. Fats have been in the low-carb news lately. I haven't seen much discussion of this study by people like Dean Ornish who support very low fat diets.

Note that the study showed that they found no evidence that saturated fat intake was associated with CVD mortality. They didn't study whether or not eating other fats were associated with CVD mortality.

But what does saturated fat intake mean? Does it mean the amount of saturated fat you eat? Or does it mean what percentage of your diet consists of saturated fat? These two things can be quite different. Yet many research reports, written by scientists who should be precise about such things, don't make it clear.

Fat intake is often reported as a percentage. For example, low fatters want us to keep our dietary fat under 30% and saturated fat under 10%. But I don't know anyone who goes into a restaurant and sits down with a calculator and a scale to make sure they don't eat more than 30% fat at that meal. (Actually, people with type 1 diabetes used to have to do just that.) Trying to calculate total fat and also saturated fat is even more difficult.

I once bought a little hand-held gizmo that allowed you to punch in your menu and it would, indeed, calculate the macronutrients in the meal. If you ate the same meals over and over again, it might have been useful. But if you ate the same meals over and over again it would have been equally useful to do the calculations on a real computer or even by hand with the aid of a book and then write them down to refer to when you had that meal.

When you ate something different at each meal, you had to locate that food among thousands of foods, decide what description best fit it and how much it weighed, and then input that.

I don't eat the same meal over and over again. I think variety is the spice of eating as well as the spice of life. When it's mealtime, I go to the fridge to see what's there and then try to make something interesting from it.

And the biggest problem I had with any nutritional gizmo was trying to decide which of the myriad choices to input for various foods. Let's say I roast a leg of lamb.

Do I want "Lamb, Australian, imported, fresh, leg, center slice, bone in, separable lean and fat, trimmed to 1/8 inch fat, raw" or do I want "Lamb, domestic, leg, shank half, separable lean and fat, trimmed to 1/4 inch fat, Choice, cooked, roasted, USDA"? I counted 44 different versions of leg of lamb in the nutrition program I have on my computer: Computer Planned Nutrition.

And how do I know how the nutritional information from lambs raised by my neighbors are closer to those of the Australian, New Zealand, or domestic lamb in this program? The lamb I eat comes from free-range animals. Do the animals used in the nutritional program? I don't know.

So even assuming I have time to comb through all 44 choices every time I sit down to eat a slice of lamb (which would probably be cold by the time I figured out the best one), I have no confidence that the lamb I'm eating has the same nutritional composition as the lamb in the program.

Some lambs are fatter than others. Of course I could trim them all evenly. But I could trim the lamb to 1/4 inch or 1/8 inch and then eat or not eat the remaining fat. Or I could leave some of the lamb and a lot of the fat that oozed out of the lamb on my plate.

I see some of the precise calculations some people do with nutritional programs as GIGO: garbage in, garbage out. The computational ability of the computer programs exceeds the accuracy of the data you put in.

The same is true of other foods. Foods have different nutritional compositions depending not only on the particular variety and size but on the condition of the soil, fertilizer, growing season, and so forth.

Furthermore, most nutritional studies rely on people's recollection of what they ate last week or last month or last year. I often can't remember what I had for breakfast, much less last week.

But I digress. I was talking about fat.

Most people don't estimate the percentage of fat in every meal they eat. You can get an estimate of what you need every day by calculating the number of calories you need every day to keep your weight stable, or to lose weight if that's what you're trying to do. Then you can calculate how many calories or grams of a food you should eat each day to reach that percentage.

For example, let's say you're trying to eat about 2000 calories a day with 30% fat. That would be 600 calories of fat. Because there are about 9 calories per gram of fat, that would be 66 grams of fat. Divide that by 28.35 (1 ounce = 28.35 grams), and you get about 2.35 ounces of fat per day, or 1.175 tablespoons (1 oz = 2 Tb). That includes the fat in your meat as well as the oil you cook in or pour on your salad.

But how do you really know how much fat is in the meat you eat?

What if you're eating a lot more or a lot less than 2000 calories a day? What if you're a large man and you're very athletic and you eat 5000 calories a day. Then you could eat 1000 calories of fat (111 grams) of day and still say you were eating a very low fat diet, only 20%.

What if you're a small woman trying to lose weight? You might eat only 1000 calories a day. Then the same amount of fat (1000 calories, or 111 grams) would constitute 100% of your diet, obviously not a likely choice for anyone. If you ate only 400 calories of fat (44 grams), you'd still be eating 40% fat, considered a high-fat diet.

You could get your fat percentage down by eating more carbohydrate calories. Let's say you increased your total calories to 2000. Then you'd be on a "nice healthy 20% fat diet." But does that many any sense? Not to me.

Now let's look at what often happens when people go on a low carb diet. Let's say your previous lunch every day was a hamburger on a bun with french fries and a regular soda. I chose ground beef and a large hamburger bun (this had less fat than a fast-food burger, but I wanted to be able to compare it with a burger without the bun), a "serving" of Burger King fries, and a 32-ounce soda. Most people would probably also add catsup, or the fast-food burger would come with a sweet sauce, but I'm ignoring that. According to my nutritional program, without those extras, you have a meal with 1358 calories, 38 grams of fat, 10 grams of saturated fat, and 200 grams of carbohydrate.

Now let's say you go on a low-carb diet. You still eat at the hamburger place because all your friends do, but now you get a large burger without the bun. In place of the bun, you order a salad of mixed greens (I used 2 cups), with ranch dressing, and water or a sugarfree soda. This meal results in 324 calories, 15 grams of fat, 3 grams of saturated fat, and 4 grams of carbohydrate.

The first meal results in 25% fat (38 grams of fat x 9, divided by 1358), because of all the calories in the soda and the potato. The second meal results in 42% fat (15 x 9, divided by 324), because the total calories are so much lower that the fat makes up a larger proportion of the meal.

But would anyone claim that a meal that included french fries and a large soda (25% fat) was healthier than a meal that included salad greens and ranch dressing (42% fat)?

I don't think so.

This is why measuring a diet by the percentage of fat can be so misleading. This is why worrying about the fat content of low-carb diets can be so misleading.

Although my current low-carb diet includes about 60% fat, I don't think I'm eating any more fat than I used to eat. What I'm not eating is all the carbohydrate I used to put underneath that pat of butter or tablespoon of oil.

Biochemist Richard Feinman said all this in a more concise and more academic way when he wrote here, ". . . it is important to recognize that percentages are misleading. There are really three degrees of freedom in design or analysis of a weight loss experiment: two of the three macronutrients and the total calorie intake. It is unlikely that the percentage rather than the absolute amount of macronutrients is the controlling variable and at least three published studies show that carbohydrate reduction is not necessarily accompanied by replacement with either fat or protein but rather caloric reduction due to the carbohydrate removed."

In trying to unravel the very complex picture of the role of fat in human health, and for us its role in diabetes control, remember to scrutinize any research articles you read to see if the reseachers were measuring absolute amounts of nutrients or their percentages.

If only percentages, take the results with a grain of salt . . . or maybe a piece of cheese.

Also see how they determined the various nutritional intakes. Did they isoloate people in a ward and feed them carefully controlled meals? Or did they provide all the food on a take-out basis and trust that the participants weren't eating anything else? Or did they just provide "guidance" by a nutritionist who told them what kinds of foods they should be eating? Or did they just ask people to fill out food questionnaires after the fact?

You also need to see how the researchers defined their terms. They can differ a lot. For example, some people call a diet that has 45% carbohydrate (225 grams on a 2000-calorie diet) instead of 55 or 60% a low-carb diet and then claim that low-carb diets do this or that. Often this information cannot be found in the abstract of the article. You have to obtain and read the whole thing.

If you're reading an article about the effects of fat, you need to determine what other foods the subjects were eating. If you're on a low-carb diet, you'll burn a lot more fat than if you're eating both fats and carbs.

Unfortunately, the news media can't deal with these subtleties. They want interesting stories. And simplistic interpretations make for better stories. A story headlined "Whortleberries cure cancer" would get more readers than a story headlined "When fed a diet of 98% whortleberry, small percentage of highly inbred white mice see improvements in obscure cancer type that never affects humans ."

But you're smarter than the average reporter. So reader beware. Read and learn. But don't take any nutritional study as the last word. And especially, don't accept fuzzy fat words like "fat intake."

Banana Cream

2010-01-29T13:31:00.000-08:00

I've always loved custard of any kind, and banana cream pie was a real treat.

Alas, I don't eat custard anymore, except for custard sauce I make with low-carb milk in the summer when my raspberry bushes are producing. They don't raise my BG very much.

I recently invented a banana cream substitute when I was trying to use up some ricotta cheese I'd bought for another recipe.

Basically, you stir some DaVinci sugarfree banana flavoring into full-fat ricotta cheese. (I find the Maggio brand is the creamiest I can get here.) Top with sugarfree whipped cream. And that's it. Pretty simple.

The ricotta has a smooth texture somewhat like custard, and when topped with sugarfree whipped cream, it really gave me the feeling I was eating banana cream.

I like the sugarfree whipped cream that comes in a can, made by Land O'Lakes, because I can use just a little at a time. You can get it at Walmart superstores. When I buy heavy cream and whip it, then I have to use up the rest of the cream or it will go bad. So I end up eating more heavy cream than I really want.

You do have to be careful with ricotta cheese, as it does contain some carbs, so small portions are in order. It was so good I went overboard, and my BG levels did reflect that.

But it made a nice change for me, and next time I'll be more careful.

Saturated Fat and Heart Disease

2010-01-18T12:51:00.000-08:00

I'm on a low-carb diet. I believe in LC diets for people with diabetes.

However, I also have an open mind. It's possible that new evidence will show that LC diets, although they improve blood glucose (BG) levels in people with diabetes, also make something else worse.

Richard Bernstein, the physician and author of LC diet book The Diabetes Solution, has lived with type 1 diabetes for many decades, most of those years on a LC diet. And the fact that he is in excellent health in his 70s argues against this possibility. However, Bernstein has type 1 diabetes, and very little insulin resistance. There's some evidence that fat increases insulin resistance. Hence, for those of us for whom insulin resistance is a big problem, perhaps fat of any kind, or maybe only certain kinds of fat, is not a great idea.

So, I have an open mind. But unfortunately, many people in the LC community seem not to. Many of them don't have diabetes, and they have gotten great results losing a lot of weight with LC diets. So they think the LC diet with a lot of fat is the answer for everyone.

And unfortunately, the LC world is just as guilty of spinning the news as the popular science writers who blame red meat for all our problems when some study showed that people eating red meat, hot dogs, french fries, no vegetables, and sweet desserts don't fare so well on some health factor.

A good example is the blogosphere response to this recent study, a meta-analysis of the association between saturated fat and cardiovascular disease (CVD). A meta-analysis is a study in which researchers combine the results from a lot of studies, some of which aren't statistically significant because of their small size, so that the overall results are statistically significant because of the larger populations in the combined studies.

Meta-analyses are notoriously questionable, because the researchers have to decide which studies to include. If you did a meta-analysis of the percentage of the population that watched the Super Bowl (assuming lots of people had studied this fascinating question) but excluded everyone who shaved every morning, the results wouldn't be very accurate.

Nevertheless, sometimes meta-analyses can suggest possible conclusions that other scientists can then investigate more thoroughly.

And that is what this study, titled Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease, did.

The authors' conclusion was that "there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD [coronary heart disease] or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat."

Two things are important here.

First, the fact that there's no significant evidence for something doesn't mean it's not true. It just means no one has proved that it's true. Several studies have concluded that there's no significant evidence that BG testing in people with type 2 diabetes results in lower A1c's, but most of us know that it does when patients are educated about how to use the results from their meters to change their diets and their exercise patterns. But no one has done the study that would show this.

And second, this study was about association, not cause. Something can be associated with something else but not be the cause of it. For example, coffee drinking is often associated with smoking, but drinking coffee doesn't make you smoke, and vice versa.

The types of studies this meta-analysis looked at were not the types of studies that can show cause.

What the authors found was that some studies showed that saturated fat consumption was associated with higher rates of CVD (heart attacks and strokes), and other studies showed that saturated fat consumption was associated with lower rates of CVD. When you combined the higher rates and the lower rates, you got rates that weren't significantly different.

However, they also noted another recent study that showed that when saturated fat was replaced by polyunsaturated fat, CVD rates went down. When saturated fat was replaced by carbohydrates (what dieticians have been recommending that we all do), CVD rates went up. They said there was some evidence that the ratio of unsaturated to saturated fats was more important than the amount of saturated fat. Hence they suggest that studies are needed that would investigate whether the other elements of the diet have more effect on CVD than the saturated fat.

The authors of Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease never say that saturated fat definitely doesn't cause CVD. They also say that "the available data were not adequate for determining whether there are CHD or stroke associations with saturated fat in specific age and sex subgroups." In other words, the jury is still out.

Nevertheless, the Internet is awash in blogs with titles like "Two major studies conclude that saturated fat does NOT cause heart disease" and "Saturated Fats Are Not Harmful."

The following are just my opinions, and I won't cite studies to back them up. I suspect that saturated fat is fine in moderation. If you want to put a couple of teaspoons of something on your vegetables, I suspect it doesn't matter if it's butter or olive oil. People on LC diets can probably eat more saturated fat because they're burning fats instead of carbohydrates for energy. I don't think eating a lot of polyunsaturated fats (vegetable oils), which are easily oxidized (damaged), is healthy.

But I don't think eating gargantuan amounts of fat of any kind is healthy, even on a LC diet. I once measured my triglyceride levels after eating an extremely high fat breakfast. You can see the results here. The triglyceride levels were astronomical.

People with diabetes probably have a disturbed lipid metabolism, so it's possible that nondiabetics would not have such astronomical triglyceride levels after pigging out on fats (for example, eating half a pizza). But headlines proclaiming that saturated fat isn't harmful will be interpreted by many people to mean that fat isn't harmful. They won't stop eating all those carbohydrates, the doughnuts and french fries and white bread. They'll just add more fat because they remember that they saw headlines saying fat doesn't cause heart disease.

The study showing no association between saturated fat consumption and CVD, despite its many limitations, is important. It should lead to more studies that will attempt to show causation or lack thereof.

I just hope the misinterpretations don't result in more unhealthy eating.

Biased Reports

2009-12-28T12:22:00.000-08:00

Now that Santa has come and gone and we don't need to worry about being good for another year, I can stop worrying that I might say something unkind in a season of joy and get back to sniping about the biased reporting we see every day.

This time it's a study suggesting that a diet high in methionine might increase your risk of Alzheimer's disease. According to the ScienceDaily summary, foods typically high in methionine include red meats, fish, beans, eggs, garlic, lentils, onions, yogurt, and seeds.

So does the researcher interviewed for the article suggest that people eat less fish, beans, lentils, and garlic?

Of course not. Instead he blames the problem on red meat:

"But people who have a diet high in red meat, for instance, could be more at risk because they are more likely to develop this high level of circulating homocysteine, [lead researcher Domenico Pratico] said."

Well, he did at least say "for instance," but you know that most readers will come away with the idea that "artery-clogging red meat" will cause Alzheimer's, and they'll forget that fish, beans, lentils, and garlic may have the same effect.

Sometimes I think it's hopeless. These people aren't real scientists, who seek the truth, whether it's what they were expecting or not. Instead, these people start out with a preconception of what healthy eating is and then do experiments to try to prove they're right. When the answers don't come out the way they want them to, sometimes they don't publish them.

I was once in a study of the cholesterol-lowering drugs Lipitor vs Zocor. At the time, Lipitor was gaining market share, and the Zocor people hoped to prove that even though Lipitor might be better for the general public, Zocor would be better for people with diabetes.

However, according to a nurse, it turned out that Lipitor worked better for the people with diabetes. And as far as I know, the results of this study have never been published.

I hope the people who read this blog are smarter than average and know how to read between the lines in these popular science reports.

We'll never get the answers if we have to rely on these biased popular reports.

Quick Chocolate Cake

2009-12-22T10:01:00.000-08:00

The holiday season is difficult for many of us, as we watch our friends gobble down allegedly delicious holiday foods. So I thought I'd mention an instant LC chocolate cake recipe I got somewhere. Can't remember where, so I can't give credit.

The nice thing about this recipe is that it's incredibly fast, so if you suddenly get hit by a yen for something sweet and chocolate but you wisely don't keep stuff like that in the house, you can whip up a batch of this in minutes.

1/4 cup nut flour (or wheat bran or rice bran)
2 tablespoons cocoa powder
1/4 teaspoon baking powder
3 to 5 packets of sweetener
2 tablespoons melted butter, or sour cream
1 tablespoon water or DaVinci syrup, any flavor)
1 egg

Mix everything together in a 2-cup microwavable glass cup and cover with plastic wrap. Cut a small slit in the center of the wrap to vent. Put in microwave for about a minute.

That's it! I'm lazy, so I usually don't bother to cover with plastic wrap and it turns out OK. I also don't see a reason to waste the DaVinci syrup, as this is plenty sweet (5 packets of sweetener made it too sweet for me), and the chocolate flavor is intense so who needs more?

You can gussy this up by adding chunked nuts. Or you could add a LC icing or swirls of whipped cream.

I never particularly liked chocolate cake; I was more of an icing person. And I preferred fruit pie to cake. But I do occasionally feel chocolate-dessert deprived, and then I whip up a batch of this and feel satisfied for another month or so.

Serotonin and Insulin Secretion

2009-11-22T07:12:00.000-08:00

Most of us have heard of serotonin (5-hydroxytryptamine, or 5-HT) as a neurotransmitter. It's the compound that is affected by the SSRI antidepressants.

Nerves use neurotransmitters to transmit messages from one nerve cell to the next. The nerve's signal arrives at the end of one nerve, which then secretes a neurotransmitter. This diffuses across the tiny space between the nerves and is taken up by the next nerve. The neurotransmitter is then reabsorbed by the first nerve and can be used again. The reabsorption also prevents the signal from becoming permanent.

The SSRIs slow down the reuptake of the neurotransmitter so its effects last longer. Serotonin can affect mood, and low levels can cause depression. Hence keeping it around longer by means of the SSRI drugs can reduce depression.

So what does all this have to do with diabetes?

A fascinating new article that appeared in the open-access journal PLOS recently shows that serotonin in beta cells is required for insulin secretion. A summary of the article appears here.

Apparently it's been known for 30 years that serotonin is synthesized in beta cells and cosecreted from the beta cells along with insulin, but no one knew why, and most textbooks -- even comprehensive ones -- didn't even mention this fact.

But this German research group showed that mice unable to produce serotonin outside the nervous system became diabetic. Infusing them with serotonin corrected the problem.

So all we have to do is take serotonin tabs and all our problems will disappear? Unfortunately, no.

The crucial factor here is whether the serotonin is inside the cell or outside the cell. High serotonin inside the cell stimulates insulin release. High serotonin outside the cell inhibits insulin release. It's the ratio that is important.

So when internal serotonin levels are high, insulin and serotonin are cosecreted. The secreted serotonin then inhibits further insulin release. Gradually the secreted serotonin is taken up again by the beta cells, until there's more inside the cell than outside the cell. Then the cell can secrete more insulin.

The authors postulate that this system is responsible for the well-known insulin pulses that occur in nondiabetic people between meals. This pulsating pattern is lost in people with type 2 diabetes.

This research is also fascinating for a more general reason. Most water-soluble hormones like serotonin, histamine, and the catecholamines were thought to work at the surface of the cell. They bind to a surface receptor in the membrane, causing conformational changes that affect the metabolism inside the cell. This is true of insulin, for example.

Other hormones, the lipid-soluble ones like thyroid hormone and the steroid hormones, get inside the cell and bind receptors in the nucleus, changing the expression of genes.

But this study showed that serotonin works inside the beta cell in a very different way. It doesn't just bind to a receptor. Instead it works by actually forming bonds with other compounds in the cell, called serotonylation. This action is very different from the way serotonin works as a neurotransmitter.

Serotonylation had previously been found in platelet-forming cells and in smooth muscle cells. Finding it in beta cells suggests that it may turn out to be a general property in many kinds of cells.

This will open the door to a lot more research on how hormones work as well as research to find new drugs that work to control hormone action.

And I hope it results in new treatments for diabetes of all kinds.

Glitazones and Weight Gain

2009-11-21T13:04:00.000-08:00

Many people who take a glitazone drug -- pioglitazone (Actos) or rosiglitazone (Avandia), also known as TZDs (thiazolidinediones) -- find that the drug works well to lower their blood glucose (BG) levels, but it also seems to make them gain weight.

Some doctors will say that the weight gain is simply fluid retention, which is a known side effect of the TZDs. That did happen to me when I was in a short clinical study of Avandia. I put on about 6 pounds during the study, but I lost them without effort when I went off the drug at the end of the study.

But the TZDs are also supposed to trigger the differentiation of precursor cells into new fat cells. The new, small fat cells aren't stuffed with fat like some of the older, large fat cells, and they're more responsive to insulin. Hence they take up more glucose, and this keeps the BG levels down.

Several recent studies have shed more light on the weight gain that occurs with the TZDs.

One study, published in the Journal of Biological Chemistry, showed that in obese mice, at least, rosiglitazone increased the expression of the VLDL receptor gene in fat cells. VLDL is the type of cholesterol particle that carries fats from the liver to the various organs that use it.

With more VLDL receptors on the fat cells, more VLDL would get bound to the fat cells, which would take up more fat. And the mice did, in fact, get fatter than the control mice, although their insulin resistance decreased.

They also showed that in certain mutant mice that couldn't bind VLDL, the effect on insulin resistance was preserved, but the mice didn't gain any weight, meaning it would be possible in theory to separate the effects on BG levels from weight gain.

Another study, in the journal Clinical Endocrinology and Metabolism, showed that pioglitazone treatment enlarges subcutaneous fat cells in insulin-resistant patients.

This is rather ironic, because obesity-related insulin resistance is associated with large fat cells, and TZD therapy is supposed to result in the birth of smaller fat cells. But in this study, although insulin resistance decreased, the size of the fat cells increased with the TZD treatment.

The TZDs work by stimulating a nuclear transcription factor called PPAR gamma. A third article described a study in humans in which they separated patients into TZD responders and TZD nonresponders. Previous studies had suggested that about 30% of patients do not respond to the TZDs.

They found that in insulin sensitive people, those without insulin resistance, feeding resulted in the expression of many genes involved with glucose metabolism. This response was blunted in people with insulin resistance.

In the insulin resistant people who responded to a TZD, the drug caused an increase in the genes that were stimulated in the insulin sensitive people. In the insulin resistant nonresponders, the expression of the same genes was not changed.

But they also noted that fat cell gene expression in muscle increased after TZD treatment, especially in those people who responded to the drug, suggesting that the decrease in insulin resistance in the drug responders was caused by more fat cells in the muscle tissue.

Hence they suggested that the fat infiltration often seen in the muscles of insulin resistant persons may not, in fact, be causing the insulin resistance. Rather, they suggest, the fat cells are absorbing extra calories from overeating and are attempting to reduce the insulin resistance.

All these studies -- and I'm sure there are many more -- are consistent in suggesting that the TZDs do work by increasing the amount of fat in the body, both subcutaneous fat and fat in muscle tissue, and perhaps elsewhere as well.

They are consistent in suggesting that the TZDs work by stimulating this increased amount of fat while at the same time reducing insulin resistance. If you're taking one of these drugs and you gain weight, don't let your doctor tell you that you're not watching your portion sizes. The drug is probably causing the weight gain.

However, the one study suggested that these two effects could be separated, although no one knows how yet.

The last study also notes the difference between drug responders and nonresponders. The TZDs don't work for everyone.

Most drugs can have both good and bad effects. For example, it turns out that the fat cell precursor cells that the TZDs stimulate to differentiate into baby fat cells are the same ones that can be turned into bone-forming cells. When you produce more fat cells, you produce fewer bone-producing cells. Hence the TZDs can contribute to bone loss, or osteoporosis.

As with all drugs, we need to weigh the pros and cons of the TZDs in light of our own particular situation. First, do they work to reduce BG levels when we take them? Or are we nonresponders? No point in risking side effects if the drug isn't working for us.

Second, are we unhappy with the amount of weight gain that results from the drugs?

Third, are we at high risk for osteoporosis so even a small loss of bone-producing cells might have terrible consequences?

Diabetes is complicated, and there are no simple answers. But the more we understand about how these drugs work, the better the decisions we can make about which drug or drugs work best for our own particular physiology.

On the Popular Press

2009-11-20T13:43:00.000-08:00

Does the popular science press help us all by spreading the word about new research? Or is it causing harm by distorting the facts?

I spent 8 years as a reporter/editor working for a small daily newspaper in Vermont, and I'm familiar with the stock complaints about the press. We heard them every day.

"You're blowing it out of proportion." Or "You just want to sell papers." Or "You misquoted me." I was once accused of misquoting a politician because I reported only what he said at a meeting and not what he had intended to say!

So I hate to jump on the "tar the press" bandwagon myself. But sometimes things really go too far.

One thing that has angered me lately is the tendency of the popular science press to blame everything on fast-food gluttony. Whenever there's an article about overeating, for example, they illustrate it with a gargantuan cheeseburger accompanied by a bucketful of French fries. Don't they know it's possible to overeat on chicken and tofu as well?

A recent Science Daily article here really went too far. This one concerned a study showing that a high-calorie diet may accelerate age-related disease. The article was illustrated by a man with a huge plate of french fries. He was eating with his hands, which were covered in catsup. There was also catsup on his face, as if he'd been grabbing the fries and stuffing them in so fast that he got catsup all over everything.

Apparently I wasn't the only person who was fed up with this sort of thing. I see that the current iteration of the story illustrates the other extreme: a plate with very little food: one shrimp, a third of a spear of asparagus, and a mushroom.

And it's not just the popular press that blames everything on fast-food gluttony. Scientists themselves tend to single out those factors.

This Science Daily story was about a study showing that people in their 60s today have more disabilities than previous generations. What do the researchers blame this situation on? Immigrants and fat people, of course.

They say that "disabilities may be linked with the changing racial and ethnic makeup of the group that recently reached or will soon be reaching its 60s, with the most rapid growth projected to be among African Americans and Hispanics -- groups with significantly higher rates of obesity and lower socioeconomic status, both of which are associated with higher risk for functional limitations and disabilities.

It's true that very extreme obesity would be likely to make people less likely to walk a quarter of a mile or climb steps. But a lot of people in the "obese" category of BMI are as fit as their thinner counterparts. Maybe the real change is that no one, thin or fat, tends to walk anywhere these days when most people have cars.

And finally, popular science writers obviously don't do any fact checking of science press releases at all. A currently hot topic in the popular press is a recent study in which some researchers did MRI on some mummies and found evidence of heart disease, as reported here. The reporters were agog.

As one said, this new study challenged "longstanding assumptions that cardiovascular disease is mainly a malady of modern societies." But low-carb author Michael Eades discussed the evidence for cardiovascular disease among ancient Egyptians in his book Protein Power, first published in 1996. And apparently the first report of aortic calcification in ancient Egyptians occurred in 1852, as a result of a study by a scientist named Czermack, as discussed in the book Mummies, Disease, and Ancient Cultures.

Let's see. That's only about 150 years ago, but scientists continued to believe that cardiovascular disease is "often attributed to urbanization, fast-food diets, smoking and sedentary lifestyles characteristic of Western societies," according to the Wall Street Journal article. Notice the reference to fast-food diets again. The assumption of the reporter is that all of society's ills are caused by fast food.

Because the Egyptians didn't have fast food, as far as we know, however, they then blame it on the fact that the upper classes (and of course the lower classes, who ate mostly bread and onions, weren't mummified) ate meat "from cattle, ducks, and geese." Again, the bias is that the only healthy diet is one devoid of meat.

I'm quite aware that the reporters who write these popular science article are most likely under tight deadlines. Maybe they have to produce X number of stories per day in order to keep their jobs, so they don't have time to do even quick Internet research on the topic, and they simply print the press releases that flood in every day.

Nevertheless, the biases that are so obvious not just among the science reporters but among the scientists as well (surely they knew that finding evidence of cardiovascular disease in mummies was nothing new; what was new was the technique they used to find it) makes the rest of us sceptical about anything we read.

I think the science reporters and even the scientists who do the research are shooting themselves in the foot.

Misleading the Public

2009-10-13T06:55:00.000-07:00

A recent article in the New York Times focused on the safety of ground beef. Apparently a lot of ground beef includes bits and pieces cut from parts of the animal that are likely to be contaminated with feces, and thus E. coli.

Not all the meat is tested before sale, increasing the chances that you'll get sick from eating it unless you cook it to death.

But another comment in the article didn't seem to arouse much comment. According to the Times article, "To finish off the Smiths’ ground beef, Cargill added bread crumbs and spices, fashioned it into patties, froze them and packed them 18 to a carton."

Bread crumbs? In ground beef? What's going on here?

According to the article, "The listed ingredients revealed little of how the meat was made. There was just one meat product listed: 'Beef.' "

When I first read this, I thought it meant that the only ingredient listed was beef, and I was outraged, thinking of all the people who have wheat allergies that could be triggered by even small amounts of wheat. Other people apparently also read the sentence that way.

But on rereading, I suspected that what the author really meant was that the only kind of meat listed on the label was beef. And I assume the bread crumbs were also listed.

I'm still angry. If I buy ground beef (and I only buy it at the local general store, which I know grinds its own), I expect to get ground beef, not ground beef plus a lot of fillers. And what about people with serious wheat allergies who eat hamburgers at parties, or at restaurants, if the ground beef comes from one of these companies that add bread crumbs to them?

We really can't trust anyone when it comes to food labels.

Another example is the new high-fiber sugar substitute sold under the Splenda label.

One problem with most commercial sugar substitutes is that they because the sugar substitutes are so intensely sweet, they need some kind of bulking agent so you can pour it out of the container. Without the bulking agent, much of the sweetener might stick to the side of the package.

And unfortunately for those of us with diabetes, the bulking agent is often glucose (listed as dextrose, which some people don't realize is the same thing) or maltodextrin, which consists of 3 to 19 glucose molecules strung together and acts essentially the same as glucose in the gut.

So when I saw that Splenda was offering a new "high fiber" form, and the ingredients were simply "soluble corn fiber and sucralose," I was thrilled. At last someone had figured out that you could use fiber instead of maltodextrin or glucose as a bulking agent.

But because I'm not too swift, it took me a bit to notice the nutritional facts, which said there were 2 grams of carbohydrate and 1 gram of fiber. Wait a minute! If only 1 gram is fiber, what is the rest of the carbohydrate?

The other versions of Splenda list 1 gram of carbohydrate, so it looked as if instead of substituting fiber for maltodextrin/glucose, they'd simply added fiber to the regular stuff and not listed the maltodextrin/glucose on the label.

So I wrote to the manufacturers and asked, "Your new Splenda with fiber contains 2 g of carbs and only 1 g of fiber. What is the other gram of carbohydrate? Maltodextrin?"

In response, I got a canned response giving the sugar equivalents for Splenda and never even mentioning the new high-fiber product. So OK, they're not going to help. I searched the Internet for answers.

According to one site, "Corn syrup is being relabeled as "Soluble Corn Fiber" in foods and artificial sweeteners, possibly to avoid consumer health concerns about high fructose corn syrup."

And from the cached page of the company that produces it, Promitor (they've removed the original page), "Soluble Corn Fiber may be labeled as “soluble corn fiber” or alternatively, it may be labeled as “corn syrup” or “corn syrup solids” depending on whether it is liquid or dry."

In other words, they take corn syrup, which includes some soluble fiber, and process it to maximize the amount of fiber and then use that as the bulking agent. Their site says that soluble corn fiber is 70% fiber, so obviously 30% is something else.

The 50:50 breakdown on the label (2 g of carbs and 1 g of fiber), instead of 70:30, is probably due to rounding. If you have 2 g of carbs that are 70% fiber, that would be 1.4 g of fiber, and if you're not using decimal places, this would round to 1. The 0.6 g of nonfiber would also round to 1.

But what isn't fiber is most likely maltodextrin and glucose, but they don't have to say that on the label, and most consumers don't t realize that they're eating corn syrup. I didn't.

Various discussions of the soluble corn fiber note that it can be used for "consumer-friendly labels." I would describe them as "consumer-deceiving labels."

I don't like it when a company tries to deceive me with "consumer friendly" terms, making me think there's no corn syrup in what I'm eating, so I'm not planning to buy any more Splenda.

Type 2 Testing

2009-10-13T06:35:00.000-07:00

I posted a blogpost at Health Central on testing in type 2, and on the basis of the number of comments I received, I gather this is a pretty hot topic for a lot of people. You can see it here.

Back Again

2009-10-13T06:22:00.000-07:00

I recently returned from a short trip to southern France, which was great. But unfortunately I and my traveling companion both returned with some kind of virus, which we probably got on the crowded plane, and I've been under the weather since then, not trusting my brain to write anything very worthwhile.

However, I'm finally seeing the light at the end of the tunnel and I've started tackling the stacking of 3 cords of wood. Maybe that's helping to cure me.

France was great for someone on a low-carb diet, as the French aren't as fat-phobic as most Americans. My first meal, in a small town along the coast, was the only thing they were serving at that hour (restaurants serve only from noon to 2 p.m., which we didn't know): a large assortment of delicious cold cuts, pates, and a green salad. I was in heaven.

Also, meals didn't come with huge mounds of mashed potatoes or rice, and corn. Of course all the meals come with bread, but I only tasted that. Some was delicious and some was mediocre, not as good as the stuff I used to make using Julia Child's bread recipe and King Arthur flour. A popular "dessert" in France is cheese, and I was able to substitute that for the sweet dessert that came along with full-course meals. Breakfast at the B&B included yogurt and "fruits rouges" (berries), cheese, and sausage along with bread and homemade jam, which I tasted.

But the woman couldn't grasp the concept of a LC diet and assumed I was gluten intolerant. When she finally grasped that I was diabetic, she then assumed I could eat other starches, just not sugar. Oh well. I survived.

I was stuffing myself with fatty cheeses along with other LC food, and when I got home I discovered I'd lost 2 pounds.

I think I need to get a grant to return to France to study this phenomenon.

Inflammation and Heart Disease

2009-09-04T13:22:00.000-07:00

We all know that chronic inflammation is a bad thing, and many of us try to eat antinflammatory foods or we take supplements that are supposed to reduce inflammation.

But like everything in human biology, inflammation may not be as simple as some people think.

In the short term, inflammation is usually a good thing. It's what protects us from infection. When you cut your skin, it usually hurts and becomes hot and red. Sometimes it swells. This is a sign of inflammation. (Doctors sometimes refer to rubor, calor, dolor, and tumor, referring to red, heat, pain, and swelling.)

What happens is that the wound releases signals that tell the body to send white blood cells to the area to repair the damage, removing dead tissue and replacing it with new tissue. Local blood vessels dilate and become leaky, allowing fluids and white blood cells to exit and get to the wound. This results in swelling, heat, and redness.

Again, short-term inflammation is a good thing. It's chronic inflammation that is supposed to contribute to chronic diseases such as diabetes and heart disease.

But a paper published last month showed that among an obscure tribe in the Amazon, chronic inflammation is the norm, but heart disease is rare.

According to the scientists, the Tsimane tribe still live a traditional lifestyle, fishing, hunting and gathering, growing crops, and also growing and using tobacco, although they smoke much less than Americans who smoke. Most of them die from infections or parasitic diseases. About three-quarters harbor intestinal worms or protozoa. Their life expectancy at birth is only 43 years.

Chronic inflammation is prevalent, and they have high levels of C-reactive protein (CRP), which is often used as a marker of inflammation in the Western world. The Tsimane also have low HDL levels, which is supposed to mean high risk of heart disease.

But the Tsimane had almost none. Not a single adult, even the elderly ones, showed signs of peripheral artery disease, a sign of atherosclerosis. Peripheral artery disease increases with age in every other population studied.

The scientists reported that no one died of a heart attack during the 7 years that they were studying the population, which consisted of about 9000 people.

What this suggests is that chronic inflammation alone is not enough to trigger heart disease in a population living a traditional lifestyle. That means they're pretty lean and get plenty of exercise every day just obtaining their food. Their food is fresh.

Of course, many of them died from infectious diseases before they were old enough to be at higher risk of heart attacks and type 2 diabetes.

And one of the flaws of this study is that the authors do not indicate how many people were in each age group for which they reported data. There were only several hundred people in the whole samples (they did more of the simple tests like blood pressure than the more complicated ones), sometimes even less, and they report the results as percentages, so you have no idea how many people were in each age group.

Nevertheless, I think it illustrates one of the flaws to the American approach to health. Too many people focus on one or two factors, try to control those with drugs, and then expect chronic diseases to go away.

It doesn't happen like this.

Our entire lifestyle makes a difference. We can't pop antioxidant and anti-inflammatory pills and think the risk of cardiovascular disease will evaporate. We need to try to live more like the Tsimane, getting exercise as we go about our daily lives and eating real foods that are as fresh as possible.

One would hope that it's not the parasites that are protecting the Tsimane from heart disease. But that's also possible. Some people theorize that allergies in the developed world have risen because our parasite loads are so low. Maybe parasites also help our arteries. One never knows. As I said, human biology is never simple.

Another possibility discussed by the authors is that the Tsimane are somehow protected by genetic differences. In my opinion, that's always a way to explain the results when they don't come out as you expected they would.

This article also illustrates another issue: the effect of preconceptions by the scientists doing the study. Most people today think thin is good. They think eating a low-fat diet is good, especially if it's vegetarian.

And the title of this article is "Inflammation and Infection Do Not Promote Arterial Aging and Cardiovascular Disease Risk Factors Among Lean Horticulturalists." In other words, they're saying, "Well, these risk factors might not work if the rest of your lifestyle is healthy, like being thin and eating a plant-based diet."

They could just as easily have said, ". . . Among Tobacco-Using Hunters With High Parasite Loads," or "Well, these risk factors might not work if you smoke, eat meat, and have a lot of worms."

Many people read only the titles of articles, and perhaps the abstracts. So any biased generalizations made there can mislead a lot of people. It takes much longer to plow through the full text of an article. But sometimes it's necessary to learn what it really shows.

Some Progress

2009-08-24T18:13:00.000-07:00

Many of us whine about doctors' lack of understanding of the diabetes research that we read. One reason for this knowledge gap is that current standards for medical education don't require that medical students be give significant instruction in some areas -- for example, statistics, nutrition, and disease prevention rather than disease treatment.

A fairly recent (well, OK, it was June 5; I get behind in my reading) editorial in the journal Science suggests that medical education in some of these areas may improve if the recomendations of the Association of American Medical Colleges and the Howard Hughes Medical Institute are followed. (The full text is free if you register.)

The report, titled Scientific Foundations for Future Physicians, says that "physicians must have a firm grounding in thebiomedical sciences and understand their relation to the physicalsciences and mathematics. For physicians to be prepared forinquisitive, critical thinking and lifelong learning, they shouldalso be able to incorporate the methods of science into theirpractice, including skeptical and critical analysis."

Wow! Skeptical and critical analysis instead of listening to drug reps and reading medical magazine summaries. Wouldn't that be wonderful!

To achieve these goals, the groups recommend changing medical education starting in the undergraduate years: "Students should arrive at medical school preparedin the sciences, including some areas not currently required,such as statistics and biochemistry."

The idea is that if first-year studenst already have a grounding in the basics, then medical school can focus on more advanced concepts, for example, "the synergistic relationships among biomedical science,research, and clinical medicine."

They also recommend more emphasis in medical school on "the physical sciencesand mathematics in biomedical research and clinical practice."

They also recommend assessing incoming students by their competency, rather than according to what courses they've taken. This should allow creative students to design their own ways of learning rather than forcing them into taking certain undergraduate courses.

Whether or not these recommendations will be followed of course no one knows. And even if they are, it will take a long time before physicians trained with the new guidelines -- better equipped to do critical statistical analyses of the latest blockbuster study of a new kind of cholesterol drug, for example -- constitute a significant percentage of the practicing physician population.

Even when they do, the problem that even a physician with a firm grasp of physical sciences, statistics, mathematics, and biochemistry as well as medicine and with a burning desire to do critical analyses still needs to have the time to do it. Not all physicans spend their afternoons on the golf course. Many of them are overworked.

Still, just the idea that people in the field are recognizing the deficiencies in the training of physicians is a good thing. Let's hope something comes of it.

Summary

2009-08-24T18:02:00.000-07:00

For anyone not subscribed to Health Central, here are links to my most recent posts there.

Thinking Outside the Box is about how success in diabetes control often stems from being able to think outside the box, applying what you learn to your own individual physiology rather than following the cookie cutter advice you may get from your health care team.

Is Type 2 Diabetes Your Fault? discusses the myth that "you brought it on yourself." Needless to say, it stimulated a lot of discussion.

Finally, Avoiding Diabetes, is an allegedly humorous post about how to avoid getting diabetes. When I read the Comments, I wondered if some people had taken it seriously!

Absent

2009-08-24T17:50:00.000-07:00

I'm afraid I've been absent lately, working through a Blogger Identity Crisis.

I've been thinking about how to deal with two blogs, this one and the one at Health Central. Initially, I was using this site for longer posts and writing shorter versions of the same thing for Health Central. But that came to be too much of a chore, figuring out how to say the same thing in a briefer way, and I found I was sometimes putting off writing something for just that reason.

So I've decided to abandon that approach and write brief, more general posts for Health Central, discussing the things people always want to seem to talk about, like diet, feeling overwhelmed, exercise, trying to lose weight, whether or not to take meds, etc. I also promised to write diabetes humor posts for them.

At this site I'll focus more on new research, both in-depth discussions and brief notes about research or other items that catch my eye.

I'll be assuming that anyone reading this blog is intelligent, already knows at least a little about diabetes, and wants to understand things in greater depth. I hope this works and I won't need to undergo another Blogger Identity Crisis!

Are Grains Healthy?

2009-07-23T13:19:00.001-07:00

Several studies have shown that the so-called Mediterranean Diet is healthy.

This is not surprising, because as interpreted by various groups, it consists mostly of whole foods instead of a lot of processed junk, and you can show that almost any reasonable diet is healthy if you compare it to the "standard American diet" that is high in trans fat and processed carbohydrates.

Definitions of the diet do differ.

As interpreted by the American Heart Association, the key features of the diet include "high consumption of fruits, vegetables, bread and other cereals, potatoes, beans, nuts and seeds"; emphasis on olive oil in place of other fats; low to moderate consumption of dairy products, fish and poultry, with little red meat, and eggs only zero to four times a week; and low to moderate amounts of wine. They suggest that the diet may have too much fat.

A WebMD article says the Mediterranean Diet features "fresh fruits and vegetables, whole grains, nuts and seeds, legumes, seafood, yogurt, olive oil, and small amounts of wine for heart health."

A New England Journal of Medicine article described the diet as being "rich in vegetables and low in red meat, with poultry and fishreplacing beef and lamb," with olive oil and "a handful" of nuts as the main source of fat.

It's clear that different people interpret the "Mediterranean Diet" differently, although they all seem to agree that it is high in vegetables and low in beef. But there are many components to the diet, and it hasn't been clear if the healthy aspects of the diet (for people in general, not necessarily people with diabetes) are because of all the components, some of them, or maybe just one or two.

So when a statistical study of the components of the diet was recently published, showing that some of the Mediterranean Diet components didn't seem to have any effect on mortality at all, I was expecting an avalanche of blog posts commenting on this.

I'm still waiting.

Most of the blog posts and articles I found simply restated what the researchers had reported in their publicity releases, without comment.

The study showed that consumption of cereals, dairy products, and fish had very little effect on the mortality of the participants in the 8-year study in Greece. In fact, in this study, increased fish and seafood consumption slightly increased mortality, although this increase was not statistically significant. But we've been bombarded with messages telling us to eat more "healthy whole grains," fish, and low-fat dairy if we want to be healthy.

Of course, the authors of the study couldn't believe that whole grains aren't healthy, so they suggested that the lack of effect of cereals might be because they didn't separate out processed cereals and whole grains.

It's possible that's true.

It's also possible that when the results of a study don't fit the preconceptions, the authors find some reason to explain it. When the results are what they expect, they accept the study as proof of their pre-existing theories.

The study did show that both low alcohol consumption and high alcohol consumption were associated with a statistically significant increase in mortality compared with moderate alcohol consumption.

They said high consumption of vegetables, legumes, fruits and nuts (which for some odd reasons they lumped together), and olive oil and low consumption of meat and "meat products" (which would included luncheon meats) were associated with reduced mortality.

Then they said that none of these results were statistically significant. This lack of statistical significance is not mentioned in the press releases.

Because the researchers were expecting the results they found for vegetables, legumes, fruits and nuts, olive oil, and meat (although they were not statistically significant), they didn't try to interpret them. For example, "meat" is a broad category. It's possible that some meats such as luncheon meats are unhealthy and other meats such as lean beef are not. Maybe nuts are beneficial but fruits are not, but because they grouped them together, there's no way to know.

Although they called the diet Mediterranean, you notice that all these foods that showed benefit are real, whole foods that hunters and gatherers could eat, rather than processed garbage. You could just as well eat these foods and call it a Whole Foods Diet or a Traditional Diet or a Neolithic Diet. Hunters and gatherers probably eat all the meat they can get, but their hunts are not always successful. Olive oil is processed but in a minimal way. You could get the same monounsaturated fat by eating the olives themselves.

I'm not a big fan of any nutritional studies because most of them are based on food recall forms. I often can't remember what I had for lunch. There's no way I can remember what I ate for the past few days or the past month or so. Nutritional researchers claim they've tested the recall and it's reasonably accurate, but I'm not convinced.

Furthermore, we're all individuals. High fruit consumption might be beneficial for people without diabetes (certainly better than high banana split consumption), but a lot of fruit will raises the blood sugar of people with diabetes.

I suppose this study is a first step. Perhaps future studies will be able to refine these results.

In the meantime, follow the advice we patients so often give. Don't accept any diet as the "best diet" until you see how it affects you individually. If your nutritionist tells you to eat a lot of "healthy whole grains," try a few whole grains and see what it does to your blood glucose levels 1 and 2 hours after you've eaten them.

Then make up your own mind.

Propaganda

2009-07-14T06:25:00.000-07:00

The readers of this blog are intelligent, so I don't think I need to comment a lot on this.

What's sad is that the people who write the headlines are so gullible. When I worked for a small daily newspaper and we got press releases, we always edited the BS out. Today, people seem to reproduce online what everyone sends them.

Science Daily does a lot of that. Sometimes you have to look hard to find out what's new in one of their articles, which focus on the names of all the scientists involved, the institution where they worked, the fact that the results were published in "prestigious" journals, and suggestions that this research opens the way for new drugs to treat diabetes.

It's nice that the pork researchers are supporting low-carb diets, but the constant barrage of specific food "cures" or "preventatives" for diabetes is making patients confused and cynical and harming them in the long run.

I've posted a satirical take on the same article here.

Lantus and Cancer

2009-06-28T06:36:00.001-07:00

Everyone seems to be talking about the recent report that insulin glargine (Lantus) might increase cancer rates. Needless to say, this is very upsetting news to a lot of people, although Lantus has been linked with cancer in the past.

But like most news stories, the facts aren't as simple as the summaries would indicate. If you like reading all the details, they're available here in full text, free.

The method of publishing these papers was interesting. Apparently the first study was submitted to the journal Diabetolgia last year. But the editors decided not to publish it without further evidence. So they commissioned three additional studies to see if the results could be reproduced. Those plus the original article are the four articles available at the journal’s Web site.

Was this irresponsible or responsible? Not publishing results suggesting some bad side effect of a drug might mean that people were harmed because they didn’t know about it. On the other hand, publishing preliminary results suggesting some bad side effect of a drug might mean that people were harmed because the huge publicity in the popular press that usually follows such news would scare patients who could be helped by the drug so they’d stop taking it.

This happened with the drug rosiglitazone (Avandia) last year. One analysis suggested that it caused heart disease, there was a huge glut of articles and blogposts saying Avandia could kill you, and a lot of people stopped taking it. Their A1cs then increased, and high A1cs also increase the risk of heart disease.

So it’s sort of a damned if you do and damned if you don’t situation.

Most patients don’t have the statistical skills to analyze research articles, especially meta-analyses, which try to combine results of numerous trials to see if they can come to overall conclusions. Because the patient populations, time frames, and endpoints being studied in different studies differ, this is difficult to do, and it’s easy to disagree with the results of a meta-analysis.

But regardless of whether or not we approve of the journal’s method of dealing with the Lantus-cancer articles, there are some things patients should understand.

In the editorial accompanying the articles, the authors make a few interesting points:

1. Type 2 diabetes is associated with increased rates of cancer of the colon, breast, and pancreas. People with type 2 diabetes have insulin resistance and hence need more insulin, either produced by their own beta cells or injected.

2. Cancers of the colon, breast, and pancreas have been associated with increased circulating levels of insulin in nondiabetic people. Obviously they wouldn’t be injecting insulin. They’re probably insulin resistant.

3. Metformin reduces the rates of cancer of the colon and pancreas but not cancer of the breast and prostate. (Metformin also seems to reduce the pancreatitis that can result from sitagliptin [Januvia].)

4. Insulin is a growth factor for both healthy cells and cancer cells in cell culture.

5. Evidence suggests that insulin doesn’t cause cancer, but it may increase the rate of growth of cancer cells that have been caused by something else.

6. Most elderly people have some early cancer cells. For example, 90% of men older than 90 years have prostate cancer cells. (The body often keeps these cells in check, or even destroys them.)

7. One early insulin analogue, B10Asp, was found to increase cancer growth in rodents and was never marketed. But "B10Asp would have passed the carcinogenicty testing to which insulin glargine was subjected and would now be in clinical use."

8. Lantus increases mitogenic potency (mitogenic means it causes cell division or transformation into another cell type, for example, a malignant one) six to eight times. The short-acting insulins (e.g., Novolog and Humalog) have little effect. Detemir (Levemir) seems to reduce the mitogenic potency in vitro, but the authors say that because of technical difficulties, this was difficult to measure.

There were all kinds of confusing factors in the four studies published by Diabetologia. For instance, they classified everyone diagnosed when older than 30 as type 2. We know that a lot of type 1s and LADAs aren’t diagnosed until later in life.

In the German study, the patients receiving regular insulin were taking larger doses than the patients taking insulin analogues. In another study, those taking only Lantus were older than those taking Lantus plus a bolus insulin. The ones taking only a basal insulin were most likely type 2s, who would need large doses of insulin, and we know that cancer rates increase with age among all groups.

In their editorial, the authors conclude that

1. “There is no evidence that insulin, however formulated, causes cancer.”

2. But “the growth of some tumor cells lines is clearly enhanced by insulin.”

3. “Circulating levels of endogenous insulin appear to be associated with cancer risk in obesity and other insulin-resistant conditions, including type 2 diabetes.”

4. “There is no evidence of harm in type 1 diabetes, or in males, or in premenopausal breast cancer.”

5. “On current evidence, the short-acting analogues do not appear to present a potential problem.”

In other words, there is evidence that very high levels of insulin, no matter what the source, may increase the growth of pre-existing cancers. People with insulin resistance (metabolic syndrome or type 2 diabetes) are at increased risk whether or not they inject insulin of any kind.

Hence, for us, the best approach would be to do whatever we can to reduce the amount of insulin that we need. Reducing our insulin resistance through exercise and, if possible, weight loss should help.

Another approach, available to everyone regardless of ability to exercise or lose weight, is to reduce the amount of carbohydrate we eat.

The less carbohydrate you eat, the less insulin you need. The less insulin you need (either your own or injected), the lower your risks of encouraging the growth of cancer cells. It seems me this is pretty easy to understand.

But some people don't seem to be able to grasp this. How long will it be before the American Diabetes Association stops telling people with type 2 diabetes to eat more carbohydrate and “Make starch the star”?

Body Build and Diabetes

2009-06-27T07:02:00.000-07:00

You can't tell if someone is diabetic simply by looking at them.

Yet a lot of people still think you can. They buy into the idea that eating too much and exercising too little causes obesity and obesity causes type 2 diabetes. Hence, if shown a bunch of photos of strangers, many would predict that the fat ones had diabetes and the thin ones didn't.

It is true that being overweight is associated with type 2 diabetes, and many people with the disease are, in fact, overweight. But not everyone who is overweight, or even obese, has diabetes, and not everyone who has type 2 diabetes is overweight.

While filing sometime recently, I came across a popular press article that I had found fascinating.

A British newspaper had asked 10 people between the ages of 35 and 50 who had never been diagnosed with diabetes to take "a blood test." The test was simply a fingerstick test in a home-type meter. If the participants said they hadn't eaten (most likely not rigorously controlled, so it wasn't a real fasting test but closer to a premeal test), any result over 5.9 mmol/L (106 mg/dL) was considered suggestive of diabetes. If they said they'd eaten recently, the cutoff was 8.9 mmol/dL (160 mg.mL).

If the results were over these limits, the people were told to see their physician for more rigorous tests. They don't say which readings were premeal and which were after eating, so one person with a reading of 8.9 mmol/L (160 mg/dL) was labeled diabetic and another with a reading of 9.1 (164 mg/dL) was labeled "needs investigation." Probably the former reading was premeal and the latter was after eating.

Here's the interesting part. They then photographed the participants wearing gym togs, so you can compare their body builds with high blood glucose (BG) readings. It's also interesting to compare the body builds with the BMIs.

In this tiny sample, there were a lot of results that go against "common knowledge."

One person labeled obese (BMI 34) had normal BG levels. A person with a BMI of 22 had high BG levels. A woman with a pear shape, which is supposed to be healthy (it's the apple shape with most of the weight in the stomach that is thought to be dangerous), had high BG levels. A woman with a lot of risk factors had normal BG levels. A vegetarian was obese. And the woman with the lowest BG reading said she got no exercise at all.

Scroll down through the initial text, which is the usual popular press stuff about diabetes, and try looking at the photos before you read the descriptions underneath them to see how your predictions compare with the facts.

Many of these participants had relatives with diabetes, which is probably one reason they volunteered for the tests. And they were relatively young. Some of those who tested normal with this fairly uncontrolled test may develop diabetes when they get older.

But it's still interesting to see how different people are and how misleading body build can be as a predictor of diabetes.

The sad thing is that because of the constant barrage of news stories saying that obesity is the cause of type 2 diabetes, many people (probably most people) believe it. And that includes a lot of physicians, who might not bother to do BG tests on someone who was thin, said they "ate healthy" (whatever that means), and got regular exercise.

With the advent of home meters, it's easy to test friends and relatives if you think they might be at risk. Just make certain you use fresh lancets when you do, as well as cleaning off the tip of the finger pricker, to avoid passing on any blood-borne diseases. Even better, ask them to get their own finger-pricking devices.

Because type 2 diabetes usually starts with elevated postmeal BG levels, measuring after a large meal, especially a carby meal, would be the best place to start. People can have normal fasting BG levels and elevated postmeal levels for years before they get a diagnosis. The earlier they learn they're at risk, the easier it will be to take corrective action, like limiting the carbohydrate content of their meals.

And if you are testing relatives, don't ignore the thin ones who exercise. Diabetes is a complex disease, and it happens to apparently healthy people too.

Beyond the Pyramid

2009-06-11T12:59:00.000-07:00

I posted an allegedly humorous blogpost over on The Health Central network.

Right on!

2009-06-01T17:36:00.000-07:00

Sometimes a cartoon says it all. This one does it for me.

It's funny, but it's also sad. So many small discoveries are magnified by PR departments and then news media that the public has become cynical about every new discovery.

Some day we'll find cures for cancer, AIDS, and diabetes, and people will read the stories in the newspaper or see them on TV and think, "Yeah, right. Next week they'll announce that the cure causes something even worse."

Sadly, this sort of thing has been going on for a long time, and I doubt that it will change in the near future.

On Antioxidants

2009-05-26T07:03:00.001-07:00

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."

Bromocriptine and Hibernation

2009-05-12T10:10:00.000-07:00

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 concept 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.

Spinning the News

2009-05-08T06:32:00.000-07:00

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.

Wrong.

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.

Still Here

2009-04-27T11:12:00.000-07:00

I'm still here. I haven't posted anything recently because I've been "under the weather" for a week or so and I didn't trust my brain to say anything worth reading.

I'm better now but also behind in so many things. I'll be back soon.

Hidden Clues

2009-04-18T18:37:00.000-07:00

I get my mail in a rural mailbox by the side of the road. Earlier this year, in the middle of winter, I found that the red flag that tells the mail carrier I have mail to be picked up had disappeared.

It was not an item that anyone would bother to steal. So I figured it had been knocked off and then a plow had buried it under one of the huge mounds of snow nearby. It would turn up in the spring, I thought.

Well, spring came, sort of, and most of the mounds of snow melted (there was still a small pile of snow on April 29, after 2 days of 80-degree weather!), but there was still no sign of the red flag. As I stood looking at the largest mound, still about 6 feet high, it occurred to me that the red flag I was sure was buried there somewhere might be analogous to the cure for type 2 diabetes.

It's there somewhere, I'm sure. But maybe it's buried under a huge mound of information that is leading people to look in the wrong places. Some day we'll find it. No one knows when. Maybe in 10 years, maybe in 10 decades. It's a complex puzzle. But I know we'll find it some day, just as I was certain my red flag would turn up.

And sure enough, a week or so later, when I went down the hill to get my mail, I saw that the huge mound of snow was only 3 feet high, and then I spotted something red. It was the flag!

The key to the diabetes puzzle hasn't been lost for lack of trying. The amount of research being done on the problem is tremendous. But what if everyone is looking in all the wrong places?

For example, we know that the body needs insulin. Insulin saves lives. Before the discovery and therapeutic use of insulin, people who got type 1 diabetes died. Now they can live long and relatively healthy lives.

But there's another hormone that is also important. That hormone is glucagon. Insulin is produced by the beta cells in the pancreas. Glucagon is produced by the alpha cells.

Everything glucagon does is pretty much the opposite of what insulin does. Insulin makes blood glucose (BG) levels go down; glucagon makes them go up. Insulin tells fat cells to store fat; glucagon tells them to release fat to be burned for energy.

And it's actually the ratio of insulin to glucagon that determines what will happen with your BG levels. In other words, high glucagon levels can do the same thing as low insulin levels. And most people with type 2 diabetes have higher glucagon levels than normal.

Normally, after a meal, the increased BG levels turn down the secretion of glucagon. When you have type 2 diabetes, this doesn't happen. So glucagon tells the liver to keep pumping glucose into the blood even when BG levels are already high. This is one reason we go high after meals.

Glucagon is also responsible for the increase in BG levels people with very little insulin production see after eating protein. Insulin does more than help glucose get into cells. It also helps amino acids (the building blocks of protein) get into cells. So if you eat pure protein, a normal person secretes insulin to help the protein breakdown products get into cells to be used to make more protein.

But if you don't eat carbohydrate at the same time and your insulin levels increase, your BG levels could go too low. So the body secretes some glucagon along with the insulin. In a nondiabetic person this system works very well.

But in someone producing almost no insulin, the protein meal still stimulates the secretion of glucagon, and with no insulin to balance it, the glucagon makes BG levels go up. The same is true of other stimuli, for example, exercise, that would normally trigger the secretion of both glucagon and a balancing amount of insulin. The trigger may still work, but if you can't produce much insulin, then the ratio becomes unbalanced and your BG goes up.

As their autoimmune disease progresses, people with type 1 tend to produce less and less glucagon, and because glucagon is one of the main hormones (another one is adrenaline, or epinephrine) responsible for bringing up BG levels when you go low, people with type 1 can have more serious problems with lows. Type 2s can also go low, but they usually have a bit more of a buffer with the glucagon.

People have known about glucagon and its effects for a long time, but most of the research in the field of diabetes has focused on insulin. There is one major exception, and this is the incretins, especially those that mimic or increase the levels of GLP-1. Byetta is the incretin mimic on the market today, and others are in the works.

The incretins stimulate the secretion of insulin; they also decrease the secretion of glucagon, thus giving a "double blow" to BG levels by stimulating glucose uptake in muscle and fat and decreasing glucose production by the liver.

Of course researchers are aware of glucagon and the aberrant responses of the alpha cells in people with diabetes. But most of the research today focuses on beta cells and insulin.

What if it turns out that the alpha cells and glucagon secretion are easier to control than beta cells and insulin? What if it turns out that some other hormone, maybe even one that hasn't been discovered yet, is actually more important than insulin deficiency and insulin resistance as a cause of type 2 diabetes?

I read one paper that suggested that leptin resistance (leptin is a hormone that controls hunger) is actually more important than insulin resistance as a cause of type 2 diabetes.

Thousands of research papers on diabetes are published every year. Somewhere the answers lie hidden. Like the red flag hidden under the huge mounds of snow, the buried answer to the type 2 diabetes puzzle will emerge some day, I'm sure.

When creative minds try to look at the puzzle in new ways, we may accelerate this process.

Fat and Diabetes

2009-04-07T08:03:00.000-07:00

The current dogma among many people, including many medical people, is that the current "diabetes epidemic" is caused by high-fat diets, which cause obesity, which causes diabetes. Thus, if someone is overweight, that person is urged to go on a low-fat diet to lose weight and not progress to type 2 diabetes.

Similarly, a person already diagnosed with type 2 diabetes is often put on a low-fat, high-carbohydrate diet in an effort to help that person lose weight. Then when their blood glucose (BG) levels go high, they're given medication to bring the BG levels down.

The rationale for this approach is based on decades-old studies showing a relation between high-fat diets and heart disease. Because people with diabetes usually die from heart disease, it was thought they should eat less fat. Eating less fat usually means eating more carbohydrate.

Now, people are beginning to criticize the science relating the high-fat diets to heart disease (some people never believed it). And in any case, a relation between factor X and factor Y doesn't always imply causation. Drink a lot of beer and you'll get drunk. You'll also pee a lot. Hence peeing a lot is related to being drunk. But peeing a lot doesn't cause intoxication. A third factor, the alcohol, caused both the intoxication and the increased urination.

Nevertheless, the popular perception remains: eat fat and you'll get fat and get diabetes.

Hence I was interested when I recently came across a study showing that mice who were predisposed to diabetes were protected from getting diabetes when they ate a high-fat carbohydrate-free diet.

Research in the 1980s had shown that substituting protein for carbohydrate protected db/db mice from getting diabetes. The db stands for diabetes, because these mice are predisposed to becoming obese and developing diabetes.

It has been shown that they have defective receptors for the hormone leptin, which is one hormone that controls appetite. Because the leptin can't work properly to turn their appetites down, they have voracious appetites and become obese.

And the effect of substituting fat for carbohydrate had previously been demonstrated in another strain, the New Zealand Obese (NZO) strain, which is considered a model for metabolic syndrome and type 2 diabetes. These mice show insulin resistance, high triglyceride levels, high blood pressure, and a low first-phase insulin response. When they get over a certain weight, their beta cells begin to die.

The new study showed the same preventive effect of fat on the db/db strain of mice.

In the cited study, performed by a German group, mice were divided into three groups: normal mouse diet (5.1% fat, 58.3% carbohydrate, 17.6% protein), high-fat diet (14.6% fat, 46.7% carbohydrate, 17.1% protein), and carbohydrate-free high-fat diet (30.2% fat, 0% carbohydrate, 26.4% protein). The mice had free access to the food and water.

The mice on both the high-fat diets did gain weight faster than the mice on the control diet. A strain of lean mice on the same high-fat diets gained more weight than control mice, but not enough to be considered obese.

The interesting thing was that the mice getting extra fat plus carbohydrate not only gained more weight than the control mice, but they also became diabetic faster. However, the mice getting a lot of extra fat but no carbohydrate got obese (fatter than the mice getting a lot of fat plus carbohydrate), but their BG levels were much lower.

They were also producing as much insulin at the end of the study as they were at the beginning, an indication that their beta cells were still healthy. Histological studies of the beta cells showed that the mice on the carbohydrate-free high-fat diet had larger, healthier beta cells than the mice in the other two groups.

Of course we all know the limitations of mouse studies. Something that works in mice doesn't always pan out to work well in humans. Nevertheless, this interesting study shows that a carbohydrate-free high-fat diet can greatly reduce the tendency to become diabetic in mice that have a strong genetic predisposition to do so.

It also shows that mice without a tendency to get diabetes can gain weight on a high-fat diet without getting diabetes.

The diet that was higher in fat than normal but still contained almost 47% carbohydrate diet did what people tell us a "high fat" diet will do. It accelerated the rate of both obesity and diabetes in a highly susceptible population.

Some researchers call a 47% carbohydrate diet a "low carb" diet because it's lower than the 60% carbohydrate diet that has been recommended by groups such as the American Diabetes Association. But it wasn't low enough for the db/db mice.

When carbohydrates were totally eliminated, the effect on the diabetes was reversed. Although the mice got obese, they didn't develop as much diabetes.

This is an example of correlation vs cause. The high-fat diet caused obesity, but the obesity didn't cause the diabetes. It was carbohydrate that was causing the diabetes, probably by killing beta cells that had a genetic tendency to be stressed.

What this means for humans is not clear. Not only do humans not always react the same as mice, but it's unlikely that anyone would want to remain on a totally carbohydrate-free diet for a long time. Even the Atkins induction diet, which has the least amount of carbohydrate for a month or so, includes a few carbohydrate foods like lettuce.

Many people are able to maintain health on a low-carb diet that includes a variety of low-carb vegetables such as broccoli, cauliflower, leafy greens, and green peppers, and even a few fruits such as berries. Going totally carbohydrate free would be difficult indeed.

However, this study suggests that it's not fat that is real culprit in causing diabetes. It's carbohydrate. The worst scenario seems to be when you mix a lot of fat with a lot of carbohydrate. This is exactly what the current "standard American diet" does. French fries (carbohydrate) cooked in oil (fat). Hamburgers (fat) in large buns with soda (carbohydrate).

If people are like mice, then adding even more fat to a diet that still contains at least 46% carbohydrate would indeed accelerate the rate of weight gain and diabetes in people with a genetic susceptibility to diabetes. People without the genetic tendency would gain a little weight, but probably not a lot, and they wouldn't get diabetes.

But how about a much lower carbohydrate diet? The low-carb diet supported by Dr. Richard Bernstein, recommends 30 g of carbohydrate a day. Others recommend 50 or up to 100 g. The percentages would depend on how many calories you're eating. On a 2000-calorie diet, 30 g would be 6%, 50 g would be 10%, and 100 g would be 20%, all far below the 46% the mice with accelerated diabetes rates were getting.

Which carbohydrate level would give the results shown in the mice when they went on a no-carb diet? No one knows. In the earlier study in db/db mice, although an 8% carbohydrate diet slowed the rate of diabetes, eventually the mice all got diabetes anyway. "Only the carbohydrate-free diet provided effective, long-term therapy," the authors wrote.

And how about the obesity? In the recent study, mice on the no-carb high-fat diet did gain a lot of weight. But the mice were allowed free access to food all day. They probably weren't concerned about low self-esteem from being fat. Humans could be taught about the potential weight-gaining effects of such a diet and counseled to eat only as much as they needed to keep hunger away.

One advantage of fat is that it does suppress appetite, so eating fewer calories on a high-fat diet is often easier than eating fewer calories on a low-fat diet.

One thing this study illustrates is that dogma can change. The science that everyone accepted as true in the past may be proven to be wrong in the future. We need to keep open minds.

Is the dietary advice being given to overweight people who want to avoid getting type 2 diabetes what is actually causing the diabetes epidemic? With counseling and a change in the official dogma about fat and diabetes, could we reverse the "diabetes epidemic"? We don't know. But we can always hope.

Addendum

I neglected to say above that of course the idea that excessive carbohydrate intake may contribute to diabetes and make existing diabetes control more difficult is not new. Dr. Richard Bernstein has been urging low-carb diets for diabetes for many years, and Gary Taubes wrote a detailed and well-documented book (Good Calories, Bad Calories) supporting the idea that fat is not the enemy, carbohydrates are. Many other people have also supported the idea of low-carb diets for health (for example, Michael Eades in Protein Power).

What was interesting about the mouse study I discussed was the fact that the fat content of the diet was extremely high for mice because of the zero carbohydrate intake, and yet the diet didn't have any of the deleterious effects on diabete onset that the low-fatters would predict. Instead, it was beneficial in a highly susceptible population.

How Reliable is Science Research?

2009-03-24T08:13:00.000-07:00

Anyone interested in science research might be interested in this blogpost.

It points out the flaws and unconsious biases found even in academic research. I think it's always interesting to see things from a different point of view, and this is a point of view of someone who has actually worked in Big Pharma.

Among other things, he says, "Moreover, since academic success is determined almost exclusively by the number and prestige of research publications. . . " When I was an undergraduate, I spent a year studying "Zoologie" at a German university.

One lab instructor had spent several years working as a postdoctoral fellow at Yale. He said he wrote up his research in order to publish a paper, and his lab leader told him no, he shouldn't write just one paper. He should break it up into five different papers, so he could have more publications on his resume.

He also says, ". . . many researchers tend to pursue the trendiest technologies and explore topics that happen to be associated with the most generous levels of research support." I agree with that too. When I was in grad school, the trendy topic was molecular biology, especially something called "phage lambda."

I was more interested in oddball things no one else was interested in. I'm now a sheep farmer and some of the people following trendy topics have Nobel Prizes and prestigious academic positions, which suggests that following trendy avenues of research does pay off.

In that respect, those of us with diabetes are "lucky," because diabetes research is now pretty trendy. Very few people are doing research on obscure diseases that only affect a few people.

We may distrust Big Pharma, which wants to find new drugs they can sell us at high prices, but at least in the process of looking for new pathways that would be responsive to drugs, they're learning more about how diabetes works.

It's a very complex disease, and as one commenter to the Washington Post piece noted, "Many questions in health, behavioral and environmental sciences (e.g.) are so complex - specifically multidimensional - that meaningful measurement is phenomenally difficult."

There will be a cure for diabetes some day. We just don't know when that will be.

Iron

2009-03-20T14:03:00.000-07:00

We need iron. Without enough iron, we'll get sick. But too much iron can kill us.

As with so many things relating to our health, it's a balancing act.

Most people who eat meat get sufficient iron. Some foods these days are also supplemented with iron. The chocolate syrup Bosco was designed to get children to consume more iron. Cooking in iron pots, especially cooking acid foods, adds iron to our diet. Multivitamins designed for younger people contain iron (especially those for pregnant women, as the fetus consumes a lot of iron).

Hence nonpregnant Western people who aren't vegetarians usually get enough iron from their diet. People in Third World countries who don't get much meat, however, are often iron deficient.

Heme iron, or the iron that is in hemoglobin, the oxygen-carrying molecule in red blood cells, is absorbed even more efficiently than the nonheme iron that you get when you eat vegetables or take an iron-containing multivitamin pill. So eating meat, especially red meat and liver, should ensure that you get enough iron.

Vitamin C will increase the absorption of iron, and large amounts of calcium or whole grains will decrease it.

Those of us over 60 probably remember all those ads for "tired blood" in the 1950s and 1960s that implied that older people were tired because they didn't have enough iron and needed to supplement with Geritol.

So should we all try to get as much iron as possible?

Nope.

There is some evidence that high iron levels contribute to heart disease, and most "senior vitamins," designed for people who are at an age at which heart disease is more likely, don't have any added iron. Some people think that losing blood every month helps to protect younger women from heart disease. This protection is lost after menopause.

Iron levels have other interesting effects on our health.

Like us, most bacteria require iron in order to grow. Our bodies are smart, and they apparently know this. So when we get an infection, our bodies start reducing the iron in our blood, especially when we have a fever.

The bacteria, in turn, try to develop ways to snatch the iron away from the proteins that carry it around and store it in our cells. Hence taking iron supplements when you have an infection is probably not a great idea.

So why am I babbling on about iron? Because there are two different iron-level conditions that are relevant to diabetes. The first is hemochromatosis, a genetic disease found most commonly among people with Celtic ancestry.

Hemochromatosis makes you absorb too much iron, and the high iron levels attack many organs in the body, including the beta cells. So people with the hemochromatosis gene are at very high risk of getting diabetes. Some people absorb enough iron that their skin turns slightly brown, and if they develop diabetes, it's sometimes called bronze diabetes because of the bronzed color of the skin.

The other condition is the exact opposite, a form of anemia, or too little hemoglobin in your blood. It occurs when you don't absorb enough iron or when you lose iron because you've lost a lot of blood. Without iron, you can't make hemoglobin, and without hemoglobin, you can't make enough red blood cells.

This condition is called, not surprisingly, iron-deficiency anemia.

A test for both these conditions is the ferritin test. Ferritin is the protein that the body uses to store iron, and it's a good indicator of overall iron levels in the body. Low ferritin could mean iron-deficiency anemia. High ferritin could mean hemochromatosis.

There's another wrinkle to the iron story and diabetes. Iron-deficiency anemia can make your hemoglobin A1c test higher than it should be on the basis of your daily blood glucose measurements. A recent study showed that increases in A1c levels often found in late pregnancy are in fact caused by iron-deficiency anemia rather than by increases in blood glucose levels.

Conversely, if you find you have iron-deficiency anemia and you treat it with iron supplements, your A1c will go down.

The reason that iron-deficiency anemia makes the A1c decrease is not clear. It may be related to the red blood cell lifespan. Some people think it's related to oxidative stress.

And although iron-deficiency anemia makes the A1c go up, hemolytic anemias make the A1c go down. Hemolytic anemia is any kind of anemia that destroys the red blood cells, as this reduces the lifespan of the cells and hence results in abnormally low A1cs.

The interpretation of the A1c test assumes the red blood cells live an average of 120 days. In fact, the actual lifetime of red blood cells even in healthy people can vary from person to person, which may be one reason some people seem to get A1c results that are either higher or lower than what they expect on the basis of their home blood glucose readings.

So many things can affect our health, and so many things can affect the lab tests we use to monitor our health.

I think the important thing is to remember that no lab test is 100% accurate for all patients under all conditions. If you get an abnormal lab test, don't panic. Sometimes it helps to have the test repeated, just in case it was lab error. Other times it's simply a suggestion that something might be wrong. Then you can work on what you think might have caused the positive lab test and see if that fixes the problem.

If you have reasons to think you might have hemochromatosis (Celtic or Scandinavian ancestry; relatives with hemochromatosis), it would be a good idea to get a test for ferritin. If you have reasons to think you might be anemic (fatigue, pale skin, rapid heartbeat, especially if you're vegetarian), it wouldn't hurt to ask your doctor for the same test.

If you don't have either and your A1c continues to differ from what you think it should be, you might just be someone whose red blood cells live longer or for a shorter time than average.

Those GG Crackers

2009-03-10T10:05:00.000-07:00

I've posted a blogpost at Health Central about the relabeling of the nutritional information for GG bran crispbreads.

For a long time, they've been advertising them as 0 net grams of carbs. Not!

Wall Street Journal Discussion

2009-03-09T08:18:00.001-07:00

I've started a discussion on the Wall Street Journal site in response to an article about jobs in the health care sector.

Someone who calls him/herself "Primary Health Care Physician" is on my side. Other WSJ readers are blaming fat people and smokers for their problems.

Sweet and Sweeter

2009-03-07T16:40:00.000-08:00

In the old days, when people with diabetes wanted to add sweetener to their food or drink, they had a choice of saccharin, saccharin, or saccharin.

Gradually new sweeteners, including Acesulfame K, cyclamate, and aspartame were added to the pot. Cyclamate was later prohibited in the United States, although it continued to be sold in Canada, because a study suggested that it increased cancer rates in rodents.

Saccharin was also reported to increase cancer rates in rodents when used in huge quantities, but it remained on the market. Many people said they had problems when they used aspartame; others said it didn’t bother them. Aspartame does break down when it is heated and isn’t recommended for cooking.

More recently, sucralose, marketed as Splenda, was added to the repertoire. And stevia, which comes from a South American plant, has been used as a sweetener although it wasn’t approved for such use in the United States and was sold instead as a “supplement” in the vitamin sections of stores. It has been used as a sweetener in Japan for some time.

You can also add a sweet taste with sugar alcohols, which are metabolized differently from regular sugars. Most of them reach the colon undigested, and bacteria in the colon digest them and produce gas, which you (and your friends) may notice if you eat a lot of these sugars. They are also good laxatives.

The names of the sugar alcohols end with “itol,” as in maltitol, lactitol, sorbitol, xylitol. Some people find these sugar alcohols don’t make their blood glucose (BG) levels go up very much; others say they do. It depends on your personal metabolism.

Unfortunately, maltitol, the sugar alcohol that is used most commonly in “sugarfree” products like candies, consists of 50% glucose, so it will raise the BG levels in most people as much as table sugar (sucrose), which is also 50% glucose.

The sugar alcohol erythritol is a little different from the others. Instead of going through the intestine undigested, much of it is absorbed into the bloodstream and then excreted unchanged by the kidneys. For this reason, it does not cause gas like the other sugar alcohols, and it has fewer calories.

I’ve described all these sugars in more detail in my book The First Year Type 2 Diabetes, and I won’t repeat that information here. Instead I’ll focus on a few of the newer sweeteners.

I never used much Splenda, primarily because it was all “cut” with maltodextrin (which is a carbohydrate made of glucose that is digested to glucose and makes your blood glucose [BG] levels increase just like starch) or glucose (listed as “dextrose” on the individual packets), or both. I did use it for a few weeks in the summer when my raspberry bushes were bearing to beat the band, as I consider it sinful to leave fresh raspberries uneaten. Uncut sweeteners like stevia are difficult to sprinkle evenly on the berries.

But now, Splenda has come out in a new formulation emphasizing fiber. Instead of maltodextrin, they’re using soluble corn fiber as a “bulking agent.” This is good news for all of us, because not only are we no longer required to add glucose or maltodextrin with the sweetener, but soluble fiber also helps keep BG levels down. Each packet contains 1 g of corn fiber.

And in 2008, the FDA began approving stevia products as GRAS (generally recognized as safe) when used as sweeteners if the manufacturers provided research results showing their safety. And a lot of manufacturers have jumped on the stevia bandwagon.

Two big boys on the sugar shelf are products combining stevia extracts with erythritol. The major new ones are made by Cargill for Coca Cola (Truvia) and the Whole Earth Sweetener Company for Pepsi Cola (Purevia). I found both these products at a grocery store in the small town where I shop.

Truvia contains only erythritol, stevia extract (rebiana), and “natural flavors,” which they don’t indicate. Purevia contains erythritol, stevia extract (which they call Reb A), isomaltulose , a little cellulose, and “natural flavors,” which they also don’t indicate. Truvia seemed a little sweeter to me, but they’re both basically the same except that Truvia doesn’t contain the isomaltulose.

Isomaltulose is made from sucrose (table sugar) and has the same number of calories. It is digested in the intestine to produce glucose and fructose, but the digestion is slower than that of sucrose, which also produces glucose and fructose, so it should have a lower glycemic index.

Some time ago I bought a similar erythritol/stevia combination (Stevita) at a local health food store. At the time, it was marketed as a “dietary supplement.”

And another stevia product, Sweet Leaf, has been on the shelves for some time. This one isn’t cut with erythritol, but with with inulin, a fiber.

Inulin is a polymer of fructose found in Jerusalem artichokes, and, like the sugar alcohols, it isn’t digested until it reaches the colon. There bacteria can break it down to release gas. It is said to stimulate the growth of “good” bacteria in the colon and some people supplement with it for that reason. Although it is made up of fructose, it doesn’t increase triglycerides as fructose does.

For some time, I’ve used the KAL brand of uncut stevia. I like it because it comes with tiny spoons that are the equivalent of 1 tsp of regular sugar. I find it sweeter than other brands of pure stevia I tried, so I need to use less. Like many other fake sugars, it becomes bitter when you use too much, so you have to be careful, but I’ve had good success with it.

Some people say they get an oregano taste when they eat stevia. I’ve found that with the unpurified stevia leaves, but not with the purified forms. But every manufacturer may purify the stevia extract slightly differently so the resulting product contains slightly different things. To me, different brands of stevia have different levels of sweetness. One kind I got in bulk at my local Coop was cheaper than the KAL brand, but about half as sweet, so I needed to use twice as much and it ended up being more expensive.

One problem with any of the supersweet sugar substitutes becomes apparent when you make a product like ice cream, which relies on the sugar to lower the freezing point as well as to sweeten. Because you use so little stevia or sucralose or saccharin if you use those to make ice cream, you end up with something that is brick hard when you put it into the freezer.

Erythritol works like sugar in this respect. I made some ice cream with pure erythritol, and it was soft and creamy even after being frozen for several days. Success at last! The new erythritol/stevia blends may work almost as well as the pure erythritol, perhaps less because the sweet stevia means you use less of the erythritol. Time will tell.

Unfortunately, erythritol is expensive. A pound of table sugar costs about $1 at the supermarket. A pound of erythritol costs about $9, a little less on the Internet, but then you also pay high shipping costs.

Another sugar that would act like table sugar for cooking is tagatose. It would also brown when cooked, like table sugar. However, the one manufacturer of tagatose decided to stop production after a short time, saying there wasn’t sufficient market for the product.

People will argue until the cows come home about which sweetener tastes the best and is the safest. Some people seem to be allergic to aspartame, for example, and others aren’t. We really won’t know the long-term effects of any of these sweeteners until they’ve been on the market for a long time. In that respect, saccharin, which has been sold for many decades, probably has the best record.

What is nice about these new products is that they give us more choice to find a sweetener that works for us. Read labels before you buy any sweetener so you know exactly what you’re buying. If you’re on a high-carbohydrate diet, the 1 g of glucose in a packet of sweetener won’t make much difference, but if you’re on a very low carb diet it could.

I think I’ll stick to pure stevia for now, but the erythritol products may be useful when I want to make my own sugarfree ice cream. I hear rumors that summer is just around the corner, and the occasional dish of homemade ice cream is pretty appealing when the weather is hot.

Starting Off

2009-03-02T13:53:00.000-08:00

Like many bloggers, I love to write. In the old days, I used to write letters. Remember letters? You typed them out on a manual typewriter, stuck them in envelopes, addressed them, slapped on 3-cent stamps, and sent them on their way.

Those days are gone, and now I send e-mail instead. I also write for fun. I've published a few books related to diabetes, and more unfinished books and stories are sitting in my files waiting for me to have the time to polish them up and find homes for them.

In the past few years, I've been doing some blogging for Health Central's diabetes pages, and I will continue doing this. But I thought it would be fun to branch out a bit with my own blog, which would give me more freedom to branch out a bit in what I say, to post occasional pictures, and mostly just to try something new.

I'm calling this blog "Wildly Fluctuating" because I'm planning to tackle wildly fluctuating topics from the very serious to the very absurd; from basic information that everyone needs to more technical stuff that might be of interest to us old timers to simple musings on the diabetes news of the week. Maybe occasionally something that has nothing whatsoever to do with diabetes. We all need a break.

Diabetes is a serious disease, and we all need to take it seriously. But we also need to take a break from time to time: we need to laugh. Thus I'll try to write something humorous from time to time.

I'll also occasionally discourse on the science of diabetes. When we have diabetes, it's nice to understand the scientific basics of topics like digestion, food composition, drug absorption, and so forth.

Health professionals, including physicians and certified diabetes educators, can provide general guidance and one-size-fits all treatment plans. But we're not all one size, and a treatment plan that works great for me might not work well at all for you. The health care people won't be at our side when we want to eat that chocolate eclair that looks so tasty. We've got to understand how food affects our health ourselves.

I tried to explain the diabetes basics in my book The First Year: Type 2 Diabetes, and the basics of diabetes prevention in Prediabetes. But new material comes out every day, and it never hurts to review what we already know.

I will give my views on the numerous diabetes news items that seem to surface every week, if not every day. The news media tend to simplify things and tell us that type 2 can be prevented by eating some food or type 1 has been cured, when in fact some food or other has been had a slight effect on the incidence of type 2 or type 1 has been cured in mice.

In fact, diabetic mice have been cured zillions of times, and at the current time, your best bet for a diabetes cure would be to be reincarnated as a lab rodent.

I've had type 2 diabetes myself for 13 years now. And I'll occasionally write about my own experiences living with this dragon, both good and bad. However, I do hope I don't become so self-focused that my blog turns into an off-topic daily diary about my favorite toothpaste or a great buy in hamburger at the local grocery store.

And one thing is certain: I promise I'll never, ever upload photos of Spot and Fluffy.

.*Only because my cats all died on the highway near my house and they haven't been replaced.