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.
Tuesday, August 2, 2011
Thursday, July 28, 2011
Spinning Science News
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?
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
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?
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?
Saturday, July 2, 2011
Warped Logic
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.
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.
Sunday, June 26, 2011
Stupid quotes: Blood glucose and complications
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.
Thursday, June 16, 2011
Leisure Time or Forced Labor? [humor]
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!
"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!
Tuesday, June 14, 2011
Insulin Receptor Downregulation
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.
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.
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