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.
Monday, April 27, 2009
Saturday, April 18, 2009
Hidden Clues
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.
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.
Tuesday, April 7, 2009
Fat and Diabetes
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.
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.
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