Sunday, November 7, 2010
AIDS, the common cold, and measles are examples of diseases that are known to be contagious. A recent article in PLoS Computational Biology describes another medical condition that is contagious--obesity.
Obviously, obesity is not commonly thought of as a transmissible condition. Perhaps if you believe that you should feed a cold and starve a fever, there might be a contagious element to obesity, but that's stretching it. However, one of the authors of the PLoS article, Nicholas A. Christakis, had observed in an earlier article in the New England Journal of Medicine that members of the Offspring Cohort of the Framingham Heart Study were 57% more likely to become obese if they had a friend who became obese during a certain interval.
Obesity and social networks
Christakis and his colleagues showed the phenomenon of the person-to-person spread of obesity in a graphic that can be viewed here. While the obesity of siblings and the obesity of spouses had an effect on the obesity of participants in the Offspring Cohort, the most important social network tie for transmission of obesity was mutual friendship. Interestingly, geographic separation did not diminish this phenomenon.
An infectious model for obesity
In 1971, the obesity of the Offspring Cohort of the Framingham Heart Study was 14%. By the year 2001 it was 29% and was continuing to increase. (Obesity was defined as a BMI of 30 or more.) In 2010, in the PLoS article Infectious Disease Modeling of Social Contagion in Networks, Hill et al. took the information from the 7500 members of the Offspring Cohort and used it to formulate an infectious disease model of obesity that they called SISa.
As described in the SISa model, the infectious equation for obesity includes a spontaneous appearance factor. Some percentage of people will spontaneously or automatically become obese in a particular year. In the Offspring Cohort, the rate of spontaneous obesity began at 0.8% in 1971 and has increased to 1.9% in 2001.
The infectious disease model of obesity also includes a remission factor that describes percentage of people who transition from obesity to a BMI below 30. The remission factor was unchanged over 30 years and was about 4% per year.
Finally the model includes an interpersonal transmission rate. That rate has increased over the years, from 0.12% for each obese friend in 1971 to 0.5% per obese friend in 2001. In other words, if a member of the Offspring Cohort had more than four obese friends, he or she would have an increased likelihood of being obese in the next year.
Transmission of obesity
In a news story in Science Daily, Dr. Hill speculated that the non-social transmission of obesity may result from unhealthy foods or increasingly sedentary lifestyles. (She did not rule out possible dietary causes such as consumption of HFCS, industrial oils or grains.) For the Offspring Cohort, the non-social transmission rate seems to have leveled off at about 2%. However, the social-network transmission of obesity continues to increase and has several interesting aspects.
It appears that the more obese friends a person has, the more likely that person is to become obese. It is the absolute number of obese friends that matters, not the percentage of friends who are obese. Conversely, the number of normal-weight friends seems to have no effect on a person's ability to avoid obesity or to recover from obesity once it occurs.
The authors speculate that the increasing prevalence of obesity provides a positive feedback mechanism. People will have more friends who are obese and will become inclined to think that obesity is "normal." When they themselves start gaining weight, they may see no reason to avoid the weight gain because several people they know and respect carry an increased amount of weight.
If we live in a society that is becoming increasingly obese, and we want to remain at or attain a normal weight, do we want to avoid making friends who are obese? Obviously not. Perhaps it will be enough to know that having obese friends can subtly influence us to believe that obesity is normal or even necessary for us to fit in with our peers. With a certain amount of effort, perhaps we can learn to accept friends who are obese without compromising our own pursuit of a journey to good health.
Tuesday, October 26, 2010
Admit it. Low-carbing is hard. You have to keep a constant eye on what you're eating. And you have to cope with the fact that the people around you are keeping a constant eye on you--trying to figure out why you eat in such a nonconventional way. Wouldn't it be easier just to take a pill to lose weight? Unfortunately, promising weight-loss drugs have a history of regulatory approval followed by withdrawal because of serious side effects.
In 1973 fenfluramine, a mixture of two isomers, dexfenfluramine and levofenfluramine, was approved for weight loss by the FDA. In 1996 the dexfenfluramine isomer was approved for long-term weight loss. These compounds produced a small but measurable amount decrease in weight for the patients who took them. When Dr. Michael Weintraub combined fenfluramine with another mildly-effective product called phentermine in a combination popularly called "fen-phen," it produced as much as a 16% weight loss in a four-year clinical trial. Word spread, and thousands of patients began to request prescriptions.
Nonetheless, by 1997 a large number of adverse events had occurred, and the FDA decided to remove both fenfluramine and dexfenfluramine from the market. Up to twenty five percent of users had experienced heart valve hypertrophy, with the degree of pathology tending to correlate with the length of time the product had been taken. Pulmonary arterial hypertension was reported as well. A 1997 article from the New York Times describes the reactions of physicians who had known that the drugs might pose a small risk but felt that it was more than counterbalanced by the public health problem of rising obesity rates.
Serotonin receptor specificity
Because fenfluramine was able to produce anorexia, researchers began to investigate its properties. It was found to work nonselectively on receptors for serotonin, one of the body's most important signaling molecules. Serotonin (also known as 5-HT) has at least seventeen receptor genes that mediate everything from moods to gut motility. As discussed in a review article by Keith J. Miller, the 5-HT1B and 5-HT2C serotonin receptors are known to suppress appetite, and fenfluramine or its metabolite norfenfluramine appear to exert their anorectic effects through these receptors.
Unfortunately, norfenfluramine also acts nonselectively on 5-HT2A and 5-HT2B serotonin receptors which are located in human heart valves. In this location it acts as a growth factor and causes hypertrophy of the valves.
In recent years, investigators have attempted to formulate drugs that activate 5-HT2C serotonin receptor but have little or no effect on the 5-HT2A and 5-HT2B serotonin receptors. Lorcaserin was designed to work in this way, and after a year in one trial, patients taking lorcaserin had lost about 4 kg more than those in the placebo group. After two years they had lost an additional two kg and reported reduction in almost all measures of diabetes and cardiovascular risk.
Although lorcaserin did not increase the risk of valvular hypertrophy or pulmonary hypertension, in October 2010, the FDA rejected the new drug application because lorcaserin had increased the incidence of tumors in rats, specifically adenocarcinoma in mammary glands and astrocytoma in the brain. It is possible that growth of these tumors is mediated through one or more of the other 5-HT receptor subtypes, and that lorcaserin nonspecifically stimulates them.
Silbutramine (Meridia) is not a 5-HT receptor agonist, but it exerts a satiety effect by blocking the reuptake of serotonin by presynaptic nerve terminals. Unlike selective serotonin reuptake inhibitors (SSRIs), silbutramine does not act as an antidepressant. Unlike fenfluramine, it does not produce valvular hypertrophy or pulmonary hypertension. It does have measurable but minimal efficacy for weight loss and was approved for use by the FDA in 1997 for the management of obesity, including weight loss and maintenance of weight loss. Thirteen years later a six-year clinical trial (SCOUT) with approximately 10,000 patients was completed. In the silbutramine group, there was a 16% increase in the risk of a set of serious events, including non-fatal heart attack and stroke, compared with the placebo group. On October 8, 2010, the FDA asked Abbott Laboratories to voluntarily withdraw silbutramine from the U.S. market.
No magic bullets
Orlistat (Xenical/Alli) is still available as a pharmacologic treatment for weight loss. It does have side effects with social significance, particularly for those who are trying to live a low-carb lifestyle. On the positive side, as of this writing it does not appear to increase morbidity or mortality when used as directed. Unfortunately that doesn't seem to be the case for anti-obesity drugs that have serotonergic actions.
Pharmaceutical companies have a powerful motivation to develop drugs that will help with weight loss. However, if history is any guide, there is a high probability that drugs with initial promise will turn out to have serious adverse effects in the long run. In the meantime, there is growing evidence that the low-carb lifestyle offers us a non-drug way to lose weight and to maintain that loss. People have been doing low-carb safely since Dr. Atkins came out with his Diet Revolution in 1972. For those who prefer a non-anecdotal approach, more and more articles are being published that show an actual health advantage for the low-carb lifestyle.
Low-carb is not easy. But it isn't impossible either. Until scientists come out with a magic pill for weight loss, we can rejoice that we have found a way to cope with our own personal version of the obesity epidemic.
Tuesday, October 19, 2010
The short answer is yes, you can be fat and and not realize that you're fat.
A recent article in the Archives of Internal Medicine used data from the 2000-2002 Dallas Heart Study to describe this phenomenon. The full article (Body Size Misperception: A Novel Determinant in the Obesity Epidemic) is not yet available, but news descriptions of it are here, here and here. The authors have presented the data in powerpoint form here.
Misperception of body size
Researchers asked 2056 obese men and women to look at line drawings like those pictured above. The study participants were asked to choose the figure that looked the most like them. Although all of the participants met criteria for obesity, eight percent of them (14% of blacks, 11% of Hispanics and 2% of whites) did not consider themselves to be obese.
Let's take a moment to define our terms. Study patients did not have the benefit of the BMI values that are printed underneath each series of pictures. I've added those because I suspected that readers would like to take the test themselves and see (1) which figure they would choose and (2) which figure actually corresponds to their body size. (You can click on the pictures to enlarge them, if necessary.) If you don't know your BMI, it can be calculated here.
As obesity grows more common, it also becomes harder to pick out which figures are thin, normal and fat. Here are the definitions according to BMI:
- Underweight = BMI less than 18.5
- Normal weight = 18.5–24.9
- Overweight = 25–29.9
- Obese = BMI of 30 or greater
In the figures above, the only underweight figure is women's drawing 1. The overweight figures are drawings 5 & 6 of both sexes. The obese figures are drawings 7, 8 & 9 of both sexes. (Note that, in this context, "overweight" and "obese" have very specific definitions.)
Back to the Dallas Heart Study. Among the eight percent of obese study participants who misperceived their body size, 66% believed they were at low risk for obesity, even though they were already obese. Although those with and without body size misperception had equal probabilities of developing diabetes, heart disease and high blood pressure, those with body size misperception were significantly less aware of their risks for these conditions.
In practical terms, this meant that fifty six percent of obese subjects with body size misperception had seen a doctor in the past year. Of those, only 38-45% had discussed diet/habits, exercise or weight loss with their physician. By contrast, among the obese patients with accurate body size perception, 74% had seen a doctor in the past year and 64-68% had discussed such lifestyle issues with their physician. This suggests that obese people who do not realize their condition will get poorer medical care as a result of their misperceptions.
BMI and health risks
Not all causes of mortality can be related to obesity. A 2007 article in JAMA did an extensive analysis of the association of BMI with particular causes of death for the year 2004 in the United States. Researchers found that obesity was not related to increased deaths from cancer, respiratory disease or injuries. However, obesity was associated with increased mortality from cardiovascular disease and from diabetes and kidney disease. When all causes of mortality are considered, the graphs look like this (source article here):
Interestingly, these graphs show that a BMI of about 25 (between normal weight and overweight) seems to be the healthiest for long-term survival, and being underweight is actually unhealthy. However, the graphs do show that as obesity (BMI=30.0 or more) increases, all-cause mortality risk increases. For that reason, it pays to have an accurate idea of our body size, and to be willing to recognize that dealing with obesity could have a beneficial effect on our personal lifespan.
Monday, October 11, 2010
Winter is on its way. Leaves are changing color; daylight is diminishing. Another sign of impending winter is the temperature change, with coats and sweaters coming out of storage to accommodate the colder weather. But have you noticed that some people need sweaters in chilly weather while others don't?
Besides adding layers of clothing, people respond to cold by decreasing internal body temperature (hypothermia), by decreasing peripheral body temperature (insulation) and by increasing energy expenditure (adaptive thermogenesis). Thanks to modern conveniences, exposure to extreme cold is uncommon. However, people still have many opportunities to experience mild cold exposure, as can happen when they move from a heated house to a cooler situation outdoors, or from a hot outdoor environment into an over-air-conditioned building. In the context of weight loss, it is interesting to note that these temperature transitions may be made more easily by those who are lean than by those who are overweight.
Heat Production Higher in Lean Subjects
A 2006 article by Claessens-van Ooijen et al. compared the effect of mild cooling and rewarming on healthy men who were lean (average BMI=21) and overweight (average BMI=29). The men wore standardized clothing and spent an hour sitting in 59°F air while covered by a duvet. Under baseline conditions there was no significant difference in energy expenditure between the two groups. In order to produce cooling, the duvets were removed for an hour. During this time both groups showed an increase in heat production, but the increase in the lean group was significantly greater. (Possible shivering was monitored and did not occur.) When the duvets were replaced, after an hour heat production returned to baseline in the overweight group but remained significantly higher than baseline in the lean group. In other words, the overweight men showed less adaptive thermogenesis in response to a mild exposure to cold.
Thermogenesis by Mitochondrial Uncoupling
One mechanism for adaptive thermogenesis was proposed by Wijers et al. in 2008. Eleven lean male subjects spent 34 hours in a respiration chamber at a baseline of 72°F and subsequently spent 82 hours in the respiration chamber without shivering under mild cold conditions of 61°F. Although the activity of the subjects decreased about 20% under mild cold conditions, their total daily energy expenditure increased by 2.8%. Muscle biopsies were taken at the end of the baseline and mild cold conditions. Analysis of the tissue showed that the cold-induced increase in total daily energy expenditure of each subject was significantly related to the amount of mitochondrial uncoupling that had occurred in his skeletal muscle. It is possible that during cold conditions, adaptive thermogenesis occurs when muscle mitochondria bypass some of their ATP synthesis in favor of dissipating energy as heat.
Brown Fat Activity Higher in Lean Subjects
Another possible mechanism for adaptive thermogenesis is the action of brown fat, also called brown adipose tissue. Unlike white adipose tissue, brown adipose tissue has small lipid droplets and many more iron-containing mitochondria, which makes it brown. Normally it functions to provide body heat to newborn humans and to hibernating animals. However, it is still present to some extent in adult humans.
In a 2009 article in the New England Journal of Medicine, van Marken Lichtenbelt et al. studied 24 healthy men, 10 lean (average BMI=22) and 14 overweight (average BMI=30). They rested in a supine position for one hour at 72°F and then for two hours at 61°F. The activity of their brown adipose tissue was assessed by PET-CT scanning that measured the uptake of a glucose isotope, 18F-fluorodeoxygluxose (18F-FDG). Example scans are shown below.
Under the thermoneutral condition of 72°F, very little of the 18F-FDG was taken up by brown fat, as shown by the lean subject on the far left. However, when the temperature was decreased to 61°, brown fat activity was significantly increased in the lean subject (center picture). It was also increased in the overweight subject seen on the right, but not as much. For the entire group, the activity of the brown adipose tissue was greater in the lean subjects than it was in the overweight ones. There was a a positive correlation between brown adipose activity and resting metabolic activity and a positive correlation with brown adipose activity and the core temperature under thermoneutral conditions. Overall, the study found that inreased BMI, but not increased age, was significantly associated with a decrease in brown adipose tissue activity.
None of these studies establishes the idea that being overweight reduces the ability of our bodies to cope with a mild exposure to cold, or that having a reduced ability to do adaptive thermogenesis makes us obese. On the other hand, they do raise the interesting possibilities that (1) losing weight might help us increase our ability to do adaptive thermogenesis, or (2) perhaps forcing our bodies to do adaptive thermogenesis might increase our ability to lose weight. As scientists love to say at the end of articles, more study is needed.
Saturday, October 2, 2010
Last time we looked at the possibility that genetics may determine whether a person is able to lose more weight on a low-carb diet or on a low-fat diet. The jury is still out on that.
However, two articles from 2005 suggest that insulin sensitivity may play an important role in whether low-carb diets or low-fat diets work better for weight loss for particular people. The first of these, Insulin sensitivity determines the effectiveness of dietary macronutrient composition on weight loss in obese women, was published in Obesity Research. The second, A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE trial was published in Diabetes Care. Both articles were short, sweet and to the point. And both concluded that if you're insulin-sensitive, you will probably do better on a low-fat calorie-restricted diet, but if you are insulin-resistant, you can expect better weight loss on a low-carb calorie-restricted diet.
The two studies were quite similar to each other, as outlined in the table above. Subjects were randomized into high-carb/low-fat (HC/LF) and low-carb/high-fat (LC/HF) diet groups. In both cases, high-carb was defined as 60% of calories, while low-carb was defined as 40% of calories. Not a dramatic difference, but because all the food was provided for the participants, it was possible to be fairly certain of what the subjects had consumed. (The amount of study food eaten plus any additional food eaten was taken into account.) In all cases, participants received a restricted number of calories.
The variable of interest in these studies was insulin resistance. In the Obesity Research study, insulin resistance was determined by measuring fasting insulin levels. Insulin-sensitive (IS) individuals were defined as those with a fasting insulin below 10 mU/L and insulin-resistant (IR) subjects were defined as those with a fasting insulin above 15 mU/L. Subjects with a fasting insulin between those two values were excluded from the study. In the Diabetes Care study, insulin resistance was determined by administration of a 75 gram oral glucose tolerance test. The subjects whose plasma insulin at 30 minutes post-glucose was less than 66 mU/L were termed low insulin secreters and those whose plasma insulin at 30 minutes was above 66 mU/L were termed high insulin secreters.
As expected, all groups lost a significant amount of weight. The findings are summarized in the two figures below. (I have modified both figures from their original forms to make it easier to compare them.)
The Obesity Research article stated that they expected a loss of approximately 1 kilogram of body weight for every 7300 deficit in calories. Therefore, their 16 week study should have produced a weight loss of at least of 6.1 kilograms, and this was indeed the case.
What was surprising was that two of the groups lost almost twice that amount of weight: the insulin-sensitive (IS) subjects who ate high-carb/low-fat (HC/LF) and the insulin-resistant (IR) subjects who ate low-carb/high-fat (LC/HF). A similar result is seen in the Diabetes Care article. All of those subjects lost an average 6 kilograms or more of body weight, but among the high insulin secreters, significantly more weight was lost when they followed a low-carb/high fat diet as compared with a high-carb/low-fat diet. Among low insulin secreters, there was a tendency to lose more weight with a high-carb/low-fat diet, but in this case the difference was not statistically significant.
It pains me to say it, but a low-carb/high-fat diet may not be the best weight loss diet for everybody. From these two studies, a person who is still insulin-sensitive could well find that a low-carb diet might actually be their worst choice. It would still work, but not as well as a low-fat/high-carb/calorie-restricted diet. On the other hand, for a person who is insulin-resistant (and if you're not insulin-resistant when you're young, you tend to get that way as you get older), a low-carb/high-fat/calorie-restricted diet appears to work the best. For whatever reason, if you follow the diet indicated by your insulin sensitivity, chances are good that you will not only lose the amount of weight predicted by the decrease in your caloric intake, but a few extra kilograms as well.
Sunday, August 22, 2010
We now have three articles in three respected journals showing that weight loss over 1-2 years on a low-carb diet is equal to or better than the weight loss seen on a low-fat diet. The figure above illustrates the weight loss in the first of those three publications, the A to Z Weight Loss Diet Study.
Although the A to Z Study showed that women in the Atkins arm of the study lost the most weight on average over a year, the researchers noticed that within each diet group, the individual weight change ranged from a loss of over 30 pounds to a gain of about 10 pounds. It seemed that another factor besides low-carb helped to determine the efficiency of weight loss for particular individuals. The scientists speculated that genetic differences might be at work.
The first discussion of the interaction of genes and the A to Z Weight Loss Diet showed up in a lifestyle article in the Wall Street Journal. The article described how Mindy Dopler Nelson and Christopher Gardner attempted to contact the 301 women in the original A to Z study and found about 140 who were willing to submit DNA by means of a cheek swab. The swabs were sent off to Interleukin Genetics and were analyzed for three genes that had been shown to have some relationship to body weight in at least three clinical studies.
The Interleukin Genetics site has a summary describing the science behind its weight management genetic tests. Briefly, the panel involves five variations in four genes. These involve single nucleotide polymorphisms (SNPs) that subtly change proteins involved in body weight by changing one of the amino acids in the protein sequence in question. Proteins, as you will recall, are linear strings of amino acids. The particular sequence and identity of the amino acids determines how the protein folds and how it interacts with other molecules within the body. Change one of the amino acids and you'll modify the way the protein works.
The first protein tested in the panel is fatty acid binding protein 2, or FABP2. FABP2 is a protein found in epithelial cells of the small intestine, and it influences fat absorption. When the alanine at position 54 of FABP2 is substituted with a threonine, this causes increased absorption of dietary fatty acids by the intestine. (The specific scientific references for these claims and the ones for the other genes listed below can be found in the Interleukin summary publication linked above.)
The peroxisome proliferator-activated receptor-gamma (PPARG) protein is expressed in fat cells and plays a role in adipogenesis. When there is a proline at position 12 of the protein, the person carrying that gene variant will find it easier to gain weight as a result of fat in the diet. By contrast, people with an alanine at position 12 of the PPARG protein will tend to lose weight more easily.
The beta-2 adrenergic receptor (BAR2) gene is involved in mobilization of fat from adipocytes in response to hormones like epinephrine and dopamine. There are two important polymorphisms of BAR2, one at positon 27 and another at position 16.
Women with glutamine at position 27 show no risk of obesity on a high carbohydrate diet, while women with a glycine at that position showed an increased risk of obesity when they adhered to a high carbohydrate diet.
Individuals who carry a glycine at position 16 of the BAR2 protein are at higher risk of weight gain over their lifetimes than those who carry an arginine at that position. Glycine-16 individuals are also less likely to lose weight in response to an exercise program.
Another type of beta adrenergic receptor, BAR3, is found in visceral adipose tissue and is involved in regulation of lipolysis, that is, the breakdown of fat. This gene was not considered in the reanalysis of the A to Z Diet Study, but it is interesting nonetheless. People with an arginine at position 64 of the BAR3 protein found it much easier to lose weight in response to exercise than those who carried a tryptophan at position 64. This variation may help explain why some people swear that they can lose weight by exercising, while others swear that exercise makes no difference to their weight loss.
A to Z Reanalysis
When the group at Stanford learned the results of these tests, they were able to group the women in their study into low-carb genotypes and low-fat genotypes. Unfortunately, since we only have press releases to guide us, the specific criteria for the genotypes is unavailable. They did say that when women with the low-fat genotype were on the very-low-fat Ornish diet, they lost an average of 14.1 pounds, while those with that genotype who were on the relatively high-fat Atkins diet averaged a loss of only 2.2 pounds. Women with the low-carb genotype lost an average of 12.3 pounds on the Atkins diet and 3.1 pounds on the Ornish diet.
This study has not yet been published in a peer-reviewed journal, but the findings are interesting nonetheless. It is fascinating to speculate that low-carb and low-fat diet and exercise plans might produce better or worse results depending upon our genes. At the same time it's important to remember that the A to Z participants were premenopausal, non-diabetic white females. Even if the findings of the Stanford group prove significant, it is impossible to tell how they will apply to older people, to diabetics, to nonwhite populations and to men. There are, however, 44 studies cited at the end of the Interleukin Genetics summary article, and these do address the function of the four target genes in many types of patient populations.
If you have $149.00 in extra cash, you might even want to take the test and see if the results comport with your experiences in various weight loss approaches. I have no financial interest in Interleukin Genetics, but would be very interested to see if there is any validity to using genetics as a strategy to assist in weight loss.
Thursday, August 5, 2010
Ladies and gentlemen of the low-carb community: We have a hat-trick.
1. On March 7, 2007, the Journal of the American Medical Association (JAMA) published an article showing that, at 12 months, women assigned to the Atkins (low-carbohydrate) diet lost more weight and experienced more favorable metabolic effects than did women assigned to follow the LEARN, Ornish or Zone diets.
2. On July 17, 2008, the New England Journal of Medicine published an article describing a two-year study of men and women in Israel. The study showed that, compared with the low-fat diet, the low-carbohyrate diet produced greater weight loss and had more favorable effects on lipids. The authors concluded that low-carbohydrate diets may be an effective alternative to low-fat diets.
3. And finally on August 3, 2010, the Annals of Internal Medicine published an article describing a two-year low-carb vs. low-fat study of men and women in the United States. The authors concluded that, "Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years."
Three refereed articles in three well-respected journals. Although the second study had some funding from the Dr. Robert C. and Veronica Atkins Research Foundation and might be faulted for that reason, the first and third were supported by the National Institutes of Health (NIH). All three studies showed that a low-carbohydrate is effective for weight loss. All three showed that metabolic effects, including an increase in HDL cholesterol, improved with the low-carbohydrate diet. And while the first study lasted a year, the last two studies covered a two-year span, demonstrating that the benefits of a low-carb lifestyle are not limited to a few weeks or months.
Currently the third article is only available for free in abstract form. However, Jimmy Moore purchased the article and did an excellent summary which can be found here. I purchased the article, too, and found that most of my observations agreed with Jimmy's, so I'll refer you over there if you would like a thorough discussion of what the article showed. [Great news! Thanks to LynMarie Daye in the Comments, we now have a link to a free PDF of the entire article: Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet.]
I'll just emphasize a few points.
First of all, the people in the third study lost an average of 11 kilograms at six months, while the average six-month loss for low-carbers in the first two studies was about 6 kilograms. That's probably because the average BMI in the third study was about 36, vs. about 31 in the other two studies. As a general rule, the more a person weighs, the easier it is to lose a given amount of weight.
Second, in the Annals of Internal Medicine study, the low-carb dieters lost (and regained) almost exactly the same amounts of weight as did the low-fat dieters. This may be because both groups received regular instructional sessions lasting from 75 to 90 minuntes throughout the two years of the study. Or it may be because the low-carb group was treated differently from the low-fat group. The low-carb group began the study at 20 grams of carbs per day, but at three months they were raised 5 grams of carbs per week until they reached a level of carbs at which they could maintain their weight. The low-fat group began the study eating 1200 to 1800 calories per day with less than 30% of their calories from fat, but they were never transitioned to a maintenance level of calories per day. In contrast with the low-carb group, at the end of the study the prescribed regimen for the low-fat group had not changed. It is hard to know how much additional weight the low-carb participants would have lost if they had been allowed to transition to their Critical Carbohydrate Level for Losing (i.e. the number of carbs that would allow them to continue losing 1-2 pounds per week) rather than being moved directly to a maintenance program.
Third, the weight loss in the low-carb group was not a loss of water weight. Both groups experienced similar reductions in lean mass (about 5%) and in fat mass (11% to 20%).
Fourth, in all three studies, the LDL cholesterol increased for the low-carb groups at three to six months, but was at or below baseline by the end of the study. Why this happens is not clear, but it seems to be a common finding when people begin a low-carb diet. Unfortunately none of the three studies measured LDL particle size, an important factor because small, dense LDL particles are more atherogenic than large, fluffy LDL particles. And people with higher HDL, as was seen in the low-carb group, tend to have the large, fluffy form of LDL cholesterol.
Fifth, an interesting aspect of the Annals of Internal Medicine study was the fact that it addressed the issue of dieting and bone loss. Both the low-carb and low-fat groups lost 1.5% or less of their bone mineral density during the course of the study. A small loss is unsurprising because the bones of both groups had less weight to carry as the study went on. However, there was no between-group difference in loss of bone mineral density in either the hip or the lumbar spine. There are blogs all over the internet suggesting that the relatively high protein intake of a low-carb diet causes calcium to be leached from bones and results in osteoporosis. The theoretical basis of this idea is shaky at best, and in a practical sense the Annals of Internal Medicine study indicates that this type of fear mongering is unfounded.
To sum it up, low-carbers now have solid scientific evidence that low-carb works for weight loss and that it improves metabolic health markers as well. If your doctor objects to your practice of the low-carb lifestyle, you might want to print out these three articles, read them, and take them along to your next office visit. For those who are skeptical about the benefits of low-carb, the positive scientific evidence is only getting stronger.
Thursday, July 29, 2010
When I began losing weight with low-carb, my motivation was not the usual one. I knew that as an obese woman, I would have very little credibility as a scientist.
That sounds odd, doesn’t it? Why would obesity trump publications and other achievements in the professional world?
This week I came across an article in the journal Obesity, “The Stigma of Obesity: A Review and Update.” The authors, Rebecca Puhl and Chelsea Heuer, give numerous examples from the literature demonstrating that obese individuals are indeed the subjects of discrimination in many areas of life.
In the area of employment discrimination, the article states,
- One study (N = 2,838) found that overweight respondents were 12 times more likely, obese respondents were 37 times more likely, and severely obese respondents were 100 times more likely than normal-weight respondents to report employment discrimination. In addition, women were 16 times more likely to report weight-related employment discrimination than men.
Weight bias is also seen in health care settings. Physicans, medical students, nurses and dieticians all expressed negative attitudes toward obese patients. Common adjectives were “lazy,” “lacking self control” and “noncompliant.” Medical students reported that severely obese patients were most frequently the target of derogatory humor among attending physicians, residents and students, especially in surgical specialties. Obese women, in particular, pick up on these attitudes. The article discusses several studies indicating that women in the United States are more likely to delay or forego preventive care as their BMI increases.
The article also addresses obesity and interpersonal relationships, including sexual relationships. One study asked 449 college students to rate six pictures of hypothetical sex partners in order of preference. The top ranking went to a healthy partner. Second was an armless partner. Third was a partner with a history of STDs. Fourth was a partner with mental illness. Fifth was a partner in a wheelchair. And sixth? You guessed it. Sixth was an obese partner. Not only that, although both men and women ranked the obese potential partner to be least desirable, the men ranked obese female partners significantly lower than the women ranked obese male partners.
Is this fair? No, it isn’t. Nevertheless, as the authors go on to describe weight bias in the media, it seems that weight bias, and particularly weight bias against women is pervasive. They conclude their article by discussing research to decrease biases against obesity and even legislation to prohibit weight discrimination.
While both of these approaches might be helpful in the long-term, for whatever reason there seems to be an intrinsic stigma against obesity. If you doubt that you have it, take a look at the picture at the top of this post and be honest about your responses. Because of this stigma, and because we all live in the real world, it seems that low-carbers have yet another reason to achieve and maintain a weight loss. Not only is a normal weight more healthy, a normal weight will give us a better chance at achieving our maximum potential in employment, in receiving health care and in forming interpersonal relationships.
Saturday, July 24, 2010
There are about 2000 counties in China. In the 1980’s, Cornell University did a large ecological study in 65 of them and published the data as something called the China Study. The study measured 367 variables in about 6500 adults. It captured data on diet, lifestyle and disease and included analyses of blood and urine samples. The individual results were grouped geographically, by county, producing a data set with 65 (or fewer) observations for each variable that was measured.
T. Colin Campbell, Ph.D. was a researcher in this study. In 2005 he published a book, The China Study: Startling Implications for Diet, Weight Loss, and Long-Term Health, using data collected from the China Study, from his own published research and from several other sources. When all of this information was considered together, on page 7 of the 2004 edition of the book Dr. Campbell concluded that,
- People who ate the most animal-based foods got the most chronic disease. Even relatively small intakes of animal-based food were associated with adverse effects. People who ate the most plant-based foods were the healthiest and tended to avoid chronic disease.
In light of what low-carbers know personally and know from the scientific literature about the benefits of eating animal-based foods, Dr. Campbell’s conclusion is quite surprising. Vegans and vegetarians commonly use The China Study as proof that their food choices are scientifically superior to those that incorporate animal products. (Take a look at the comments on Amazon.com for just a few examples.) What’s a low-carber to think?
In 2005 Chris Masterjohn wrote a critique of The China Study. Masterjohn pointed out that the data showed that intake of animal protein did not correlate with mortality for all cancers. Although Campbell had tried to connect animal protein intake to cancer mortality through a set of six biomarkers like plasma copper and urea nitrogen, the relationships between animal protein intake, the biomarkers and the eventual deaths from cancer were poorly documented. Masterjohn also showed that Campbell had taken his own research on the tumor-promoting activity of casein in cancer-prone rats to make the astounding statement on page 104 of the book that “casein, and very likely all animal proteins, may be the most relevant cancer-causing substances that we consume.” This seems to be a bit of a logical stretch.
The discussion lay more-or-less dormant until 2010 when Denise Minger, a 23 year old English major and self-described data junkie, happened upon the raw China Study data and wrote a lengthy description of her criticisms of the book. In a 2001 symposium Dr. Campbell had summed up some of the findings of the China Study and a subsequent China Study II. He said, “Plasma cholesterol in the 90-170 milligrams per deciliter range is positively associated with most cancer mortality rates. Plasma cholesterol is positively associated with animal protein intake and inversely associated with plant protein intake.” After spending 1 ½ months of working with the raw data from the China Study, Ms. Minger found that the data in fact showed no statistically significant relationship between the intake of animal protein and cancer. (It also showed no statistically significant relationship between the intake of plant protein and cancer.)
So, how could Dr. Campbell describe a positive correlation between increased intake of animal protein and cholesterol and between increased cholesterol and cancer, while the raw data showed that there was no one-to-one relationship between intake of animal protein and cancer? The answer: confounding factors. Schistosomiasis is a common disease in China. It is caused by a worm not normally found in plant-based food nor in animal-based food but in contaminated water. Ms. Minger found that as schistosomiasis increases, plasma cholesterol increases significantly. (This may be the result of negative effects of schistosomiasis on normal liver function.) As schistosomiasis increases, the rate of colorectal cancer also increases significantly.
In other words, in counties where schistosomiasis was present, one would expect that people who had high cholesterol would also tend to have more colorectal cancer. Hence the presumed relationship between high cholesterol and cancer mortality in China would actually reflect a factor that had nothing to do with diet. And when Chinese counties with zero schistosomiasis infection are compared with respect to the relationship between total cholesterol and the rate of mortality from colorectal cancer, the correlation between the two variables disappears. In other words, Dr. Campbell’s reasoning that eating animal protein is associated with high cholesterol is in turn associated with increased cancer mortality is invalid. The data was presented in a way that it implied a relationship, but the relationship disappears with a more detailed analysis.
From there, Ms. Minger went on to dismantle one after another of Dr. Campbell’s assertions regarding the use of animal-based foods and damage to health. Other laypeople with statistical experience (here and here) also did their own data analysis and reinforced her conclusions.
Dr. Campbell responded to Ms. Minger’s criticisms here. His main objections seemed to be that she used adjectives (!), that she used univariate correlations (so did he) and that she was probably unable to have made her analyses without outside help.
Ms. Minger’s very detailed response to Dr. Campbell is here.
If you have time to read all of these links, they provide fascinating insight into the analysis and potential applications of an important ecological study. If you don’t, the bottom line is this: when you encounter a scientific study that seems to contradict everything you know about a particular subject, be sure to take a very careful look at the data to see if it might have been cherry-picked, over-interpreted, or analyzed without reference to potential confounding factors. If anything like this has happened, the conclusions of the investigators may not necessarily reflect what the data actually shows.
Thursday, July 15, 2010
(Warning: Most of my posts are science-based, but this one comes from my own experiences, i.e., n=1. Forewarned is forearmed, so here we go.)
One of the things I noticed before I began low-carbing was that after I ate a meal, I could only go a couple of hours before I had to have a snack. Hunger would overwhelm me, and since my willpower isn't great, I would give in. Eventually I became fat and prediabetic.
Then came low-carb. I could eat and leave the table satisfied. I could eat only at meals and not feel ravenously hungry between times. But as the years went by, I noticed that my between-meal hunger started to return. It wasn't as bad as before, but my willpower hadn't improved any and I would start snacking to the point that I was eating mass quantities of low-carb food almost every day. I found Dr. Atkins' Accel diet pills, and those seemed to help. Until the Atkins company quit making them. Next, somebody introduced me to the original formulation of Leptopril and that kept the hungries at bay fairly well. Until they changed the formula. Finally, the Country Life Diet Power pills seemed to help a bit, but eventually those became unavailable, too. And after that, I couldn't find another over-the-counter diet pill that worked for me.
In the world of weight loss and weight maintenace, calories don't count as much as carbs, but they do count. My weight was increasing slowly but surely and there seemed to be nothing I could do about it. I tried drinking lots of water. I tried different kinds of fiber. I tried zero-carb. I made charts of the ingredients of the diet pills that had worked to curb my hunger, and I couldn't figure out what the magic combination was.
When the between-meal hunger hit, I would look at the extra ten pounds of fat I was carrying and wonder--why, if I'm eating very low carb and if I have this stored fat available--why can't my body switch over and use some of that stored fat for energy?
A couple of weeks ago, when the hunger monster attacked about two hours after breakfast, for some reason I went to the kitchen and made a cup of regular coffee. No artificial sweetener and no whitener. Just black instant coffee in a cup. I sipped some of the coffee, put the cup on my desk and went back to work. The hunger abated for an hour or so, but then it returned. I sipped some more of the black coffee and the hunger went away again. I had lunch as usual, but sure enough, about two hours later the hunger monster came knocking. Again I sipped some coffee and it went away. I repeated this until dinner. After dinner I knew I couldn't drink caffeine or I wouldn't sleep, so I sipped on a diet soda instead and that seemed to work. I had eaten a reasonable amount of food at my three meals, and I didn't wake up hungry during the night.
The second day was easier. I knew that if the hunger monster hit, I would be able to switch my body into fat-burning mode by sipping the coffee. It worked, and it has worked ever since.
It's important to state that each day I have had a shake for breakfast, fatty meat, cheese and a few veggies for lunch and fatty meat, cheese and a few veggies for dinner. In other words, I've been careful to eat sufficient-but-not-too-much complete protein, to eat fat to provide energy, and to keep the carbs low. I don't eat until I'm full. I figure out what I need to eat and eat that. Then I stop. I have kept taking all my normal supplements and I've been drinking at least 60 ounces of water a day. The difference is that, by sipping black full-caffeine coffee whenever I start feeling between-meal hunger, I can put the hunger monster at bay. I hate the taste of the coffee, but the fact that I'm essentially using it as a drug seems to make that okay. I once again can eat three reasonable meals three times a day and be satisfied. Thoughts of food no longer rule my life.
In conclusion I'll do a little speculation. For some reason, my body seems to need a spike in epinephrine to switch from food-storage to fat-burning mode. And it seems to need several little spikes over time, rather than one big spike. That may be why certain over-the-counter (OTC) diet pills worked for me and others didn't. Most OTC diet pills contain caffeine in some form, but it may be that the three effective ones delivered the caffeine slowly enough to keep my fat burning process in motion. I've tried taking caffeine pills and those don't work for me. I've tried drinking cups of coffee and that doesn't work. There seems to be something about the slow ingestion of black coffee that makes the difference.
As I said, n=1. This may work for me and for nobody else. But I'm posting it in case somebody else is doing pure low-carb and finds it impossible to fight off between-meal hunger. Erasmus is a zero-carber who says his Satisfactometer is broken. I think my Satisfactometer is broken, too, but maybe, just maybe, I have found a way to cope with it. No guarantees, but in case this works for someone else, I thought I'd share.
Thursday, July 1, 2010
After people have low-carbed for a while, they start to look better and feel better. As their health improves, one of the natural questions to ask is, "If I feel this good by dropping the carbs, wouldn't I feel even better if I ate organic food?" When this question is asked in the form of scientific studies, the short answer is, "Probably not."
To be sure, the alternative medicine community makes many claims for organic food. In Alternative Medicine Review, Walter J. Crinnion, a Nutritional Doctor, states that organic foods contain higher levels of certain nutrients, lower levels of pesticides, and may provide health benefits for the consumer. Please click the link for an extensive list of references.
On the other hand, in 2010 in the American Journal of Clinical Nutrition, Dangour et al. interviewed experts, searched bibliographies, and checked peer-reviewed articles with English abstracts. They found a total of 12 studies that evaluated health effects following the use of organic compared with conventionally produced foods. The authors reported that the largest study showed a 36% reduction in risk for allergic eczema when children under two consumed organic dairy products. Other than that, the majority of the studies showed no differences resulting from organic foods versus conventionally produced foods in nutrition-related health outcomes.
In one sense, this is not surprising. A 2009 literature review by the same group showed that there were very few differences in nutrients between organic and conventionally produced foods. In crops, eleven nutrient categories were analyzed. Conventionally produced crops had a significantly higher content of nitrogen, while organically produced crops had a significantly higher phosphorus and more acidity. The other eight categories were not different between the two groups. An analysis of the database on livestock products found no differences in nutrients between organic and conventionally produced products.
This finding is supported by the UK Food Standards Agency which found that nutrient levels vary as a result of freshness, storage conditions, crop variety, soil conditions, weather conditions and how animals are fed, rather than as a function of whether the food is produced in an organic or a conventional manner. They caution that while single papers may show differences in the nutritional content of a particular food, it is important to evaluate the weight of evidence across a range of published papers.
An important consideration favoring organic food is that organically grown foods have about one third the pesticide residues as do conventionally grown foods. A study in elementary age children found that their urinary organophosphorus pesticide metabolites were significantly lower when a conventional diet was replaced by one with organic food items. However, chemical pesticides are not the only ones available. It is important to note that while organic farming does not allow the use of synthetic pesticides, it does permit the use of plant-derived pesticides including Bt, pyrethrins and rotenone, and all of these exhibit varying degrees of toxicity in humans.
Another concern is ecological rather than health-related. Organic farming requires more land per unit of food produced. Repeated use of soil for growing crops makes it necessary to use fertilizer. In place of chemical nitrates and ammonia, organic farmers must obtain and apply manure and use crop rotation with leguminous plants to return nitrogen to the soil. When soils are phosphate-depleted, conventional farmers can use highly soluble chemically-made superphosphate while organic farmers must use poorly soluble rock phosphate. These practices, along with the poorer efficiency of organic pesticides and the need to till the land frequently to prevent weeds, means that the production of food is up to 50% less efficient when it is done organically. (See Reference 15 here.)
Even if a country has plenty of land to devote to food production, there are a couple of other items that should be considered. The use of manure rather than chemicals as fertilizer introduces the presence of bacteria, especially in fruits and vegetables that are eaten fresh. Because organic food production does not use antibacterial techniques such as food irradiation or chemical washes, it is very important to wash organic foods before they are consumed. Finally, organic foods tend to spoil more quickly than their conventionally produced counterparts, which makes it necessary to buy them when they are fresh and to use them up quickly. This is especially important with grains, seeds and nuts which are liable to produce mold and its associated toxins.
As is frequently the case, I can't come down on one side or the other in the case of organic versus conventional food. Sometimes people have worries about the possible effects of agricultural chemicals. Sometimes they prefer the taste and smell of organically produced food. Sometimes they simply want to get back to a more natural way of living. If that's the case, and if they are aware that eating natural foods is not completely risk-free, then they should go ahead and buy organic food. But speaking from a scientific perspective, and looking at groups of people rather than at individuals, it's probably fine to buy and eat food that is produced in conventional ways.
Thursday, June 24, 2010
No, this blogpost won't address the ethics of writing out the answers for an exam on your hand. In the context of low-carb, cheating means going off the diet for a short time or for a long time.
One of the hardest concepts about low-carb dieting is that it's for life. Those of us who have dieted all our lives are used to losing weight, regaining it, and losing it one more time. We may have sets of "fat" and "skinny" clothes in our closets to accommodate this lifestyle. Unfortunately, low-carb doesn't work that way.
When we follow the low-carb lifestyle, we learn to eat meat, eggs and cheese for protein, green vegetables and berries for vitamins, and lots of delicious fat to give us energy. If we stay away from the carbs we find that our appetites are satisfied and we start to to lose weight. Our skin and hair improve, our HDL increases and our triglycerides decrease, our elevated blood sugars become less of a problem, and gradually even our blood pressure starts to come into a normal range.
But what if we step out of our normal routine? What if we go to a restaurant? It's easy to take a roll out of the bread basket or eat a few chips with the salsa that's on the table. And after the meal is over, it's hard to resist dessert, especially if there is a sugar-free version available.
The body is able to adapt to all sorts of things, and an indulgence once in a while probably doesn't hurt. Our paleo ancestors no doubt ran onto the odd honeycomb or patch of blueberries and were able to stuff themselves with no ill effects. The difference, however, is that in the paleo world, when the honey or the berries were gone, they were gone. In the 21st century, the restaurant is available several times a week and so are the rolls, chips and desserts.
For low-carbers, especially low-carbers with insulin resistance, this spells trouble. Eating moderate protein and relatively high fat does not protect a person from the effects of insulin unless that eating is done in the relative absence of carbs. Add carbs (and the rolls, chips and sugar-free desserts do have carbs) and insulin will be released. And as long as insulin is present, any excess calories will be converted to fat, which will be stored our fat cells and then kept trapped there until our blood insulin comes back to a low level. Even if a low-carber is able to convince himself that the cheat didn't count, that he "deserved" the cheat or that he really eats very few carbs on most days, his body will tell the tale.
The scale always fluctuates day-to-day, but as the rolls, chips and desserts become a more constant feature, eventually the fluctuations will start to trend upward. The low-carber may be able to brag that he fits into a certain size, and his mirror may lie to him about it for a while, but eventually the signs of "Dunlap's disease" (the belly done-laps over the belt) will become undeniable. Excellent lab values will start to return to their previous levels. It may be possible to get away with low-carb cheating in the short term, but not in the long term. Unlike the proctor on a test, the body is always paying attention.
What to do? That depends on the low-carber. First of all, we have to decide if sticking to the program is worth the effort. Were we happier when we were fatter but had fewer food restrictions? Are we able to live with a loss in overall health if that gives us the opportunity to eat certain types of food?
If the answer to both questions is yes, then it's our body and our life. Low-carbing is an individual decision, not a regime to be imposed on unwilling participants by a group of food Nazis.
If the answer to one or both questions is no, then it might be time to go back and remind ourselves why we've chosen this way of eating. We can make lists of what life was like before low-carb and what changes happened after. We can re-read the books by Dr. Atkins and the Drs. Eades as a reminder of what does and doesn't work on low-carb. We can get involved in one or more low-carb bulletin boards. We might search around the internet to find new blogs about low-carb and paleo eating to get a new infusion of energy. Or we could even start a blog to help give back to others what low-carb has given us.
Cheating happens. But it's within our power to decide if it continues to happen. I'm hoping that any readers who find themselves in a cheating situation will use this reminder to take the steps they need to, to get back on a happy healthy low-carb path, and to keep on keeping on.
Thursday, May 27, 2010
One of the more interesting graphs shows that there is not much of a relationship between average cholesterol and rates of death from heart disease. Ancel Keys used seven carefully selected countries to "prove" the opposite, but the countries used for this graph tell another story.
Here's a graph that should be completely unsurprising to a low-carber. It shows a steadily increasing consumption of sugar in the United Kingdom and the United States and, beginning about 1900, a dramatic increase in rates of obesity.
Starting in about 1970, people in the United States began substituting high fructose corn syrup (HFCS) for table sugar. Interestingly, there was also an increase in the incidence of diabetic end stage renal disease during that time. Correlation is not causation, but the values do increase in a similar manner.
End stage renal disease is one of the complications of diabetes, which has also been increasing in the United States.
Sugar consumption, and in recent years HFCS consumption, has been increasing. Has anything else been increasing? Yes, we have been using more wheat flour per capita in the United States.
We are also eating more carbohydrates as a percentage of our total calories.
Not only are we eating a higher percentage of carbs, we are also eating more total calories per person every day.
All of these observations are consistent with (but do not prove) the hypothesis that eating refined carbohydrates can result in the diseases of civilization. However, other factors may also contribute to the increase in metabolic diseases during the past century, and here are some more graphs to consider in that regard.
It is possible that insufficient fiber can be blamed for an increase in health problems. I couldn't find a graph that described fiber consumption over time, but did find one on vegetable consumption. It appears that we are eating more vegetables (and presumably more fiber) than we used to.
It's possible that products that are subject to "sin taxes" could contribute to health problems. Although the introduction of cigarette smoking could be associated with the arrival of Western civilization and its diseases, it is interesting to note that the per capita consumption of cigarettes has actually declined since 1977.
Total alcohol consumption has decreased, too.
As discussed in a previous post, a high intake of omega-6 fats promotes the formation of inflammatory intermediates. Another possible explanation for the increased incidence of the diseases of Western civilization is the increased use of omega-6 rich vegetable oils in place of animal fats. As usual, correlation is not causation, but as shown in the graph below, the production of soybean oil for food consumption went from close to zero in 1935 to 25 pounds person per year in 1999.
Consumption of canola oil has also increased dramatically, from zero in 1984 to seven pounds per person per year in 2004, while the consumption of olive oil went to about two pounds per person per year and the consumption of butter declined.
What do all of these graphs prove? Not a thing. Although they show associations, they cannot prove causation. But I present them for your consideration because they do give us some things to think about as we enjoy a low-carb summer. Have a happy, healthy June!
Friday, May 21, 2010
The man in the picture has insulin resistance and what the Heart Scan Blog" calls "wheat belly," right? Wrong. He has a hormone problem, but in this case the hormone isn't insulin, it's cortisol.
Insulin, which we discuss frequently on this blog, is a storage hormone. In response to ingestion of carbohydrates, and to a lesser degree of amino acids, the pancreas releases insulin. As a result, within minutes to hours, carbohydrates, amino acids and fats are stored after each meal.
Cortisol is a glucocorticoid hormone that is released from the adrenal glands in response to stress. The stress can be physical or emotional. The effects of cortisol in the body occur over hours to days and include suppression of the immune system, suppression of inflammation and an increase in blood glucose. When people survived by hunting, or when they were involved in combat, elevated cortisol would allow a person to ignore pain and illness in order to concentrate on the task at hand. It would also provide excess glucose in the blood, allowing the person additional energy to fuel the brain and muscles in extreme situations.
Both insulin and cortisol are powerful hormones. Too much insulin for too long will eventually result in insulin resistance, a condition in which more and more insulin must be secreted to produce normal insulin responses in tissues such as muscle, brain and liver. Too much cortisol for too long produces an increased risk of infection, reduced bone density, increased muscle weakness and excess glucose in the blood. Cushing's syndrome is the result of having excessively high cortisol for several years. Take another look at the picture at the beginning of this post. The patient looks like a person with metabolic syndrome, doesn't he? But this person actually has Cushing's syndrome.
Cushing's syndrome can be caused by an adrenal or pituitary tumor, or it may be the result of taking high doses of glucocorticoids for a long period of time. People who do not have these tumors and who do not take exogenous glucocorticoids do not have to worry about Cushing's syndrome, but the man in the picture does illustrate the point that there may be metabolic side effects from stress-induced hypercortisolism.
In a May 2010 review in the American Journal of Physiology-Endocrinology and Metabolism, Dake Qi and Brian Rodrigues described the effects of glucocorticoids on insulin-responsive tissues. Many of the studies in the review used dexamethasone, a synthetic glucocorticoid that is about 50 times as potent as cortisol and produces robust reactions in a short period of time. However, clinical experience with excess cortisol secretion supports these observations. At any rate, excess glucocorticoids will produce:
- Decreased glucose uptake and utilization in muscle and adipose tissue.
- Increased gluconeogenesis and glucose output by the liver.
- Increased triglyceride storage in the liver.
- Increased fatty acid uptake, fat synthesis and fat storage in adipose cells.
Readers of the previous post will recognize that these symptoms are consistent with insulin resistance. What makes it complicated is that there are many different molecules involved in insulin signaling, and each of these can be regulated on several levels. Any of the signaling intermediates can be synthesized more slowly or more rapidly, degraded more slowly or more rapidly, and activated or inactivated through phosphorylation or dephosphorylation by various kinases or phosphatases at numerous sites. These multiple levels of regulation mean that insulin resistance can be achieved through one mechanism when excess cortisol is involved and through another mechanism when excess insulin is involved. Consequently it is possible that both hormones working together can achieve more damage to insulin signaling pathways than one hormone acting alone.
Stress is able to produce a ten-fold increase in cortisol secretion. If the stress is chronic, it is possible that this alone could result in insulin resistance and eventually in the symptoms of the metabolic syndrome. This has been postulated by Anagnostis et al. in The Pathogenetic Role of Cortisol in the Metabolic Syndrome: A Hypothesis.
As we have noted, when primitive cultures adopt Western lifestyles, within about twenty years they can expect to begin experiencing the chronic diseases of Western civilization. While the carbohydrate hypothesis postulates that a diet of refined carbohydrates is the chief cause of insulin resistance and ultimately of the metabolic syndrome, it is also possible that the stress associated with the Western lifestyle is a contributor to insulin resistance. Stress and cortisol secretion are unavoidable, but in the absence of mammoth hunts and hand-to-hand warfare, those of us who wish to avoid the symptoms of insulin resistance would do well to avoid stress while also minimizing our intake of refined carbohydrates.
Thursday, May 13, 2010
The metabolic syndrome is a symptom set that includes the following: increased truncal obesity, high blood pressure, high blood glucose, low HDL cholesterol and high triglycerides. As anyone who has observed adults and even children in Western countries can confirm, the metabolic syndrome is becoming more and more prevalent. In Good Calories Bad Calories, Gary Taubes uses several lines of argument to show that one unifying explanation for the development of the metabolic syndrome is the prior development of insulin resistance.
Interestingly, one of the arguments Taubes does not use for his hypothesis is something called the "knockout mouse." The knockout mouse is not a small pugilist with boxing gloves. Instead, it is a genetically engineered mouse in which one or more genes have been turned off (knocked out) through targeted deletions. If we want to know what the effect of insulin is on a particular tissue, one approach is to delete the expression of the insulin receptor in that tissue.
The first attempt at an insulin receptor knockout mouse was to remove insulin receptor expression from the entire mouse. These mice were smaller than normal but were born alive at term. Shortly after birth they developed diabetic ketoacidosis and died. This was not helpful to the investigation of the relationship of insulin receptor signaling to various metabolic conditions, and the investigators moved on.
Because muscle insulin resistance is thought to be important in the development of type 2 diabetes, the next group of knockout studies involved mice that lacked insulin receptors specifically on muscle tissue. These mice had normal levels of blood glucose and plasma insulin. However, they had a 74% decrease in insulin-stimulated glucose transport into their muscle tissue. This caused blood glucose to be preferentially taken up by adipose tissue. Although these mice did not develop overt symptoms of diabetes, they demonstrated two of the features of the metabolic syndrome: increased fat mass and high triglycerides.
Another tissue targeted for insulin receptor deletion was the liver. By two months of age, the mice lacking liver insulin receptors had high levels of serum insulin but were were hyperglycemic in the fed state. To a great extent this was found to be attributable to the fact that insulin was unable to suppress the production of glucose by the liver. This suggests that hepatic insulin resistance is necessary for the onset of overt diabetes.
Because insulin receptors are widely distributed in the brain, investigators also developed a neural insulin receptor knockout mouse. The brains of these mice were normally developed, but the mice showed increased food intake and moderate diet-dependent obesity. It is known that the brain is able to regulate hepatic glucose production. When these neural-knockout mice were given exogenous insulin, they were only about half as effective as normal mice at suppressing hepatic glucose output.
Finally, the insulin receptor was uniquely deleted in the pancreatic beta cells of another group of mice. The investigators were expecting the pancreas to sense glucose concentrations directly rather than to use insulin signaling as an intermediary. To their surprise, mice that lacked pancreatic beta cell insulin receptors showed both a decreased ability to sense glucose and an insufficient secretion of insulin in response to glucose. Some, but not all, of the mice developed diabetes.
For those who would like to read more about these experiments, additional information can be found here and here. The use of insulin receptor knockout mice is a rather blunt instrument to determine whether insulin resistance can be implicated as the cause of the development of the metabolic syndrome. And mice are not people. Nonetheless, it is interesting to note that the deletion of insulin signaling in various tissues can produce obesity, high triglycerides, poor suppression of glucose output by the liver and both impaired pancreatic production of insulin and insufficient release of insulin in response to glucose.
Tuesday, May 4, 2010
Today's question is: What if you know that the dietary-saturated-fat-and-cholesterol hypothesis doesn't work very well to explain heart disease, but at the same time you don't want to admit that eating too many refined carbohydrates might be the cause?
Answer: You put the blame on fiber. Or rather on not eating enough fiber.
In 1972, Peter Cleave tried to explain to a U.S. Senate Select Committee that when primitive cultures adopted Western eating patterns, they also began to experience the diseases of Western civilization, including diabetes, heart disease and hypertension. Cleave pointed out that the fat and cholesterol hypothesis of heart disease did not explain this transition, but that the adoption of a diet rich in refined carbohydrates did account for it rather elegantly. The Senators reached the only logical conclusion. They refused to believe Dr. Cleave. Dr. Ancel Keys had so completely won the argument that dietary fat was the cause of heart disease, that any alternative hypothesis had to be rejected out of hand.
The Senators were left with the problem of how to explain the increased incidence of heart disease in transitioning cultures. Enter a famous medical missionary, Denis Burkitt. While working in Uganda, Dr. Burkitt had noticed that Africans produced several times more feces than people in Western countries. He hypothesized that the presence of dietary fiber produced the absence of the diseases of Western civilization. Burkitt collected over 800 anectodal reports showing that primitive peoples ate high fiber foods, while Westernized cultures tended to eat foods that were nutritionally dense and low in bulk, not providing enough volume to allow the intestines to remain healthy. This idea made sense to the granola-eating counterculturalists of the time. More importantly, it did not contradict Ancel Keys' diet-heart hypothesis.
Forty years later, the need for high fiber in the diet has become received wisdom. Some studies show that eating more dietary fiber is associated with lower all-cause mortality, for example Dietary fiber intake in relation to coronary heart disease and all-cause mortality over 40 y: the Zutphen Study. Other studies show no relationship between fiber intake and all-cause mortality, including this one, The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART).
For the purposes of low-carbers, several of the studies on the relationship of glycemic load with the risk of type 2 diabetes may be instructive. The glycemic load is the glycemic index of each food eaten, multiplied by the number of carbohydrate grams of that food eaten, summed for all items consumed during a day. In two studies (here in women and here in men), Salmerón et al. showed that the combination of a high glycemic load and a low cereal fiber intake increased the risk of type 2 diabetes when compared with a low glycemic load and high cereal fiber intake. The figure below is taken from the women's study.Looking at the X axis, at all levels of intake of cereal fiber, the relative risk of diabetes decreases as the glycemic load goes from high to medium to low. On the Z axis, at all levels of glycemic load the relative risk of diabetes decreases as the cereal fiber intake goes from low to medium to high.
Let's say that two low-carbers eat an identical number of carbs. One eats high-glycemic foods and has a high glycemic load. The other eats low-glycemic foods and has a low glycemic load. Both of them will need to release insulin to dispose of the carbs, but the first low-carber will have to release insulin in spikes to counteract the rapid rise of his blood glucose, while the second low-carber will be able to get by with a more gradual release of insulin. As Sullivan et al. have shown here, there is reason to believe that insulin spikes contribute to the development of insulin resistance.
How does fiber fit into the equation? The traditional explanation is that fiber fills us up. However, experiments done with caloric dilution show that when low-calorie foods are subsituted for higher-calorie ones, humans are well able to adjust their consumption of food to maintain their customary caloric intake. Another function of fiber is that it slows the absorption of nutrients from food. In other words, the addition of fiber can be expected to lower the effective glycemic index of high-, medium- and low-glycemic index carbohydrates. The relationship of the total amount of fiber to the total number of carbs to the glycemic index is probably quite complex, which may explain why many of the fiber-health studies do not show clearcut relationships between fiber intake and outcomes such as heart disease, type 2 diabetes, obesity and cancer.
In other words, if low-carb is good and low-glycemic index carb is good, the addition of fiber to all of that might be better. Low-glycemic-index foods like broccoli and nuts do tend to contain more fiber, so perhaps the point is moot for low-carbers who are careful about the type of carbs they consume. In any case, there is good evidence that lowering carbohydrate intake and lowering the glycemic index of those carbs is protective against the diseases of Western civilization. The data on the benefits of fiber intake is not overwhelming, so use your own judgment to decide what level of fiber intake might be right for you.