Low-Carb for You

Impaired Mitochondrial Function and Obesity, Part Two

2011-11-21T20:40:00.000-06:00

Last time we learned that extremely obese people, weight-reduced people and possibly people who will eventually become obese all appear to have a harder time oxidizing fatty acids for fuel than do lean people. Because fatty acids are oxidized in the mitochondria, researchers have begun to look for mitochondrial defects as an explanation for this problem.

Possible defects
Several types of mitochondrial defects have been observed. These are summarized by M.M. Rogge and by J.A. Houmard in their review articles. (The picture above comes from the Rogge article.) Both reviews cite a 2002 study by Kelley et al. that used electron microscopy to show a 35% decrease in skeletal muscle mitochondrial area in obese vs. lean subjects. In some obese subjects, but not lean subjects, there were also large vacuoles which appeared to be degenerated mitochondria. Obese subjects also tended to have mitochondria with less clearly defined inner structure and narrower cristae.

The reviews also cite a 2005 study by Ritov et al. showing lower mitochondrial DNA content (fewer mitochondria) in obese subjects and reduced electron transport chain activity of the mitochondria, even after adjustment for the reduced mitochondrial content. This is consistent with a number of studies that show an increase in activity of certain glycolytic enzymes and a decrease in activity of other enzymes related to oxidative function in obese vs. normal-weight subjects. (See the two review articles for lots of references.) One of the important enzymes that has a lower activity in obese subjects is carnitine palmitoyltransferase 1 (CPT1, the smallest green rectangle in the drawing above), the enzyme that regulates and facilitates the entry of long-chain fatty acids into the matrix of the mitochondria.

To summarize, there are several possible reasons that obese people may have a harder time oxidizing fatty acids than they should. (1) They have fewer mitochondria. (2) They have smaller mitochondria. (3) Their mitochondria have structural problems that are visible by electron microscopy, and some of their mitochondria may even have degenerated completely. (4) Their mitochondria have reduced oxidative activity.

Now what?
So far, I have painted a fairly bleak picture. It’s even bleaker when you read the articles I’ve referenced and realize that while metabolic flexibility is poor in obese people, it’s even worse in people with type 2 diabetes. (I’ve cited only the lean vs. obese in this discussion, but many of my citations also include a type II diabetes group as well, and these typically perform worse than the obese subjects do.)

It’s possible that some people have a genetic predisposition against metabolic flexibility. However, because obesity and type 2 diabetes become more prevalent with increasing age, it’s also possible that we are gradually poisoning our mitochondria, so that our surviving mitochondria are the ones that prefer to metabolize carbohydrates. These survivors not only tend to shunt fatty acids into storage, but they also resist metabolizing the fatty acids that are mobilized out of storage between meals. Our low energy production (and the easy availability of food) encourages us to eat more carbohydrate to provide the ATP we need for daily life. We could propose various possible mechanisms for gradual mitochondrial poisoning but at this point it is only speculation. In any case, we can’t change our genetics, and we can only hope that what we currently call a healthy lifestyle is genuinely healthy for our mitochondria.

Possible interventions
On the positive side, there do seem to be a few things we can do to improve our metabolic flexibility. The first of these is mild-to-moderate exercise. In 2007 Solomon et al. described a 12-week program of moderate aerobic exercise in older obese people that improved (decreased) their respiratory quotient by 0.04. In 2010 Meex et al. asked older male type 2 diabetics to exercise twice a week for 30 minutes on a cycling ergometer and to perform resistance exercise once a week. Before the training program, their metabolic flexibility was about 60% of that of a group of matched controls. After twelve weeks, their metabolic flexibility was the same as that of the control group, and the protein content of their electron transport chain proteins had increased by 275%.

It is possible that more vigorous exercise may not be as helpful as mild-to-moderate exercise for restoration of metabolic flexibility. When the body’s AMP to ATP ratio increases, it activates adenosine monophosphate (AMP) kinase. In order to restore high ATP levels, the AMP kinase does a number of things including downregulation of physical activity and upregulation of feeding behavior. Because of this, it may be necessary for a mitochondrially impaired individual to titrate their exercise so that there is just enough to promote mitochondrial flexibility but not so much that it would cause an AMP kinase-mediated drive to eat more and exercise less.

Once metabolic flexibility is somewhat restored, it is important to take advantage of it. Because carbohydrate will always be metabolized first, it makes sense to decrease the availability of this substrate to the mitochondria. Meals should be low in carbohydrate, moderate in protein and relatively high in fat, to keep the mitochondria in fat oxidation mode as much as possible. Snacks should be avoided because each time carbohydrate is consumed, it moves to the front of the line in the mitochondrial queue. (For an interesting discussion of the effect of exercise, high-fat meals and improvement of the respiratory quotient in healthy young men, see Smith et al.)

As mentioned earlier, carnitine palmitoyltransferase 1 (CPT1) is a major control point for the entry of long-chain fatty acids into the mitochondrion. A third strategy for improving fatty acid oxidation is to circumvent CPT1 by consuming medium-chain fats like coconut oil and butter, rather than fats that contain long-chain fatty acids. Medium-chain fatty acids are metabolized differently than long-chain fatty acids because they can diffuse across plasma membranes without the help of transporter proteins. Thus, they can find their way into the mitochondrial matrix and present themselves to the beta oxidation machinery, to the TCA cycle, and to the electron transport chain without the need to deal with gatekeeper CPT1 proteins that are either downregulated or present in insufficient amounts. According to Houmard, circumvention of the CPT1 chokepoint may be helpful in increasing fatty acid oxidation and decreasing insulin resistance. However, this line of reasoning involves a fair amount of handwaving and probably needs a clinical study or two to back it up.

Conclusion
There it is. Mitochondrial dysfunction may be a plausible explanation for some forms of obesity. If mitochondria fail to oxidize fatty acids, both ingested and de-novo synthesized fatty acids will be preferentially routed to and will tend to remain in storage. The fact that weight loss by itself does not improve fatty acid oxidation in mitochondria explains why it is so easy to regain weight on a diet that is fairly high in carbohydrate. The fact that mitochondrial defects can be accumulated over time explains why a person can eat all sorts of foods and remain a normal weight while he or she is young, but when middle-age approaches, as often as not, so will the middle-age spread.

There are lots of other explanations for obesity, and this may not be a definitive one. But if you suspect that it might apply in your own case, it may be worth it to try (1) a mild-to-moderate level of exercise, (2) a low-carb, moderate-protein, high-fat diet and (3) replacing some of the long chain fatty acids you've been eating with medium chain ones. Enjoy that exercise machine or walking program and bon appétit!

Impaired Mitochondrial Function and Obesity, Part One

2011-11-15T11:26:00.000-06:00

As obesity increases around the world, it’s natural to wonder why so many people are packing on the pounds. The standard answer—calories in exceed calories out—sounds reasonable, but in practice the conscious limitation of calories does not seem to work very well for controlling obesity. A few weeks ago Peter at Hyperlipid described an idea about the obesity problem that’s completely different. Defective mitochondria. I’d like to expand on that here. If you already know about mitochondria, skip the next section. If you’re like me, you’ve forgotten what you knew and a review wouldn’t hurt. (If, on the other hand, you are a true-blue biochemist, you'll notice that I'm gliding over some details in order to make the explanation easier to understand.)

Mitochondria explained
Mitochondria are granular organelles found in the cytoplasm of most eukaryotic cells. They have an outer membrane, and a multiply-folded inner membrane. Inside the second membrane is a viscous matrix containing a large number of proteins used to produce energy for the cell. The picture of a mitochondrion above comes from a 2009 review article by M.M. Rogge, The role of impaired mitochondrial lipid oxidation in obesity. If you click on the picture to open it in a new window, it will be easier to follow this discussion.

The brown elliptical line represents the outer membrane of the mitochondrion. The gray area is a somewhat schematic representation of the inner membrane. That membrane actually follows the folds (cristae) surrounding the white matrix, but this level of detail would make the picture confusing. Just say that the gray area is the inner membrane. The whole mitochondrion resides inside the cytosol of the cell, which, as you will recall, has a cell membrane of its own.

At the top of the picture are three columns, representing the three macronutrients available to cells: Triglycerides (fats), Glucose (representative of carbohydrates) and Amino Acids (from proteins). These have already made their way inside the cell and are presenting themselves to the mitochondrion as potential sources of cellular energy.

(1) Triglycerides have to be broken down to free fatty acids and then converted to fatty acyl-CoA in order to cross the two membranes and enter the mitochondrial matrix. There they are converted to many two-carbon units of acetyl-CoA by beta oxidation and produce some energy. The two-carbon acetyl-CoA units are converted to more energy by feeding into the TCA/citric acid/Krebs cycle, illustrated at the center of the mitochondrion. High-energy molecules are produced (NADH and FADH₂), and these go to the respiratory chain that resides in the inner mitochondrial membrane. This is represented by the yellow ovals labeled I, II, III and IV at the bottom of the drawing. The respiratory chain uses NADH and FADH₂ to produce ATP, which in turn provides energy for the cell.

(2) Glucose is first broken down by glycolysis into two molecules of pyruvate in the cytosol. The pyruvate is transported across both of the mitochondrial membranes and is converted to two of the two-carbon acetyl-CoA units in the matrix. Just like the acetyl-CoAs from free fatty acids, the two acetyl-CoAs from a molecule of glucose feed into the TCA cycle and ultimately produce ATP through the respiratory chain.

(3) Amino acids are also converted into forms that can cross the mitochondrial membranes and feed into the TCA cycle. This is presented for completeness, but will not be discussed in detail.

Metabolic flexibility
When a meal of fats and carbohydrates is eaten, both substances are taken up into cells. Although both macronutrients are available to be converted into energy, typically the mitochondrion will use the carbohydrate first. The insulin that is secreted in response to carbohydrate ingestion inhibits fatty acyl-CoA oxidation and routes fatty acyl-CoA toward fat synthesis in the cytosol. Insulin enhances glucose oxidation by upregulating the enzyme that converts pyruvate to acetyl-CoA and feeds it into the TCA cycle. By a multistep feedback mechanism this also inhibits carnitine palmitoyltransferase 1 (CPT1, the smallest green rectangle in the drawing), the enzyme that mediates the transport of fatty acids into the mitochondrial matrix.

In normal cells after an hour or two, insulin will decline and less glucose will be available to the mitochondrion. Free fatty acids will still be present in the cytosol and will finally be allowed to transit as fatty acyl-CoA into the mitochondrion via carnitine palmitoyltransferase 1. Once inside the matrix, they will produce energy through beta oxidation, the TCA cycle and the respiratory chain. This is called metabolic flexibility. When carbohydrate is present, the mitochondrion will preferentially use carbohydrate. When free fatty acids are present but carbohydrates are in short supply, the mitochondrion will normally switch over to using fatty acids for fuel.

Mitochondria use different amounts of oxygen when they metabolize carbohydrates and fats. This is expressed as the Respiratory Quotient (RQ) or the Respiratory Exchange Ratio (RER). When carbohydrate is used as fuel, more CO₂ is produced for a particular amount of oxygen consumed and the RQ is higher. The RQ number for pure carbohydrate is approximately 1.0. When fat is used for energy, less CO₂ will be produced for a particular amount of oxygen and the RQ will be lower. The RQ for pure fat is about 0.7. The RQ for protein varies with the specific amino acid content but is about 0.8. Now we get to the meat (pun intended) of the matter.

Impaired metabolic flexibility
Since the early 1990’s, evidence has been accumulating that obese individuals have a depressed ability to oxidize free fatty acids in skeletal muscle. It further appears that defects in the mitochondria of skeletal muscle are responsible for this impaired lipid oxidation. Two review articles that discuss these phenomena are Intramuscular lipid oxidation and obesity by J.A. Houmard and The role of impaired mitochondrial lipid oxidation in obesity by M.M. Rogge.

It is possible to measure the relative use of carbohydrate or fat for fuel by the mitochondria by measuring the Respiratory Quotient. However, it is also possible to measure the ability of mitochondria to oxidize fatty acids by infusing radiolabeled palmitate (a free fatty acid or FFA) into a patient and subsequently measuring the appearance of radiolabeled CO₂ as an indication that the palmitate has been oxidized.

Houmard cites an article in which Thyfault et al. compared [¹³C] palmitate oxidation in three groups of women. They studied lean controls (average BMI was 23), extremely obese women (average BMI was 41) and weight-reduced women (had undergone gastric bypass surgery at least a year before, had lost at least 100 pounds and had an average BMI of 34). When they infused [¹³C] palmitate into these women, the results were surprising. The lean controls oxidized about 66% of the [¹³C] palmitate in the basal state and about 85% of it during exercise. However, not only the extremely obese women but also the weight-reduced women oxidized much less palmitate under basal and exercise conditions. In addition, the low percentage of [¹³C] palmitate oxidation was almost identical in the extremely obese and the weight-reduced women. One would hope that weight reduction would improve metabolic flexibility, but apparently it does not.

According to Houmard, the decrease in free fatty oxidation by extremely obese and weight-reduced subjects is supported by a series of studies done at East Carolina University in Greenville, North Carolina. As shown in the figure above, biopsies of skeletal muscle, muscle homogenate and primary muscle cell culture all showed a large decrease in fatty acid oxidation by extremely obese subjects (and in some cases by weight-reduced subjects) when compared with lean controls. Both in vivo (real life) and in vitro (test tube) studies seem to confirm that obese subjects and weight-reduced subjects have difficulty with the oxidation of fatty acids.

Even pre-obese subjects may be destined for fatness because their mitochondria prefer to oxidize carbohydrates rather than fats. Rogge cites two longitudinal studies (Zurlo et al., 1990 and Seidel et al., 1992) that indicate that normal weight subjects who demonstrated preferential oxidation of carbohydrates rather than fatty acids were more likely to gain weight over time. However, these findings were not supported in a subsequent longitudinal study published by Katzmarzyk et al. in 2000. It is possible that some of us are doomed to become fat because we start our lives with mitochondria that prefer to oxidize carbohydrates and oxidize fatty acids relatively poorly. Or not. The data from the literature is not overwhelming on this.

To be continued…
That’s probably enough for this time. I have a bunch more to say, but there is a limit to how much science can be absorbed at one sitting. I do promise that it won’t be two months before I publish Part Two: How can defective mitochondria explain the difficulty some people have with the oxidation of fatty acids and what can be done about it?

Low-Food-Reward versus Low-Carb

2011-09-06T16:37:00.000-05:00

It appears that low-carb research is currently in the doldrums, but low-carb arguments are keeping everybody interested, especially the one going right now at Whole Health Source. The blog owner, Stephan Guyenet, has a PhD in neurobiology and studies the neurobiology of body fat regulation. His blog was thought of as one that advocated the Paleo diet, which is broadly similar to a low-carb type of diet. Then in April of 2011 Stephan wrote a blogpost entitled Food Reward: a Dominant Factor in Obesity, Part I, and everything seemed to change. Stephan stated,

The human brain evolved to deal with a certain range of rewarding experiences. It didn't evolve to constructively manage strong drugs of abuse such as heroin and crack cocaine, which overstimulate reward pathways, leading to the pathological drug seeking behaviors that characterize addiction. These drugs are "superstimuli" that exceed our reward system's normal operating parameters. Over the next few posts, I'll try to convince you that in a similar manner, industrially processed food, which has been professionally crafted to maximize its rewarding properties, is a superstimulus that exceeds the brain's normal operating parameters, leading to an increase in body fatness and other negative consequences.

In other words, when the brain perceives that a food is highly palatable or provides excessive food reward, a superstimulative effect will cause overall caloric intake to increase and will raise the bodyweight setpoint.

After a considerable back and forth between Stephan and his readers, he finally put up a summary post, Roadmap to Obesity. He concluded, "The basic idea is that in genetically susceptible people, excessive food reward/palatability/availability and inactivity cause overconsumption and an increase in the body fat setpoint, followed by the eventual accumulation of fat metabolites and inflammation in the hypothalamus, which exacerbate the problem and make it more difficult to treat. Other factors, such as micronutrients, gut flora, fiber, fat quality, polyphenols, sleep and stress, may also play a role."

The blog you are currently reading subscribes to the carbohydrate hypothesis of obesity. Here it is as described by Gary Taubes:

This alternative hypothesis of obesity constitutes three distinct propositions. First, as I've said, is the basic proposition that obesity is caused by a regulatory defect in fat metabolism, and so a defect in the distribution of energy rather than an imbalance of energy intake and expenditure. The second is that insulin plays a primary role in this fattening process, and the compensatory behaviors of hunger and lethargy. The third is that carbohydrates, and particularly refined carbohydrates-- and perhaps the fructose content as well, and thus perhaps the amount of sugars consumed-- are the prime suspects in the chronic elevation of insulin; hence, they are the ultimate cause of common obesity.

Briefly summarized, the low-food-reward diet consists of simple foods such as gently cooked tubers, meats and vegetables. It minimizes added fats, added sugars, and added flavorings including salt, herbs and spices. The macronutrient breakdown is high carb, adequate protein and low fat. The low-carb diet consists of foods that are low in carbohydrate, moderate in protein and fairly high in fat. The use of salt is permitted and the use of herbs and spices is encouraged. Whole foods and natural foods are preferred, but many low-carbers also include low-carb food products such as protein shakes, protein bars and diet soda.

Okay, that's enough with the background. Superficially, if people are eating healthy whole foods, they should be healthy, right? So what's the problem? There are several of them.

Problem One--Cause and Effect
The low-food-reward diet assumes that food is similar to a drug. When palatable food is eaten, dopamine D2 receptors are stimulated and down-regulated in a manner similar to that seen in drug addiction. According to Johnson and Kenny in a 2010 rat study, "overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating."

While this may be true in rats, it seems a bit extreme in humans. One does not see addicted fatties mugging people or robbing houses to support a Twinkie habit. Indeed, a person who has just gorged on Twinkies does not present with the symptoms of, say a cocaine user. For 15-60 minutes after the ingestion of cocaine, a person will experience alertness, confidence, euphoria and high energy. A person who has overdosed on Twinkies will tend to experience quiet contentment and lethargy. While both drug-addicted people and people with obesity are observed to have lower than normal levels of the dopamine D2 receptor, it is possible that the causes of this condition are different. The real-world behaviors seen in drug addicts with low dopamine D2 receptors are certainly different from those in food-rewarded people with low dopamine D2 receptors.

The low-carb diet assumes that carbohydrate ingestion prompts a release of insulin by the pancreas in order to maximize storage and utilization of the glucose that will shortly be entering the circulation. Insulin is a hormone that acts through a transmembrane receptor on the surface of most cells. When insulin is present in high concentration and/or for long periods of time, insulin receptors are downregulated. This produces a condition called insulin resistance, meaning that a higher concentration of insulin will be required to effect insulin signaling in a particular cell. In the short term, insulin resistance is reversible. Just lower the blood insulin for several hours or days and eventually the usual number of insulin receptors will return to the cell surface. However, when insulin has been kept chronically high for years, the resilience of the system goes away. Eventually, insulin resistance becomes a constant feature. The liver resists turning off gluconeogenesis. Muscles resist taking up glucose. In most people, fat cells remain insulin responsive, but eventually they too bcome resistant to fat storage and will release free fatty acids from fat depots.

It is not certain that chronic high insulin alone produces insulin resistance. For instance, genetic susceptibility and inflammatory processes may also play a role. However, once the symptoms of insulin resistance are observed clinically, taking steps to reduce chronic high insulin will permit at least a partial recovery of insulin sensititivity. Not coincidentally, these actions will also cause the loss of fat while sparing the loss of lean muscle mass.

Problem Two--Scientific Training
In general, people with PhDs come to science in a way that differs from MDs. They are taught to break down large questions into small pieces and to look at differences between carefully controlled groups. They use dishes of cells, strains of rodents, and matched groups of human subjects. This makes it easier to see significant changes between groups that differ only (one hopes) because of the treatment variable. However, PhDs must always be careful to remember that their conclusions may not be valid outside the tissue type/rodent strain/particular human subjects they have studied. Scientific studies of this type are useful because they provide guidance about what might work to treat a particular condition or disease. They do not provide absolute truth about what must work to treat a particular condition or disease.

Unlike PhDs, MDs tend to be found in a clinical rather than an academic setting. While MDs are interested in scientific studies, they must also be aware that what works on paper may not be particularly successful when treating patients. The body has lots of counterregulatory systems, and what takes place in an isolated dish of cells may be prevented from happening the context of an entire organism. What is true for a particular type of rat may not follow the physiology of a human being. What happens in the short term in a controlled environment for a selected group of people may not be the case for a large number of free-range humans. MDs in active practice will tend to gravitate toward approaches that are successful for their patients, particularly if they are treating patients with similar conditions. Examples of this in the low-carb community are Robert Atkins in the treatment of obesity, the Drs. Eades in the treatment of obesity, Richard Bernstein in the treatment of diabetes and William Davis in the treatment of coronary heart disease.

Problem Three--Practical Experience
The idea of a low-food-reward diet has apparently been around at least since 1965 when Hashim and Van Itallie used a feeding machine that dispensed bland liquid food through a straw. They noted that morbidly obese volunteers lost a great deal of weight on that regimen. However, no follow-on studies were published. Many other diets have come and gone in the interim, including the standard low-fat diet promoted by much of the medical community, and none of these has been particulary successful.

A possible exception to this rule has been the low-carb diet. Starting with the publication of Dr. Atkins' Diet Revolution in 1972, the low-carb diet in one form or another has been found to be useful in weight loss and in the promotion of various aspects of good health such as decreased blood pressure, decreased blood glucose and improvement in other metabolic markers. (See here for a summary of three articles in top-tier scientific journals.) Judging by comments in health-related blogs, this has been the anedotal experience of many ordinary people who have tried the low-carb lifestyle. Nearly 40 years after Dr. Atkins wrote his book, there appears to be good evidence that low-carb eating provides lasting benefits with regard to weight loss and health.

Several commenters say that they have tried the low-food-reward approach to eating and have been successful with it. This may be true in the short term. In the long term, it remains to be seen whether following a low-food-reward diet will be of benefit in people who have eaten the standard American diet for 20 to 50 years, in people with type 2 diabetes, in people who have heart disease and/or in people who lose weight and then attempt to maintain the weight loss over many years. It might work in theory. We will need to wait several decades to see if it works in practice.

Post Script
An excellent comparison of the food reward and the carbohydrate hypotheses of obesity can be found at Peter's Hyperlipid blog. Peter has much more training and experience in physiology than I do, and he presents several very important refutations of journal citations that seem to discredit the carbohydrate hypothesis. It may take a couple of readings to absorb his point-by-point analyses, but it will be very much worth the time invested.

Vacation // Can Leptin Keep You Light?

2011-05-30T18:42:00.003-05:00

On May 31 hubby and I leave for a 14-day vacation in Northern Europe. I will have limited access to the internet, so go ahead and leave comments if you wish, but they may end up in comment limbo for a fairly long time. I probably won't be able to respond to questions very well, and you may have to wait until I return to get a detailed answer.

While I'm gone, I'll give you something to think about. During the last few days I've been having fun over at Stephan Guyenet's Whole Health Source blog. Commenters have been discussing his post on Food Reward: a Dominant Factor in Obesity, Part IV and have started thinking about the effect of leptin on the prevention of weight regain following a significant weight loss. Commenter ItsTheWooo2 has lost over 160 pounds but is now faced with the lifelong challenge of maintaining that weight loss. She noticed that when she began taking injectable synthetic leptin as an experimental treatment for hypothalamic amenorrhea, the leptin made it much easier for her to stay at her goal weight. Wooo has some rather strong opinions, but she also explains herself well, and the comments are worth reading if you have the time.

During the discussion, Stephan mentioned the work of Rudolph L. Leibel at Columbia University. Conveniently, one of the commenters gave a link to a blogpost summarizing Dr. Leibel's work on lepin, Why is it so Hard to Maintain a Reduced Body Weight? The blogger, Arya M. Sharma, M.D., has a couple of followup posts entitled Why Hyperleptinemia is Not Leptin Resistance and Using Leptin to Treat Obesity.

If you would like to look at some of the primary literature on the topic, here are several articles: Low Dose Leptin Administration Reverses Effects of Sustained Weight-Reduction on Energy Expenditure and Circulating Concentrations of Thyroid Hormones
[2002], Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight [2005], and Leptin reverses weight loss–induced changes in regional neural activity responses to visual food stimuli [2008].

It has been nearly ten years since the first of these studies was published. One wonders why such an efficatious drug is not being prescribed far and wide for the maintenace of weight loss. According to Dr. Sharma, this has to do with a peculiarity in the regulations of the FDA. Drugs can be licensed for weight loss, but except in extremely rare cases, leptin does not work for weight loss. However, the FDA does not recognize a need for drugs to preserve weight loss once it has happened. Leptin is a drug that works for a condition that the FDA does not believe exists. The FDA does not understand that, while weight loss is hard, weight maintenance is even harder. If you think that synthetic leptin might help you hold on to your hard-won weight loss, it might be time to send the FDA a letter.

Why Do Low-Carb?

2011-05-17T21:06:00.002-05:00

If you have done much reading about the low-carb lifestyle, you have heard about insulin. Insulin is a hormone secreted by the pancreas after we eat carbohydrate or to a lesser extent when we eat protein. Insulin is important because it binds to the insulin receptor, which is found on the surface of most of the cells in the body. The figure above shows the surface of a cell with a molecule of insulin bound to its receptor.

Insulin signaling
The insulin receptor is made of four protein subunits. The two beta subunits pass from the exterior through the cell wall and into the interior of the cell. When insulin binds to its receptor, the receptor auto-activates and begins to affect a large number of signaling proteins that reside within the cell. As illustrated on the left side of the drawing, some of these proteins propagate growth signals to the nucleus of the cell. We’ll deal with those later. The proteins shown on the right side of the drawing transmit metabolic signals into the cell. Depending on the type of cell, this signaling cascade can cause the uptake of glucose and amino acids into the cell, the synthesis of glycogen in the cell, the synthesis of protein in the cell, the cessation of lipolysis in the cell and the inhibition of de novo glucose synthesis in the cell.

Insulin sensitivity
So far so good. Insulin is such a powerful hormone and it has so many effects that its absence is incompatible with life. However, an excess of insulin is not particularly good either. When too much insulin is present, the metabolic signaling cascade becomes too strong. The cells defend against excessive signaling by degrading some of their insulin receptors and by making fewer receptors to replace the ones that have been destroyed. Some of the intermediate signaling proteins are also downregulated in various ways. The cell is said to have become “insulin resistant.”[1]

Normally insulin resistance is not a problem. As insulin levels fall, the synthesis and/or activation of signaling intermediates resumes and the cell becomes ready for the next onset of insulin release. In native cultures like the Inuit, where carbohydrate intake is low, the levels of blood insulin only rise a modest amount in response to ingested protein. In non-Westernized cultures like the Kitavans of Papua New Guinea, a large amount of carbohydrate is consumed, but it comes in the form of sweet potatoes, cassava, taro and yams.[2] These people have a low fasting insulin that decreases with age. [3] Kitavans also have low obesity, low diastolic blood pressure, and low-to-no incidence of stroke or ischemic heart disease. If Kitavans can maintain insulin sensitivity and good health while eating a high carbohydrate diet, why should we even consider the challenges of attempting a low-carb diet?

What kinds of carbs?
The answer probably involves the types of carbohydrates we consume rather than the absolute percentage of carbohydrates in our diet. Post-800 AD, the Aztec consumed maize as their most important staple. They were known to suffer from dental problems, obesity and heart disease.[4, Comments] The ancient Egyptians ate bread and porridge made from wheat and used barley to make beer.[5] They suffered from periodontal disease, and atherosclerosis was found in 60% of those who lived past age 40.[6] In Good Calories Bad Calories (pp 89-97), Gary Taubes gives numerous examples of native peoples (Gabonese, South Africans, Native Americans, Melanesians) who did not experience chronic diseases such as obesity, diabetes and heart disease until after well-meaning explorers and settlers, beginning in about the middle of the nineteenth century, brought them large quantities of white flour and sugar.

Permanent insulin resistance
Although the proof is only inferential, it appears that carbohydrates such as refined grains, beer and sugar may have the ability to cause permanent insulin resistance in susceptible individuals who consume them. The effect is not immediate. For some reason, after years of eating these types of food, some people progressively lose the ability to reset their metabolic insulin response system. Muscle cells require more insulin to take up glucose. Liver cells require more insulin before they will stop making glucose through gluconeogenesis. It becomes harder to shut down lipolysis and it becomes more difficult to maintain muscle mass. On the other hand, the action of insulin as a growth signal is not impaired (see the left side of the figure above). A steady, high level of insulin produces proliferation and migration of vascular smooth muscle cells, and these in turn play an important role in diseases such as hypertension, atherosclerosis and cardiovascular disease.[7]

Strategies
It appears that once the metabolic insulin signaling system is broken, it cannot be repaired. It can be treated with drugs, or it can be managed by eating foods that minimize the release of insulin. For those who spend their lives eating the types of carbohydrates that indigenous peoples do, insulin is a good and faithful servant. It helps them metabolize and store their food for later use and performs a myriad of functions without causing insulin resistance. But for those who have spent too many years indulging in sugar, high-fructose corn syrup, refined grains, beer and other easily digestible carbohydrates, it may be necessary to switch to a diet that keeps insulin secretion at a minimum, i.e., a diet low in all kinds of carbs, in order to achieve and maintain a healthy lifestyle.

Magical, Mystical Coconut Oil

2011-04-03T20:43:00.011-05:00

(This is another post referencing my own experiences. I present it in case someone else might want to give coconut oil a try for weight issues.)

The past
Coconut oil is the stuff that used to make movie popcorn taste like movie popcorn. When somebody realized that coconut oil is 90% saturated fat, things changed in a hurry. Movie popcorn began to taste more like the cardboard tub it comes in, and coconut oil became hard to find. Recently coconut oil has come back into favor in the low-carb world, and it can be purchased in health food stores and even in grocery stores.

I began using coconut oil several years ago and noticed that when I did so, I was better able to control my weight. I didn't mind the taste too much, but I was no particular fan of it either. (Nutiva seems to me to be the best-tasting brand so that's what I buy, but there are many other extra virgin organic coconut oils on the market.)

The present
About two months ago, as a sort of personal experiment, I began eating two tablespoons of coconut oil for breakfast. Just 250 calories of coconut oil, plus my supplements, seemed to hold me until lunch, which was a surprise. Not only that, I didn't seem to be quite as hungry during the rest of the day. Not only that, I seemed to do much better at weight maintenance than I have for many years. I was curious about why it worked, but didn't have the time to puzzle it out.

The explanation
Then one day as I was reading an article over at the Heart Scan Blog, I happened upon a comment by Might-o'chondri-AL (#23 in the list). He explained that coconut contains a 12-carbon saturated fat called lauric acid, and that lauric acid upregulates the secretion of glucagon-like peptide (GLP-1). GLP-1 in turn increases satiety by slowing stomach emptying.

I checked out the fatty acid profile of coconut oil and found that, sure enough, it contains about 50% lauric acid. Next I did a Google search and found a journal article that backed up the rest of Might-o'chondri-AL's statements: Effects of intraduodenal fatty acids on appetite, antropyloroduodenal motility and plasma CCK and GLP-1 in humans vary with their chain length.

The data
The article reported that in 2004 a group of investigators did a 90-minute duodenal infusion of water (control), capric acid (a saturated fatty acid with 10 carbon atoms) or lauric acid (a saturated fatty acid with 12 carbon atoms) into twelve healthy, normal-weight, male volunteers. They administered only 0.375 kcal/min in the treatment groups, but the contrast between the capric acid (C10) group and the lauric acid (C12) group was quite large.

By 45 minutes of infusion, plasma GLP-1 increased significantly and stayed high in subjects who received C12, while plasma GLP-1 in the C10 group was no different from control. (Remember, GLP-1 slows gastric emptying.) Cholecystokinin (CCK) is a peptide hormone that also produces satiety by decreasing the rate of gastric emptying. By 30 minutes, both C10 and C12 had increased CCK over control, but C12 did so to a greater extent. Gastro-duodenal motility was measured directly using a manometric catheter. Consistent with the GLP-1 and CCK levels, C12 suppressed both antral and duodenal pressure waves while C10 did not. Finally, at the conclusion of the infusion, subjects were offered a buffet meal. Subjects who had received C12 ate significantly less than those who had received C10 or water. In other words, intraduodenal infusion of lauric acid (C12) decreased gastric motility and suppressed the appetites of subjects who received it.

More data
A 2010 review article by Little and Feinle-Bisset confirmed these findings and added a few more. The presence of fatty acids like lauric acid in the intestine (and possibly even in the mouth) stimulates the secretion of hormones that suppress gastric emptying (GLP-1, CCK, and peptide YY) as well as down-regulating the hunger hormone ghrelin. A lauric acid infusion also appears to be able to signal the brainstem and hypothalamus directly via the vagus nerve and a CCK receptor mediated pathway. In addition to all of that, lauric acid is classified as a medium chain fatty acid. Unlike longer-chain fatty acids, it can be absorbed directly from the gut, transported to the liver, and there be readily converted into ketone bodies and used for energy rather than for fat storage. Both in suppressing energy intake and in improving energy utilization, the lauric acid found in abundance in coconut oil looks like a good candidate to help with weight loss and weight maintenance.

To be fair, the Little and Feinle-Bisset review article goes on to state that some studies have shown that a high-fat diet or the presence of obesity may attenuate the effects of fat intake on slowing gastric emptying and decreasing energy intake. However, none of the studies they cite were done in the context of a low carbohydrate intake.

The result
In any case, after reading these articles, I now understand why coconut oil seems to be such a help to me in weight maintenance. Whether that will hold true in the long term or whether it will work for other people is not certain, but for now personal experience seems to be backed by a fair amount of science.

Deep Thoughts

2011-02-12T18:37:00.009-06:00

(This blogpost is mostly about me and not about science. For those who come here for the science, please feel free to skip it.)

As time passes, it becomes more and more obvious that the low-carb lifestyle offers many metabolic benefits. It reduces blood sugar and blood insulin, lowers blood pressure, decreases triglycerides and raises HDL cholesterol. For a summary of these effects, check out my blogpost reviewing three low-carb studies published in three well-respected journals.

Nevertheless, the reason most of us started doing low-carb was not for its health benefits but for weight loss. And unsurprisingly the three studies also showed that low-carbing works as well or better than other forms of dieting for weight loss and weight maintenance.

Nearly eight years ago I read Dr. Atkins' New Diet Revolution (DANDR)and was struck by the fact that his approach to dieting was based on solid science and was presented in a way that was easy to understand. Before long, I knew the book inside out and followed it to the letter. I did indeed make my goal weight and have (almost) maintained it since then. (For those who like to see if I practice what I preach, I report my weight weekly on the Maintain Lane at Low Carb Friends.) Recently I began re-reading DANDR and had a couple of thoughts that I'll share with those of you who are using the low-carb lifestyle to lose weight. You can decide if they're deep thoughts or not.

1. Low-carb is good for weight loss, but it's not perfect.

The low-carb boards on the internet are populated with hundreds of people who have lost some weight doing low-carb, but have not managed to make it to goal. It goes without saying that if you lose weight on low-carb, you have to keep doing low-carb or the weight will come right back. But why is it so hard for us to get all the way down to our goal weight even if we keep our carbs strictly below 20 or even very close to zero?

In DANDR, Dr. Atkins says to count carbs not calories. One of the reasons this works is that low-carbing produces what Dr. Atkins called a "metabolic advantage." As we change over from metabolizing carbs for energy to metabolizing fat for energy, our bodies perform somewhat inefficiently. If we use Ketostix, we'll see that we excrete a large amount of unused energy in the form of urinary ketones. We also tend to experience an increase in body temperature. However, after a year or so of low-carbing, we become fully keto-adapted and our bodies are able to utilize nearly every scrap of the energy we consume. The Ketostix no longer change color.

One of the things that doesn't change over time is that low-carbing keeps our insulin levels lower than they would be on a high-carb diet. This means that our bodies are better able to mobilize our stored fat, and we don't experience the constant hunger that results when we can't properly access our fat stores. In addition, foods that are high in fat and protein tend to satitate us much more quickly than do carb-rich foods. Finally, the ketosis produced by low-carbing has the wonderful side effect of decreasing our appetite.

So by counting carbs we can lose some weight, and we may even lose a large amount of weight. However, the sad truth is, Calories Count. In the long run, the number of calories we take in must be less than the number of calories we expend. Granted, when we low-carb we may be able to burn more calories than our peers thanks to a faster metabolism, a greater willingness to exercise, and the loss of ketone calories by excretion. But we can't fool Mother Nature. In order to lose weight, the calories in must be less than the calories out.

I had suspected this before, but just this week I've proven it to myself by using Dr. Atkins' Fat Fast. I have done low-carb and I've done zero-carb, but the most weight I could get off was a fraction of a pound a week. By doing the Fat Fast, I've stayed at 1000 calories per day and the weight has fallen off. Yes, it's nearly zero carbs, but as I said, I've done zero-carb and have lost weight at a snail's pace, if at all. What I haven't done before is intentionally cut my calories. To be sure, the Fat Fast is not a healthy long-term weight loss plan, but it does show that if carb counting alone isn't producing a weight loss, carb counting plus calorie counting is the next necessary step.

2. Too much protein can act like too many carbs.

While Dr. Atkins had lots to say about controlling our carb intake, for some reason he didn't warn his readers that eating too much protein can mimic the effect of eating too many carbs. People who have type 1 diabetes, or people who have type 2 diabetes and are using insulin, know something that most of the rest of us don't know. Eating excess protein raises your blood sugar.

Back in the summer of 2009 I wrote three blogposts on this topic: Protein Intake and Blood Glucose Levels, Observations on Protein Intake in Low-Carbers and How Can Eating Excess Protein Raise Blood Glucose? My readers participated in gathering data for these posts, and what we discovered was that when excess protein is consumed, it is converted to glucose. In younger people this did not show up on the blood glucose meter. In most cases they were able to secrete enough extra insulin to maintain a postprandial blood sugar in the vicinity of 85 mg/dl. However, in both low-carbers and zero-carbers over 50, it was not unusual to have a 30-40 mg/dl rise in blood glucose after consuming a large amount of protein.

Dr. Atkins did say that eating lots of protein has never been shown to cause kidney damage. And consuming good quality protein is essential to maintain our bones, muscles and organs. But for those of us who watch our carbs religiously, it's also important to watch our protein intake. A large excess of protein acts like carbs and can have a similar effect, especially in people who are prone to diabetes.

In closing, most of what Dr. Atkins said in his books has stood the test of time. But from my personal experience, a couple of points seemed to go missing. For those who are having a hard time making it to their goal weight, it might be helpful to consider (1) the importance of counting calories and (2) the carb-like effects that can be caused by excess protein intake.

Bigger

2011-02-05T12:35:00.006-06:00

Thanks to the work of TV doctors, the American Heart Association and the American Diabetes Association, most Americans are convinced that a high fat intake is bad and exercise is good. As a result, knowledgeable Americans try to avoid fat and get at least some exercise. They eat meat that is as lean as possible, they use butter substitutes on their toast, and they do their best to emphasize high-fiber, low-cholesterol foods. They try to walk or jog regularly, and some even manage to buy memberships at a gym. How's that working out for us?

Not very well, according to a recent study in the British journal Lancet. The article carries the rather long title National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. The authors measured worldwide obesity in terms of BMI or body mass index, which compares a person's weight to his or her height. A BMI between 25 and 30 is considered overweight, and a BMI over 30 is considered obese.

Worldwide vs. U.S. obesity
The bottom line of the study was that, between 1980 and 2008, worldwide obesity has approximately doubled. For adult men, the percentage has gone from 4.8% to 9.8%. For adult women, the percentage went from 7.9% to 13.8%. And that wasn't all. Obesity-wise, America has left the average world citizen in the dust. In 2008, the number of obese American adults was not just one in ten. It was one in three.

Not only that, during nearly thirty years, the U.S. saw the fastest rise in BMI, about 1 full BMI point per decade, to an average BMI of 28 in 2008. In an interview, one of the lead authors of the study, Majid Ezzati of the Imperial College in London, suggested that remedies might include taxing sugar-containing foods and encouraging transportation by bicycle.

Some good news
Dr. Ezzati noted that, despite their increasing BMIs, the richer countries of the world had reduced average systolic blood pressure and average total cholesterol during the years of the study. This is surprising because, according to the National Health and Nutrition Examination Survey (NHANES), overweight and obesity raises the risk of hypertension and high LDL cholesterol. Dr. Ezzati suggested that improved screening and treatment, using less salt and eating unsaturated fats may have contributed to the decline in average blood pressure and cholesterol in the face of steadily increasing BMI. He did not give a relative value to each of these variables and did not note that the richest countries of the world tend to rely heavily on prescription drugs for the treatment of both hypertension and high cholesterol.

Even worse than the U.S.
Do you remember my first blogpost of 2011, suggesting that my readers observe the food choices of the people around them and the health status of the same individuals? The South Pacific island nation of Nauru provides some interesting data in that regard. The Lancet study noted that the people of Nauru have an average BMI of about 34, the highest in the world. Traditionally Nauruans ate ibija fish, coconuts (a very high-fat food) and the fruit of the pandanus tree. After phosphate was discovered on the island, they started selling it and using their income to buy Western foods. Today their most popular dish is chicken marinated in cola, fried, and accompanied by lots of Coke to wash it down. In 1991 the World Health Organization reported that half of Nauruan adults aged 30-64 had diabetes. Although Nauru has free health care, the life expectancy at birth is 59 for men and 64 for women.

Food for thought
One wonders if the rapid rise in obesity in the U.S. might be related to the media-promoted drive to shun fats and embrace carbohydrates, beginning in about 1970. Or if the amazing obesity rate of the Nauruan people may have something to do, not with fat alone, but with the addition of copious quantities of sugar to a fat-rich diet. Just observations, not proof. But it's something to think about.

Here's Looking At You

2011-01-02T15:26:00.005-06:00

It's January 2, and already many New Year's resolutions have been tossed onto the ash heap of history. As an alternative for my readers, I thought I would offer a different type of resolution for the coming year. The resolution is in three parts.

Part 1
For the remainder of 2011, make mental notes of what your friends, relatives and acquaintances are eating.

You don't need to write anything down, but you can if you wish. Without staring or making comments, just start paying attention to what the people around you are eating and what they talk about eating. Do they tend to eat lots of foods that contain wheat flour? Do their preferred foods contain sugar or high fructose corn syrup? Or do they stick primarily to meat, cheese, eggs, nuts and vegetables? (Be sure to keep in mind that the purpose of this exercise is to gather data, not to confront people with their dietary sins.)

Part 2
After you have a fairly good idea of everybody's dietary lifestyle, start to make notes about their health status.

This is the second stage of your data-gathering project. It will be fairly easy to see if people are a normal weight or if they are fat and getting fatter. Other information often comes out in conversation. Are they having trouble with high blood pressure? Do they complain of painful joints? Are they beginning to discuss issues that relate to the control of blood sugar? Or are they generally healthier than other people of their age?

Part 3
As 2011 progresses, start to compare your two sets of data and see if you can detect any correlations.

Although I come to the discussion with preconceived ideas, this is your life and these are your data. We get messages from the TV, from our doctors and from the people around us about what food is good for us and what food isn't. Some of those messages spring from the profit motive and others come from dogma that we hold without knowing exactly why we hold it. This time you will be collecting your own data based on what you see, not on what somebody else tells you to see.

Seeing is believing
There it is -- a pain-free three-part resolution that could change your life. In 2011 simply begin to observe dietary choices and note which ones seem to correlate with good health and which ones don't. Correlation is not causation of course, but my guess is that 2011 will not be over before you start to make some long-term modifications in the way you eat. In so doing, you may well find that 2011 brings positive changes that you weren't even expecting.

Is Obesity Contagious?

2010-11-07T14:36:00.004-06:00

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.

Interventions
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.

Serotonin's Siren Call

2010-10-26T15:58:00.003-05:00

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.

Fen-Phen
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.

Lorcaserin
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
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.

Can You Be Fat and Not Know It?

2010-10-19T11:17:00.009-05:00

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.

Definitions
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.)

Behavioral associations
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.

Cold Temperatures, Adaptive Thermogenesis and Obesity

2010-10-11T13:52:00.006-05:00

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.

Pure Speculation
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.

Insulin Sensitivity Affects Weight Loss

2010-10-02T19:34:00.006-05:00

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.

Experimental Design
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.

Insulin Resistance
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.

Results
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.

Take-Home Lessons
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.

Genetics May Affect Weight Loss

2010-08-22T18:55:00.007-05:00

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.

Genetic Test
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.

FABP2
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.)

PPARG
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.

BAR2
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.

BAR3
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.

Low-Carb versus Low-Fat

2010-08-05T17:28:00.007-05:00

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.

Truth and Consequences

2010-07-29T12:11:00.004-05:00

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.

This discrimination took the form of derogatory humor, pejorative comments, lower pay, denial of promotions and firing.

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.

Thoughts on the China Study

2010-07-24T18:53:00.006-05:00

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.

Managing Hunger

2010-07-15T10:24:00.003-05:00

(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.

Organic Food versus Conventional Food

2010-07-01T10:56:00.003-05:00

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.

Cheating

2010-06-24T14:21:00.003-05:00

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.

Vacation!

2010-05-30T16:58:00.002-05:00

Fun with Graphs

2010-05-27T15:41:00.015-05:00

For the next few weeks, I will be on an overseas vacation. In the meantime, I've been searching on Google and have come up with a set of graphs that should be interesting to look at and consider in the context of low-carbing. Most, but not all, of the data comes from the United States. These graphs are provided without any context to describe how the data was collected or how valid it might be. They just provide something to think about. If you want to enlarge any graph, just click on it, and it will open in a larger version.

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!

Cortisol Versus Insulin

2010-05-21T15:44:00.006-05:00

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.

Insulin Resistance and the Metabolic Syndrome

2010-05-13T10:12:00.006-05:00

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.

The Fiber Hypothesis

2010-05-04T10:49:00.012-05:00

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.

Food Nazis?

2010-04-29T07:34:00.004-05:00

When low-carbers begin following the low-carb lifestyle, they start to feel free. Free of the hunger that forces them to eat every few hours even though they are morbidly obese. Free of enslavement to particular foods that they have never been able to resist. And after a while, free of many, many pounds of fat that they have been hauling around everywhere, all the time.

Low-carbing is an odd way to eat, but the freedom makes it worth the trouble of figuring out a new way to shop and a new way to eat out in restaurants. There are many low-carb bulletin boards and blogs for support. There is more and more scientific evidence demonstrating the superiority of low-carbing in the control of diabetes and heart disease and its efficacy in weight loss as well. The recent appearance of the paleolithic approach to low-carbing has given a common-sense aspect to the low-carb lifestyle. When observers object to low-carb food choices, low-carbers can point out that this is the way humans have eaten for millennia. It's only recently that humans began to eat lots of refined carbohydrates, and with that change in diet, perhaps not coincidentally, humans also began to experience the diseases of Western civilization.

So far, so good. But as I look back on my recent blogposts and those of other bloggers, I have started to notice a more rigid, regimented (shall we say Nazi-like?) aspect to the world of low-carbing. Some examples:

It's good to eat fat, but be sure the fat has the right omega-3 to omega-6 ratio.
It's good to eat nonstarchy vegetables, but remember that broccoli has goitrogens and tomatoes are nightshades. And wheat, even whole wheat, contains many compounds that can damage the human digestive tract.
It's good to eat meat, but it should be grass fed, not grain fed.
It's good to eat eggs and chicken, but they need to be free range.
It's good to eat seafood, but watch out for the mercury.
It's good to avoid sugar, but it's better to avoid artificial sweeteners as well.

The list could go on and on.

In the last couple of days I've noticed one low-carber who seems to be on the edge of dropping out because of the difficulty of following all the extra rules all at once. Another works 60 hours a week and is not sure he has the time required to be sure all his food meets the higher standards for healthy low-carb eating. A third concern is that, although low-carb foods tend to cost more than the Standard American Diet, the more strict versions of low-carbing become prohibitively expensive for people on a limited budget.

Low-carbing is literally a lifesaver for people who are on their way to diabetes, heart disease, and morbid obesity. Some people have additional health issues, and it is fine to refine the low-carb lifestyle to help address those needs.

However, it's important for low-carbers to remember that we don't need to sacrifice the good for the sake of the perfect. For those who are new to the low-carb lifestyle, or for those who don't have the concentration, the time or the money to pursue all the ins and outs of healthy eating, can I make a plea for mercy?

Let's not become low-carb food Nazis. Low-carbing is a gift. Please let people enjoy the freedom it provides. If they want to add additional aspects to it, fine. If not, we can rejoice that they are at least doing something that will significantly improve the quality of their lives. With that knowledge, we can follow our own set of dietary rules while giving other low-carbers the freedom to choose what additional modifications they will or will not follow.

Is Diabetes Caused by Refined Carbohydrates?

2010-04-22T20:28:00.006-05:00

Last week we criticized Good Calories Bad Calories. This week we shall praise it. In chapter 6 of GCBC, Gary Taubes discusses Captain Thomas Latimore Cleave, a physician who believed that the common chronic diseases of Western civilization could be linked to the consumption of refined carbohydrates. Cleave had observed that non-Western societies tended to remain healthy even if they ate relatively large amounts of low glycemic index carbohydrates such as brown rice, wholemeal flour, non-starchy vegetables and nuts. But when a cultural group switched from traditional foods to white rice, white flour and sugar, the chronic diseases of civilization would begin to appear. To illustrate this, Cleave prepared the chart at the top of this post, which has been scanned from page 116 of GCBC. The dashed line shows per capita sugar consumption in England and Wales from just before 1905 to just after 1945. Sugar consumption increased during prosperous times and decreased during periods of wartime rationing. If diabetes had no relation to sugar intake, one would expect that deaths from diabetes (diabetic mortality) would gradually decrease as (1) injectable insulin was introduced and (2) medical treatments in general improved. Instead, until 1945 the index of diabetic mortality increased and declined in parallel with the consumption of sugar. Correlation is not causation, but the close relationship between sugar consumption and deaths from diabetes bears serious consideration.

Since 1945, the use of antibiotics to treat infection, the widespread use of home blood glucose monitors and the advent of new drugs to treat diabetes has dramatically reduced the death rate from diabetes. Nevertheless, there seems to be a steadily-increasing incidence of diabetes, particularly of type 2 diabetes. A recent article in Science Daily describes a study showing that type 2 diabetes has reached epidemic proportions in China. The scientists estimated that 9.7% of adult Chinese have diabetes and 15.5% have prediabetes. The prevalence of both conditions is higher in urban areas. Possible causes may include longer lifespans, increased smoking, decreased physical activity, increased air pollution, increased food consumption and decreased food quality.

Along the lines of Dr. Cleave's hypothesis about the relationship of refined carbohydrates and diabetes, in 2007 the Archives of Internal Medicine published an article suggesting one possible cause for the increase of diabetes in China. Its title was "Prospective Study of Dietary Carbohydrates, Glycemic Index, Glycemic Load, and Incidence of Type 2 Diabetes Mellitus in Middle-aged Chinese Women".

The study spent 4.6 years observing a cohort of about 64000 Chinese women with no history of diabetes or other chronic disease at baseline. These women were between 40 and 70 years old and lived in seven communities in urban Shanghai. They were divided into sets of quintiles according to several measures of carbohydrate intake. Adjustments were made for possible confounding factors including age, education, income, occupation, smoking status, alcohol consumption, total daily energy intake, physical activity, body mass index, waist-to-hip ratio and presence or absence of hypertension.

When confounding factors were eliminated, it was found that in middle-aged Chinese women, the percentage of carbohydrate in the diet was positively associated with the risk of developing type 2 diabetes. When glycemic index was considered, the higher the glycemic index of the food eaten, the more likely the women were to develop type 2 diabetes. In Shanghai, rice is a main staple food, contributing 73.9% of dietary glucose load (calculated by multiplying the total carbohydrate of a food by the glycemic index of the food and summing the values for all foods over a day). When women were stratified according to the amount of rice they ate, the group eating the most rice (over three cups of cooked rice per day) had a relative risk of 1.78 of developing diabetes as compared with those eating the least rice (less than two cups of rice per day).

For this group of Chinese women living in an urban area, carbohydrate intake averaged between about 260 and 340 grams per day. The largest part of their diet consisted of rice, which has a glycemic index of 55 (glucose=100). In this population, when adjusted for other factors predisposing to diabetes, a diet high in carbohydrates with a high glycemic index was associated with a higher risk of type 2 diabetes. Does this mean that diabetes is caused by refined carbohydrates? No, but once again, the close association between a higher intake of refined carbohydrates and a higher incidence of type 2 diabetes is worth serious consideration.

Good Calories Bad Calories Is Not Necessarily Infallible

2010-04-13T11:39:00.008-05:00

When Good Calories Bad Calories (abbreviated here as GCBC) was published in 2007, the low-carb community was ecstatic. Dr. Robert Atkins and the Doctors Eades had discussed the scientific basis for the low-carb lifestyle, but their writings were usually presented in the context of clinical observations. With GCBC, Gary Taubes gave low-carbers 460 pages of tightly reasoned discussion and another 113 pages listing many specific citations from the scientific literature.

For a layperson, the book was not easy to read, but with effort it was comprehensible. At last low-carbers had access to information that cast doubt on the hypothesis that excessive consumption of fat raises cholesterol levels, which in turn causes heart disease and early death. Taubes presented plausible evidence for an alternative hypothesis--that excessive carbohydrate consumption, not fat consumption, is the cause of diabetes, heart disease, hypertension and even cancer.

Since the publication of GCBC, two interesting things have happened. (A) GCBC has moved into the position of holy writ in the eyes of many low-carbers and (B) several low-carb blogs and forums have arisen to discuss the scientific and practical aspects of low-carbing.

A rereading of GCBC in 2010 shows that many of its ideas have been supported by the subsequent publication of prospective dietary studies, including Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet, published in the New England Journal of Medicine. However, recent discussions in the blogosphere show that some statements in GCBC may need to be reconsidered.

Specifically, on page 394 of the hardbound edition of GCBC, Taubes states, "By the mid-1960s, four facts had been established beyond reasonable doubt: (1) carbohydrates are singularly responsible for prompting insulin secretion; (2) insulin is singularly responsible for inducing fat accumulation; (3) dietary carbohydrates are required for excess fat accumulation; and (4) both Type 2 diabetics and the obese have abnormally elevated levels of circulating insulin and a 'greatly exaggerated' insulin response to carbohydrates in the diet..."

Let's address these statements in order.

1. Although consumption of carbohydrates does prompt insulin secretion, it is a well-known physiological fact that consumption of proteins also prompts insulin secretion. The amount of insulin released in response to protein is about a third of that released in response to carbohydrate on a gram-for-gram basis, but the increase is still measurable. Dr. Mike Eades has an illustration of this on page 37 of the paperback edition of Protein Power. Scientific articles measuring the insulin release in response to protein can be found here and here. Insulin response to various foods in terms of 120 minute area under the curve can be found in Table 4 here.

2. Insulin release does promote the storage of fat in adipocytes, but it is not the only signaling protein that produces fat storage. Acylation Stimulating Protein (ASP) is secreted by fat cells and allows fat to be removed from chylomicrons and stored in fat cells. Acylation Stimulating Protein permits the body to store fat in the absence of insulin. The process is discussed here by Dave Dixon and here by Petro Dobromylskyj (Hyperlipid).

3. While it is difficult to accumulate excess fat in the absence of dietary carbohydrates, it is not impossible. On various discussion boards, a few zero-carbers have related anecdotal evidence that they gained weight while eating large amounts of protein and fat. From a theoretical perspecive, on pages 388-392 of GCBC Taubes goes into great detail about the necessity of glycerol phosphate for the storage of fat in adipose tissue. (Glycerol phosphate is the precursor to the molecule used as the backbone of a triglyceride, the storage form of fat.) On page 392 Taubes says, "Dietary glucose is the primary source of glycerol phosphate. The more carbohydrates consumed, the more glycerol phosphate available, and so the more fat can accumulate. For this reason alone, it may be impossible to store excess body fat without at least some carbohydrates in the diet and without the ongoing metabolism of these dietary carbohydrates to produce glucose and the necessary glycerol phosphate." This sounds logical. However, biochemists know that glycerol phosphate can readily be produced from protein via glyceroneogenesis. The absence of dietary carbohydrate in no way prevents the synthesis of triglycerides from a high-protein or even a high-fat diet.

(4) It is true that high insulin is often associated with type 2 diabetes, but it is important to remember that type 2 diabetics do not always have an excess of circulating insulin. Instead they have insulin resistance. If their body tries to control high blood glucose levels with excess insulin production by the pancreas, this can result in beta cell burnout and a patient who actually has less endogenous insulin production than a person without diabetes.

As described here the scientific method is an ongoing process. Good Calories Bad Calories is an excellent book and provides many good arguments for the low-carb lifestyle. But the scientific method requires that we keep testing and evaluating our hypotheses, and it is important to realize that not everything we read in GCBC will necessarily stand the test of time.

Eat Fat for Weight Loss

2010-03-30T09:37:00.006-05:00

As most low-carbers already know, eating fat produces satiety. But in some cases, eating fat also helps a dieter lose weight.

It turns out that the chain length of the fatty acids in the triglyceride is an important factor in choosing a fat that promotes weight loss. Most of the fats found in a normal diet will contain long-chain fatty acids. That is, most of the triglycerides we eat will have fatty acids that contain between 13 and 22 carbons. These long-chain fatty acids are digested in the gut, where they are packaged into chylomicrons. The chylomicrons are moved into the lymphatic system and eventually enter the blood at the left subclavian vein in the upper chest. (A review of the process can be found here.)

When the chylomicrons reach the blood, the long-chain fatty acids in them can be absorbed by any cell, including fat cells, that contain lipoprotein lipase. Once these fatty acids are absorbed into a fat cell, they are still available for later mobilization into the blood via hormone-sensitive lipase. But in insulin-resistant individuals, the activity of hormone-sensitive lipase is down-regulated by high insulin levels. In those people, stored fat tends to remain in storage.

Medium-chain fatty acids contain from 6 to 12 carbons. (In a normal diet, the most common source is probably butter, which contains about 10% medium-chain fatty acids. For those who shop the health food aisles, another source is coconut oil, containing about 66% medium chain fatty acids.) Medium-chain fatty acids are processed differently in the gut. Because they are more water-soluble, they tend not to be packaged into chylomicrons. Instead, they are absorbed from the gut directly into the blood as free fatty acids. Medium-chain fatty acids are bound to serum albumin in the blood, and in that form they travel to the liver where they are used primarily for energy production. Some are converted to ketones that are in turn used for energy by many of the cells of the body.

A 1996 review article by Bach et al. discussed the fact that, compared with long-chain triglycerides, medium-chain triglycerides have more rapid delivery to the liver, higher oxidation rates, poorer rates of incorporation into fat cells, and greater control of satiety. However, there were some counteracting factors that suggested that eating medium-chain fatty acids might not produce the expected reduction in body weight.

After that review article was published, Marie-Pierre St-Onge and her colleagues began studying the effect of human diets that were either rich in medium-chain triglycerides or rich in long-chain triglycerides. The medium-chain triglyceride oil contained primarily caprylic (8 carbons, saturated) and capric (10 carbons, saturated) fatty acids. The long-chain triglyceride oil was olive oil, which contains primarily oleic acid (18 carbons, monounsaturated).

In a randomized crossover controlled feeding trial published in 2003, energy expenditure was measured before and up to 5.5 hours after eating a breakfast meal. Although both groups saw increases in fat oxidation and energy expenditure following the meal, the medium-chain triglyceride group saw larger increases at some though not all of the timepoints after the breakfast meal. The medium-chain triglyceride group also saw a trend toward lower energy intake at the subsequent lunch meal. Not surprisingly, over the four-week duration of the study, the medium-chain triglyceride group saw a significant loss of total adipose tissue of about 1.8 pounds. The reduction in adipose of the olive oil group did not reach significance.

In 2008 Dr. St-Onge and colleagues performed a 16-week double-blind non-crossover weight loss study in overweight men and women. Once again, the groups were divided according to diets containing either medium-chain triglycerides or olive oil. Women consumed 1500 calories per day and men consumed 1800 calories per day, with about 12% of these calories as the prescribed study oil. At the end of the study, those who consumed medium-chain triglyceride oil had lost about 3.7 more pounds of body weight than those in the olive oil group. The loss of total fat mass was also about 3.2 pounds greater in the medium-chain triglyceride group compared with the olive oil group.

These findings are consistent with those of other investigators, both for animal models of obesity and for humans. In 2007 a group in China performed a pilot study to see if other health parameters are affected with the ingestion of medium-chain triglycerides. For ninety days, forty moderately overweight type 2 diabetic patients were given either 18 grams per day of medium-chain triglycerides or 18 grams per day of corn oil. The medium-chain triglyceride group showed a reduction in body weight, a reduction in waist circumference, a decline in serum cholesterol, an increase in serum C-peptide and a reduction of insulin resistance.

The studies discussed in this blogpost are not definitive, and much more research will be necessary to see if medium-chain triglycerides are an effective tool for reducing obesity. Nevertheless, it is encouraging to see that, at least in an experimental setting, these fats are able to decrease fat mass in both overweight men and women over time.

To Eat Saturates or Not to Eat Saturates?

2010-03-24T19:35:00.004-05:00

As we discussed in the previous post, saturated fats are not fats that are saturated with calories or saturated with cholesterol. "Saturated" is a chemical term that can be thought of as a measure of the stability of a particular fat in the presence of heat, light and oxygen. Saturated fats are more stable than monounsaturated fats and much more stable than polyunsaturated fats. Saturated fats are generally solid at room temperature. The richest sources are from animals (lard, butter, tallow) or from tropical plants (coconut oil, palm oil).

When heart disease began to become prevalent in the 20th century, scientists looked for a cause and decided that saturated fats were a good candidate. By the end of the 20th century most people thought that the science was settled--eating saturated fats causes heart disease. But studies are starting to accumulate that suggest that this isn't necessarily so.

Two articles (abstracts here and here) by Ronald Krauss and colleagues were recently published in the American Journal of Clinical Nutrition. They did an analysis of twenty one prospective cohort studies (i.e., these were actual clinical studies, not just correlational number crunching) and examined the relationship between intake of saturated fat and the risk of coronary heart disease, stroke and cardiovascular disease. This type of analysis depends on the integrity of the authors in selecting the studies to be analyzed, especially if the authors have a bias toward a particular outcome. With that caveat, it is noteworthy that the authors concluded that "there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD [coronary heart disease] or CVD [coronary vascular disease]." (There was also no significant association with stroke, and the authors stated that results were not affected by age, sex or the quality of a particular study.)

The authors noted that when studies replaced saturated fat with a higher carbohydrate intake, this resulted in increased triglycerides, smaller LDL particles and reduced HDL cholesterol. In the studies that replaced saturated fat with mono- or polyunsaturated fat, patients saw a reduction in their LDL cholesterol, but they also reduced their "good" HDL cholesterol.

But these were the only studies that showed no relationship between saturated fat and cardiovascular disease, right? Not exactly.

In his blog, Dr. Michael Eades describes a group of 264 men who entered a study after experiencing their first heart attack. From 1957 to 1963 the treatment group ate a diet with about 13.5% saturated fat. The control group continued to eat their normal diet, which probably contained about 25% saturated fat according to Dr. Eades' ballpark estimate. After six years, both groups had the same heart attack relapse rate and the same death rate.

Eades also describes a study in which patients with ischemic heart disease ate either a high-saturated fat diet, a diet in which most of the fat was olive oil or a diet in which most of the fat was corn oil. After two years, 75% of the high-saturated fat group was alive and free from a second heart attack. Fifty seven percent of the olive oil group was alive and heart attack free at the completion of the study. And the corn oil group had only 52% alive and heart attack free at the end of two years.

Finally, a 2004 study by Mozaffarian et al. examined the progression of coronary atherosclerosis in postmenopausal women with established coronary heart disease. Comparing the intake of saturated fatty acid among these women over three years, they found that the intake of saturated fat was inversely related to the rate of progression of coronary atherosclerosis, and was unrelated both to unstable angina and to death from myocardial infarction. Unexpectedly, investigators saw a positive association between polyunsaturated fat intake and the rate of narrowing of the coronary arteries. This was particularly true in women with diabetes, lower HDL cholesterol, a lower protein intake and a higher carbohydrate intake. (It is important to note that this was a correlational study and the outcome could be affected by confounding factors that were not identified.)

To eat or not to eat saturated fat? It appears that it is up to the individual. Some studies have shown a slightly increased risk of heart disease with consumption of saturated fats, but many studies show no correlation at all. On the other hand, the increased consumption of carbohydrates, particularly refined carbohydrates, is associated with increased triglycerides, decreased LDL particle size, and decreased HDL cholesterol, all of which are associated with increased risk of cardiovascular disease. If we have to choose between fat and carbohydrate for heart health, it appears that fat may be the better choice.

Saturated Fats/Unsaturated Fats

2010-03-18T19:11:00.009-05:00

Since Dr. Ancel Keys and his colleagues formulated and promulgated the diet-heart hypothesis in the 1960's, the idea of eating saturated fat has become anathema in most nutritional circles. When Americans were told that that consumption of saturated fat was positively correlated with the incidence of heart disease, they began to eat more of the "heart-healthy" mono- and polyunsaturated fats and fewer of the saturated ones. In spite of that, the number of hospital discharges with cardiovascular disease as the first listed diagnosis has continued to increase in the U.S. This is especially surprising in light of the fact that the percentage of U.S. adults who smoke has declined from over 40% in 1965 to about 20% in 2007. Is it possible that saturated fats are not as evil as they have been portrayed?

To begin the discussion, it is important to understand that a saturated fat is not saturated with calories or with cholesterol. In this case, "saturated" is a chemical term, and it means that the molecule in question is saturated with hydrogens--that is, it contains the maximum number of hydrogens it can hold. Here are two fatty acids, one saturated and the other unsaturated:

In the fatty acid at the top, the carbon-carbon bond between the two green C's is a single bond. Each green carbon holds two hydrogens, and they are saturated with hydrogen. In the fatty acid at the bottom, there is a double bond between the two green C's. Each of those carbons holds one hydrogen. The carbons do not hold as many hydrogens as they possibly could and they are therefore unsaturated. This particular fatty acid has only one unsaturated carbon-carbon bond, so it is monounsaturated. If it had two or more unsaturated bonds, it would be polyunsaturated.

The important thing about unsaturated fatty acids is that the presence of a double bond weakens the carbon-hydrogen bonds on the carbons next to the double bond. In the picture above, those carbon-hydrogen bonds are marked with green asterisks. That doesn't sound particularly interesting until we understand what happens when those hydrogens are removed by something like oxygen, heat or metal ions. As soon as we remove one of the vulnerable hydrogens, our heart-healthy unsaturated fatty acid becomes a free radical. In other words, it contains an unpaired electron and it becomes extremely chemically reactive.

Once the first free radical is formed, the generation of free radicals from unsaturated fatty acids happens in a self-propagating manner. One free radical can interact with other unsaturated fatty acids to produce more free radicals, which in turn produce even more free radicals, and so on. Besides damaging the fatty acids, these free radicals can also destroy other molecules, including vitamins and proteins. In addition, the free radicals are able to react with oxygen to produce hydroperoxides. These eventually break down into aldehydes, which produce the odors and flavors associated with rancidity.

The reactivity of fatty acids increases with the number of double bonds they contain. Stearic acid is an 18-carbon saturated fatty acid. If we add one double bond, it becomes one hundred times more likely to form a free radical. If we add three double bonds, it becomes 2500 times more likely to form a free radical. The health effects of saturated versus unsaturated fatty acids won't be addressed until the next blogpost, but it is certain that saturated fatty acids are far more stable than their unsaturated counterparts.

There are several ways to decrease the likelihood of free radical formation and rancidification in fatty acids. One is to be sure that heat is not used to extract the fatty acid from its source. In the case of unrendered animal fats, this is not a problem. In the case of vegetable fats, cold pressing ensures (at least it does in the EU) that the oil will not be heated above about 80 degrees Fahrenheit. Unfortunately the U.S. definition of cold pressed is not particularly rigorous, so it may be necessary to check websites or make telephone calls to the manufacturer to determine the temperature a particular brand of oil reaches as it is extracted. When fat is used for cooking, it is important to realize that the higher it is heated and the longer it is heated, the more likely it will be to form free radicals.

Another strategy to avoid free radical formation and rancidification in fats and oils is to be sure that they are kept away from light, particularly UV light. It is also helpful to keep fats and oils away from oxygen. They should not be stored for long periods, and once a container is opened, it should be used up as quickly as possible.

As we have already seen, some polyunsaturated fats are necessary for growth and for optimal health. However it pays to know which fats are which and to be careful with respect to the amounts and types of dietary fats we consume. In closing, here is a table that presents the approximate composition of some common fats, arranged from the lowest to the highest percentage of polyunsaturated fatty acids.

Deadline

2010-03-11T10:19:00.004-06:00

I have a project and a deadline in the real world, so I probably won't be able to blog for a while longer. Questions and comments on previous blogposts are still welcomed, however. (Be sure to include in the comment which specific post you're commenting on. Blogger doesn't provide that information and sometimes I can't find the comments after I've accepted them.)

In the meantime, I know you'll keep moving forward on your journey into good health.

More on Omega-3 and Omega-6

2010-03-03T20:47:00.004-06:00

Omega-3 and omega-6 fatty acids are long-chain polyunsaturated fatty acids. They cannot be synthesized by the human body, but are important for growth, for cardiovascular health and for immune function. They may also be involved in a variety of other health-related issues including the prevention of cancer and of central nervous system disorders. Their effects are somewhat non-specific, but because the omega-3s in particular have shown positive effects in many controlled double-blind prospective scientific studies, people who are interested in nutrition are also interested in the omega-3 and omega-6 fatty acids. This blogpost, and the previous one, attempt to explain a few principles that may make it easier for readers to evaluate their own use of these essential fatty acids.

The omega-3 and omega-6 fatty acids are unbranched molecules ranging from 16 to 24 carbons in length and carrying from two to six unsaturated bonds. The most common forms are illustrated above. When they are ingested in the diet, these polyunsaturated fatty acids gradually become incorporated into the phospholipid bilayers that form the cell walls of most of the cells in our bodies. As phospholipids, the omega-3 and omega-6 fatty acids affect the flexibility and permeability of the membrane surrounding each cell. They also exist in equilibrium with the unsaturated free fatty acids that circulate in our blood. It is this pool of free fatty acids that is used by the body as precursors for the eicosanoid signaling molecules, i.e., the prostaglandins, thromboxanes, leukotrienes and prostacyclins.

From a survey of the omega-3 literature, it appears that the longer the molecule, the more biologically potent it is. (An example is found here.) The body is able to convert one form of omega-3 fatty acid to another, but it is not particularly efficient at it. For instance, although flax seed oil is rich in alpha-linolenic acid (ALA), ALA (18 carbons) is converted into EPA (20 carbons) at an efficiency of about 5-10% and into DHA (22 carbons) at an efficiency of about 2-5%. Recent studies indicate that in some individuals the conversion rates may be less than 1%. By contrast, EPA and DHA can be obtained directly from fish oil and require no modification to provide maximum protection against conditions such as coronary artery disease. Vegetarians and those who are allergic to fish will be able to eat extra ALA to compensate for the poor conversion rate to EPA and DHA, but they must bear in mind that not all omega-3s are created equal.

Another consideration in omega-3 and -6 fatty acid intake is the interchangeability of the omega-3 and omega-6 fatty acids in the eicosanoid synthesis pathways. Take a look at the figure above. EPA (eicosapentaenoic acid) is an omega-3 fatty acid with 20 carbons and five double bonds. AA (arachidonic acid) is an omega-6 fatty acid with 20 carbons and four double bonds. Superficially, they look very similar. These molecules also look similar to the enzymes involved in eicosanoid synthesis and, as such, they compete with one another. Metabolites of omega-6 fatty acids, particularly metabolites of arachidonic acid (20 carbons), are significantly more inflammatory than those of omega-3 fatty acids. This becomes important because the Westernized diet has a fatty acid ratio of omega-6 to omega-3 that falls between 10:1 and 30:1. If our dietary raw material is almost all omega-6 fatty acids, the metabolites will be predominately pro-inflammatory. For some interesting lists of omega-6 sources, see here. I can't vouch for the accuracy of the lists, but in general they provide some surprising insights.

One way to decrease the omega-6-derived inflammatory intermediates is simply to replace omega-6 polyunsaturated fats with saturated and monounsaturated fats. (A recent journal article suggests that eating saturated fat is not as dangerous as previously thought.) Saturated and monounsaturated fats provide energy, but they cannot be converted into eicosanoid signaling molecules. Another strategy is to take advantage of the metabolic competition between omega-3 and omega-6 fatty acids by replacing the intake of omega-6s with omega-3s. Although the omega-3 fatty acids can be pro-inflammatory when eaten to excess (probably more than three grams per day), in general they will form less-inflammatory signaling intermediates and will also decrease the omega-6-stimulated production of small pro-inflammatory proteins called cytokines.

A review article on omega-3 fatty acids suggests setting a goal of an omega-6 to omega-3 ratio between 1:1 to 1:4, though it gives no rationale for these numbers other than speculation that that was the ratio consumed by our ancestors. The article also recommends consuming fatty fish three times per week. Unfortunately the oceans are no longer pristine, and fish tend to contain pollutants such as mercury, PCBs and dioxin. For those who prefer not to take the risk, purified fish oil supplements are available from manufacturers who use high-vacuum, low-temperature molecular distillation to purify their fish oils. Another source of EPA and DHA is krill oil, which comes from animals that are low on the food chain and therefore low in pollutants. Krill oil is quite expensive, however. Meat, eggs and plant sources also contain omega-3s in varying amounts. For the obsessive-compulsive, here is a list of the total omega-3 content of 200 calories' worth of various foods.

Omega-3 and omega-6 fatty acids are essential for life. They also affect the quality of life in positive and negative ways. Because they are stored in the phospholipid bilayers of our cell membranes, they take a long time to act. They must build up, reach an equilibrium with their free fatty acid form in the blood and then be converted to intermediates. For that reason, it may take weeks or months before a negative effect starts to decline or a positive effect is noticed. However, there are many scientific articles that indicate that it may be worth the time, effort and expense of attending to our intake of these essential fatty acids.

Essential Fatty Acids (Omega-3 and Omega-6)

2010-02-24T11:37:00.004-06:00

Certain dietary deficiency diseases are quite straightforward. For instance, if we don't consume enough vitamin C for a long period of time, we will develop scurvy. Children who don't get enough vitamin D and/or calcium, will suffer from rickets. Adults with a persistent deficiency of vitamin D and/or calcium will eventually experience osteopenia and perhaps osteoporosis.

Other dietary deficiencies produce less obvious symptoms. As early as the 1920's, it was noted that a complete dietary deficiency of fatty acids produced impaired growth in animals. When this was investigated farther, it was found that the omega-3 and omega-6 fatty acids were particularly important for growth and development.

Now a detour to explain some nomenclature. Fatty acids are the carbon chains that are attached to glycerol backbones to form triglycerides. Illustrated above are three such fatty acids, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The zig zag lines are a form of shorthand that circumvents the necessity of writing out all the carbons and hydrogens found in these molecules. Each inflection of the zig zag (plus the right end of the zig zag) represents a carbon atom. Count these points on ALA, and you will find 18 carbon atoms. On DHA there are 22. The straight lines between the points represent covalent bonds. A single straight line between two carbons is a single bond, also called a saturated bond. A double line between two carbons is a double bond, also called an unsaturated bond. You can see that all three of these fatty acids contain several unsaturated bonds, which is why they are called polyunsaturated fatty acids.

On the left of each fatty acid molecule is a carboxyl group, which is used to join the fatty acid to the glycerol backbone. On the extreme right is the omega (or final) carbon. In each of the fatty acids shown above, at carbon #3, there is a double bond. The presence of that bond means that these are omega-3 fatty acids. Fatty acids that have a double bond at carbon #6, but not at carbon #3 are called omega-6 fatty acids.

Back to the dietary deficiency story. In a review article, William Lands describes how further research showed that omega-3 and omega-6 fatty acids are somewhat interchangeable, but that omega-6 fatty acids are particularly important for maintaining skin integrity, renal function and the process of birth. Omega-3 fatty acids may be more important in the support of visual and neural functions.

As Lands describes it, in 1963 it was discovered that one of the omega-6 fatty acids could be converted to a signaling molecule called a prostaglandin. Prostaglandins act on the vascular system, affect platelet aggregation and regulate inflammation. Further research revealed that omega-3 and omega-6 fatty acids could be converted to a large set of short-lived locally-acting signaling molecules called eicosanoids. Along with the prostaglandins, these include thromboxanes, leukotrienes and prostacyclins. Representative examples are illustrated below. (Both figures in this post are modified from figures found at Wikipedia.)

There are dozens of eicosanoid molecules, and each of them has many actions. Because of this, there is no simple relationship between a deficiency of omega-3 and omega-6 fatty acids and a defined profile of symptoms. When taken in optimal amounts, the eicosanoids promote the health of the cardiovascular system, the central nervous system, and the immune system. For scientific citations, please see the extensive Notes and References section at the end of the Wikipedia article on Omega-3 Fatty Acid. Positive effects have been shown for lowering blood pressure, improving blood lipid profiles, decreasing the risk of stroke and preventing psychotic disorders.

In a practical sense, a Westernized diet provides an abundant supply of omega-6 fatty acids and a relatively poor supply of omega-3 fatty acids. During the past few decades, healthy eating recommendations have caused us to transition from animal fats, rich in omega-3 fatty acids, to corn oil, safflower oil, cottonseed oil, peanut oil and soybean oil, which are all rich in omega-6 fatty acids and poor in omega-3 fatty acids. This is important because, when it comes to omega-6 fatty acids, we cannot say that if a little is good, a lot is better. An excess of omega-6 fatty acids causes these molecules to form inflammatory intermediates which are relevant to processes such as asthma, arthritis and atherosclerosis.

A review article by Artemis Simopoulos describes how these inflammatory intermediates can be counteracted by decreasing our intake of omega-6 fatty acids and increasing our intake of omega-3 fatty acids. Unfortunately, in the modern world, it takes some thought and financial resources to balance our intake of omega-6 and omega-3 fatty acids. That will be the subject of the next blog post.

Caffeine and Weight Loss

2010-02-16T18:40:00.004-06:00

In 2004 the Food and Drug Administration banned the sale of dietary supplements containing ephedra in the United States. Although studies had shown a beneficial effect of the combination of ephedra and caffeine for weight loss in trials of six months or less, there were many reports of heart attacks, strokes, seizures and death caused by ephedra. This caused the FDA to discourage and finally to prohibit the sale of dietary supplements containing ephedrine alkaloids.

Caffeine, however, remains readily available in the form of coffee, tea, chocolate and over-the-counter pills. Does caffeine alone have a beneficial effect on weight loss?

It may, but if it does, the effect is slight. By inhibiting an enzyme that degrades intracellular cyclic AMP, caffeine is able to promote thermogenesis and stimulate fat oxidation. However, the long-term effect of these changes is not dramatic. From 1986 to 1998, Lopez-Garcia et al. studied the effect of changes in caffeine intake in a total of 58,000 health care professionals. Caffeine intake was calculated from the self-reported weekly consumption of coffee, tea, soft drinks and chocolate. Participants were divided into quintiles according to the amount that their caffeine intake had varied, from a net decrease to a net increase over the twelve years of the study. Each quintile gained weight during the study, but in the quintile that had increased its caffeine intake the most, less weight was gained. How much less? Slightly under a pound. Over twelve years. It is also important to note that this was a correlational study, and as we have learned, correlation does not equal causation.

One of the interesting aspects of caffeine consumption is that it is associated with an increase in insulin resistance. In this 2005 article in Diabetes Care, Lee et al. show that lean, obese and type 2 diabetic men experienced a 33-37% reduction in insulin sensitivity immediately following ingestion of a capsule containing caffeine equivalent to about 2-3 cups of coffee. The references in the article confirm that other investigators found similar results in single-dose administration of caffeine, but none of these the addressed the effect of chronic caffeine ingestion on insulin resistance.

This is important because in their discussion Lee et al. point out a paradox. The consumption of coffee (as opposed to consumption of pure caffeine) has an inverse relationship with the incidence with type 2 diabetes. Van Dam et al. saw a dose-response relationship between increasing coffee consumption and a declining risk of type 2 diabetes in younger and middle-aged women. This was true both for caffeinated and decaffeinated coffee. Granted, this was another correlational study, but it does raise the interesting possibility that there is a non-caffeine component of coffee that provides a protective effect against type 2 diabetes. Potassium, magnesium, chlorogenic acid, quinic acid, trigonelline and lignan secoisolariciresinol have all been proposed as possible agents for improved glucose metabolism in coffee drinkers, but the association is mostly speculative.

To summarize, from the literature, it appears that caffeine does not provide much help with weight loss, but on the average it does not hinder it either. Caffeine increases insulin resistance in the short term, but it may or may not do so in the long term. For those who get their caffeine fix by drinking coffee, it is possible but by no means certain that the coffee itself contains one or more compounds that have a beneficial effect on glucose metabolism. As of this writing, the use of caffeine on a low-carb diet is up to the dieter. The science is far from settled.

Cinnamon and Blood Glucose

2010-02-09T20:45:00.004-06:00

The other day I was at Sam's Club, pushing my cart past the supplement section on the way to the meat counter. As I glanced at the shelves, I noticed something new. There was a bottle containing 500 mg capsules of cinnamon (specifically, ground Cinnamomum cassia bark). On the one hand, I had heard that cinnamon was able to improve blood glucose levels, but I hadn't read any of the papers. On the other hand, my fasting blood glucose levels had been in the 100 mg/dl range for a while, even though I eat less than 10 grams of carbs per day. I had been taking chromium supplements, but they didn't seem to have much of an effect. Since the cinnamon capsules weren't particularly expensive, I decided to take a chance and I bought them.

When I got home, I pulled up some of the scientific papers on cinnamon and saw that a reasonable dose would be about 1.5 grams per day. I took a capsule at breakfast, lunch and bedtime and the next morning my blood glucose was 95. To my amazement, the readings continued near that value throughout the week. I told a prediabetic friend about this, and she decided to try it as well. She too noticed a drop of about 5-10 mg/dl in her blood glucose levels. Next, my husband told one of the people at work about my experience. She has type 2 diabetes and is taking both oral hypoglycemic agents and a bit of insulin. She tried the cinnamon capsules and her blood glucose levels fell by 50 mg/dl.

Alrighty then. I decided it was time to read the scientific papers and see if there was anything to these anecdotal experiences. This blogpost will summarize my findings, such as they are.

In 2003 a paper by Khan et al. appeared in Diabetes Care. It described a group of 60 people who had type 2 diabetes and were being treated with sulfonylurea drugs. They were divided into six groups, with the first three taking 1, 3 or 6 grams of cinnamon daily while the second three were given placebo capsules of 1, 3 or 6 grams of wheat flour. After 40 days of treatment, the placebo groups experienced no change in fasting serum glucose, but the three treatment groups experienced decreases of 25%, 18% and 29%. There did not appear to be a dose-response because all three levels of cinnamon intake produced similar results.

This result was not totally unexpected because cinnamon had been observed to have insulin-enhancing activity in laboratory studies. With that in mind, several groups performed prospective clinical trials with cinnamon in human beings. Five of these studies were reviewed by Baker et al. in 2008. They concluded that the use of cinnamon did not significantly alter hemoglobin A1c or fasting blood glucose in patients with type 1 or type 2 diabetes.

However, other studies showed that there was an improvement in blood glucose with cinnamon. Zeigenfuss et al. used an aqueous cinnamon extract to treat prediabetic subjects and saw no effect at six weeks, but at twelve weeks observed an 8.4% drop in fasting blood glucose. In 2007 Wang et al. studied women with polycystic ovary syndrome (PCOS), a hormone disorder associated with insulin resistance. After eight weeks of treatment with a cinnamon extract, these women experienced significant declines both in fasting blood glucose and in two measures of insulin resistance. In 2009 Paul Crawford studied a heterogenous group of poorly controlled type 2 diabetics in a primary care setting. Their medications and dietary recommendations were left unchanged, but the treatment group received an add-on dose of 1 gram of cinnamon per day in an open-label study. After 90 days, the treatment group had significantly lowered its hemoglobin A1c from 8.47 to 7.64.

A 2008 lecture by Richard A. Anderson gives some insight into the possible mechanisms of cinnamon enhancement of insulin sensitivity. When insulin binds to its receptor, it starts a signaling cascade that begins with the autophosphorylation of the insulin receptor. In the presence of cinnamon extracts, this autophosphorylation is more robust. Not only that, cinnamon inhibits the dephosphorylation of the insulin receptor, which further enhances the signal. Cinnamon also increases the amount of insulin receptor proteins and of other proteins in the insulin signaling pathway. Cinnamon is not a substitute for insulin, but it does make insulin signaling more sensitive to the insulin that is present in the blood.

In summary, it appears that supplementation with cinnamon may provide a small but significant improvement in insulin sensitivity. It appears to have a greater influence in people with poorly controlled blood sugar, especially in those who are taking drugs that enhance insulin secretion by the pancreas. In people who are pre-diabetic, the glucose-lowering effect seems to be less. In fact, when cinnamon is given to normal subjects, it does not decrease their blood glucose, but instead reduces their postprandial serum insulin. Although the anecdotal experiences I related at the beginning would suggest that cinnamon has an immediate effect on blood glucose, from the scientific literature, it appears that it may take up to 12 weeks to exert its actions.

Even though cinnamon is found in practically every kitchen in the Western world, it is important to note that some people are allergic to cinnamon. If you decide to try cinnamon supplementation, be careful to look for rashes, inflammation of the mucous membranes or even trouble with breathing. Be sure to discontinue the cinnamon if any of these symptoms occur.

That said, it appears that supplementation with cinnamon may be helpful as part of a strategy to normalize blood glucose levels.

Induction Flu

2010-02-01T20:34:00.004-06:00

Those of us who have done low-carb for years are happy to sing the praises of the low-carb lifestyle--decreased weight and increased energy, plus improvements in blood pressure, triglycerides, HDL and blood glucose numbers. But in much the same way that the joy of having a new baby diminishes our memory of the pain of childbirth, we find it easy to forget that one of the aspects of low-carbing is very hard. It's called Induction flu, or Atkins flu.

On the Standard American Diet (very aptly named the SAD diet) we are used to eating low fat, moderate protein and high carbohydrate. Our body's primary source of energy comes from the burning of hundreds of grams of carbohydrates we consume every day. When we change from a SAD diet to a low-carb diet, we abruptly remove the macronutrient that has provided most of our energy. Eventually our energy will come from the fat we eat, but in the meantime our bodies have a huge transition to make.

Every nucleated cell in our body contains 46 chromosomes with over 3 billion base pairs of DNA. In that DNA is the information needed to make the enzymes required for us to metabolize both carbohydrates and fats into energy. Although the information is there, it is not translated into enzymes unless those enzymes are actually needed. A person eating a SAD diet will have all the enzymes he or she needs to convert carbohydrates into energy, but very few of the enzymes needed to convert fat into energy.

Typically a low-carb diet is begun at a level of 20 to 30 grams of carbohydrate a day. Suddenly the carbohydrate conversion enzymes no longer have a substrate. They initiate Plan B, which is to utilize the glycogen stored in the liver and muscle tissue. Glycogen is converted to glucose, which is converted to energy. After about a day, glycogen is depleted, and the body moves to Plan C. It notices that fat is available in abundance, and it upregulates the machinery to transcribe the necessary codes from the DNA into RNA, and then to translate that into the enzymes that are required to metabolize the fat into energy. Unfortunately this takes a day or two, and in the meantime the new low-carb dieter starts to experience Induction flu.

The symptoms of Induction flu are not those that are normally associated with dieting. Instead of ravening hunger and cravings, there is a headache and nausea. The dieter may be irritable and lack energy and concentration. Chills and fever are not typical symptoms, but other than that, it feels like the flu and will last for about two days.

What to do? First of all, recognize that this is a transitional state and that it will end. Second, pamper yourself. This does not mean that you dive headfirst back into the carbs, but drink plenty of water, sleep, take a hot bath, take NSAIDs or acetaminophen, watch a good video or read a good book. One of the best strategies is to find a supportive friend either on the low-carb boards or in real life to commiserate with. Simply knowing that this stage is coming and planning for it is one of the keys to getting through it.

Sometimes new low-carbers try to change everything all at once. If you're a caffeine addict, you might want to wait until Induction is over before you give up the caffeine. If you are resolved to start an exercise regime along with the low-carb diet, it might be better to wait until you have recovered from the Atkins flu before you hit the pavement or go to the gym. If you are lightheaded or start having muscle cramps, consider taking a potassium supplement or using Lite Salt or a KCl salt supplement on your food. Low-carb diets have a diuretic effect and tend to make the kidneys excrete potassium.

It takes several weeks for the body to become fully keto-adapted, that is, to complete the conversion from from carb utilization to fat utilization for energy. However, the worst of the process should be over by the end of Day 3. At that point the benefits of low-carbing (increased energy, decreased appetite and a sense of freedom from the enslavement to rising and falling insulin) should start to predominate. Low-carbing is a continuous learning process, but once the Induction flu is over, it's a worthwhile journey into good health.

Glyceroneogenesis, and Other Reasons for Fat Storage on Zero Carb

2010-01-27T18:19:00.003-06:00

This week I have an extra set of responsibilities in real life and have had a hard time finding time for a new blog post. Fortunately I recently learned of an excellent article by LynMarie Daye, Is the Fable of Unfettered Fat Burning Derailing Your Low Carb Diet?

The author explains in clear and well-referenced terms how the body is able to store fat in the relative absence of insulin. As she says, only type-1 diabetics have a total absence of insulin, and it is true that they cannot store fat. However, the rest of us have a low baseline level of insulin at all times, and in that situation, Acylation Stimulating Protein is able to promote fat storage even when blood insulin levels remain low.

It is also true that fat storage requires the presence glycerol 3-phosphate to form the backbone of the triglyceride molecule. However, simply refraining from eating carbs is not sufficient to stop the synthesis of glycerol 3-phosphate. Even in a state of prolonged fasting, the body is able to use its own muscle protein to synthesize glycerol 3-phosphate. This metabolic pathway is called glyceroneogenesis, and it is illustrated in the figure above.

If you have ever wondered how it is possible to eat no carbs whatsoever and still gain weight, LynMarie Daye provides a thorough treatment of the issue. I highly recommend her article.

Ghrelin, the Hunger Hormone

2010-01-19T18:03:00.004-06:00

A hormone is a chemical that is produced in one part of the body, is released into the blood, and is able to regulate activities in other parts of the body. One example would be insulin, which is produced in the pancreas, but affects the function of tissues throughout the body, including muscles, brain and liver.

Insulin is important for food storage and satiety. Another hormone that plays a role in energy homeostasis is ghrelin, a 28-amino acid peptide discovered in 1999. Its name includes the Proto-Indo-European root word "ghre," meaning "to grow." Ghrelin is produced in the hypothalamus, kidney and pituitary gland, but most of it is synthesized in and released by the stomach. The picture below (credit to Rae Silver, Joseph LeSauter and Donald Pfaff) shows a photomicrograph of the stomach wall. The hormone ghrelin has been specifically tagged and can be seen in the form of black dots.

Ghrelin has many actions, but the most prominent one is that it increases hunger by stimulating neurons in the arcuate nucleus of the hypothalamus, especially the neurons that express neuropeptide Y and agouti-related protein. Neuropeptide Y and agouti-related protein are both potent stimulators of appetite. Not only that, neuropeptide Y and agouti-related protein also enhance appetite by reducing the action of the appetite inhibitor proopiomelanocortin. As might be expected, people who are given injections of ghrelin become voraciously hungry and eat more than they otherwise would.

Ghrelin does have a specific role in the energy management of the body. Researchers at Columbia and Rockefeller Universities have shown that ghrelin is released in a circadian manner, prior to the onset of mealtimes. This pattern is illustrated in the graph below.

Just before mealtime, ghrelin is released from the stomach and acts on the hypothalamus to induce food-seeking behavior. In some ways this is a very adaptive mechanism. Rather than allowing a person to continue various activities and deplete energy stores, ghrelin acts to remind us to start seeking food and begin preparing for a meal. As soon as food reaches the stomach, ghrelin levels drop dramatically and stay low until an hour or so before the next meal is normally eaten.

Because of ghrelin's role in enhancing hunger, it is a prominent target of anti-obesity strategies. However, counteracting ghrelin has proved harder than one might expect. When a large part of the stomach is removed in weight loss surgery, ghrelin levels do drop in the short term. However, within a year post-surgery, ghrelin production recovers and patients tend to have higher blood levels of ghrelin than they did before the surgery. Even when mice are bio-engineered to lack the ability to produce any ghrelin whatsoever, their body weight gain and 24-hour food intake remain unaffected, suggesting that there are redundant appetite control systems that promote food intake in spite of the fact that ghrelin levels have been reduced to zero.

Although ghrelin-related strategies for hunger control do not look promising at this time, knowing about this hormone can still help us on a cognitive level. When the clock is moving toward lunch or dinner-time and we find ourselves obsessing about food, it's good to know that we aren't actually starving. We are simply getting a signal from our stomachs that it is time to start foraging for food. Because most of us live in a situation where food is as close as the nearest refrigerator or pantry, we can smile and tell ourselves that all is well. Thanks to modern civilization, we won't have to pick up a spear and run down an unsuspecting wild animal or rush out to gather roots and berries. The food will be there when it's needed, and we can calmly go back to our activities until it is time to eat.

Essential Carbohydrates

2010-01-12T22:04:00.005-06:00

The most obvious characteristic of a low-carb diet is that it is low in carbohydrates. The original Atkins diet recommends that dieters start its Induction phase with essentially zero grams of carbohydrates. The 2002 version of the Atkins diet allows dieters to do Induction with up to twenty grams of carbohydrates. The Protein Power diet begins its Phase I Intervention stage at thirty grams of carbohydrates. As all of these diets progress, additional carbohydrates are introduced in a controlled manner, but even at maintenance, most low-carbers eat no more than 100 grams of carbohydrate per day.

By contrast, the US Department of Agriculture recommends that both children and adults eat 45-65% of their daily calories as carbohydrates. That can mean well over 300 grams of carbohydrates per day for a person consuming a 2000 calorie diet.

What happens if we ignore the USDA guidelines and don't eat enough carbs every day? Carbohydrates are popularly thought to be essential for providing energy. Specifically they are thought to be necessary to provide fuel for the brain and to refill stores of glycogen in muscles and in the liver.

The American Diabetes Association tells us that the brain and central nervous system normally have a daily requirement of about 130 grams of carbohydrate in the form of glucose. However, after a period of adaptation, most of these tissues are also able to use ketones as an energy source. This reduces the carbohydrate requirement to about 30 grams of glucose per day. As low-carbers with Ketostix already know, ketones are produced in abundance from the fats and amino acids consumed on a low-carb diet. The remaining need for thirty grams of glucose can easily be met through a metabolic pathway called gluconeogenesis, which allows the body to use amino acids from proteins and the glycerol backbones from fats to synthesize glucose in the absence of any carbohydrate intake.

Glycogen, which is a storage form of glucose, can similarly be replenished by the glucose made through gluconeogenesis. As far as the general energy requirements of the body, these can be met very efficiently both by the utilization of dietary fat and by the mobilization of stored fat.

Carbohydrates, therefore, are not an essential element of a healthy diet. There are essential fats, which include the omega-3 and omega-6 fatty acids. Because they are not produced by the body, omega-3 and omega-6 fatty acids must be consumed in order to ensure the normal function of the nervous system, heart and immune system. There are essential amino acids, including isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Although some amino acids can be synthesized by the body, these eight cannot. Unless they are ingested, and ingested in the proper amounts, the body is unable to assemble all of the structural and enzymatic proteins that are needed to sustain life.

By contrast, there is no disease state associated with an insufficient intake of carbohydrates. It is true that the body needs carbohydrates for energy within certain types of tissues, for synthesis of the backbones of DNA and RNA, and for signaling purposes, but it is well able to synthesize all of these from the raw materials provided by the amino acids in the proteins we eat.

For those of us raised on the dogma of eating low-fat and high-carb, this is hard to believe. But if we think about our caveman ancestors, we realize that they didn't have access to pasta, potatoes or rice, or even high-carb fruits and vegetables on a regular basis. They were able to survive and reproduce without a high carbohydrate intake because, amazingly enough, there is no such thing as an essential carbohydrate.

Welcome, New Low-Carbers!

2010-01-05T12:09:00.004-06:00

You'd been hoping to lose weight all through 2009, but never quite managed it. Then came Thanksgiving. After the big meal and the family time, you washed the dishes, put away the leftovers, dug out the Christmas decorations, and as you made the house ready for the season you hoped to do better in December. Of course, you had forgotten about the holiday goodies that would be brought into your office as treats for everybody. They sat there in all their deliciousness, and it was just too hard to resist them.

Christmas arrived. Only Scrooge would decline the traditional foods that various relatives and friends had prepared. A week of polishing off the remaining treats has left you with a closet of clothes that no longer fit and a temptation to try a weight-related New Year's resolution one more time.

What makes your 2010 resolution different from your previous weight-loss resolutions? This time you're doing low-carb! You have gone to the Internet to investigate low-carbing and to make contact with people who can encourage and advise you. You have a book (Dr. Atkins' Diet Revolution or Mike and Mary Dan Eades' Protein Power), and you have decided to read it and follow what it says.

What's different about low-carbing? Low-carbing allows us to work with the way our body works rather than fighting against it. When we eat foods with lots of carbs (bread, pasta, potatoes, most desserts and snacks), our bodies can't use all of those calories at once. Our pancreas releases the hormone insulin to store the nutrients in our cells. Between meals, the nutrients are released and are used for energy.

However, as we age, the store-and-release cycle sometimes starts to break down. We eat the carbs and store the nutrients, but when it comes time for our cells to release the nutrients, they resist doing so. The body needs energy but the cells don't want to release it. So the body moves to plan B. It commands us, "EAT MORE." Sure enough, we load up on more carbs and for a little while we have the energy we need. The excess energy from our snack is stored in our cells, but once again the cells resist releasing it when we need more energy a few hours after we've eaten. As this vicious cycle deepens, we notice that we are eating, getting hungry, eating again, getting hungry again and steadily gaining weight. We can try ignoring our appetite, but our bodies are clever. They will make the drive for food relentless. If our willpower holds, our bodies will assume they are in a starvation situation and will retaliate. They will throttle down our core temperature and make us less energetic. Sound familiar?

Low-carb eating circumvents the broken store-and-release cycle. Eating low-carb food means we will be eating mostly protein and fat. Both protein and fat are stored after meals, but the process is more gradual. With very few carbs, less insulin is needed, and this means that body's cells are more likely to make the switch from storage mode to release mode between meals. The presence of dietary fat (in the absence of carbs) will signal the cells that starvation is not imminent, and will tell the body that there is no need to lower body temperature and energy level.

What about calories? When our body is utilizing its own stored energy, it will naturally adjust our appetite to be content with a lower calorie intake. That's hard to believe, but most people will spontaneously start eating less as they become adapted to a low-carb way of eating. They are no longer putting a part of each meal into permanent storage, and are actually able to mobilize the energy their body has been hoarding against what it thinks is a famine. With low-carbing, self control is necessary when it comes to food choices, but the constant battle against raging hunger is over.

That's it in a nutshell. The practice is harder than the theory, but that's why the books by Dr. Atkins and the Eades are there. Psychological support is available from online bulletin boards such as Low Carb Friends.

You can do it. Your body will actually help you when you work with it rather than against it. And those clothes in your closet will soon be too big rather than too small. Happy Low-Carb Year!

Scientists Behaving Badly

2009-11-29T20:39:00.007-06:00

The premise of this blog is that the scientific method can be used to support or invalidate the tenets of the low-carb lifestyle. While science can never claim to establish the final truth of a particular hypothesis, it is the best instrument we have to approximate the truth of something that is falsifiable, that is, something that is capable of being tested by experiment or observation.

Although science is an excellent tool, we must be careful to remember that science is performed by human beings who are not perfect. Low-carbers are already aware of the problematic work of Dr. Ancel Keys. Among Dr. Keys' most important publications was the Seven Countries Study. This study helped establish the diet-heart hypothesis when it found that in seven specific countries, the cardiovascular disease rate was positively correlated with average serum cholesterol and per capita intake of saturated fatty acids. In 1957 two scientists, Jacob Yershalmy and Herman Hilleboe, noted that data were available from 22 countries, not just seven. They published a paper showing that when all 22 countries were analyzed, the cholesterol/saturated fat correlation to heart disease became much weaker, and the incidence of heart disease was more strongly related to sugar intake. Even though it seemed that Dr. Keys might have cherry picked his data, his diet-heart hypothesis has nonetheless prevailed over the years.

The science of Anthropogenic Global Warming (AGW) doesn't have much to do with low-carbing, but it does have a great deal to teach us about the practical aspects of whether to believe or disbelieve a particular scientific finding. In November 2009, a series of e-mails was made available on the internet, purporting to be from the Climate Research Unit (CRU) at the University of East Anglia in Norwich, England. As of this writing, their authenticity has not yet been denied, and these e-mails now form the heart of what has been termed Climategate.

What does Climategate have to tell us about how to evaluate scientific claims with a skeptical eye?

First, if the scientists refuse to release their raw data, it's not a good sign.

Phil Jones (head of the CRU) and Tom Wigley (University Corporation for Atmospheric Research in Boulder, Colorado) discuss here how to avoid releasing data in response to a Freedom of Information request. Dr. Jones is so averse to scrutiny of his data that he admits to clearing e-mails off his computer here and advises his colleagues to do the same here. (AR4, referenced in this link, is the Fourth Assessment Report of the UN's Intergovernmental Panel on Climate Change (IPCC), released in 2007. The AR4 allowed AGW supporters to claim a consensus in favor of anthropogenic global warming.)

Second, if the scientists select or massage their data to make it obey their hypothesis, it's a bad sign.

Dr. Jones has a problem because his data shows declining recent temperatures rather than rising ones. Here he tells three of his colleagues, "I've just completed Mike's Nature trick of adding in the real temps to each series for the last 20 years (ie from 1981 onwards) amd from 1961 for Keith's to hide the decline." Trick? Hide the decline? What might that mean?

"Mike" is Michael Mann, the creator of the Hockey Stick graph that used tree ring data to show no warming in the Medieval Warm Period, but a sudden, dramatic increase in global temperature in the late 20th century. In this article, Stephen McIntyre and Ross McKitrick show that the hockey stick graph is the result of overweighting data from American bristlecone pines and from using a non-centered principal component analysis that will almost always produce a hockey stick endpoint, even from random numbers.

"Keith" is Keith Briffa, whose tree ring data from the Yamal Peninsula of Siberia also showed a hockey stick pattern of recent global temperatures. Except that when Briffa's 12 tree cores (the red line on the graph below) are compared with 34 cores from the same area analyzed by Stephen McIntyre (the black line), the larger sample does not show the hockey stick pattern, suggesting that Briffa's 12 tree cores were unrepresentative of the local tree growth patterns and should not have been used to infer patterns of climate change for the Yamal region of Siberia, let alone for the whole planet.

Finally, if the scientists collude to allow some points of view to pass the peer review process while preventing other points of view from being expressed, it's a very bad sign.

Scientific journal editors decide which submitted papers will get reviewed, who the reviewers are, and whether the papers eventually get published. Here Tom Wigley tells Timothy Carter that they must get rid of an editor of the journal Climate Research. The man subsequently resigned. Here Tom Wigley and Michael Mann discuss a troublesome editor at Geophysical Research Letters (GRL) and whether he could be ousted because his presence may bring other AGW skeptics on board. Several months later the editor has left his post and here Michael Mann says, "The GRL leak may have been plugged up now w/ new editorial leadership there." Here Phil Jones is also having trouble with a new editor of the journal Weather, published by the Royal Meteorological Society (RMS). Dr. Jones says he has complained about the editor to the RMS chief executive, but if that doesn't work, he will not send any more papers to the RMS and will resign from the organization. When a group of scientists consciously engages in encouraging some editors and intimidating others, it's not particularly surprising if their papers tend to get published in the peer-reviewed journals while those of the scientists with opposing views do not.

Presumably scientists who hide data, who change data to fit their preconceived ideas and who conspire to see that only their data is published may nevertheless have reached correct conclusions. That would be the "fake but accurate" defense. However, it is much more likely that scientists who behave in this way have something to hide. Whenever you learn that a scientist in any field has engaged in one or more of these questionable activities, be very careful of whatever that scientist has to say.

Narcissism: When Low-Carbers Hurt Other People

2009-11-22T18:16:00.005-06:00

Narcissus, a young hero in Greek mythology, saw his image in a pool of water, fell in love with it and was unable to leave the beauty of his own reflection. He has given his name to an Axis II personality disorder described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), narcissistic personality disorder.

There is no laboratory test for the diagnosis of narcissistic personality disorder. Typically a trained psychiatrist or psychologist will evaluate a patient who, by early adulthood, demonstrates grandiose thinking or behavior, has an unusual need for admiration, and shows a lack of empathy for other people. These maladaptive patterns must be present in a variety of contexts.

In addition, a person with narcissistic personality disorder will demonstrate five or more of the following criteria (taken from the DSM-IV):

Has a grandiose sense of self-importance (e.g., exaggerates achievements and talents, expects to be recognized as superior without commensurate achievements)

Is preoccupied with fantasies of unlimited success, power, brilliance, beauty, or ideal love

Believes that he or she is "special" and unique and can only be understood by, or should associate with, other special or high-status people (or institutions)

Requires excessive admiration

Has a sense of entitlement, i.e., unreasonable expectations of especially favorable treatment or automatic compliance with his or her expectations

Is interpersonally exploitative, i.e., takes advantage of others to achieve his or her own ends

Lacks empathy: is unwilling to recognize or identify with the feelings and needs of others

Is often envious of others or believes that others are envious of him or her

Shows arrogant, haughty behaviors or attitudes

While it is tempting to do amateur psychology, that is not the point of this blogpost. Only a professional can diagnose and treat narcissistic personality disorder. Nevertheless, it is important for laypeople to be aware that this condition exists, and that it exists in the low-carb community in particular.

Low-carbers are vulnerable. Typically they have been overweight for many years and have a poor self-image as a result. Many have tried and failed at various weight loss schemes. Couple those experiences with the societal stigma against overweight people, and self-worth becomes almost nonexistent.

Along comes low-carb. For once, these formerly-obese people find themselves successful at something. They are able to move their bodies, to buy clothes, and to go out in public without a sense of shame. And, in some cases, they find a mentor who is able to take advantage of all their vulnerabilities.

The mentor provides a diet outline that seems to work. The mentor creates an internet community that gives support and a place to belong to people who were formerly outsiders. All of that is good.

But if the mentor has narcissistic personality disorder, the mentor starts to overstate the benefits of his or her diet plan without commensurate proof (Point #1). The mentor sets himself or herself up as the ideal example of the diet plan (Points #2 and #4). The mentor begins to lay down specific rules that require either automatic compliance or, failing that, expulsion from the community (Points #3 and #5). The mentor may show friendliness, charm and empathy when it provides an advantage (Point #6), but in the end will behave in an arrogant, abusive manner toward people who have disappointed him or her in any way (Point #9).

In my experience, low-carbers tend to think the best of people, even of people who abuse them. When they encounter a person with narcissism, they often hope that by careful reasoning or sympathetic friendship, they can help that person see his or her problem, deal with it, and adopt a more successful style of living. Unfortunately, the treatment of narcissism requires psychotherapy (see this PDF for a fascinating outline of what's involved), and even then the treatment is unlikely to be successful if the patient is not a willing participant in the therapy.

In the meantime, when you encounter another low-carber who is self-absorbed, who believes himself or herself to be superior to others, who belittles others, and who is willing to manipulate others to achieve his or her own ends, recognize that this is a person who can derail your journey into good health. It may be difficult, but if the person is harming you while he or she claims to be helping you, it may be time to end this relationship and develop new ones in the low-carb community.

Water

2009-11-15T17:18:00.005-06:00

For low-carbers, the design of an eating plan often focuses on carb counts, calories, and essential vitamins and minerals. With the array of tasty and nutritious foods that are available to low-carbers, it's easy to overlook another important aspect of low-carbing--water intake.

Water keeps our tissues hydrated, provides an environment for enzymatic reactions to occur, and in the form of blood, water carries vital nutrients to cells that need them. Water also dissolves and removes the toxins from our bodies in the form of urine--1.5 quarts a day in the average adult.

One of the interesting aspects of Dr. Atkins' New Diet Revolution and Protein Power by the Drs. Eades is that both call for the daily intake of at least eight 8-ounce glasses of water per day. In Dr. Atkins' case, he says that only water counts as water for the purposes of the diet (page 230 of the paperback version of the book). The Eades say that any water-based fluid will work, as long as it doesn't contain calories (pp.103-105 of the paperback version of the book). Their counsel is, in fact, "Drink Till You Float." Whichever guideline you choose, if you decide to drink coffee or tea, remember that caffeine is a diuretic, and you will need to drink extra fluid to compensate for this. Both caffeine and artificial sweeteners can slow weight loss in some people, and if you are one of them you may wish to make other choices for your fluid intake.

One of the unique reasons for monitoring water intake during low-carb dieting is that most low-carb weight loss comes from the breakdown of body fat. Some of the body fat is burned to create ATP through the TCA cycle and oxidative phosphorylation, as was described in the previous post. However, some of the fat will be burned incompletely and will be converted to molecules called ketones. Ketones are also able to be used for the production of ATP, but if an individual is not totally keto-adapted, the body will allow some of them to be breathed out, or excreted in the urine and the stool. Drinking plenty of water makes it easier for the body to get rid of the excess ketones.

As the body adapts to a ketogenic diet, or as carb intake increases, fewer ketones will be produced. Even so, long-time low-carbers will continue to spill ketones if their fat intake is high and their carb intake is low, and they will benefit from an increased water intake.

Water has a few other properties that make it an important part of a low-carb diet. If plenty of water is ingested every day, less water will need to be reabsorbed from the colon, making it easier to have bowel movements. Some people have a propensity toward urinary tract infections. Drinking lots of water prevents urinary stasis and makes these infections much less likely. Similarly, although kidney stones have many causes and many treatments, in a person with a history of kidney stones, a universal preventive strategy includes drinking well over three quarts of water per day. Finally, low-carb dieters freqently begin to do more exercise as a result of having enough energy to resume physical activity, or in order to improve their overall health. Because less water is retained on a low-carb diet, those who engage in strenuous exercise programs need to be sure that they drink plenty of water so that they do not inadvertently become dehydrated.

Often, thirst alone is not a good indicator for drinking water. This is especially true as people age and their bodies are less able to sense dehydration. In order to keep water intake at an optimal level, it may be necessary to fill a container or a set of containers in the morning and consume the water throughout the day, so that by bedtime all that day's water has been consumed. It may take a while, but drinking lots of water will eventually become a habit. Be sure to drink extra water when you engage in vigorous exercise, on days that are hot and humid, during the winter heating season, when you are at high altitude, and when you are sick.

Water is an important part of a low-carb diet. And the best news of all? It doesn't contain a single carb!

Cancer and Carbs

2009-11-08T19:32:00.008-06:00

Cancer has numerous causes, including ionizing radiation, cigarette smoking, infection with the Epstein-Barr virus, and overexposure to the sun, among many others. When a cell becomes cancerous, it faces several challenges. One of these is energy production.

The molecule called ATP (adenosine triphosphate) is called the energy currency of the cell. Energy is stored in the phosphate bonds of ATP, and when these are broken in a controlled manner, the energy can be used to fuel metabolic reactions, to replicate DNA, and to permit cell division. Much of our cellular machinery is devoted to the production of ATP. As illustrated above, the high energy bonds of ATP can be created using reactions that involve the breakdown of glucose molecules. Even better substrates for ATP energy storage are the acyl groups of fatty acids. (Energy can also be stored in ATP from the breakdown of amino acids and several other types of molecules, but for simplicity's sake, those pathways have been omitted here.)

Once the raw materials (pyruvate from the glucose and acyl groups from the fatty acids) enter the mitochondria, they encounter a very complex network of enzymatic proteins that function to produce most of the ATP for the cell. To give an idea of what this involves, the picture below shows the complexes required in the mitochondrial membrane just to accomplish the oxidative phosphorylation part of the ATP production process.

Normally the cells of the of a mature organism are differentiated into particular types that are specifically associated with various tissues such as brain, skin, and bone. They are strictly regulated with respect to their division and growth, and they require oxygen for the production of the majority of their ATP. By contrast, more primitive cells such as embryonic cells, are able to multiply rapidly without constraint and are mostly anaerobic. While cancer typically begins in differentiated cells, as those cells start to divide in an unregulated fashion, they start to de-differentiate and begin to resemble more primitive cells. As the cancerous cell mass grows, it may begin to be cut off from the oxygen supplied by the blood. This in turn can cause it to adopt a less complicated way of producing ATP, anaerobic glycolysis, which is also called fermentation.

Anaerobic glycolysis provides much less ATP than could be obtained from aerobic glycolysis plus the TCA cycle plus oxidative phosphorylation, but it has the advantage that it does not require oxygen. All it requires is glucose. Fat cannot feed into the anaerobic pathway. Protein can, but it is a fairly complicated process. It is therefore logical to speculate that a very low-carb diet might slow the growth of cancers, particularly the ones that are highly de-differentiated and rely mostly on anaerobic glycolysis.

This idea is far from proven. However, there is some interesting information in a review article recently published in the Journal of Cancer Research and Therapeutics, Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. (To get to a free PDF version of the entire article, click on the link. When it opens, click on the little Adobe Acrobat icon that follows the words "To download PDF version of the selected article click here.") The authors present evidence that a ketogenic (i.e., low-carb) diet can be of value in slowing the growth of cancer, both in mice with implanted brain tumors and in two children with advanced stage brain tumors.

Do carbs cause cancer? No, probably not. But they might contribute to cancer growth, and it is conceivable that in the future, a ketogenic diet might be considered along with resection, chemotherapy and radiation as part of a treatment plan for cancer.

Correlation

2009-10-26T21:25:00.007-05:00

Correlation is a measure of the interrelatedness of two variables. If we observe that one variable always increases when a second variable increases, the two variables are said to be strongly positively correlated.

On the other hand, if one variable always decreases when a second variable increases, the two are said to be strongly negatively correlated. If we increase one variable and a second variable neither increases nor decreases, there is no correlation between the variables.

The cohort study is one of the methods scientists use to discern if there is a correlation between variables. A cohort is a defined group of people who are systematically observed over a particular period of time. Data is collected at specified intervals, and outcomes such as the presence or absence of a particular disease are also recorded. It is important the cohort be large, carefully measured, and not prone to attrition.

One of the largest cohort studies ever undertaken is the Nurses' Health Study. It began in 1976 with a group of female registered nurses aged 30 to 55, but the study has expanded to a second and now a third phase which have enrolled a total of over a quarter of a million participants.

Why nurses? As a group, they are used to responding to technical questionnaires, and they have demonstrated a professional motivation to continue participating in the study. Thanks to reports from their next-of-kin, their deaths are also followed up, including reviews of autopsy findings and other records.

More than one hundred refereed papers have resulted from the data collected. Among the titles are:

Cigarette smoking and risk of stroke in middle-aged women

Dietary fat intake and risk of coronary heart disease in women

A prospective study of moderate alcohol drinking and risk of diabetes in women

A prospective study of postmenopausal estrogen therapy and coronary heart disease

From these four papers, it is easy to see the some of the variables being compared and correlated in the Nurses' Health Study. Cigarette smoking and stroke; dietary fat intake and coronary heart disease; moderate alcohol drinking and diabetes; postmenopausal estrogen therapy and coronary heart disease. From reading the News section of the Nurses' Health Study, website, one might assume that these types of correlations have a cause-and-effect relationship.

This is not necessarily correct. Take another look at the fourth article in the bullet points, A prospective study of postmenopausal estrogen therapy and coronary heart disease, which was published in the New England Journal of Medicine 1985. This study and several like it identified a correlation between hormone replacement therapy and a decrease in the incidence of coronary heart disease in older women. Possible mechanisms were proposed, and it became a consensus opinion that, in the words of the paper's abstract, "postmenopausal use of estrogen reduces the risk of severe coronary heart disease."

This correlational wisdom lasted over a decade. Eventually scientists did a randomized controlled clinical trial of hormone replacement therapy in older women, the Heart Estrogen/Progestin Replacement Study or HERS. Published in 1998, the HERS study showed that women who already had heart disease would increase their risk of a heart attack if they received estrogen therapy. This was followed in 2002 by the Women's Health Initiative (WHI), another randomized controlled clinical trial, which concluded that hormone replacement therapy increased the risk of heart attack and stroke for postmenopausal women.

Since then, much speculation has ensued. It is possible that the women in the Nurse's Health Study who took estrogen were beneficiaries of the adherer effect. That is, because they initiated and adhered to what they thought was a preventive regimen of hormone replacement therapy, these nurses may have been more likely to engage in other preventive behaviors that do tend to produce longer and healthier lives.

Taking estrogen requires spending extra money for prescriptions and for medical followup. It is possible that the nurses who took estrogen belonged to higher socio-economic groups than those who did not. The correlation between estrogen use and better heart health may have been seen because both variables were positively related to income level.

A third explanation comes from a more careful analysis of the data from the Women's Health Initiative. It suggests that some of the discrepancies result from a time component in the effect of hormone replacement therapy on coronary heart disease in women. It appears that there is a small, nonsignificant decrease in coronary heart disease when women initiate hormone replacement therapy within ten years of the onset of menopause. If hormone replacement therapy is initiated more than ten years after menopause begins, the risk of coronary heart disease rises in proportion to the time elapsed. These effects were probably present in both the cohort studies and the randomized trials, but because the women were not originally stratified and compared according to the time that had elapsed after onset of menopause, the results of the studies were at odds.

The take-home lesson? In a correlation study there are always variables that aren't expected--in this case an adherence effect, a socio-economic effect, and an age stratification effect. Although the papers taken from a cohort study may be done carefully, and although the authors try to address every confounding variable they can think of, there is no way to be sure that a particular correlation equals causation. We can use a correlation study to create a likely hypothesis, but we must always test the hypothesis (preferably with many approaches in many carefully randomized controlled trials) before we can begin to accept its validity.

I've Lost the Weight. Now, How Do I Keep It Off?

2009-10-18T18:55:00.021-05:00

When I recently completed my annual set of questionnaires from the National Weight Control Registry (NWCR), it dawned on me that many of my readers may not be aware of the NWCR. It's time to rectify that.

The National Weight Control Registry is a long-term longitudinal study of individuals 18 and older who have lost at least thirty pounds and have maintained that loss for a year or more. (If you meet those criteria and would like to enroll in the NWCR, you may do so here.) The database was started in 1994 and now contains the records of over 5000 individuals. Registry members have lost an average of 66 pounds (range: 30 to 300 pounds) and have kept at least 30 pounds off for an average duration of 5.5 years (range: 1 to 66 years). Eighty percent of registrants are women and twenty percent are men.

The NWCR does not offer diet advice and it does not perform randomized clinical trials. What it does do is collect a large amount of anecdotal information from a group of people who have been successful at long-term weight loss maintenance. The investigators request data annually from hundreds of volunteers using several long questionnaires. They then systematize and compare the data in various ways to suggest possible strategies that might be helpful to people who have lost weight and would like to maintain the loss.

Because the study group is self-selected and because they are not following any specified experimental protocol, the papers derived from this data cannot be used to support or disprove scientific hypotheses about maintenance of weight loss. However, while the public waits for large-scale randomized clinical trials of weight maintenance strategies, the observations made by the NWCR can give guidance to individuals who would like to maintain a significant weight loss. What works for one person may not work for another, but there is a chance that what has worked for many successful maintainers may also work for a particular aspiring maintainer.

That said, let's look at some of the observations made by the National Weight Control Registry. These have been published in articles in refereed journals that are listed here.

Of the NWCR members who have successfully maintained their weight loss,

78% eat breakfast every day. Only 4% report never eating breakfast.

75% weigh themselves at least once a week. More than 44% weigh themselves at least once a day.

62% watch less than 10 hours of TV per week.

90% exercise, on average, about 1 hour per day. The most common activity is walking, done by 76%.

Most NWCR members lose and maintain their weight loss using a low-calorie, low-fat approach to eating. However, there are a few low-carbers. In 2007, Phelan et al. published Three-Year Weight Change in Successful Weight Losers Who Lost Weight on a Low-Carbohydrate Diet in the journal Obesity. They compared 96 low-carbohydrate participants with 795 others, all of whom had enrolled in the NWCR between 1998 and 2001.

As one might expect, the low-carbers and the other Registry members (referred to here as the control group) approached maintenance in significantly different ways. By the end of Year 3, the low-carb group reported consuming more calories per day than the control group (1610 kcal vs. 1340 kcal), with a greater percentage of their food in the form of fat (59% vs. 33%). The low-carbers were less likely to endorse holding back food intake (15% vs. 62%) as a means of controlling weight, though they did specifically avoid eating carbohydrates (17% of calories vs. 47% of calories). Finally, the low-carbers indicated that they had expended significantly fewer calories in exercise per week than the control group did (1119 kcal vs. 2246 kcal).

The bottom line of the NWCR observations is shown in Figure 1 from the study, which is reproduced below. Note that weights are expressed in kilograms.

The low-carb participants lost slightly less than the other participants prior to study entry. Both groups regained some weight over the ensuing three years. (For those who are concerned about the intent-to-treat analysis, the authors report that the dropout rate was not significantly different between the two groups.) In the discussion, the authors conclude, "Comparing those individuals in the Registry who lost weight using a low-carbohydrate diet (n=96) vs. those who used other dietary strategies (n=795) we found no significant differences in magnitude of 3-year weight regain."

To reiterate, all of this data is anecdotal. It is compiled from a series of self reports, and as such is vulnerable to subjective errors. Nevertheless, a visit to the website of the National Weight Control Registry provides a great deal of interesting information, and suggests that successful long-term weight control may be possible on a low-carb diet.

The Scientific Method

2009-10-11T18:17:00.008-05:00

Aristotle was a Greek philosopher who lived from 384 BC to 322 BC. His works contain the first known formal study of logic, which he applied in many areas of life, including the field of science. Aristotle made extensive observations of natural phenomena and then applied logic to these observations in an effort to systematize them. Sometimes these logical inferences were correct, for example his deduction that the Milky Way is not shaded by the earth from illumination by the sun because the sun is too large and the stars are too distant for this to occur. Sometimes Aristotle's reasoning led to incorrect conclusions, such as his belief that the sun, stars and planets circle the earth. And occasionally Aristotle's conclusions were incorrect because his observations were not as careful as they might have been--for instance, he believed that men have more teeth than women, and that heavier objects fall faster than lighter ones.

Aristotle believed that observations coupled with reasoning could decipher the laws of the universe. He discounted experiments as artificial contrivances with little relevance to the natural world. When isolated events contradicted the laws of the universe as he understood them, they were regarded as "monsters" that could be ignored. Because Aristotle was very highly thought of as a philosopher and logician, it was regarded as a form of heresy to contradict the laws of science Aristotle had deduced from his observations. For that reason, his incorrect scientific ideas carried a great deal of weight at least until the 1500's.

In the 1500's, men such as Francis Bacon and Galileo Galilei brought changes to the study of science. Bacon rejected the idea of science by logical reasoning and syllogism. He advocated the use of observation, hypothesis and experiment leading to a gradual and systematic formulation of general axioms which could be disproven if evidence came forth to contracdict them (the scientific method, illustrated above). Galileo, as every schoolchild knows, availed himself of technology that had not been available to Aristotle. His telescope revealed that satellites orbited the planet Jupiter and that the planet Venus had phases just like the moon. While logic dictated that the earth was the center of the universe, experimental observations made by an Italian physicist indicated that this could not be the case.

When science was dominated by the application of deductive reasoning, scientific progress was slow to nonexistent. Even highly educated people believed in such things as phlogiston and spontaneous generation. Thanks to the scientific method, experiments were performed by Antoine Lavoisier, one of the men who discovered oxygen, and we now realize that burning is not a process of releasing an invisible, weightless substance called phlogiston, but a process of oxidation. Thanks to the scientific method in the hands of Louis Pasteur, we know that flasks of broth do not become cloudy by creating bacteria on their own, but that microscopic organisms can reproduce and multiply in a broth that initially appears clear.

With all of this in mind, it is surprising that some 21st century health experts wish to return to the days of science by deductive reasoning. While certain phenomena may appear to be true by anecdote or under certain conditions, without a systematic comparison of different interventions, there is no way to know for sure if eating a particular type of diet is good for weight loss, weight maintenance or (more importantly) the avoidance of the diseases of Western civilization. As Gary Taubes says at the conclusion of Good Calories, Bad Calories, "What's needed now are randomized trials that test the carbohydrate hypothesis as well as the conventional wisdom. ...it's hard to imagine that this controversy will go away if we don't do them, that we won't be arguing about the detrimental role of fats and carbohydrates in the diet twenty years from now. ...it's hard to imagine that the cost of such trials, even a dozen or a hundred of them won't ultimately be trivial compared with the societal cost."

Some investigators are doing randomized clinical trials, such as the A TO Z Weight Loss Study to compare diets such as Atkins, Ornish, Zone and a standard low-fat/high-carbohydrate diet. More of these studies need to be done, so that we can understand the specific health effects of eating various types of diets in various types of people over extended periods of time. And even in the context of low-carbing, it would also be helpful to have studies that examine the effect of eating saturated fats vs. polyunsaturated fats; eating at least 12-15 carbs' worth of vegetables per day vs. eating very few plant foods; including dairy vs. avoiding dairy in our diets; and taking various supplements vs. using no supplements. Until we have the studies to confirm or disprove our presuppostions, we are on shaky ground, just like Aristotle. Most of the time he was correct. Some of the time he was not. Without the scientific method, it's hard to know which is which.

Science by Syllogism

2009-09-21T15:59:00.016-05:00

A syllogism is a three-step deductive argument that moves logically from two premises to a conclusion. For example,

Premise #1: All whole foods are nutritious foods.
Premise #2: All whole foods are tasty foods.
Conclusion: Some tasty foods are nutritious foods.

If we assume that both of the premises are true, then logically the conclusion must also be true.

One way to express this is with a Venn Diagram.

The circle on the left represents all nutritious foods. The circle on the right represents all tasty foods. In the middle are whole foods, which are both nutritious and tasty. And we can see from the Venn Diagram that the conclusion of our syllogism is valid: Some tasty foods are also nutritious foods.

In November 1935 the explorer Vilhjalmur Stefansson published a series of articles called Adventures in Diet in Harper's Monthly Magazine. In these he described the health and diet of the Inuit, an indigenous people group of the arctic and subarctic of Canada. Sometimes low-carbers like to use Stefansson's descriptions to design scientific syllogisms. Once again, we will assume that the premises are accurate.

Premise #1: The early 20th century Inuit were free of the diseases of civilization.
Premise #2: The early 20th century Inuit ate meat, fat, and very little plant matter.
Conclusion: If a person in the 21st century eats meat, fat and very little plant matter, he or she will be free of the diseases of civilization.

Let's look at the Venn Diagram.

On the left are people who are free of the diseases of civilization. (For those unfamiliar with the term, the diseases of civilization have a greater prevalence in Westernized societies and include dental caries, obesity, heart disease and type-2 diabetes.) In the circle on the right are people who eat meat, fat and very little plant matter. In the center, occupying both the right and left circle, are the early 20th century Inuit. The Venn Diagram shows that there is an area of overlap between freedom from diseases of civilization and Inuit eating habits. The early 20th century Inuit fall in that area. But where do we find 21st century eaters of meat, fat and very little plant matter? They are not on the diagram, or if they are, we have no idea if they are in the area where the two circles overlap. The syllogism is invalid.

The other problem with the second syllogism is the definition of terms. Premise #2 states that, "The early 20th century Inuit ate meat, fat, and very little plant matter." For the Inuit, meat and fat meant seal, whale and polar bear, as well as arctic fish, which was sometimes eaten rotten. Plants meant grasses, tubers, roots, berries and seaweed. How many 21st century low-carbers would be willing to eat this type of food for an entire lifetime?

Science is done by making observations and formulating hypotheses. Logic does enter into the process, but logic is not enough. Once the hypothesis is formulated, it must be tested. The essential difference between science and syllogism is the experiment. The well-designed and repeatable experiment is the gold standard of science. If it turns out according to the hypothesis, the hypothesis remains intact and is subject to further testing. If the experiment does not turn out according to the hypothesis (and at least 90% of the time it will not), the hypothesis may need to be refined.

It is tempting to speculate that non-Inuit people living in Western cultures will be able to eat beef, pork, chicken and produce purchased from grocery stores or local farmers and experience the same health benefits observed in the early 20th century Inuit. However, without experiments comparing these two diets head-to-head in people of similar genetic background, engaged in similar lifestyles, over many years, it must be acknowledged that this type of justification for low-carb eating is based on syllogism, not on science.

---------------------------------------------------------------
Coincidentally, Jenny at Bloodsugar 101 Diabetes Update has just posted on the use of idyllic fantasies as arguments to support low-carbing: Let's Not Twist History To Support Our Beliefs.

Soon!

2009-09-20T21:18:00.003-05:00

For my readers who are missing their weekly dose of biochemistry, I should have something up tomorrow. Thanks for your patience!

Sleep Loss and Insulin Resistance

2009-09-06T20:43:00.008-05:00

I'm sleepy! As people in the modern era try to fit more activities and increasing responsibilities into their lives, how often do we hear this complaint, or even make the complaint ourselves? There just aren't enough hours in the day, it seems, and we compensate by cutting back on sleep. As the population ages, with people become more overweight and more subject to obstructive sleep apnea, the problem of getting enough rest is compounded.

We expect sleep deprivation to make us less alert. But one of the side effects of sleep loss is quite unexpected--both voluntary sleep restriction and disordered breathing during sleep result in insulin resistance. This is surprising on an intuitive level. Logically, we would expect that the less time we spend sleeping, the more time we would spend in being active and burning up extra calories. Many studies indicate that this is not the case.

Although most mammals sleep for a few hours at a time throughout the day, humans expect to get most of their sleep during a single seven to nine hour period. This entails a prolonged fast, and several mechanisms are present in human beings to enable this to occur. Cortisol is at a low level as sleep begins. Growth hormone is secreted to allow fatty acids that were stored during waking hours to be mobilized and used as fuel. During the first part of sleep, glucose levels increase because there is a decrease in the utilization of glucose in the brain and in the peripheral tissues. The increase in blood glucose is followed by an increase in insulin secretion. As sleep progresses, REM sleep causes the brain to use up some of the glucose, and the secreted insulin lowers the glucose levels further. The sleep cycle nears its end with cortisol levels starting to rise and continuing to do so until about 30 minutes after awakening, preparing the sleeper to face the challenges of the upcoming day.

Insufficient sleep or disrupted sleep interferes with this ordered hormonal cycle. In a review published in 2005, Spiegel et al. described the effects of sleep disruption on healthy adults. In sleep-deprived subjects, there was an increase in evening cortisol levels and in nighttime growth hormone concentrations. In the early part of the day, their glucose levels were higher and their insulin levels were lower. They also showed an increased appetite for food with a high carbohydrate content. Insufficient sleep is also associated with long-term weight gain. In light of that, another interesting finding was that sleep-deprived subjects saw a decrease in the satiety hormone leptin, and an increase in the appetite-stimulating hormone ghrelin.

Voluntary curtailment of sleep is one thing. Sleep disturbance can also occur as a result of obstructive sleep apnea (OSA). Obstructive sleep apnea is caused by the temporary collapse of soft tissues in the throat, resulting in the cessation of breathing many times during the night. The affected person may awaken with the sensation of not having rested properly, but be completely unaware that his breathing has been interrupted. If obstructive sleep apnea is suspected, the diagnosis can be made by polysomnography in a sleep lab.

As one might expect, obstructive sleep apnea also interferes with the sleep cycle. In 2002, Ip et al. showed that obstructive sleep apnea is also associated with insulin resistance, and that the fasting insulin level and insulin resistance both increased as the hourly number of apnea (no breathing) or hypopnea (very shallow breathing) episodes increased. Patients with obstructive sleep apnea have increased sympathetic (fight or flight) activity when they are awake as well as when they are asleep. The sympathetic hormone epinephrine causes glucose release and glucose synthesis, and its ongoing presence in people with obstructive sleep apnea could account for at least part of their observed increased in insulin resistance.

With all of that in mind, here are some suggestions for those who would like to do something about chronic sleep problems:

If you aren't reserving enough time for sleep, remember Benjamin Franklin. "Early to bed and early to rise makes a man healthy, wealthy, and insulin-sensitive." (I might have made up that last part.)

If you are having trouble sleeping, you may wish to consult this list of suggestions from the University of Maryland: Sleep Hygiene: Helpful Hints to Help You Sleep.

If you have obstructive sleep apnea, there are several possible approaches including weight loss, oral appliances, continuous positive airway pressure (CPAP), and even surgery. Here is a discussion of some of the options from the Mayo Clinic.

Insulin resistance. It's not just the result of a high-carb diet. Who knew?

Control of Overeating

2009-08-30T20:39:00.025-05:00

For many of those who have just started low-carbing, one of the best aspects of the diet is a new-found freedom from the constant need to eat. A low-carber can consume a reasonable portion of food, feel full, and not have to eat again until his or her next scheduled meal.

At least, that's true for many low-carbers. However, some low-carbers find that they still overeat, or that they continue to crave carbohydrates. What then?

One of the more interesting solutions to the overeating problem has been described by diabetes expert Dr. Richard K. Bernstein. He has observed that in some patients, Byetta (generic name, exenatide) is able to curb overeating and carbohydrate cravings. Byetta is an injectable drug that works very much like the natural gut hormone glucagon-like peptide-1 or GLP-1.

GLP-1 is one of the incretin hormones. Whenever food is eaten, GLP-1 is secreted by the L cells in the intestinal mucosa. GLP-1 has several actions:

It stimulates the release of insulin.
It inhibits the release of glucagon.
It slows stomach emptying.
It increases satiety.

When GLP-1 is given in an intravenous infusion to patients with type 2 diabetes, it is able to reduce blood glucose even in severe diabetes. Unfortunately, because GLP-1 has a half-life of about two minutes, it cannot be taken in the form of single injections. The drug Byetta is called an incretin mimetic because it is able to activate the same receptors used by GLP-1. Byetta's advantage is that, because it has a slightly different structure than GLP-1, Byetta has a half-life of about 2.4 hours.

In the treatment of diabetes, Byetta is typically given by injection twice a day, an hour before a meal is eaten. However, because of the 2.4 hour half-life, this means that Byetta cannot provide complete 24-hour control of blood glucose. For that reason, Byetta needs to be taken in combination with other oral hypoglycemic agents such as metformin and the thiazolidinediones. It is able to perform functions #1 and #2 of GLP-1, but it does not do them very well.

However, in its use for functions #3 and #4 (delay of stomach emptying and promotion of satiety), Byetta is much more promising. During a three-year open-label study of Byetta, an unexpected result was noticed. Investigators found that participants lost an average of 12 pounds over the three years, with one in four of these losing an average of almost 29 pounds.

Because of these observations, Dr. Bernstein began using Byetta to help treat overeating in patients who were in the early stages of diabetes. In Dr. Bernstein's Diabetes Solution, he says that he advises his patients to inject 5-10 micrograms of Byetta about one hour before the times when snacking or overeating typically occur. The maximum daily dosage of Byetta is 20 micrograms per day, permitting as many as four injections daily.

Patient reports indicate that Byetta reduces appetite and/or carb cravings for many people but not for all of them. There is no way to predict beforehand who will or will not respond, but it takes only about a month to determine whether a particular person is in the group that can benefit from the weight-loss aspects of the drug. If it does work, it gives the patient the opportunity to train himself or herself in the habit of eating healthy low-carb foods in moderate portions. In that way Byetta is somewhat similar to weight-loss surgery. It is able to give the patient a period of time to adapt to eating less food and making better food choices, but the use of Byetta also allows the patient to avoid the dangers of anesthesia, surgical wound healing and impaired absorption of vital nutrients.

The Ketogenic Diet and Epilepsy

2009-08-23T21:31:00.014-05:00

The logo in the picture above belongs to the Charlie Foundation. "Charlie" is Charlie Abrahams, the son of a Hollywood producer named Jim Abrahams. In 1993, at 20 months of age, Charlie had been having up to 100 epileptic seizures a day. Although he was on several powerful anti-seizure medications, and had even had brain surgery, Charlie's seizures continued. His parents tried everything they could think of to help him. Finally they learned of an old treatment for epilepsy called the ketogenic diet. It consisted of approximately 90% fat, with adequate protein for growth and a very small amount of carbohydrate.

The ketogenic diet had originally been invented in the 1920's. Early in that decade, a physician named Hugh Conklin began to treat children with epilepsy by having them consume only water for 10 to 25 days. Amazingly, when the children resumed normal eating, many of them were found to be seizure-free for long periods of time. Although enforced fasting was a difficult treatment for these children, at that time it was considered a reasonable alternative to a lifetime of constant seizures. Eventually investigators discovered that seizure reduction could also be achieved with a diet that produced many of the effects of starvation while providing sufficient calories for survival and growth. The key was that the diet was very high in fat and very low in carbohydrate and, like starvation, it produced a large amount of ketone bodies including acetoacetate and beta hydroxybutyrate.

Low-carbers know that on a standard American diet, the tissues of the brain use glucose as their primary fuel. They also know that on a low-carb diet, after a period of metabolic adjustment, most of the tissues in the brain are able to use ketone bodies for fuel. For low-carbers, this is just an interesting fact. However, for children in the 1920's with epilepsy, it had profound implications. By maintaining a high level of ketones and a low availability of gluocose for their brains to use as fuel, many children were able to reduce or avoid epileptic seizures altogether.

Then in 1938, a new drug called Dilantin (phenytoin) was introduced. Dilantin proved to be such an effective anticonvulsant that physicians began to turn their attention to pharmaceutical interventions for epilepsy, and the dietary approach to the treatment of epilepsy was all but forgotten. By the 1990's, Johns Hopkins Hospital was one of the few places that treated epileptic children with a ketogenic diet, and even they initiated treatment on only about ten patients per year.

That's where Charlie Abrahams entered the picture. After two days on the Johns Hopkins ketogenic diet, Charlie was seizure-free. (Remember, he had been having up to 100 seizures per day.) After a month, he was off all of his seizure medication. Understandably, his parents were impressed. They used their resources and contacts to establish the Charlie Foundation in order to help other parents whose children were not responding well to standard epileptic treatments.

Fifteen years later, Charlie Abrahams himself is still doing well and can be seen to be a normal teenager in a video filmed in 2008. Because of the resurgence of interest in the ketogenic diet, in 2007 the American Academy of Pediatrics published a review article called The Ketogenic Diet: One Decade Later. The article discusses the dramatic increase in the use of the ketogenic diet for the treatment of epilepsy. Although the mechanism by which the diet reduces seizures is still a matter of speculation, the diet appears to be effective in children of different ages and can be used to treat both generalized and partial seizure disorders. About half of the children who initiate the diet are not able to follow it long-term, but among the rest, about 10%–15% of are seizure-free one year later, while another 30% experience a 90% reduction in seizures. For those who cannot follow the strict ketogenic diet, a small study using a diet that approximated Atkins Induction found that 65% of patients had a 50% reduction in seizures and 35% had a 90% reduction.

The review article as well as the website for the Charlie Foundation make fascinating reading. If you have epilepsy or if you have a child who has epilepsy, it is important to contact experienced professionals before attempting to do the ketogenic diet. It turns out to be much more complicated than just picking up a copy of Dr. Atkins' Diet Revolution and forging ahead on your own. But there appears to be lots of help available for those who would like to consider using a ketogenic diet an an additional approach to the management of difficult-to-control epilepsy.

Natural Chemicals

2009-08-16T18:22:00.008-05:00

My training is in chemistry. Because of that, I tend to see the world as an array of chemicals, from the the cotton in my clothes to the gasoline in my car. But a comment on last week's post reminded me that in recent decades we have been trained to see chemicals in two different classifications--natural and man-made. We have been taught that natural things are by definition good and man-made things may very well be bad and could hurt us in the long run. For those of us who are interested in healthy eating, the distinctions have particular significance. In the world of low-carbing, are natural foods the safest foods? Not necessarily.

One of the natural foods we have been discussing lately is fructose. It's found in high-fructose corn syrup, of course, but it is also found in fruits and honey. Regardless of where it's found, fructose is fructose. The molecule stays the same. And the molecule fructose, when eaten in large quantities, is able to produce a fatty liver, protein glycation, and even gout.

Another natural food is potatoes. Potatoes are not recommended on low-carb diets, but some of us can't keep away from the french fries and chips. Potatoes are in the nightshade family of vegetables and contain the glycoalkaloids solanine and chaconine. These chemicals are acetyl cholinesterase inhibitors and are used to protect the potato from attack by fungus and insects. Unfortunately, they also have a negative effect on some people. They can produce joint pain and symptoms of digestive inflammation, and even mental confusion in a few cases. Cooking destroys some but not all of the glycoalkaloids in potatoes.

Whole wheat is beloved of those who promote a natural lifestyle. Wheat contains proteins called lectins, which act as a primitive immune system for a plant. When wheat is eaten by bacteria, insects, rodents or humans, the ingested lectins are able to bind to cell walls and membranes and cause the clumping of cells, as well as inappropriate cell division and hormone reactions. These effects can cause inflammation and damage to the lining of the small intestine, as well as possible autoimmune reactions if the lectins are absorbed into the circulation. Cooking or baking is able to break down some lectins but not all of them. It is interesting to note that early agriculturalists knew how to decrease lectin content by sprouting and fermenting the wheat they harvested.

Corn oil is another all-natural product that is used both in cooking and in the manufacture of margarine. Corn oil is high in total polyunsaturated fatty acids as well as omega-6 polyunsaturated fatty acids. A recent study in Sweden has shown an association between omega-6 fatty acid intake and breast cancer. A 2006 study showed that the addition of omega-6 fatty acids to prostate tumor cells doubled their growth rate in culture. Another study showed a similar result in a strain of mice that was bred to be susceptible to prostate cancer.

What does all of this mean? Is anything safe to eat? Probably not, but there are obvious risks to fasting indefinitely.

What these examples imply is that a description of "natural" is not a guarantee of safety. Not only that, it wouldn't matter if the foods described above were grown in an organic way on local farms or in the conventional way on huge industrial farms. The natural chemicals (fructose, glycoalkaloids, lectins, omega-6 fatty acids) would be there whether or not organic farming methods were followed.

Fortunately for us, experience has shown that humans are well able to tolerate small amounts of toxic substances. However, for those who are interested in following a maximally healthy lifestyle, each food needs to be considered on its own. Animals defend themselves with horns and hooves. Plants defend themselves with chemicals. Some of these chemicals are beneficial, but some are not, and it pays to be aware of the differences.

Diet Drinks, Ups and Downs

2009-08-09T20:15:00.010-05:00

Diet drinks are one of the mainstays of the low-carb community. Diet Coke, Diet Pepsi, Diet Rite and many more provide fairly palatable carb-free alternatives to sugar-laden soda pop.

Some low-carbers drink all sorts of diet drinks and claim they have no problems with them. Others state that diet drinks cause them to gain weight or cause them to stall in their weight-loss programs, almost as if they were drinking the full-sugar equivalents. One of the ways to look at this phenomenon is to see if diet drinks cause the release of insulin.

One possibility is that the sweet taste of the diet drinks causes a cephalic or first-phase insulin response. Two 1995 studies by Teff, Devine and Engelman had normal-weight men sip and spit solutions that contained either water, aspartame, saccharin, or sucrose. Blood was drawn before and at two-minute intervals after the solutions were tasted. They found no significant increase in plasma insulin, even though the men had tasted the sweetened solutions for as long as three minutes.

Another possibility is that the presence of a sweet taste in the gut causes the release of peptides, and these in turn increase the secretion of insulin as part of a second-phase insulin response. It has recently been found that there is a TR2+T1R3 sweet taste receptor in the intestinal endocrine cells of the gut. In 2007, Margolskee et al. demonstrated that sucralose (brand name, Splenda) could activate this receptor in dishes of intestinal endocrine cells and cause the release of two incretin hormones, GLP-1 and GIP. In a whole organism, the incretin hormones would be expected to promote the release of insulin.

In 2009, Jin Ma et al. tested this hypothesis by infusing 500 ml of various solutions into the stomachs of seven healthy humans. (Putting a solution directly into the stomach bypassed any possible cephalic insulin response.) The first solution contained 50 grams of sucrose in water. The remaining solutions were: normal saline, 80 mg of sucralose in normal saline, and 800 mg of sucralose in normal saline. Of the four solutions, only the sucrose solution caused an increase in blood glucose. And contrary to the findings expected from the intestinal endrocrine cell study, only the sucrose caused an increase in GLP-1, GIP and insulin. The saline and sucralose solutions had no effect. Fujita et al. saw similar results when diabetic Zucker rats were given gastric boluses of solutions of glucose, sucralose, saccharin, acesulfame potassium, and stevia. Only the glucose solution affected the blood glucose, and only the glucose solution
increased the plasma GLP-1 and GIP levels. The artifically-sweetened solutions had no effect.

To drink or not to drink? A recent review of the literature in the American Journal of Clinical Nutrition noted that the use of nonnutritive sweeteners has increased along with the increase in Body Mass Index (BMI) in the United States. However, the authors found that if this is a cause-and-effect relationship, most of the mechanisms by which it is postulated to occur cannot be supported by current evidence. As we can see from the studies cited above, it appears that increased first-phase or second-phase insulin secretion is probably not a good explanation for any gain in weight as a result of diet drinks. As always, research is ongoing, but for now it looks as if diet drinks can be consumed without undue worry about their effect on insulin secretion and an insulin-associated gain in weight.

Blood Glucose, Cancer, and Coronary Heart Disease

2009-08-02T22:09:00.017-05:00

Elevated blood glucose is most often associated with the symptoms of diabetes, such as retinal damage, kidney failure and peripheral neuropathy. However, the consequences of hyperglycemia are not confined to diabetics. As blood glucose values rise in nondiabetics, it is possible for them to experience an increased relative risk of cancer and of coronary heart disease as well.

In 2007, Par Stattin and colleagues published a prospective study that investigated a possible relationship between hyperglycemia and the risk of various forms of cancer. More than sixty thousand Swedish men and women with no previous history of diabetes were studied over a 13-year period. During that time approximately 2,500 cases of cancer were identified in the study group. The investigators looked at the relationship between fasting glucose levels and the risk of cancer in this nondiabetic population. Among the participants who had elevated fasting blood glucose, there were small but statistically significant increases in the relative risk for several specific types of cancer. These included pancreatic cancer, cancer of the urinary tract and malignant melanoma. In women there was an increased risk of endometrial cancer. Among women less than 49 years of age, there was an increased risk of breast cancer. On the other hand, in men there was actually a decrease in the risk of prostatic cancer as fasting blood glucose levels rose.

Nondiabetics were also shown to have an association between glycemic control and the risk of coronary heart disease in a 2005 study published in the Archives of Internal Medicine. In a prospective study, investigators followed 1321 nondiabetic adults to assess a possible relationship between the level of hemoglobin A1c (HbA1c) and the incidence of coronary heart disease.

Hemoglobin A1c measures the percentage of glycated hemoglobin in a patient's red blood cells. The HbA1c value provides a picture of a person's average blood glucose control for the previous 2 to 3 months. The normal range for HbA1c in people without diabetes is
4% to 6%. For diabetics, the American Diabetes Association recommends that the HbA1c be maintained at 7.0% or less.

The nondiabetic patients in the coronary heart disease study were followed for 8 to 10 years. In order to remove possibly confounding variables, when the data was analyzed, it was adjusted for age, race, sex, BMI, blood pressure, LDL cholesterol, HDL cholesterol, triglycerides and smoking status. The adjustments for these risk factors allowed the investigators to examine whether hyperglycemia might provide an independent risk factor for coronary heart disease. They found that when HbA1c was below 4.6%, the adjusted data showed no apparent relationship between glycemic control and an increased risk of coronary heart disease. However, as the HbA1c rose above 4.6%, the adjusted data showed that not only did the risk of coronary heart disease rise, but it did so at an ever-increasing rate. The study found that the risk of coronary heart disease in nondiabetics rose 2.4-fold with every 1% increase in HbA1c above 4.6%.

Findings similar to those seen in both of these studies have also been reported by other investigators, and references can be found within each paper. However, it is important to remember that correlation does not equal causation. The relationship between increased blood glucose in nondiabetics and the incidence of cancer or the incidence of coronary heart disease may rest upon variables that are not as yet defined. However, it is worth noting that it may be important even for nondiabetics to keep an eye on their fasting blood glucose and their HbA1c.

Glycosylation and Glycation

2009-07-26T13:19:00.004-05:00

In light of recent discussions about increased protein intake producing a rise in blood sugar, this seems to be a good time to repeat a post from 2008. It helps explain why elevated blood sugar can present potential long-term health risks.
---------------------------------------------------
When proteins are assembled in our cells, sometimes specific sugar molecules are attached to them in carefully-defined ways. This is called glycosylation. Enzymes add the sugar molecules to help proteins fold properly and to route proteins to various places inside and outside the cell. Glycosylation patterns also help our bodies to distinguish proteins that are "self" versus "not-self" and are useful in immune responses. Glycosylation results from controlled reactions and is important for our biochemical wellbeing.

When we have glucose in our blood (and if we're alive, we do), sugar molecules are also added to proteins in a random fashion. The random addition of sugar molecules to proteins is called glycation. If only single glucose molecules have been added to a protein, when the blood sugar level drops, the glucose can detach and the protein will again be normal. But if blood glucose remains high, more sugars will be added. These will rearrange and crosslink, eventually producing something called an Advanced Glycation Endproduct or AGE. One example of an AGE is hemoglobin A1c, the form of hemoglobin found elevated amounts in the red blood cells of poorly-controlled diabetics. Evidence suggests that many other proteins in our bodies are also converted into Advanced Glycation Endproducts by elevated blood sugar. Glucose and fructose in the blood interact with and crosslink these other proteins in our bodies, forming AGEs that accumulate in our eyes, kidneys, arteries, nerve endings, joints and skin. The end result of AGE accumulation can be retinal disease, kidney failure, atherosclerosis, peripheral neuropathy, frozen joints and cracked skin.

Although our bodies have mechanisms to cope with the identification and disposal of AGEs, the AGEs gradually accumulate and stiffen our tissues. The elasticity of youth is slowly replaced by the physical degeneration of old age. In other words, crosslinked AGE proteins produce in us the symptoms we associate with old age. This happens in all people, but the process is made worse and happens more quickly in the presence of elevated blood sugar.

(The illustration is taken from the cover of the journal Science, March 23, 2001.)

How Can Eating Excess Protein Raise Blood Glucose?

2009-07-21T12:52:00.012-05:00

It is almost an article of faith among low-carbers that the low-carb lifestyle is able to lower blood glucose values in diabetics and pre-diabetics. It would be logical to assume that the lower the carbohydrate intake, the lower the corresponding blood glucose. But recent observations in a limited sample of people who were doing something very close to zero-carbing suggest that this is not necessarily the case.

Donald K. Layman has done some interesting work on the effect of dietary protein on glycemic control that may help explain this phenomenon. In an article in The Journal of Nutrition, he presents a diagram of the glucose-alanine cycle, which appears in modified form above.

For those who are not familiar with this type of diagram, here is a brief explanation. Ingested protein enters the gut and is digested into amino acids. The amino acids are taken up in the blood and proceed to the liver, where many of them are metabolized. However the branched-chain amino acids leucine, isoleucine and valine are unique. Although they constitute 15-25% of protein intake, they experience very little metabolism in the liver. Most of the branched-chain amino acids, abbreviated BCAA, continue to move through the circulation and are eventually absorbed by muscle cells.

In muscle cells the branched-chain amino acids have two possible fates. First, when branched-chain amino acids enter a muscle cell, they promote protein synthesis. Our muscle tissue is continually undergoing repair, and because of this each of us has an individual daily protein need. If sufficient high-quality protein is consumed, this repair is able to take place without loss of lean muscle tissue.

Second, if there is an excess of amino acids in the muscle cells, the surplus branched-chain amino acids enter the pathway of energy production. In order to do this, they must have their amino group (NH₃)removed in a process called transamination. The amino group from a BCAA is transferred to a molecule called alpha-keto-glutarate to form the amino acid glutamate. Next, another transamination transfers the amino group from the glutamate to pyruvate, transforming the pyruvate into the amino acid alanine. The alanine leaves the muscle cell and travels to the liver, where it is turned into pyruvate by removal of the amino group, and then the pyruvate is turned into glucose by gluconeogenesis. The liver sends the newly-synthesized glucose into the blood, where it can be taken up by muscle cells and broken down once again into pyruvate. Each pyruvate is ready to accept another amino group from one of the branched-chain amino acids, and the cycle repeats itself until the branched-chain amino acids have been used up.

The glucose-alanine cycle explains why it is possible to have an elevated blood glucose while eating essentially only meat and fat. Normally, leucine signals the muscle cells to synthesize protein and maintain lean body mass. When an excess of branched-chain amino acids is available, leucine serves as a metabolic signal to muscle cells telling them to upregulate their use of BCAA as a fuel, while simultaneously downregulating their use of glucose as a fuel. Any glucose that appears in the cell is preferentially broken down into pyruvate, which is used to accept excess amino acid nitrogen (NH₃ groups) and allow them to be removed them from the cell in the form of alanine. In the liver, the alanine is recycled into glucose, and the glucose is returned to the blood until it is no longer needed to mop up excess NH₃ groups in peripheral tissues.

If this pathway is correct, it shows that excess amino acids not only provide the raw materials for glucose synthesis in the liver, but they also require additional glucose synthesis in the liver in order to allow branched-chain amino acids to be converted into energy.

Metabolic regulation is a huge topic, and this post presents only a small piece of it. Once again, please do not modify your lifestyle in accordance with what you read here. In the overall context of a human organism, it may be incomplete or even incorrect. However the glucose-alanine cycle does provide a possible explanation for what some people have seen with regard to a higher-than-normal blood sugar while eating essentially zero carbohydrates.

Observations on Protein Intake in Low-Carbers

2009-07-13T17:45:00.021-05:00

Last week I asked if people doing low-carb or zero-carb might be willing to test their blood glucose before and after meals and report their results. Many finger sticks later, we have a few tentative observations. Please note, this was NOT a scientific study in any way. Don't change your life or your eating habits based on what you read here. The purpose of this post is to consider ideas and to raise possibilities, particularly if you have been having trouble succeeding on low-carb or zero-carb. That said, here are the patterns that seemed to emerge from the data.

1. Some people, particularly people over 50, do have an increase in blood glucose following meals that are either entirely or mostly meat and fat. Dr. Bernstein says the optimum level of blood glucose is 83 mg/dl. For zero-carbers over 50, the fasting blood glucose was often somewhere between 95 and 110 mg/dl and could even go as high as the high teens. For long-time low-carbers over 50, fasting blood glucose was usually somewhere in the 80's. In both low-carbers and zero-carbers over 50, it was not unusual to have a 30-40 mg/dl rise in blood glucose after consuming a large amount of protein, such as a 12-ounce ribeye. Because protein is slowly digested, blood glucose levels sometimes stayed elevated for three to five hours or longer. It is important to remember that at blood sugars above about 100 mg/dl, insulin is secreted and its presence keeps fat in the fat cells. This may explain why low-carbers over 50 have such a hard time losing weight if they eat as much protein as they want. Insulin levels stay elevated for long periods, forcing most of what they eat into storage, and keeping it there until insulin levels finally come down again.

2. Most people under age 50 do not have a rise in blood glucose following a meal, even a large meal, that is mostly meat and fat. I had three participants in the under-50 group whose blood sugars stayed approximately in the 80's following meals ranging from a 1/3 pound hamburger to a ribeye steak. Two of them told me that they occasionally see rises to near 100 mg/dl, but often there is no rise at all.

3. Decreasing protein intake in two participants over 50 to the amount recommended at Blood Sugar 101 caused a decline in average pre-meal blood glucose to the low 90's and post-meal glucose values between about 90 and 110 mg/dl. In fact, both of them started losing weight again after several months of eating as much protein as they wanted and gradually gaining weight.

4. And then there were the outliers, which I shall address below.
Two participants occasionally experienced a fall in blood glucose following a low-carb meal. Neither has been diagnosed with diabetes. Nevertheless (unless they were eating more carbs than usual), their blood glucose sometimes declined after they had eaten a low-carb meal of meat and vegetables. One was a man and one was a woman. One was under 40 and one was over 60. The woman, SC, suggested to me that it might have something to do with the fact that she is a super-taster. When I checked with the other one, who happens to be Jimmy Moore, it turned out that he is also a super-taster. Just to be sure, I checked with super-taster Cleochatra. She did not have blood glucose data to give me, but she said, "I can tell when I've eaten a carrot, even when it's been hidden in a dish, because my stomach is growling within minutes and I want to dive face first into various vats of puddings. I can say in all honesty, artificial sweeteners made me starve...and when I'm VLc I feel fantastic. No woobly or feelings of hunger at all." Later she specified that Splenda and the sugar alcohols are the artificial sweeteners that affect her.

[In the comments, Mariasol asked what made a person a super-taster. Although there are tests for this ability, I simply used an informal question as a criterion: If I poured out five unlabeled dixie cups of Diet Rite, Diet Pepsi, Diet Coke, Coke Zero and Splenda Coke, could you correctly label each cup with the brand, based on taste alone? If your answer to that question is yes, you probably are a super-taster. Subsequently, I have been told that when a super-tasters are cooking something and then add in the salt, they can smell the salt. Just like everything else in this post, the super-taster information has been collected in a non-rigorous manner, so please do not take it as settled science.]

From a limited sample size of three, I can speculate that super-tasters are the ones whose insulin is on a hair-trigger. As soon as they eat, or maybe even before they eat, they secrete enough insulin to nail any food that might appear in the stomach. And if that food happens to be diet soda, it's possible that the insulin secretion occurs anyway. This can either trigger hunger pangs, or if the diet soda is consumed continuously, can keep insulin levels relatively high and thus prevent fat mobilization and weight loss.

All of this is anecdotal. It didn't come down on tablets at Mt. Sinai, so various parts of it could be wrong. But I present it as something worth thinking about in the context of a low-carb lifestyle.

Very many thanks to Cleochatra, ES, D, Jimmy Moore, K, KM, LR, SC, SG, SO, V, VS, P and U for providing data that was used in this blogpost.

Protein Intake and Blood Glucose Levels

2009-07-05T22:04:00.019-05:00

Low-carbers know that when a person eats foods that contain carbohydrates, his blood glucose will rise. As the pancreas releases insulin in response, the blood glucose levels will gradually return to normal.

What happens when a person eats protein? Insulin is released in response to protein as well, enabling the amino acids to be removed from the blood and stored in the tissue. The cells don't know the insulin is there to remove amino acids from the blood, so they will take up glucose from the blood as well. To prevent hypoglycemia, the liver gradually releases glucose into the blood to replace the glucose that has been stored.

In the graph above, the white lines show us that when a normal person eats 50 grams of protein, the blood glucose remains the same out to five hours after the meal, even though a significant amount of insulin has been released. The person with type 2 diabetes is represented by the yellow lines. His blood glucose levels start out at a much higher level, but when he eats 50 grams of protein, his blood glucose levels also stay steady out to two hours and then actually begin to drop because a great deal of insulin has been released. These graphs are found at Metabolic response of people with type 2 diabetes to a high protein diet.

It is important to realize that the response to protein in both the diabetic and non-diabetic person are happening in people who are not low-carb-adapted. Low-carbohydrate-adapted people are able to make all the carbs they need through gluconeogenesis. Their brains and muscles have switched over to the use of ketones and fatty acids for fuel, and the 40 or so grams of glucose they need for glucose-requiring tissues are readily converted from glycogenic amino acids and the glycerol backbones of triglycerides. So, what happens when a person who eats very low carbs has a meal of protein? For a rather extreme example, look at the graph below.

Lex Rooker is a very dedicated and meticulous individual who posts at the Raw Paleo Forum. (In no way do I either support or condemn what Lex does regarding his diet, but his journal certainly makes fascinating reading.) For about two years, Lex ate a single daily meal in the afternoon, at the time marked by an asterisk on the graph. This meal contained 150 grams of protein and consisted of 68% fatand 32% protein. As you can see, his blood glucose remained rock-steady at about 106 mg/dl throughout the day. But a couple of hours before he ate, it would drop to 95 mg/dl. After he ate a meal consisting solely of meat and fat, his blood glucose would rise about 25 mg/dl, returning to baseline in about four hours. (The graph shows a rise of 15 mg/dl, but he refers to the amount of the rise several times, so this may be an error in the graph.)

At one point Lex decided to switch things up a bit. He kept his calories the same, but ate only 90 grams of protein per day, making the ratio 80% fat and 20% protein. His baseline blood glucose dropped into a range between 68 and 78. After his single daily meal of meat and fat, his blood glucose would rise about 15 mg/dl, though it would take longer than before to come down to baseline. It appears that decreasing the amount of protein intake also decreases the amount of glucose released into the blood of a low-carb-adapted person.

People who are not low-carb-adapted do not do much gluconeogenesis because they get plenty of glucose from their diet. People like Lex Rooker who eat no carbs at all, apparently do quit a bit of gluconeogenesis. Low-carbers fall somewhere in between those two points. This provokes a question to which I do not currently have an answer: What does a normal blood glucose curve look like in a low-carber? If he chooses to eat only meat and fat at a particular meal, does his blood glucose rise or does it stay steady? If he eats a few carbs with each meal, does it rise less, or does it rise more than it would without the carbs?

In other words, this time it's not a blog, it's a bleg. If anybody has data on what a normal (or abnormal) daily blood glucose curve looks like in a low-carber, would you please share that information in the comments? Thanks!

(If any of the graphs are too fuzzy to read, just click on them and you'll get a clearer version.)

Glycogen Stores Energy

2009-06-28T20:08:00.015-05:00

Adipose or fat tissue stores most of the body's energy reserves in the form of triglycerides. The body is also able to store a limited amount of energy as carbohydrates, and it does it in the form of glycogen.

Glycogen is a large, complex molecule made up of branched chains of glucose molecules. The illustration above, found at Wikipedia, shows a cross section through the middle of a spherical glycogen molecule. At the center is a glycosyltransferase enzyme. The enzyme takes glucose-6-phosphate (the form of glucose found inside a cell) and strings it together as long, branched chains. In the picture above, each tiny circle represents a glucose molecule. The glycogen molecules are therefore large polymers of glucose which are then packed together and stored in granules in the cytosol of liver and muscle cells.

Glycogen makes up as much as 10% of the weight of the liver and represents about 100 grams of glucose in the adult human. Glycogen in the liver can be broken down first into glucose-6-phosphate and then into glucose. In the form of glucose it can be released back into the circulation. In a previous post we have seen that release of glucose from liver glycogen is the body's chief means of maintaining a normal blood sugar between meals.

Glycogen can also be stored in skeletal muscle, as illustrated in the figure below.

When glucose is present in the blood (and in a living person, it always is), a muscle cell is able to take up the glucose both actively and passively. Once the glucose is inside the muscle cell, the glucose molecule is phosphorylated. This adds a large ionic group which makes it impossible for the glucose to diffuse back out of the muscle cell. The phosphorylated glucose then has two possible fates.

It can proceed directly into glycolysis and be turned into pyruvate. If there is enough oxygen available, the pyruvate will enter the mitochondria and be turned into lots of ATP, the energy currency of the cell. If there is not enough oxygen available, the pyruvate will be turned into lactic acid plus a little ATP. The buildup of lactic acid produces a sensation of pain, and the pain will continue until the lactic acid diffuses back out of the muscle cell, a process which takes about an hour.
Alternatively, the phosphorylated glucose may instead be stored in the muscle in the form of glycogen. Muscle glycogen makes up only 1-2% of the weight of skeletal muscle, but because the body contains so much skeletal muscle, the total quantity of muscle glycogen in an adult is about 200 grams.

What makes muscle glycogen different from liver glycogen is that when muscle glycogen is broken down, it cannot leave the cell. Muscle cells lack the enzyme that removes the large ionic phosphate group from the glucose, and the glucose cannot be returned to the blood. For that reason, the phosphorylated glucose must be used inside the muscle cell. What then?

No problem. The phosphorylated glucose feeds right into the glycolytic pathway inside the muscle cell, where it is turned into pyruvate and lots of ATP or into lactic acid and a little ATP, depending on the amount of oxygen available to it.

When we hear about carb loading for athletic events, it is tempting to think that most of the energy in our muscles comes from carbohydrates. It does not. There is only a little glycogen stored in each muscle cell, and it is easily exhausted. Compare the 200 grams of total muscle glycogen with the pounds of fat available in a healthy individual, and it becomes obvious that muscle cells must use free fatty acids for most of their energy. This is illustrated on the right side of the illustration above. As seen previously (How Are Fats Metabolized?), once the free fatty acids are inside the cell, they are broken down very efficiently to produce much more ATP than could be obtained from an equal number of glucose molecules. However, when an extra burst of energy is needed, muscle cells are able to use the glucose they have stored in glycogen granules to supply a little more ATP than they would normally receive from using fatty acids alone.

Low-Carb Doesn't Work!

2009-06-18T15:31:00.011-05:00

Low-carbers hear it over and over. "I can't get to goal." "Nobody I know has reached goal." "Almost all the low-carb gurus are obese."

There are many reasons for weight loss to slow or stop while low-carbing. Read any of Dr. Atkins' books or follow any of the low-carb websites and you will find lots of possible explanations, including factors like low thyroid function and yeast infections.

Another reason for failure to lose weight and for weight regain on low-carb is seldom mentioned. An example is pictured above--low-carb substitutes for high-carb foods. (The picture is taken from a post about a low-carb sponge cake at Cafe Nilson.) But low-carb substitute foods are still low-carb! Why should they interfere with a low-carb diet?

A 2005 study on binge eating in rats may give some insight. In one experiment, the rats were separated into two groups, food-sated and food-restricted. They were then exposed to several food choices, including normal rat chow and a cereal called "Choc and Crisp" which appears to be a German version of Cocoa Krispies. The food-restricted rats took about three minutes to find the rat chow, and they ate about half a gram of it. By contrast, they found Choc and Crisp in only ten seconds and when they reached it, they ate nearly five grams of it.

As expected, the food-sated rats were not interested in the rat chow. They took about 20 minutes to wander over to it and when they got there, they didn't eat it. However, even though these rats had already eaten until they were full, the food-sated group took one fiftieth of that time (25 seconds) to find the Choc and Crisp, and once they reached it, they ate 3 grams of it, or 60% of the amount the food-restricted rats had consumed.

To confirm these responses, each rat was put on a runway with a food-filled box at the other end. When the goal box contained rat chow, it took the food-sated group about 40 seconds to reach the goal, while the food-deprived ones took about 10 seconds. Not surprising. However, when the goal box contained Choc and Crisp, both groups made the trip in about five seconds, though the food-restricted group was a little faster. One might expect that after the first day, the rats would be less excited about the Choc and Crisp, but the time needed to reach the goal boxes persisted over ten consecutive trial days.

The obvious conclusion is that if you feed pet rats with Cocoa Krispies, they will probably get fat. A less obvious inference might be that if a low-carber is freqently exposed to low-carb versions of very enticing high-carb foods, he or she will probably eat those foods to excess. The rat study indicates that the easy availability of very palatable foods may shut off the body's ability to adjust food intake to match energy expenditure. What happens in a rat does not necessarily happen in a human, but their tendency to eat much more of a very palatable food is definitely something to consider when low-carbers have a hard time reaching or maintaining their goal weight.

How Are Fats Metabolized?

2009-06-09T15:34:00.012-05:00

In a previous post we saw that the fats we eat are made up of a group of molecules called tri-glycer-ides--three fatty acids covalently bonded to one glycerol backbone. In a subsequent post we learned that triglycerides are absorbed, packaged and transported to the cells of the body through the circulatory system. In muscle cells these triglycerides can be used for energy, and in adipose tissue (fat cells), they can be stored for future use.

What happens when it is time to use the fat we have stored in our bodies? The first thing that must happen is that insulin levels must be low. In the presence of low insulin, the hormones glucagon from the pancreas or epinephrine from the adrenal glands will stimulate the activity of hormone-sensitive lipase (HSL). Hormone-sensitive lipase (plus another enzyme called diacylglycerol lipase) will convert a triglyceride stored in a fat cell back into one glycerol molecule plus three fatty acids.

Once the fatty acids are detached from the glycerol backbone, they are able to dissolve in the cell wall of the adipocyte or fat cell. From there they are able to diffuse passively out of the adipocyte back into the blood, where they attach themselves to serum albumin and are carried throughout the body. The free fatty acids are able to diffuse passively into tissues as well.

Once inside one of the body's cells, the free fatty acid is activated with a "handle" called CoA. (Pronunciation note: CoA rhymes with "No Way." It does NOT rhyme with Boa.) The fatty acid plus its handle is called acyl-CoA. The acyl-CoA heads for a mitochondrion, a small organelle that functions as the powerhouse of most cells. Once inside the mitochondrion, the acyl-CoA is dismantled, two carbon units at a time. Each time a two-carbon unit is released, energy is produced from the breaking of the covalent bonds. Not only that, the two-carbon units themselves enter something called the TCA or tricarboxylic acid cycle where they are broken down further to produce carbon dioxide plus even more energy.

The energy released by all of these chemical reactions eventually results in the formation of many molecules of adenosine-5'-triphosphate or ATP. ATP molecules are the energy currency of the cell. The energy contained in ATP molecules is used for activities such as building the tissues the body needs, fueling the reactions that enable the body to move, and coordinating the activities the body needs to stay alive.

Did you ever wonder why robots need some sort of external or rechargeable power supply but people do not? The robot relies on electricity for its energy source. People, by contrast, rely on ATP for their energy and, amazingly enough, that ATP can be produced from something as simple as the fat they eat for dinner.

The Swedes Are Eating More Butter!

2009-06-01T23:51:00.011-05:00

The graph above shows tons of butter (ton/år) sold per year in Sweden. From April 2007 to April 2008, sales of butter in Sweden went up by 13%. Therein lies a tale.

Doctor Annika Dahlqvist was a family practitioner at the Njurunda clinic in Sweden when her daughter, a physician in training, took part in a low-carbohydrate dietary study. The results were so impressive that Dr. Dahlqvist tried the low-carb diet for herself. She was pleased that she was able to lose weight, and she also noticed that her problems with gastrointestinal inflammation and fibromyalgia were significantly improved. She began recommending a low-carb, high-fat (LCHF) diet to her patients who suffered from type 2 diabetes and obesity.

The idea of a low-carb, high-fat way of eating was no more welcome in Sweden than it has been in the United States. In December 2005, the chairman of the Swedish National Association of Dieticians made a formal complaint to the Swedish National Board of Health and Welfare, questioning Dr. Dahlqvist’s low-carb dietary advice and suggesting that it might jeopardize the safety of her patients. Dr. Dahlqvist was threatened with the loss of her medical license.

Although Dr. Dahlqvist’s LCHF diet was quite compatible with a traditional Atkins-type diet, she stopped treating patients and instead began working on a blog and giving lectures to spread the word about LCHF.

Flash forward to January 17, 2008.

Professor Christian Berne, one of Sweden’s leading diabetes experts, had carefully investigated the case against Dr. Dahlqvist and presented his findings to the Swedish National Board of Health and Welfare. He said, “...a low-carbohydrate diet can today be said to be in accordance with science and well-tried experience for reducing [obesity] and type 2 diabetes...a number of trials has shown no effects in the shorter run and that no evidence for it being harmful has emerged in systematic literature researches performed so far. [There is] no scientific support yet for treatments in excess of 1 year. A thorough evaluation of long time treatment results is therefore an important demand on the practitioner.”

By objecting to the low-carb, high-fat diet, the chairman of the Swedish National Association of Dieticians had inadvertently given it validation. In fact, because of the governmental investigation into the scientific support for LCHF, the diet was approved as an alternative approach for the treatment of type 2 diabetes and obesity. New Board guidelines are expected to be completed by autumn of 2009.

As for Dr. Dahlqvist, she continues to lecture, to blog, and to gain in popularity in her native land. In 2008, Radio Västernorrland listeners chose her as Personality of the Year. The seventy percent who voted for her said, “...she stood up against the Health and Welfare and Food Administration's current dietary recommendations, campaigning instead for a diet she believes in—low in carbohydrate but high in natural animal fat.”

Even more impressively, Swedish consumers have started to consider whole milk and butter more natural and healthful than reduced-fat products and are now changing their habits to buy more of the former and less of the latter. There are still plenty of dietary traditionalists in Sweden, but for some people at least, butter is now a health food.

What Happens to the Fat We Eat?

2009-05-21T21:13:00.008-05:00

(The illustration is a simplification of a figure in the 2007 Encyclopedia Brittanica. If it seems too fuzzy to decipher, click on it to see a clearer version.)

For the low-carber, fat is an important macronutrient. What happens when we eat fat?

One of the important aspects of fat is that it is not water-soluble. In order to begin the digestion process, the liver makes bile, which in collected in the gallbladder and is secreted into the small intestine. The bile acts as a detergent. The bile salts in it have a lipophilic side, which binds to the fat droplets, and a hydrophilic side, which suspends the droplets in the watery mixture of the food we have just eaten.

The triglycerides or fats in the suspended droplets cannot be absorbed by the intestine. To accomplish absorption. the pancreas secretes an enzyme called pancreatic lipase into the small intestine, Pancreatic lipase breaks down each triglyceride molecule into two free fatty acids plus a monoglyceride. "Mono" means one, and in this case it means that one of the fatty acids remains attached to the original glycerol backbone. When the triglyceride is broken down into subunits, it is able to pass into the absorptive cells of the intestinal mucosa. After the three subunits have transited the wall of the intestine, the fatty acids are added back to the glycerol backbone and they form a triglyceride once more.

Inside the cells of the intestine, triglycerides are packaged into chylomicrons. Chylomicrons are large diameter (75-1200 nanometer) particles that contain a bit of protein, a bit of cholesterol and lots of triglycerides. The chylomicrons are not secreted directly into the blood but into the lymphatic system. They eventually arrive at the thoracic duct and then are deposited into the blood at the left subclavian vein. Once they enter the blood, they are transported into capillaries and are able to reach the entire body.

One of the proteins in a chylomicron is called apo C-II. This protein has the ability to activate an enzyme called lipoprotein lipase or LPL. Lipoprotein lipase resides on the capillary walls of tissues that have a high requirement for triglycerides, such as cardiac muscle cells, skeletal muscle cells and fat (adipose) cells. The activated lipoprotein lipase acts on the triglyceride molecules (called triacylglycerols in the illustration above) stored inside the chylomicron. It hydrolyzes or breaks down the triglycerides into two fatty acids plus a monoglyceride. Just as we saw in the intestine, intact triglycerides cannot pass through the cell walls, but when they are hydrolyzed into subunits, they can be absorbed into the cells. Once inside, they can be used for energy in the muscle cells or reassembled into triglycerides and stored in the adipose cells.

When we eat a piece of bacon, we start with fat and end with fat (or for the low-carber--energy from the fat). But, as you can see, there are may steps involved in getting from the beginning of the process to the end.

What Is Fat?

2009-05-12T20:35:00.016-05:00

Low-carbers spend lots of their time thinking about fat, both in terms of the excess girth on their bellies and hips, and as an important macronutrient. Although fat is a perfectly natural substance, it may surprise you to know that fat is a chemical.

In chemical terms, fats are referred to as triglycerides. They are composed of two types of subunits. The first subunit, glycerol, is shown above. Although the glycerol portion is not the most important subunit of a fat, it is the root of its chemical name, triGLYCERide. Glycerol has a three-carbon backbone, depicted by the vertical line of C's in the figure above. The active groups in glycerol are the -OH or hydroxyl groups.

The other subunits are called fatty acids. There are three of them in each fat molecule; hence the prefix TRIglyceride. In the example above, each fatty acid contains a chain of carbons represented by a horizontal row of nine C's. In real life, the length of the chains can be from four C's to twenty eight C's. The chains do not have to be the same length within the triglyceride--any assortment is possible. The active group in the fatty acids is known as a carboxylic acid and is also shown above.

The active groups of the three fatty acids are joined to the active groups of the glycerol backbone though a process called esterification. For those who are interested in the enzymatic reactions involved, they are described here. At any rate, three fatty acids attached to one glycerol backbone produces a TRI-GLYCER-ide, a triglyceride, which is one molecule of fat.

That's probably enough biochemistry for this time. There will be more fascinating facts about fats in later posts. :-)

Be Encouraged!

2009-05-03T15:40:00.011-05:00

As most of my readers know, low-carbing is a lifestyle, not a quick weight-loss diet. Early in the process of low-carbing, weight is often lost rapidly, and some of the health improvements come right away. But as weeks move into months move into years, changes come more slowly and more gradually. Reading a diary or meeting an old friend will be a reminder that the low-carb life is better, but day-to-day excitement gradually morphs into an overall feeling of wellbeing.

As low-carbing becomes a way of life, what used to be a black-and-white eating plan begins to become shades of gray. What about eating a slice of Smart Carb bread instead of using a lettuce wrap on my sandwich? I miss bread, and this bread even contains exta (incomplete) protein. Could I substitute one or two low-carb Monster Energy drinks for a couple of bottles of water? They sure taste good and give me a mental and physical boost after all.

There are all sorts of low-carb substitutes for high carb foods. There are many vendors ready to sell them to us, and lots of cookbooks to show us how to make them ourselves. We see low-carb forums with large areas devoted to recipes. And if we try low-carb substitutes, in the short term it very often does not hurt. But what happens in the long term?

In April 2009 there was a Nutrition & Metabolism Society conference in Charleston, South Carolina. Jimmy Moore attended and posted pictures of some prominent low-carbers on his menus blog. Please check out the pictures of low-carb experts Laura Dolson and Dr. Mary Vernon. Another low-carb expert, Dana Carpender, also seems to be having weight issues. Jimmy Moore himself has recently reported that he weighs 246 pounds (an obese-level BMI of 30.7) with a body fat percentage (measured on a bathroom scale) of 31.5.

How could this be? These are prominent low-carbers. Please click on and scroll through the websites of Laura Dolson, Dr. Mary Vernon--note the array of fruit across the top, Dana Carpender and Jimmy Moore's menus blog for a clue.

Does this mean that low-carbers are doomed--doomed to gain weight in the long run? No. It does mean that the basic low-carb formula of complete protein, healthy fat and a few low-carb vegetables is hard to maintain over time. Dr. Michael Eades recently had a blogpost that graphically demonstrated that two groups of people living under similar circumstances could have drastically different outcomes for health and longevity. The hunter-gatherers had periods of starvation and fairly short lifespans, but were healthy in most respects. The agriculturalists had access to the same array of animal proteins, but they preferred to eat carbs. They were willing to suffer from increased infant mortality, painful defects in bone formation, dental cavities and bone infections in order to get a high percentage of calories from carbs rather than animal sources.

The pull of carbs and carb-replacements is strong. For one thing, they taste good. For another, the culture we live in encourages high-carb eating. But for those who are hanging in there and eating complete protein, healthy fat and low-carb vegetables, keep up the good work! In the long run, you're doing what is best for your body and in the long run, you will reap the rewards.