Glyceroneogenesis, and Other Reasons for Fat Storage on Zero Carb

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

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

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!

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

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

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):

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


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


3. 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)
   


4. Requires excessive admiration
   


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


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


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


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


9. 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

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

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

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?

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

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

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.

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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!

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

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

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:

1. It stimulates the release of insulin.
2. It inhibits the release of glucagon.
3. It slows stomach emptying.
4. 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

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

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

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

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.