Tuesday, December 16, 2008

Type 1.5 Diabetes

Type 1.5 diabetes, as the name implies, falls between type 1 and type 2 diabetes. It manifests some of the symptoms of both types, and it is important because it affects about 15% of those diagnosed with diabetes.

Type 1 diabetes is characterized by the presence of autoantibodies against insulin or against certain components of the insulin-producing system such as glutamic acid decarboxylase (GAD), tyrosine phosphatase or the islet cells themselves. These autoantibodies cause the patient's own immune system to kill the beta cells of the pancreas, making the patient unable to produce any endogenous insulin.

Type 2 diabetes is characterized by insulin resistance and diminished production of insulin by the pancreas. If a patient is well-managed, this kind of diabetes can be controlled for many years by diet, excercise and oral medication.

Type 1.5 diabetes has characteristics of type 1 and type 2. Like type 2, its onset is in adulthood, and the pancreas is able to produce insulin for several years. Like type 1, it often occurs in thin people, and it often involves autoantibodies to GAD or islet cells. Unlike type 1, in type 1.5 diabetes, the autoantibodies work much more more slowly. However, their destruction of beta cells is relentless, and within 5-10 years of diagnosis, patients with type 1.5 diabetes will require insulin.

Type 1.5 diabetes is sometimes called Mature Onset Diabetes of the Young (MODY), Latent Autoimmune Diabetes in Adults (LADA), slow onset type 1 diabetes, or double diabetes. As might be expected, each of these terms involves specific criteria and there is disagreement about who falls into which category. Leaving the questions about specific terminology aside, why should it matter that about 15% of the diabetic population is neither type 1 nor type 2?

It matters because type 1.5 diabetics are often misdiagnosed as type 2 diabetics. It matters because type 1.5 diabetics will initially respond to dietary modifications and oral medication, but because their condition stems from the death of beta cells rather than insulin resistance, eventually they will not. Physicians who are not familiar with type 1.5 diabetes may not understand why a misdiagnosed type 1.5 diabetic has stopped responding to standard treatments and may assume that the patient is no longer complying with their instructions. (This happens often enough that physicians have good reason to suspect noncompliance as an explanation for poor diabetic control.) If the patient knows that he or she is following the doctor's guidelines, it might be a good idea to ask for autoantibody tests to see if destruction of the pancreatic beta cells is taking place. As in every other aspect of health care, it becomes important for the patient to become an active participant in the monitoring and management of his condition.

Monday, December 8, 2008

Type 2 Diabetes

Type 2 diabetes is a condition affecting slightly more than 7% of Americans. It used to be called adult-onset diabetes, but we now know it can occur in children as well as in adults. Another term for it was non-insulin-dependent diabetes mellitus (NIDDM), but about 30% of type 2 diabetics are treated with insulin.

Type 1 diabetes begins with death of insulin-producing beta cells in the pancreas. Typically this happens over a period of weeks or months and is not reversible. Type 2 diabetes may begin with a diminished production of insulin by the pancreas. Several risk alleles have been identified and have been found to have an additive effect, resulting in decreased glucose sensitivity in the pancreas of people who have not yet developed overt diabetes. This condition may go undetected for years, only becoming evident when the patient starts to experience insulin resistance. Often this happens during pregnancy, when the mother's body becomes less responsive to insulin during the third trimester. Gestational diabetes is a temporary condition, but can be an early indicator of a predisposition to type 2 diabetes. More often, as a person ages and becomes overweight, his or her muscles, liver and pancreas gradually develop increasing resistance to the action of insulin, and the symptoms of hyperglycemia start to appear. Insulin resistance in the liver may lead to overproduction of glucose by the liver, causing even more hyperglycemia. Hyperglycemia, in turn, may initiate a process called apoptosis (programmed cell death) in the pancreas, resulting in a pancreas that is significantly smaller and less able to produce insulin than the pancreas of a person who does not suffer from type 2 diabetes.

Unlike type 1 diabetes, the progression to type 2 diabetes usually occurs over several years. It does not typically result in the death of all the beta cells of the pancreas, but the ability of the pancreas to regulate blood glucose is significantly compromised. The presence of a genetic component is even more significant than it is in type 1 diabetes. In fact, if a person has a relative with type 2 diabetes, chances are 80% that the person will develop type 2 diabetes in his or her lifetime. With that in mind, it is a good idea to monitor fasting and postprandial glucose levels to see if blood sugars are starting to trend outside the normal range. If symptoms are detected early and the condition is managed appropriately, the progression to fullblown type 2 diabetes can be slowed or perhaps prevented altogether.

If you would like to do some more reading on the progression to type 2 diabetes, here are some links:

Metabolic Syndrome

Reactive Hypoglycemia

Reversing Insulin Resistance

(For those who are interested, the picture at the top is a Texas snowman.)

Tuesday, December 2, 2008

Type 1 Diabetes

The pancreas is a multifunctional organ that sits below and behind the stomach. As an exocrine organ, it empties digestive enzymes into the gut at the level of the duodenum. The pancreas is also an endocrine organ, synthesizing insulin in its beta cells and glucagon in its alpha cells, and secreting those hormones into the blood.

Normally the pancreas performs its functions silently and efficiently. However in some cases the beta cells of the pancreas are vulnerable to an attack by the body's own immune system. For about three million Americans, the pancreatic beta cells are no longer functional, resulting in a condition called type 1 diabetes.

The cause of type 1 diabetes is not entirely clear. The peak age of diagnosis is 14 years, but type 1 diabetes can develop at any age. There is a genetic contribution--twenty percent of patients have a relative who also has the disease. The presence of other autoimmune disorders is a predisposing factor, and childhood viral infections such as rubella, cytomegalovirus and coxsackie B may trigger the condition. In any case, in these patients the body's immune system targets the beta cells of the pancreas and renders them unable to produce insulin.

Before Drs. Banting and Best discovered insulin in 1921, the diagnosis of type 1 diabetes was a death sentence. Victims had continuous thirst and voracious appetites, but without endogenous insulin to control their blood sugar, they wasted away because they could not properly utilize the food they ate. A very low carbohydrate diet could forestall the inevitable for several years, but most died before the age of 30.

With the advent of exogenous insulin therapy, a new set of problems arose for type 1 diabetics. Blood glucose could be controlled, but if it was poorly controlled, it would eventually result in eye, kidney and nerve diseases. If too much insulin was injected, it could result in severe hypoglycemia and even death. Dr. Richard K. Bernstein is a physician who developed type 1 diabetes in 1946 at the age of 12. He tells a fascinating story, showing how difficult it was in those days to match insulin dose to blood glucose level. The advent of the glucometer enabled patients to monitor their blood glucose much more accurately, but it also led to the temptation to eat large amounts of carbohydrates and then "cover" the carbs with injected insulin.

Today the American Diabetes Association recommends that diabetics eat 25-35% of calories from fat, 15-20% from protein and 45-55% from carbohydrates. By contrast, Dr. Bernstein proposes that eating a large number of calories as carbohydrates produces a large variability in blood glucose and a high level of difficulty in controlling blood sugar. To counteract this, he suggests something called the Laws of Small Numbers, which entails eating only small amounts of slow-acting carbohydrate, and no fast-acting carbohydrate at all.

Which approach is correct? No definitive scientific comparison is available, but this review notes that when the ACCORD study attempted tight glycemic control in type 2 diabetics through drug therapy, the study had to be terminated because of high mortality. By contrast, the reviewers cite a long list of references that indicate that dietary control of hyperglycemia is able to improve many of the long-term consequences of diabetes. Type 1 diabetics are unable to completely avoid the use of exogenous insulin, but the strategy of eating very small amounts of carbohydrate that require only small amounts of insulin, appears to be worth serious consideration.

Monday, November 24, 2008


Metformin (brand name Glucophage) is a member of the class of antidiabetic drugs called biguanides. Unlike the sulfonylureas such as glipizide, metformin does not decrease blood glucose by increasing the plasma concentration of insulin. Instead it works in several other ways to accomplish its purpose.

Metformin exerts its main effect, suppression of gluconeogenesis, by inhibiting the ATP production of the mitochondrial respiratory chain. Mitochondria are little organelles inside most of the cells of our bodies. Their job? To convert the precursor molecule ADP (adenosine diphosphate), into ATP (adenosine triphosphate), a molecule that is used to provide the energy required for many metabolic processes. Our bodies produce a little ATP by breaking down glucose in a process called glycolysis. But most of our ATP is provided when two-carbon units enter the tricarboxylic acid (TCA) cycle and are burned in the mitochondrial respiratory chain to produce carbon dioxide and water. From that link, here is a pictorial representation of the mitochondrial respiratory chain.

When metformin interferes with the conversion of ADP to ATP, the ratio of ATP to ADP decreases. When this ratio decreases, there is a resultant decrease in the activity of pyruvate carboxylase, which is the first enzyme used in the process of gluconeogenesis. The inhibition of pyruvate carboxylase significantly decreases the amount of gluconeogenesis the liver can perform. As we have seen previously, when the liver becomes insulin resistant, it will raise blood glucose by continuing to do gluconeogenesis even when blood sugar levels are normal. Although metformin does nothing directly to reverse insulin resistance in the liver, it is able to use the complex series of events beginning with the inhibition of ATP production in mitochondria to partially block the synthesis of excess glucose by the liver.

(As an aside, the inhibition of gluconeogenesis may cause an increase of lactic acid in the blood, lactic acid being one of the building blocks used for gluconeogenesis. In extreme cases this can lead to lactic acidosis, but the phenomenon is relatively rare with metformin.)

The second major effect of metformin is that it is able to decrease blood glucose by improving glucose uptake in muscle cells. Glucose cannot pass into muscle cells simply by diffusion; it requires specfic transport proteins to carry it into the cell. Studies have shown that metformin increases the number of the glucose transporters GLUT1 and GLUT4 in the plasma membrane of muscle cells. More glucose transport proteins means more glucose can be moved into insulin-resistant muscle cells, which in turn lowers blood glucose.

Although metformin has several other actions that reduce blood glucose, these two are the major ones. Unlike injected insulin, or oral drugs that increase insulin secretion, metformin does not cause an increase in insulin resistance, nor does it cause weight gain. However, it is important to note that metformin does not reverse insulin resistance. It simply acts to lower blood glucose in a non-insulin dependent manner.

Tuesday, November 18, 2008

Alcohol and the Low-Carb Lifestyle

About six weeks ago, Woodswalker asked me to write a post addressing the role of alcohol in a low-carb diet. This is a huge topic, but I will present a few thoughts for consideration. If you have questions or comments, please remember that I am a biochemist, not a psychiatrist.

Alcohol, also known as ethanol, contains seven calories per gram. That's somewhat less than fat at nine calories per gram, and quite a bit more than carbs and protein at four calories per gram. Pure grain alcohol contains zero carbs. It is not an essential food. The metabolism of ethanol is fairly straightforward.

The first pathway happens mainly in the liver and is constitutive. ADH is the enzyme alcohol dehydrogenase. ALDH is the enzyme acetaldehyde dehydrogenase, and TCA stands for the tricarboxylic acid (Krebs) cycle. The second pathway is also found in the liver and is inducible--that is, it can be upregulated if the body is required to detoxify large amounts of alcohol on a consistent basis. MEOS stands for mitochondrial ethanol oxidizing system.

If a meal is consumed that contains alcohol, carbs, protein and fat, the calories from the alcohol will be processed first. This means that fat will not be used for energy until all the calories from the ingested alcohol have been burned. If a signficant number of calories of alcohol are ingested, this will postpone or even prevent fat burning. Drinking hard (i.e., distilled) liquor by itself does not affect insulin secretion, but when hard liquor is consumed with food, it increases insulin resistance and insulin secretion. Hard liquor also contains quite a few calories per ounce. By contrast, an ounce of mixed drinks, wine or beer will have fewer calories from ethanol. However, mixed drinks, wine and beer all contain carbohydrates, and, if they are consumed in quantity, will result in insulin secretion and eventual weight gain.

According to Dr. Michael Eades (see the comment at 31 October 2008, 21:34), a single glass of dry wine per day can improve insulin sensitivity and can assist with weight loss. For those who can stop at one glass of wine, that's great. But remember that alcohol is a psychoactive drug, and as such, it lowers inhibitions. In the low-carb context, it is important to note that alcohol can lower inhibitions against consuming carbs, and inhibitions against consuming a second glass of wine as well.

Alcohol stops gluconeogenesis. Gluconeogenesis is the process used by the liver to keep blood glucose levels within normal limits. If a person consumes lots of carbohydrates, an alcohol-induced cessation of gluconeogenesis will probably not even be noticed. However, if a person consumes alcohol while doing very low-carb, he is likely to experience a fall in blood sugar followed by a compensatory release of adrenaline. This can lead to heart palpitations which will be relieved by drinking orange juice or eating a high-glycemic food. Unfortunately, this regimen is not conducive to longterm success on a low-carb diet. If a low-carber notices that alcohol consumption is followed by the symptoms of low blood sugar, it may be necessary for him to drink less than a full serving to minimize the undesirable side effects.

Wednesday, November 5, 2008

More on Insulin Control

The previous post discussed a three-legged stool approach to dealing with reactive hypoglycemia. The three legs of the stool are critical for lowering blood insulin and restoring insulin responsiveness. They are:

-Eating low-carb
-Eating moderate protein
-Waiting 5-6 hours between meals

Overall, these three appear to be the most important strategies for lowering blood insulin and restoring insulin responsiveness. However, a scan of low-carb websites suggests some additional ideas for improving insulin control.

-Avoid "sweet"
For 18 days Jimmy Moore did a "Sweet"-Free Challenge. He avoided all artificial sweeteners, including those in diet soda. The taste of sweet, even if it comes in a zero-calorie product, can be enough to trigger an insulin release from the pancreas.

-Be careful with alcohol
Dr. Mike Eades discusses alcohol consumption in the comments section of a recent post at his blog. In response to a commenter, Lowcarb convert, Dr. Mike says Studies have shown that a glass of wine per day helps with weight loss, but if you can’t stop with just one - and I’m one of those who has difficulty in doing so - cold turkey may be the better strategy. In response to that, another poster, Tom, says For me, wine is a gateway drug…to carbs! Alcohol lowers inhibitions, including inhibitions against eating carbs, and eating carbs leads to the release of insulin. A word to the wise is sufficient.

-When you eat carbs, make them low-glycemic carbs
Dr. William Davis discusses Quieting the insulin storm in a recent post at his blog. He points out that some foods, like wheat and cornstarch, have a higher glycemic index than table sugar. The higher the glycemic index, the more rapidly blood sugar will rise, and the more insulin will be released by the pancreas in response.

-Eat healthy fats at every meal
Healthy fats make up the caloric difference between an individual's daily caloric need and the calories provided by low carbs plus moderate protein. Fats provide energy, promote satiety and can be consumed with no insulin required whatsoever.

-Avoid eating a large volume of food at one sitting
In his book The Diabetes Solution, Dr. Richard Bernstein discusses the fact that simply overstretching the stomach causes the release of insulin. This effect happens without reference to what type of food is consumed. It occurs whenever the stomach has been distended--by overeating or by eating large servings of high fiber foods. (According to Dr. Bernstein, it even happens when the stomach is distended with air.) To avoid oversecreting insulin, it is preferable to avoid eating one large meal and two small ones, but instead keep all three meals at a similar volume of food.

Monday, October 27, 2008

Reactive Hypoglycemia--An Experiment?

Reactive hypoglycemia is a condition which is characterized by unusually low blood sugar that occurs one to four hours following a meal. The symptoms are the typical ones for low blood sugar--shakiness, light-headedness, weakness, confusion, anxiety, depression, hunger, pounding heartbeat and sweating.

Progressive development of insulin resistance is often the cause of reactive hypoglycemia. When the pancreas becomes insulin resistant, it is unable to release the proper amount of insulin in response to the stimulus of carbohydrates and proteins. Sometimes the pancreas will overshoot its estimate of the amount of insulin needed to store ingested carbs and proteins. The excess insulin produces hypoglycemia and its associated symptoms. A more detailed explanation of the process can be found in my original post called Reactive Hypoglycemia. (Be sure to read the comments section.)

Reactive hypoglycemia can be diagnosed with a glucose tolerance test. If the test is positive, the patient will typically be advised to eat every 2-3 hours to relieve the symptoms. Although freqent ingestion of food does keep blood sugar from falling too low, it will not provide a long-term resolution of the underlying problem.

One of my readers, Alex, who blogs at Low Carb New England, entered the discussion on the original post with the story of how he has been dealing with reactive hypoglycemia since he was a teenager. Over the years he has systematically tried many different approaches and has taken careful note of what result each personal experiment has produced. To summarize briefly, Alex initially tried eating less sugar and eating frequent meals, but eventually he gained nearly 100 pounds. Next he investigated low-carb eating. By using the Atkins diet, he lost weight and many of his symptoms improved considerably. In an effort to reduce the remaining symptoms, Alex tried eliminating artificial sweeteners and caffeine, and this helped somewhat. He also tried extremely low-carb and even no-carb eating, which didn't help.

Eventually Alex realized that he needed to limit his protein intake to the amount recommended by Drs. Mike and Mary Dan Eades in The Protein Power Lifeplan. (Remember, eating protein also causes insulin release, and thus can contribute to insulin resistance.) Again, his symptoms improved, but were not entirely gone. The final piece of the puzzle seemed to arrive when he read my first comment under the Reactive Hypoglycemia post and decided to try waiting 5-6 hours between meals to allow his insulin levels to come back to baseline and give his body a chance to re-establish a normal level of insulin sensitivity.

After a month of using this three-legged stool approach (low-carb/moderate-protein/5-6 hours between meals) to dealing with reactive hypoglycemia, Alex has finally experienced relief from the symptoms of reactive hypoglycemia. He gives a much more complete version of the story on his blog in a post called "I'm back!" (For those who don't have access to The Protein Power Lifeplan, another method of calculating one's daily protein need can be found here.)

And now I've reached the main point of this post. If the three-legged stool approach (illustrated in the picture above) has worked for Alex, would it work for anybody else out there who has reactive hypoglycemia? Each leg of the stool is designed to reduce insulin resistance and, one hopes, to restore some degree of insulin sensitivity in muscle, liver, brain and pancreas. If any of my readers is interested in trying to follow this plan for a few weeks or a month, I would be very interested in getting your feedback. If this method actually works, it's possible that a series of anecdotal experiences could convince a low-carb researcher to design a study to see if using the three legs of the stool is an improvement over frequent feeding as a way to treat reactive hypoglycemia. If these informal personal experiments don't work, that's also important information. It's possible that there are other pieces of the puzzle that aren't obvious, or perhaps that the mechanisms of reactive hypoglycemia are different from one individual to the next. If you decide to try this, please be very careful, and please don't do anything that would put your health in danger. That said, if you try it and you have observations you would like to share, please put them into the comments and we shall see where this might lead.

Wednesday, October 22, 2008

Does Exercise Produce Weight Loss?

Common wisdom suggests that exercising will cause a person to lose weight. Superficially this makes sense. A 150 pound person at rest will use about 60 calories an hour. If this person jogs at 5 mph for an hour, he or she will use an additional 540 calories per hour. Because a pound of fat represents 3500 calories, a faithful jogger should lose a pound every 6.5 days. However, as exercisers can attest, this does not seem to work out in the real world. Why would that be?

1. Vigorous exercise can produce physical stress. Stress in turn causes the release of cortisol, which stimulates carbohydrate synthesis (gluconeogenesis) for quick energy. Gluconeogenesis produces an elevation in blood glucose which then stimulates insulin release. If this sequence happens repeatedly during days and months of an ongoing exercise program, it becomes more and more likely that the chronically physically-stressed person will start gaining weight.

2. Vigorous exercise can cause fatigue. The person who exercises may be expending more calories during his workout, but if he becomes exhausted by his efforts, he may compensate by conserving energy (being more sedentary or even napping) during his other daily activities.

3. Exercise in the form of resistance training may cause the exerciser to overestimate how much energy his body consumes post-exercise. A 2006 article by Ralph La Forge states that, for the non-athlete, the excess post-workout oxygen consumption is less than 100 calories per day.

4. Vigorous exercise may cause the body's homeostatis mechanisms for fat storage to overcompensate. Exercise activates the enzyme lipoprotein lipase (LPL) in muscle tissue, allowing muscles to take up fatty acids as fuel. Once the exercise stops, the activity of LPL in muscle decreases and the activity of LPL in fat tissue increases. Calories will be pulled into fat cells and stored there to prepare for the next round of exercise. Although an individual's appetite might be depressed immediately after a workout session, later in the day there may be a more-than-compensatory drive to eat to replace lost fat stores.

5. Exercise plus frequent meals can cause weight gain. Eating frequently prevents both leptin levels and insulin levels from returning to baseline. As earlier posts have discussed, persistently elevated leptin levels can hinder satiety signals and cause excess consumption of calories. Elevated insulin levels will produce storage of those excess calories as muscle and as fat. Underweight bodybuilders use exercise plus frequent meals as a method to gain weight. However, without careful monitoring, overweight body builders can also gain weight on this regimen.

Exercise is a good thing. It can strengthen the heart and lungs, elevate mood, create a better physique and improve stamina. But for a number of very good reasons, exercise by itself does not necessarily produce weight loss, and if the circumstances are right, it may even result in weight gain.

Monday, October 13, 2008

Transgenerational Obesity

Americans are getting fatter. According to a recent article in Obesity, by 2030, 86.3% of American adults will be overweight. The average adult BMI (Body Mass Index) is now 28, which is in the overweight range. By 2030 the average adult BMI is predicted to be 31.4, which is well into the obese range.

One factor that contributes to this phenomenon is the fact that fat mothers produce fatter offspring. In some senses this is not surprising. If there are genes that predispose to obesity, those will be passed down from parents to children. If there are lifestyle choices that contribute to an increased BMI, children will learn those by example from their parents.

What is not expected is the presence of a multiplier effect in generational obesity. In both rats and mice that are susceptible to obesity, a fat rodent mother gives birth to offspring which will become fatter than she was, and they, in turn, give birth to pups which grow up to be fatter than they were. The same phenomenon happens in humans. It is harder to observe in humans because it takes decades to progress from mother to daughter to granddaughter, while rodents can easily produce several generations in a few months or years. In rodents it is also much easier to control for genetic and environmental factors.

In both rodents and humans, the cause of the multiplier effect has not been established. It could result from a relatively high blood sugar in the mother causing the fetus to produce extra insulin-secreting cells in the developing pancreas. This could lead to increased insulin resistance and subsequent obesity as the child matures into an adult. It is possible that the high levels of leptin in an obese mother could cause her fetus to become leptin resistant. Methylation studies described in the rat reference above, suggest that maternal obesity may produce long-term modifications in the regulatory regions of obesity-related genes in her offspring. These modifications would be epigenetic, not mutational modifications. In other words, the actual DNA coding sequence is not changed, but while the fetus is in the womb, the 3-dimensional conformation of its DNA is modified, causing obesity-related genes to be more or less easily expressed even after the baby is born.

There is also evidence that the cycle of increasing transgenerational obesity can be broken. In 2006 an article in Pediatrics described a group of 113 obese mothers who had undergone biliopanceatic diversion (BPD) surgery for weight loss. This group of mothers had 45 childen before the surgery and 172 after the surgery. All were followed for 2-18 years. Comparing the 172 children born after BPD surgery with the 45 born before it, the prevalence of obesity decreased by 52% and severe obesity decreased by 45%. The effect was gender-specific, with the prevalence of overweight in the daughters decreasing from 56% to 42% and in the sons decreasing from 50% to 25%.

Apparently obesity does not have consequences just for the obese mother, but its effects extend into the lives of her children as well.

Sunday, October 12, 2008

I'm Back!

Thanks to all the people who left excellent comments on my archived posts. Each one of your observations has been very much appreciated. As I've realized during this month of real-life challenges, the most important information about the science of low-carbing can already be found on the previous posts in this blog.

Woodswalker tactfully pointed out that the subject of low-carbing may not be inexhaustible. She's right. There are lots of interesting aspects of low-carb that we will address in the future, but the basics involve a few well-known principles of biochemistry and physiology. Medical students have learned about these for years, but once they graduate into the world of practicing medicine, they seem to absorb the dogma about low-fat/low-cholesterol/low-calories and forget about their original training.

So, a word to the wise. Go back often. Review frequently. Remind yourself of the many scientific reasons we have for low-carbing. Most of the mainstream medical and nutritional community hasn't caught up to us yet. Someday it will. In the meantime, let's do all we can to keep ourselves on the path to good health that low-carbing provides.

Sunday, August 24, 2008

Eat Fat to Lose Fat

Many aspects of the low-carb lifestyle are surprising. For example, the successful low-carber soon learns that he or she must eat fat to lose fat. Why would that be?

A possible explanation comes from a couple of studies published last summer in Cell Metabolism, one by Inagaki et al and one by Badman et al. For those who are interested in the specifics, see the PDFs here and here. These studies were performed in mice but were quite exhaustive and appear to have application to humans as well.

The requirement for eating fat to lose fat begins with a cellular receptor called peroxisome proliferator-activated receptor-alpha or PPAR-alpha for short. PPAR-alpha is a protein found inside liver cells. When dietary fat diffuses into the liver cell as fatty acids, the fatty acids are able to bind to PPAR-alpha and activate it. Activated PPAR-alpha then binds to another protein called the retinoid X receptor or RXR, and these dimerized proteins in turn are able to bind to the cell's DNA. In so doing, they enhance the production of a third protein--fibroblast growth factor-21 or FGF-21.

FGF-21 is secreted by the liver and produces several effects. In white adipose tissue, it stimulates lipid breakdown. The breakdown of stored lipids allows them to be used as fuel. In the liver, FGF-21 upregulates ketone body production. Ketone bodies provide another source of fuel. The two studies showed that production of FGF-21 was greatly enhanced when the mice were fed a low-carb/high-fat (ketogenic) diet. When few carbohydrates are provided in the diet, but the diet does contain fat, mice are able to switch to an efficient mode that allows them to consume stored fat for energy. Mice are not people, and the usual admonition applies--more research is required. But the observation that a ketogenic (low-carb/high-fat) diet allows mice to produce lots of FGF-21, mobilize fat stores and upregulate ketone production suggests an explanation for what low-carbers know by experience--you have to eat fat to lose fat.

Wednesday, August 20, 2008

Calories Count

One of the great things about low-carbing is that (at the beginning anyway) low-carbers don't need to count calories.

Low-carbers do have to learn what a normal portion size is--a portion of macadamia nuts is 1/4 cup, not half a bag. A portion of cucumbers is 1/2 cup, not a whole cucumber. Low-carbers also need to learn that it's okay to subtract fiber carbs from their carbohydrate count. Once that's accomplished, it becomes a simple matter to look up various foods, figure out the carb content and add up the number of carbs consumed in a day. The target number is normally in the double digits, which is a fairly easy calculation for those of us who are arithmetically challenged.

Since low-carbers count grams of carbohydrate, does that mean that for low-carbers calories don't count? No. Calories do count.

Typically in a low-calorie versus a low-carb scientific study, the low-calorie group is given a target number of daily calories while the low-carb group is given a target number of daily carbs. When the results are tabulated, the net caloric intake will be compared between the two groups. Rather surprisingly, the two groups will have ingested almost the same number of calories. Examples are the recent study published in the New England Journal of Medicine and the A to Z Weight Loss Study published last year in JAMA. See Table 2 in each link for comparisons of daily energy intake from group to group.

Why do low-carbers unconsciously limit calories when they count carbs? One reason is the action of the signaling hormone leptin, discussed in the previous two posts. As low-carbers become more sensitive to the signals provided by leptin, they have an improved ability to perceive satiety. Their brains detect the leptin released by their fat stores and turn off the hunger signal at a caloric level that will allow them to use some of their fat stores for energy. The study group that eats a low-calorie diet without carbohydrate restriction will have a harder time getting the satiety signal. The participants in that group will have to turn off their eating at an intellectual level. When they have eaten the allowed number of calories, they have to consciously make themselves stop eating.

In comparison studies of weight loss, both the carb counters and the calorie counters end up eating approximately the same number of calories. Both groups lose weight in approximate proportion to their decrease in energy consumption. One of the considerations in choosing a weight-loss diet is the ease of complying with the diet. A controlled carbohydrate diet severely restricts the consumption of carbohydrate-containing foods but allows the dieter to eat to satiety. By contrast, a controlled calorie diet allows the dieter to eat balanced portions of whatever he or she wants, but requires the dieter to stop eating even if satiety has not been reached. As always, it's a tradeoff. The dieter decides which parameters are most important to him or her and chooses the diet that best fits those needs.

Friday, August 15, 2008

Leptin Resistance II

As described in the previous post, leptin is a hormone released by white adipose cells in the body. Leptin allows the brain to keep track of the body's fat stores. It also permits the brain to sense satiety in response to food intake. One of the ways to overcome triglyceride-induced leptin resistance is by following the low-carb lifestyle.

That's fine at the beginning of the weight-loss journey. But what happens to a low-carb dieter who is successful? What happens when a large percentage of the body's fat stores have disappeared?

In a formerly-fat person, leptin will still be released in response to insulin secretion. However, because there is less body fat to synthesize leptin, the consumption of food will cause less leptin to be released into the circulation. After a meal, the signal for satiety won't be as strong. If a person wishes to maintain a lower body weight, it will become important to maximize the response to the leptin that is released.

The illustration above shows leptin on the outside of a cell, bound to its receptor (the pincer-like structure that crosses the plasma membrane or cell wall). The leptin receptor transmits several signals into the cell, including signals for satiety and increased thermogenesis. Another signal that is sent causes the production of a protein called SOCS-3, a member of the family called Suppressors of Cytokine Signaling. SOCS-3 is a protein that shuts down the signaling of the leptin receptor. The pattern of a signal producing a response which then produces downregulation of the response is quite a typical one in the body. Including an automatic off switch on metabolic reactions keeps reactions under tight regulation and control.

In the case of leptin signaling, it is normal for the leptin response to be downregulated within a few hours. The SOCS-3 protein shuts off the satiety signal and allows the rate of metabolism to decrease. Within a short time, the SOCS-3 protein itself is degraded and the leptin diffuses away from its receptor. This in turn resets the leptin system, allowing it to be ready to respond in time for the next meal. The result is a cycle of eating, satiety, and the gradual return of hunger. Unfortunately for the person who has successfully lost weight, this system can also become leptin resistant.

Consider the case in which leptin is released continuously from the fat cells. One way this could happen is when frequent small meals are eaten. Each feeding will cause the release of insulin, which in turn will cause the release of leptin. The constant presence of leptin on its receptor will prevent the receptor from resetting itself. It will no longer be able to send adequate signals for satiety and increased thermogenesis. The result, inevitably, will be weight gain.

One way to counteract this type of leptin resistance is to allow five to six hours to pass between meals. This will allow the receptor to reset itself and to become sensitive to leptin the next time leptin is released. Even though less leptin is produced by the diminished fat stores, if meals are taken at 5-6 hour intervals, if meals are eaten slowly to allow the leptin signals sufficient time to reach the brain, and if a low-carbohydrate lifestyle is maintained, this will allow the available leptin to have a maximal effect in producing its desired effects of satiety and increased thermogenesis.

Saturday, August 9, 2008

Leptin Resistance I

Leptin, pictured above, is a hormone produced by fat cells. When we eat a meal containing carbohydrate and/or protein, our pancreas releases insulin. Insulin, in turn, causes the body's fat cells to release leptin into the circulation.

The receptors for the hormone leptin are found in the brain, most abundantly in a structure called the arcuate nucleus of the hypothalamus. When leptin binds to its receptor, it sends several sets of signaling cascades into the brain. Since food has just been eaten, one set of signals acts to downregulate the appetite, while another set of signals tells the body to increase its metabolic rate to burn the calories that are now available. So far, so good.

But what if the leptin receptors in the arcuate nucleus fail to "see" the leptin that has been released by the fat cells? Leptin in the blood does not simply diffuse into the brain. It has to enter the brain through a specific transport system. In 2004 it was shown that high triglycerides in the blood will prevent leptin from being transported into the brain. In other words, a fat person can eat a meal, release plenty of leptin, and his brain will receive only a weak signal that it needs to downregulate appetite and upregulate metabolism. That person is leptin resistant. Because of the leptin resistance, his body will create a higher set point for appetite and a lower set point for metabolic rate than it would normally need.

Obviously this is not a good situation. If a person has leptin resistance, can it be circumvented? How can the resistant leptin receptors in the hypothalamus "see" the leptin that is being produced by the fat cells of the body?

Because excessive serum triglycerides are blocking the entrance of leptin into the brain, one possible solution would be to reduce serum triglycerides. As we have discussed in a previous post, numerous studies have shown that low-carbohydrate diets consisently and significantly reduce the level of triglycerides in the blood. (See Volek & Feinman, Table 4, percent change in TAG.) As triglyceride levels decline, leptin responsiveness increases. With this in mind, it is not surprising that people who eat a low-carb diet experience better control of their appetite and an increase in metabolic rate compared with those whose meals are higher in carbohydrates.

When people follow a low-carb lifestyle, the leptin they produce is able to reach their leptin receptors, to tell their brains that they are full and to upregulate their body's metabolism to utilize the food they have just eaten. Because they have lowered their serum triglycerides, their bodies will have a lower set point for appetite and a higher metabolic rate than they did when their brains were not "seeing" the leptin that their fat cells were producing.

If a low-carber decides to return to his or her former way of eating, triglycerides will rise and the set points for appetite and metabolism will restabilize at their previous values. Inevitably, any weight that was lost will eventually return. The regulation of leptin sensitivity helps explain why low-carb eating does not work very well as simply a short-term diet, but needs to be done over the long term as a lifestyle change.

Thursday, July 31, 2008

Jimmy Moore Is Losing Weight!

Jimmy Moore is one of the "stars" of the low-carb movement. In 2004 he followed Dr. Atkins' New Diet Revolution and took his weight from 410 down to 230 pounds.

He wrote a book about it, Livin' La Vida Low-Carb, and launched a blog with the same title. Since then, Jimmy has started many more blogs, interviewed the movers and shakers in the weight-loss community and served as an inspiration for people who want to experience the satisfaction of losing weight successfully.

But all was not perfect in the world of Jimmy Moore. In December 2007 he began to do resistance training. Long story short--in the process of building up strength and muscle mass, Jimmy gained 30 pounds and couldn't seem to get rid of it. He has kept a current account of these adventures in his Low-Carb Menus blog.

Fast-forward seven months. Jimmy finally seems to have found a method that works. Here it is:

1. He has stopped eating desserts and low-carb products. Even though Jimmy always ate strictly low-carb, he counted net carbs. That meant that he subtracted insoluble fiber, soluble fiber, sugar alcohols, glycerin, maltodextrin, and similar low-glycemic-impact carbohydrates. He ate Atkins bars and Dreamfields pasta, as well as low-carb brownies, cookies, muffins, ice cream, chips and wraps. Except for insoluble fiber and possibly erithritol, eventually all of these carbs have to be dealt with as carbs. In order to store or metabolise them, the pancreas must release insulin. And when insulin is released, fat stays trapped inside fat stores and is not available for burning.

2. He is eating much less protein. Protein is important for building and repairing muscles. But eating protein also causes insulin to be released. It's important to eat enough protein to keep the body in good shape, but if too much is eaten, insulin levels stay high, and the excess protein can be converted to glucose through gluconeogenesis.

3. He is waiting about six hours between meals and is doing very little snacking. Eating low-glycemic-impact carbohydrates and protein every few hours keeps insulin levels elevated continuously. Eventually the insulin signaling system down-regulates itself, and the muscles, liver and brain gradually become resistant to insulin. Waiting five to six hours between meals allows insulin levels to decline to baseline or near baseline. This in turn permits hormone-sensitive lipase to mobilize fatty acids from fat deposits. The body can use free fatty acids for fuel while the insulin signaling system has a chance to reset itself.

4. He is eating fewer calories. One of the best aspects of low-carbing is that it's easier to count carbs than calories. In the initial stages of low-carb weight loss, the anorectic effect of ketosis and the satiety-producing effects of moderate protein and high fat all work together to limit the number of calories consumed without requiring much conscious effort on the part of the dieter. However, in the words of Robert C. Atkins, "I never said calories don't count." As weight is lost and as the body becomes more efficent at low-carb living, eventually it becomes necessary to become aware of the number of calories eaten versus the number of calories used for resting energy expenditure, activity energy expenditure and thermogenesis. The advantage of dieting the low-carb way is that when fewer calories are eaten, the body does not have to slow down its metabolic rate to conserve energy. Low carbs mean a low insulin level, which gives the body ready access to the energy it has stored in adipose tissue.

Jimmy Moore's experiences are his own, and may or may not apply to others who are trying to lose weight or maintain a weight loss. But they do provide real-world insight into how low-carbing works on a practical basis.

An Update (October 12, 2008)

Jimmy followed this regimen until the middle of August and took his weight down to about 255. He then joined Isabeau Miller's FitCamp for two weeks and began doing all sorts of vigorous exercise, which he has faithfully continued during the subsequent weeks. To avoid muscle weakness and exhaustion during workouts, Jimmy experimented with adding in healthy extra carbs. He also returned to eating his favorite low-carb products and began eating more often. Bottom line: On October 3 and again on October 11 Jimmy weighed in at 270 pounds.

It is commonly believed that increased exercise results in weight loss. In Jimmy Moore's case, increased excercise has twice resulted in weight gain. Some of the weight gain is undoubtedly muscle, but the correlation between significantly increased exercise and significantly increased body weight is surely a cause for concern. As Jimmy continues to use various approaches to return to his 2004 weight of 230, it will be instructive to see which strategies work for him and which don't.

Monday, July 28, 2008

Reactive Hypoglycemia

When we think about blood glucose, we usually think about hyperglycemia, or excess blood glucose. But sometimes we can have too little glucose in our blood. The symptoms are lightheadedness, anxiety, and hunger. Low glucose can even produce shakiness and heart palpitations. This post discusses one of the causes of low blood glucose, reactive hypoglycemia.

Reactive hypoglycemia is important because it can be one of the steps on the path to type 2 diabetes. It is one of the possible responses to a six-hour glucose tolerance test, illustrated in the graph above. The normal person, represented by the red line, has ingested a large bolus of glucose at zero hours. The beta cells of his pancreas have released the appropriate amount of insulin, and while the amount of glucose in his blood has spiked a little, within 2.5 to 3 hours it has come back into the normal range of 70-110 mg/dl, which corresponds to a value between 4 and 6 mmol/L on the graph above. Once the extra glucose has been safely stored, insulin levels decline and the liver takes over.

As discussed in the previous post, the liver can release its stored glycogen in the the form of glucose, and it can also make glucose by gluconeogenesis. Between meals, the liver uses these two processes to keep blood glucose in the range between 70-100 mg/dl or 4-6 mmol/L.

After a person eats carbohydrates, his liver shuts down its production of glucose via glycogenolysis and gluconeogenesis. That makes sense. If the person is ingesting glucose, why would he want to add more glucose to that amount?

When a person eats protein, the situation is a little different. Insulin must be released to store the amino acids building blocks of the protein. But insulin is nonspecific. As it promotes the storage of amino acids, it will also drive glucose from the blood. Without some compensatory mechanism, the process of storing the amino acids would also produce severe hypoglycemia. In steps the pancreas. This time the alpha cells of the pancreas release the hormone glucagon. Glucagon tells the liver to release some of its glycogen in the form of glucose. The liver also begins to do gluconeogenesis to make more glucose. Thanks to the liver, glucose levels can be maintained while insulin is busy telling the body to store its new supply of amino acids. Once the nutrients are stored, the liver goes back to its baseline functions and enables the blood sugar to continue in its normal range.

So far, so good. But as diabetes develops, the liver is one of the organs that becomes insulin resistant. When the liver becomes insulin resistant, its production of glucose becomes dysregulated. The liver can no longer turn off its glucose output in response to carbs, or regulate its glucose output properly in response to protein.

Think about that. The person with insulin resistance may not be eating carbs, but his liver is making carbs (that is, glucose) all the time. In order to control the resultant high blood sugar, the pancreas must produce more insulin. That will get the blood sugar down in the short term, but in the long term it will make the liver more insulin resistant. Eventually, still more unwanted glucose will be produced by the liver, and even more insulin will need to be released by the pancreas.

In the process, the pancreas itself starts to suffer insulin resistance. It releases insulin erratically. Sometimes it allows the blood sugar to go too high. At other times the pancreas overshoots the required amount of insulin and the blood sugar drops too low. This leads to the phenomenon called reactive hypoglycemia, which is shown in the black line in the graph above. The person represented by the black line has ingested a large amount of glucose, but his pancreas has responded by releasing too much insulin, and his blood glucose has fallen below the normal range. Over time, reactive hypoglycemia can eventually progress and intensify to the condition of the person represented by the brown line, which is prediabetes.

We tend to think of type 2 diabetes as a condition characterized by high blood sugar. It is, but for many people, one of the steps on the road to type 2 diabetes is actually low blood sugar. If a person is not a diabetic but is experiencing episodes of low blood sugar, it might be time for him to consult a physician. It could be a important warning sign and an indication that he might need to make some changes in his lifestyle.

The figure is from the Hypoglycemic Health Association of Australia.

Wednesday, July 23, 2008

Glucose, Glycogen and Gluconeogenesis

We have glucose in our blood at all times. Where does it come from?

The first and most obvious source is from the carbohydrates in our food. Most of the complex carbs we eat, from sugar to pasta, can be broken down into glucose monosaccharides and will be absorbed into the circulation in that form. The illustration above is taken from page 329 of Lippincott's Illustrated Reviews-Biochemistry. It shows the effect of a meal of 100 grams of pure glucose. The large spike of glucose is metabolized or stored within about three hours.

If we do not eat any more food after that 100 grams of glucose, our blood glucose levels nevertheless must be maintained. If we are well-fed, our livers store about 80-100 grams of glucose as glycogen. The liver is able to convert glycogen back into glucose by means of a process called glycogenolysis. The blue line on the graph shows that, over the next few hours, the liver releases glucose back into the blood on an as-needed basis.

What if we continue to fast? Eventually, we run out of liver glycogen. If you look at the green line in the graph, you'll see that it gradually rises. This line represents gluconeogenesis, which we have discussed before. In the absence of ingested carbohydrates, and even after our liver glycogen is depleted, our liver is able to make glucose out of glycogenic amino acids and the glycerol backbones of fatty acids. It takes several hours or even days for this process to ramp up.

What if we are not fasting but are simply low-carbing? The ramping-up of gluconeogenesis is one of the reasons that people who are new to low-carbing experience something called the "Atkins flu" when they start eating 20 grams of carbs or less per day for the first time. They are not starving, but their bodies have to get used to manufacturing new glucose out of amino acids and glycerol rather than absorbing ready-made glucose from the gut. Once gluconeogenesis is established, our bodies can readily make glucose from the protein we eat.

However, even when it is well established, gluconeogenesis is not a quick-response system. Because it takes us several hours to digest a protein meal into its constituent amino acids, followed by more time to convert the amino acids into glucose, the process of gluconeogenesis is relatively slow. However, the glucose we produce can be used to replenish the glycogen in the liver, and liver glycogen is a quick-response system.

Once we are adapted to a low intake of carbohydrates, we have two means of stabilizing our blood sugar. Gluconeogeneis provides a baseline of glucose production from the protein we eat. Because the fuel needed for gluconeogenesis ebbs and flows, the new glucose made by this process ebbs and flows. Fortunately our stored liver glycogen is available to make up the difference, assuring a steady stream of glucose for baseline functions for our brain, red blood cells and other tissues that require glucose as fuel. If we need an extra burst of energy, or if a big protein meal causes our insulin to spike and our glucose to plummet, our stored liver glycogen is also there to step in the gap and provide the glucose necessary to keep our blood glucose within normal limits.

When we first start low-carbing, it's hard to understand that (if we choose to) we never need to eat another gram of carbohydrate again. But once our good friend the liver is adapted to the process, it can provide all the carbs we need through gluconeogenesis and glycogenolysis.

Tuesday, July 22, 2008

Comfort Food

Even though the media and the medical commmunity have generally been skeptical of the low-carb lifestyle, many people now know that low-carbing is a healthy way to live and an excellent way to lose weight.

But what about people who know that low-carbing is a healthy lifestyle and DON'T choose to follow it, even though the consequences are significant? Why would they go ahead and indulge in food that is high in carbohydrate and low in nutrition instead of being careful about their food choices? Specifically, how can a person deliberately choose:

  • Comfort food plus diabetic retinopathy (i.e.,blindness)?

  • Comfort food plus erectile dysfunction?

  • Comfort food plus a lifetime of diabetes medication?

  • Comfort food plus death from heart disease?

  • Comfort food plus a degree of obesity that puts their livelihood in jeopardy?

People who understand low-carbing, understand that low-carbing has a good track record of improving all of those health conditions. In light of that, why do so many of them either not follow or stop following the low-carb lifestyle? The answer could be serotonin. Serotonin is a neurotransmitter, or signaling molecule, found in the brain. It has many actions, but one of them is modulation of mood. If we don't have enough serotonin, one result is that we can become depressed.

Serotonin is manufactured in our bodies from a large neutral amino acid called tryptophan. Tryptophan is one of the amino acids found in the protein we eat. So if we're depressed, why can't we just eat more tryptophan to drive the production of more serotonin?

As you might expect, it is not that simple. Tryptophan is too large to diffuse into the cells in our brain by itself. For our brain cells to take it up, tryptophan must be carried into the cells by means of a transporter. The problem is, tryptophan has to compete for transport with the other large neutral amino acids--phenylalanine, tyrosine, isoleucine, leucine and valine. Tryptophan tends to get lost in the shuffle.

How, then, can we get extra tryptophan into our brain? Amazingly, the answer is insulin. If we eat a meal or a food high in carbohydrate, insulin will be released and will sweep the other large neutral amino acids out of the blood and into our muscles. However, tryptophan is different. It will tend to stay behind and bind to albumin in the blood. But once the albumin-bound tryptophan reaches the capillaries of the brain, the transporters there will be ready to take up the tryptophan, increase the brain concentration of it, and drive the synthesis of serotonin. The result? A pervasive feeling of sleepiness and contentment.

For people who are anxious or depressed, this is a hard feeling to walk away from. What if we knew that a temporary fix for our bad feelings was right inside the freezer or refrigerator or cupboard? No prescription necessary. The comfort food found in our pantries might not be the best choice for us in the long run, but we have to realize that sometimes our eyes won't stay focused on the long run. The bad feelings will come. The comfort foods will always be available. Recognizing that, this might be a time for all of us good low-carbers to sit down and plan a strategy that provides comfort when we need it, but doesn't rely on comfort food.

Saturday, July 19, 2008

Is the Tide Turning?

See that logo? The New England Journal of Medicine is one of the premier scientific journals in the world. It is in the top tier of the top tier of medical journals.

Contrary to popular opinion, it is possible to get mediocre research published. You can present a preliminary poster of your findings at a scientific meeting and it will appear in a volume summarizing all the posters from that meeting. You can submit your manuscript to a journal that will simply print it for you without any pesky review by your scientific peers.

But if you want credibility for your work, you send it to a respected journal where two or more qualified scientists will analyze it, tear it apart and ask you many questions about how you can back up your claims. The more respected the journal, the more likely that your submission will not pass muster and will be returned to you for submission elsewhere. In the scientific world, it's not just "publish or perish." The quality of the journals in which you publish is also extremely important.

For that reason, it is very significant that on July 17, 2008, the New England Journal of Medicine published an article entitled Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. The study enrolled 322 Israelis (men and women, average age 52, diabetic and non-diabetic) who worked at a nuclear research facility and were moderately obese. They were divided into three groups.

The Low-Fat group adhered to the guidelines of the American Heart Association (AHA). They ate 30% fat, and were permitted very little saturated fat and cholesterol. Men were limited to 1800 calories per day and women were limited to 1500 calories per day.

The Mediterranean Diet group ate 35% fat, mostly in the form of olive oil. They ate lots of vegetables and were instructed to get their protein from chicken and fish. Men were limited to 1800 calories per day and women were limited to 1500 calories per day.

The Low-Carbohydrate group ate 20 grams of carbohydrates per day for two months, followed by a gradual increase to a maximum of 120 grams of carbs per day. Participants were told to choose vegetarian sources of fat and protein. Daily calories were not limited.

The results were not unequivocally in favor of the Low-Carb group. They had the poorest long-term adherence rate to their diet (78%). Their fasting plasma glucose levels did not improve. Their blood pressure, LDL cholesterol, insulin and leptin levels and high molecular weight adiponectin all improved, but there was no significant difference in the degree of improvement among the three diet groups.

Compared with the other two groups, the Low-Carb group did see a significant drop in their weight, in their glycosylated hemoglobin, and in their ratio of total cholesterol to HDL cholesterol. In several other markers, the Low-Carb and the Mediterranean diet groups were not different from each other, but showed significant improvement over the group following the AHA-recommended Low-Fat diet.

One of the criticisms made against the low-carb diet is that it might not be safe or effective in the long term when compared with the standard American Heart Association low-fat diet. This study specifically addressed that question. It is notable that in the Discussion, the authors of this article state, "In this 2-year dietary-intervention study, we found that the Mediterranean and low-carbohydrate diets are effective alternatives to the low-fat diet for weight loss and appear to be just as safe as the low-fat diet." The wobble you just felt was the tide turning.

This study has received wide publicity in print and on television. It is possible that, at long last, the medical community and the media are beginning to question the dogma that the only healthy diet is a low-fat diet.

Wednesday, July 16, 2008

Fructose II

Sucrose, also known as table sugar, is a disaccharide. In the gut, it is split into its constituent monosaccharides--glucose and fructose. Sucrose is frequently replaced by high fructose corn syrup (HFCS) in commercially prepared foods and soft drinks. High fructose corn syrup is a mixture of about 45% glucose and 55% fructose. You probably knew all of that already.

The important thing about sucrose and HFCS is that they are the main sources of fructose in the American diet. As we saw in the previous post, when fructose is metabolized in the liver, it is most likely to be broken down into glycerol 3-phosphate and acyl-coA, which are then assembled into triglycerides, i.e., fat.

Eat fructose, create fat. But that's not the end of the story. Fructose increases glucose metabolism in the liver by mobilizing an enzyme called glucokinase. The liver takes up more glucose than it normally would, and the excess glucose is also synthesized into fat.

In addition to fructose-induced lipogenesis, other long-term effects of fructose have been observed in experimental animals and in humans. Although fructose produces a very small insulin response, long-term use of fructose nevertheless induces insulin resistance, which eventually results in fructose-induced hypertension. Somewhat surprisingly, the low concentration of insulin released after fructose ingestion also means that there is a low satiety response to fructose. It is possible to consume a great deal of fructose without feeling full. Finally, fructose is 10-17 times more effective than glucose in producing Advanced Glycation Endproducts--the crosslinked matrix of proteins and sugars that accumulates in our tissues and stiffens them.

In 1960, the average American consumed approximately 110 pounds of sweeteners per year, mostly in the form of cane and beet sugar. Since then, the use of table sugar has declined, but the use of high fructose corn syrup has more than replaced it. Americans now consume an average of over 140 pounds of sweeteners per year. Because half of those sweeteners by weight is composed of fructose, the potential negative health effects are worth serious consideration.

If you're interested in learning more about fructose metabolism:

Sunday, July 13, 2008

Fructose--Not as healthy as it appears to be

What if there was a food that could easily be converted to fat in your body? You would think that that food would be on the list of substances to avoid among those who are weight-conscious. You would be wrong.

Fructose is the sugar is found in most fruits. Like glucose, it is a simple sugar, but our bodies handle fructose in a special way. Look at the diagram below, which appears in Fructose, weight gain, and the insulin resistance syndrome by Sharon Elliot and coauthors.

The metabolic pathways for glucose are on the right side of the diagram. Note that there are many steps between glucose and the final product in this figure--acyl glycerols (triglycerides) which are packaged into VLDL (Very Low Density Lipoproteins) and sent out into the body for storage as fat. Depending on the body's needs, glucose can be used for energy via glycolysis and the citric acid cycle, and it can be stored as glycogen. If glucose is present in excess, it can be converted to triglycerides in the liver, but that is only one of many options.

For fructose, there are fewer choices. Fructose by itself does not stimulate insulin release. If insulin is low and glucagon is high, fructose can enter the gluconeogenesis pathway and be turned into glucose. But we seldom eat pure fructose. If we eat fructose with other carbohydrates, or if we eat it in the form of table sugar, the more likely situation is that insulin will be high and glucagon will be low. This will direct the fructose to be converted into the intermediates for fatty acid synthesis, and then into triglycerides. The result will be a phenomenon called fructose-induced lipogenesis.

Photo of apples: FreeDigitalPhotos.net

Thursday, July 10, 2008

Reversing Insulin Resistance

It is commonly thought that weight loss is required to reverse insulin resistance. A small study of obese type 2 diabetics indicates that this may not be the case. Ten diabetic patients, seven of whom were on diabetes medications, checked into a hospital with an average weight of 252 pounds. For seven days they acted as their own Control group. They ate their normal diets, averaging 3111 calories and 309 grams of carbohydrate a day. On day 7 their blood glucose and blood inuslin levels were measured over a 24 hour period. The time course of glucose and insulin is represented by the black circles in the graphs below.

On day 8 the patients remained in the hospital and became the Low-carbohydrate diet group. They were switched to a low-carbohydrate diet which included 21 daily grams of carbohydrate, plus as much fat and protein as they desired. Adherence to the low-carbohydrate diet was confirmed by measurement of urinary ketones. After two weeks on this diet, blood glucose and blood insulin levels were again measured over a 24 hour period. The time course of glucose and insulin after two weeks of eating low-carb is represented by the blue circles in the graphs above. (For the sake of reference, the 6mmol/L Glucose Level is roughly equivalent to a glucometer reading of 100 and the 8 mmol/L Glucose Level is roughly equivalent to a reading of 150.)

There were no set mealtimes, so all of the curves are fairly flat. Nevertheless, it is easy to see that a diet of 309 grams of carbohydrate a day produced high glucose levels around the clock and high insulin levels during waking hours. By contrast, just two weeks of eating 21 grams of carbohydrate a day brought blood glucose levels to a normal range and kept insulin levels low both during waking hours and at night.

Other measures of insulin resistance reflected the values shown in the graphs. In just two weeks on the low-carbohydrate regimen, glycosylated hemoglobin fell from 7.3% to 6.8%. Insulin sensitivity improved by approximately 75%, while plasma triglycerides decreased by 35% and cholesterol levels decreased by 10%.

During the last two weeks of the study, patient weights also decreased by an average of 1.8%. Although it might be possible to attribute the large improvement in lab values to this small decrement in weight, it seems more likely that both the weight loss and the rapid improvement in insulin resistance was attributable to the patients' adherence to a low-carbohydrate diet.

Monday, July 7, 2008

Low-Carb at the Movies

Analyst Maxwell Smart is briefing agents at the secret U.S. government spy agency CONTROL. What does it mean, he asks rhetorically, that agents at the enemy terrorist organization KAOS have been overheard discussing muffins?

His answer: "Muffins are comfort food. Why would they eat comfort food unless they were nervous about something?"

Hmmm. Where did that come from? In this summer's theater version of the old TV series, "Get Smart," we learn that that the handsome and heroic secret agent Maxwell Smart was once very fat. When his partner, Agent 99, tells him that she used to look like her mom, Max responds, "I used to look like two of my moms, put together."

Flashbacks show us that, in order to advance from analyst to agent, Smart had to lose 150 pounds. And how did he do it? By low-carbing. References to low-carbing and to the fact that big people have feelings, too, abound throughout the movie.

Would-you-believe that low-carbing has again reached the mainstream? Probably not, but seeing it discussed in a serious way on the big screen is certainly is an encouraging development.

Friday, July 4, 2008

Metabolic Syndrome

In several recent posts we've mentioned something called "metabolic syndrome." What is metabolic syndrome?

Metabolic syndrome is not a disease, but rather a set of symptoms that frequently appear together in patients as they grow older. Typically these symptoms include obesity, low HDL cholesterol levels, high triglyceride levels, high glucose and insulin levels, and high blood pressure. As these symptoms worsen, patients with metabolic syndrome frequently progress to type 2 diabetes and cardiovascular disease. If we could somehow prevent or reverse the symptoms of metabolic syndrome, it seems logical that we could correspondingly decrease the incidence of type 2 diabetes and cardiovascular disease.

Obesity is one of the characteristics of metabolic syndrome. Because obesity is easy to observe, it is commonly assumed that metabolic syndrome is caused by obesity. However, a careful inspection of the markers associated with metabolic syndrome reveals that they are all related to insulin resistance.

While weight loss will relieve some of the symptoms of metabolic syndrome, weight loss is notoriously difficult to accomplish and even harder to maintain. The good news is that carbohydrate restriction, even in the absence of dramatic weight loss, is effective in alleviating all of the aspects of metabolic syndrome.

In a study published in the New England Journal of Medicine, 63 obese patients were assigned to a low-carb/high-fat/high-protein diet or to a high-carb/low-fat/low-calorie conventional diet. They were given little follow-up to mimic typical dieting conditions. The graph above summarizes the findings. Light blue bars represent low-carbers at 6 months and dark blue bars represent low-carbers at 12 months. Light red bars represent high-carbers at 6 months and dark red bars represent high-carbers at 12 months.

Although the low-carb group lost more weight than the high-carb group, at 12 months the difference was not significant. The low-carb group experienced a slight decline in systolic blood pressure while the high-carb group experienced a slight increase. HDL cholesterol was significantly higher and triglycerides were significantly lower and in the low-carb group at 12 months. Finally, there was less insulin released in the low-carb group at 6 months, though the difference was no longer significant at 12 months.

Jeff Volek and Richard Feinman have compiled a review of over 30 dietary studies, tabulating the effects of carbohydrate restriction on the markers associated with metabolic syndrome. As we might expect, some studies show great differences and other show little or none. However, taken together, the studies show that while both low-carb diets and conventional diets are associated with an overall decrease in weight, low-carb diets also typically produce the following
  • an increase in HDL cholesterol
  • a decrease in triglycerides
  • a decrease in glucose levels
  • a decrease in insulin levels
  • a decrease in blood pressure

In other words, a review of the scientific literature shows that dietary carbohydrate restriction is a reproducible way to improve the features of metabolic syndrome.

Tuesday, July 1, 2008

Roots and Branches

What are the diseases of civilization? Measles? Whooping cough? AIDS?

No--you can get all of those diseases without being civilized!

The diseases of civilization are conditions that appear in indigenous populations within about 20 years of significant contact with Western culture. They include dental caries, ulcers, gallstones, appendicitis, diverticulitis, constipation, obesity, asthma, varicose veins, diabetes, high blood pressure, cardiovascular disease, stroke and cancer. Early twentieth century missionaries from Albert Schweitzer in Africa to Samuel Hutton in Labrador noticed that prior to Western contact, these populations experienced such diseases rarely if at all. However, as decades passed and the local people began to adopt Western culture, inevitably Western diseases would gradually appear and eventually become prevalent.

Western civilization brought modern medicine and good public health practices. Why should it also bring poor health? It is possible that an increase in smoking, a decrease in physical activity, high fat consumption and resultant obesity explain why local populations became progressively less healthy over time. However, another explanation is that arriving Westerners brought with them foods that would not spoil over long ocean voyages. White flour, white rice and sugar do not provide much in the way of vitamins and minerals, but they keep well, are fairly cheap, contain necessary calories, and taste very good. They are also rich in easily digestible carbohydrates.

(Illustration inspired by Dave Hatch of Green Bay, Wisconsin)

Look at the tree above. In the branches are many of the diseases of Western civilization. Conventional wisdom says that obesity is at the root of the tree, and that obesity results from too much food and too little exercise. In the tree above, however, we see refined carbohydrates as the root cause. Too much carbohydrate leads to too much insulin release and too much insulin leads to a host of symptoms which eventually manifest themselves as the diseases of civilization. What is the root cause of these diseases--obesity or an excessive intake of carbohydrates? A lot depends on which answer is the correct one.