Thoughts on Obesity, Part I

From the US Centers for Disease Control website:

Since the mid-seventies, the prevalence of overweight and obesity has increased sharply for both adults and children. Data from two NHANES surveys show that among adults aged 20–74 years the prevalence of obesity increased from 15.0% (in the 1976–1980 survey) to 32.9% (in the 2003–2004 survey).

In hunter-gatherer and some semi-agricultural societies, obesity is rare. In most, it's nonexistent. Wild animals typically do not accumulate enough fat to interfere with vigorous exercise, and when they do, it's because they're about to hibernate or migrate. Wild animals also tend to have similar amounts of body fat between individuals (at a given age and sex), unlike industrialized humans. This makes me think that obesity is an unnatural effect of our current lifestyle. Whatever the cause, it's getting progressively more common.

According to certain nutrition experts, we know exactly what causes overweight. It's a character flaw known as overeating. Calories in, calories out. And the cure is to eat less. The problem is, this treatment has a poor record of efficacy.

Restricting calories is also fraught with problems. Each person's metabolism has a preference for a specific body composition within the context of a particular lifestyle. If total calories are restricted without changing diet composition, the body reacts vigorously to maintain homeostasis. Energy expenditure is reduced; muscle and organ mass diminish. The psychological effects are particularly bad, as anyone can tell you who has been on a low-calorie diet. In 1944, Ancel Keys undertook a calorie restriction trial in conscientious objector "volunteers" in Minnesota. They remained on a 1,570-calorie diet that was low in fat and protein and high in carbohydrate, for 24 weeks. Hardly a draconian calorie count. Here's a quote from the study:

As starvation progressed, fewer and fewer things could stimulate the men to overt action. They described their increasing weakness, loss of ambition, narrowing of interests, depression, irritability, and loss of libido as a pattern characteristic of "growing old".

Some of the men ended up suffering from neurosis and borderline psychosis before the end of the study, one culminating in self-mutilation. This is what we're being prescribed for weight loss?

There are some diet trends that have associated with rising obesity in the US. Per capita calorie consumption has increased. This increase is due to a higher consumption of carbohydrate. Total protein and fat consumption have been almost identical for the past 30 years. This period also saw increases in the consumption of unsaturated vegetable oils, hydrogenated vegetable oils and high-fructose corn syrup. It's hard to say from this association which of these factors (if any) has caused us to gain weight in the last 30 years, but it certainly isn't total fat or protein. Fortunately, we have other clues.

Visceral Fat

This week, I stumbled upon a very interesting series of articles from the lab of Dr. Nir Barzilai.

The first article I came across showed that surgical removal of the visceral fat deposit of rats increased their lifespan. Visceral fat (VF) is the "beer belly", and consists of the perinephratic fat around the kidneys and the omental fat in front of the intestines. It doesn't include subcutaneous fat, the fat layer under the skin.

VF is tightly associated with the metabolic syndrome, the quintessential "disease of civilization" that affects 24% of Americans (NHANES III). It's defined by three or more of the following criteria: high blood pressure, large waist circumference, low HDL cholesterol, high triglycerides, and high fasting glucose. The metabolic syndrome is associated with a 3-4-fold increase in the risk of death from cardiovascular disease, and a 6-fold increase in the risk of developing type II diabetes. From a review on the metabolic syndrome (parentheses mine):

The most common alteration related to the impaired glucose metabolism with aging is the progressively increased fasting and postprandial [post-meal] plasma insulin levels, suggesting an insulin-resistant state.

This is all well and good, but who cares? What's to say VF plays any role other than as a simple marker for overweight?

The longevity paper led me to Dr. Barzilai's previous papers, which answered this question rather thoroughly. Rats raised on standard rat chow, which is a sad little compressed pellet made of grains and added nutrients, develop elevated insulin and insulin resistance with age, just like humans. Unless they don't have VF. Rats that had their VF surgically removed did not develop insulin resistance or elevated insulin with age, despite rebounding to their original total fat mass rather quickly (VF accounts for ~18% of total fat in these rats). These parameters are unaffected by removing an equal amount of subcutaneous fat, which has been shown in human liposuction patients as well.

Removing VF also improved diabetes-prone Zucker rats, which are profoundly insulin-resistant (leptin receptor loss-of-function). It kept wild-type rats just as insulin-sensitive as calorically restricted controls, which had a small amount of VF. This shows that VF isn't just a passive player; it's essential for the development of insulin resistance. It also shows, along with human studies, that insulin resistance is not an inevitable consequence of aging.

Adipose (fat) tissue is being increasingly recognized as an important endocrine (hormone-secreting) organ. It produces many different hormones that affect insulin sensitivity and appetite regulation, among other things. These hormones are collectively known as fat-derived peptides (FDPs). At least one of these FDPs, TNF-alpha, promotes insulin resistance.

Dr. Barzilai's group went on to explore the mechanism of VF contributing to insulin resistance. They increased the rate of glucose flux into the fat tissue of rats by infusing either glucose or insulin into the bloodstream. These treatments both cause increased glucose uptake by fat cells. What they saw when they dissected the rats was striking. The VF had ramped up its production of FDPs from 2- to 15-fold, while the subcutaneous fat had barely changed. Incidentally, insulin increased glucose uptake by VF twice as much as subcutaneous fat.

I'll say this again, because it's important. They forced glucose into VF cells, and those cells dramatically upregulated FDP production. And again, no visceral fat, no FDPs.

In earlier papers, he also showed that the removal of VF dramatically reduces the expression of TNF-alpha and leptin (two FDPs) in subcutaneous fat on a longer timescale, showing that VF and subcutaneous fat communicate to alter the metabolism. Again, TNF-alpha promotes insulin resistance, making it a possible link between the fat tissue and peripheral effects. VF removal had no effect on triglycerides, suggesting that they're only a marker of insulin dysfunction rather than a cause.

Now to take this research to its logical conclusion. Here's a plausible sequence of events leading up to the metabolic syndrome:

• A meal high in quickly digested carbohydrate elevates blood glucose. OR, excessive fructose causes insulin resistance in the liver which leads to high fasting glucose.
  

• Visceral fat responds by increasing production of FDPs.

• FDPs, directly and/or indirectly, cause insulin resistance in the liver, muscle and other tissue. Liver insulin resistance causes alterations in lipoprotein ("cholesterol") profile (more on this in another post). Fat tissue remains insulin-sensitive.

• The vicious cycle continues, with increased visceral fat size and glucose uptake increasing FDP production, which makes the liver more insulin resistant, which increases glucose production by the liver, etc.
  

Book Review: Blood Sugar 101

I just finished reading "Blood Sugar 101" by Jenny Ruhl. It's a quick read, and very informative. Ruhl is a diabetic who has taken treatment into her own hands, using the scientific literature and her blood glucose monitor to understand blood sugar control and its relationship to health. The book challenges some commonly held ideas about diabetes, such as the notion that diabetics always deteriorate.

She begins by explaining in detail how blood glucose is controlled by the body. The pancreas releases basal amounts of insulin to make glucose available to tissues between meals. It also releases insulin in response to carbohydrate intake (primarily) in two bursts, phase I and phase II. Phase I is a rapid response that causes tissues to absorb most of the glucose from a meal, and is released in proportion to the amount of carbohydrate in preceding meals. Phase II cleans up what's left.

In a person with a healthy pancreas, insulin secretion will keep blood glucose under about 130 mg/dL even under a heavy carbohydrate load. The implications of this are really interesting. Namely, that blood glucose levels will not be very different between a person who eats little carbohydrate, and one who eats a lot, as long as the latter has a burly pancreas and insulin-sensitive tissues.

Most Americans don't have such good control however, hence the usefulness of low-carbohydrate diets. This begs the question of why we lose blood sugar control. Insulin resistance seems like a good candidate, maybe preceded by leptin resistance. As you may have noticed, I'm starting to think the carbohydrate per se is not the primary insult. It's probably something else about the diet or lifestyle that causes carbohydrate insensitivity. Grain lectins are a good candidate in my opinion, as well as inactivity.

Diabetics can have blood glucose up to 500 mg/dL, that remains elevated long after it would have returned to baseline in a healthy person. Ruhl asserts that elevated blood sugar is toxic, and causes not only diabetic complications but perhaps also cancer and heart disease.

Heart attack incidence is strongly associated with A1C level, which is a rough measure of average blood sugar over the past couple of months. It makes sense, although most of the data she cites is correlative. They might have seen the same relationship if they had compared heart attack risk to fasting insulin level or insulin resistance. It's difficult to nail down blood sugar as the causative agent. More information from animal studies would have been helpful.

Probably the most important thing I took from the book is that the first thing to deteriorate is glucose tolerance, or the ability to pack post-meal glucose into the tissues. It's often a result of insulin resistance, although autoimmune processes seem to be a factor for some people. Doctors often use fasting glucose to diagnose diabetes and pre-diabetes, but typically you are far gone by the time your fasting glucose is elevated!

I like that she advocates a low-carbohydrate diet for diabetics, and lambasts the ADA for its continued support of high-carbohydrate diets.

Overall, a good book. I recommend it!

The Liver: Your Metabolic Gatekeeper

As I've been learning more about the different blood markers of metabolic dysfunction, something suddenly occurred to me. Most of them reflect liver function! Elevated fasting glucose, low HDL cholesterol, high LDL cholesterol, high triglycerides and high fasting insulin all reflect (at least in part) liver function. The liver is the "Grand Central Station" of cholesterol and fatty acid metabolism, to quote Philip A. Wood from How Fat Works. It's also critical for insulin and glucose control, as I'll explain shortly. When we look at our blood lipid profile, fasting glucose, or insulin, what we're seeing is largely a snapshot of our liver function. Does no one talk about this or am I just late to the party here?!

I read a paper today from the lab of C. Ronald Kahn that really drove home the point. They created a liver-specific insulin receptor knockout (LIRKO) mouse, which is a model of severe insulin resistance in the liver. The mouse ends up developing severe whole-body insulin resistance, dramatically elevated post-meal insulin levels (20-fold!), impaired glucose tolerance, and elevated post-meal and fasting glucose. Keep in mind that this all resulted from nothing more than an insulin resistant liver.

LIRKO mice had elevated post-meal blood glucose due to the liver's unresponsiveness to insulin's command to take up sugar. Apparently the liver can dispose of one third of the glucose from a meal, turning it into glycogen and triglycerides. The elevated fasting glucose was caused by insulin not suppressing gluconeogenesis (glucose synthesis) by the liver. In other words, the liver has no way to know that there's already enough glucose in the blood so it keeps on pumping it out. This is highly relevant to diabetics because fasting hyperglycemia comes mostly from increased glucose output by the liver. This can be due to liver insulin resistance or insufficient insulin production by the pancreas.

One of the interesting things about LIRKO mice is their dramatically elevated insulin level. Their pancreases are enlarged and swollen with insulin. It's as if the pancreas is screaming at the body to pick up the slack and take up the post-meal glucose the liver isn't disposing of. The elevated insulin isn't just due to increased output by the pancreas, however. It's also due to decreased disposal by the liver. According to the paper, the liver is responsible for 75% of insulin clearance from the blood in mice. The hyperinsulinemia they observed was both due to increased secretion and decreased clearance. Interestingly, they noted no decline in beta cell (the cells that secrete insulin) function even under such a high load.

Something that's interesting to note about these mice is they have very low blood triglyceride. It makes sense since insulin is what tells the liver to produce it. Could this have something to do with their lack of beta cell dysfunction?

The really strange thing about LIRKO mice is that their blood glucose becomes more normal with age. Strange until you see the reason: their livers are degenerating so they can't keep up glucose production!

LIRKO mice reproduce many of the characteristics of type II diabetes, without degenerating completely into beta cell death. So insulin resistance in the liver appears to reproduce some elements of diabetes and the metabolic syndrome, but the full-blown disorders require other tissues as well. As a side note, this group also has a skeletal muscle-specific insulin receptor knockout which is basically normal. Interesting considering muscle tissue seems to be one of the first tissues to become insulin resistant during diabetes onset.

So if you want to end up like your good pal LIRKO, remember to drink high-fructose corn syrup with every meal! You'll have fatty liver and insulin resistance in no time!

I have a lot more to say about the liver, but I'll continue it in another post.

The Miracle Diabetes Cure You Don't Know About

What would you say if I told you there's a cure for type II diabetes that's effective in 83% of people, extremely rapid, and requires no lifestyle changes? Would you think I was crazy? Well maybe I am, but the cure exists nevertheless.

All it requires is a little intestinal mutilation. It's called gastric bypass surgery. It's an anti-obesity surgery where the digestive tract is re-routed, bypassing 95% of the stomach as well as the duodenum and jejunum, which are parts of the upper small intestine.

The effect was first reported in 1995 by Dr. Walter Pories. Initially, researchers thought the cure was simply from caloric restriction due to a smaller stomach volume, but since then the story has become much more interesting. The key finding was published in 2004 by Dr. Francesco Rubino, who showed that bypassing the duodenum and jejunum but not the stomach of type II diabetic rats was enough to cure their diabetes. The effect wasn't due to caloric restriction, since both groups ate the same amount of food.

What this suggests is that there's some kind of feedback coming from the upper small intestine that affects glucose control and insulin sensitivity. What could be causing it? It just so happens there are some pretty good candidates: hormones called GLP-1 and ghrelin.

I'm going to dive into this and see if I can figure out what's going on.

Sorry for the cheesy post title, I'm practicing for my best-seller. Maybe I should add the word "secret"? How about this: "101 Secret Diabetes Cures THEY Don't Want You to Know About".

Diabetes and Your Small Intestine

In the last post, I introduced you to the remarkable antidiabetic effect of gastric bypass surgery. It rapidly reverses diabetes in 83% of patients, and it seems to be due to bypassing the upper small intestine specifically, rather than caloric restriction. This points to a special role of the upper small intestine in regulating food metabolism. I told you I was going to look into the mechanism of why this effect happens, and here's the short answer:

It's complicated and no one understands it completely.

Now for the long answer. Nutrient homeostasis is very important and we have sophisticated ways of coordinating it among different tissues. Part of the small intestine's job is telling the body that nutrients are on their way into the bloodstream. Two ways it conveys this signal are by secreting hormones into the bloodstream, and by sending signals to the brain and liver via parasympathetic nerves.

The small intestine secretes dozens of hormones, one category of which is called the incretins. Incretins by definition increase the secretion of insulin by the pancreas, among other things. They were discovered when researchers realized that oral glucose elicits more of an insulin response than intravenous glucose. The reason is that cells in the upper small intestine secrete incretins when they detect glucose.

There are two known major incretin hormones that are secreted by the small intestine, GIP and GLP-1. There was a recent study by the lab of Blanca Olivan which looked into the levels of incretins in patients who had undergone Roux-en-Y gastric bypass, a common type in which 95% of the stomach and part of the upper small intestine is bypassed.

Their results are very interesting! Compared to controls losing an equivalent amount of weight on a low-calorie diet, the bypass patients saw a HUGE increase in their oral glucose tolerance test (OGTT) GLP-1 secretion (9.8 vs 112.5 pmol/L), a large increase in GIP secretion, and a corresponding increase in insulin secretion (575 vs 769 pmol/L). Two-hour OGTT blood glucose levels went from borderline diabetic to "normal", by American Diabetes Association standards. Fasting glucose and insulin dropped substantially. The bypass group gained considerable glucose control, better than the matched controls on a low-calorie diet.

It looks like part of the mechanism involves whipping the pancreas to produce more insulin in response to glucose. It also affected fasting insulin, although that could simply be due to calorie restriction because it went down in both groups. Interestingly, non-diabetic patients who get a Roux-en-Y bypass often get reactive hypoglycemia, where their pancreas overproduces insulin after a meal and they get dangerously low blood sugar. Dr Mary-Elizabeth Patti calls it "diabetes reversal in people who don't have diabetes". So the effect doesn't seem to be specific to people with diabetes.

There is some suggestion that the effect on incretins is due to bypassing the duodenum, which is part of the upper small intestine. Here's how the (very sophisticated) reasoning goes: when the duodenum doesn't get glucose dumped on it, that somehow increases release of incretins by the small intestine further along the line.

There's actually an antidiabetic drug that mimics GLP-1; it's called Byetta. There's another that inhibits the breakdown of GLP-1 called Januvia. A second effect of GLP-1 is to delay stomach emptying, which both drugs do. They have been effective for some diabetics.

Well this turned into a long post, so I'll follow up on the parasympathetic (nerve) signaling of the small intestine next time.

Lessons From the Pima Indians

At 38% and climbing in 2006, the Pima indians (Akimel O'odham) of Arizona have the highest rate of diabetes of any population in the world. They also have staggering rates of obesity (~70%) and hypertension.

Things were very different for them before 1539, when the Spanish first made contact. They lived on an agricultural diet of beans, corn and squash, with wild fish, game meat and plants. As with most native people, they were thin and healthy while on their traditional diet.

In 1859, the Pima were restricted to a small fraction of their original land along the Gila river, the Pima Reservation. In 1866, settlers began arriving in the region and diverting the Gila river upstream of the reservation for their own agriculture. In 1869, the river went dry for the first time. 1886 was the last year any water flowed to the Pima Reservation in the Gila river.

The Pima had no way to obtain water, and no way to grow crops. Their once productive subsistence economy ground to a halt. Famine ensued for 40 desperate years. The Pima cut down their extensive mesquite forests to sell for food and water. Eventually, after public outcry, uncle Sam stepped in.

The government provided the Pima with subsidized "food": white flour, sugar, partially hydrogenated lard, and canned goods. They promptly became diabetic and overweight, and have remained that way ever since.

The Pima are poster children for mainstream nutrition researchers in the US for several reasons. First of all, their pre-contact diet was probably fairly low in fat, and researchers love to point out that they now eat more fat (comparable to the average American diet). Another reason is that there's another group of Pima in Mexico who still live on a relatively traditional diet and are much healthier. They are genetically very similar, supporting the idea that it's the lifestyle of the American Pima that's causing their problems. The third reason is that the Mexican Pima exercise more than the Arizona Pima and eat a bit less.

I of course agree with the conclusion that their lifestyle is behind their problems; that's pretty obvious. I think most Pima know it too. If they got their water back, maybe things would be different for them.

However, the focus on macronutrients sometimes obscures the fact that the modern Pima diet is pure crap. It's mostly processed food with a low nutrient density. It also contains the two biggest destroyers of indigenous health: white flour and sugar. There are numerous examples of cultures going from a high-fat diet to a lower-fat "reservation food" diet and suffering the same fate: the Inuit of Alaska, the Maasai and Samburu of Kenya, tribes in the Pacific Northwestern US and Canada, certain Aboriginal groups, and more. What do they all have in common? White flour, sugar and other processed food.

The exercise thing is somewhat questionable as well. True, Mexican Pima exercise 2.5 times more than Arizona Pima, but the Arizona Pima still exercise much more than the average American! Women clock in at 3.1 hours a week, while men come in at a whopping 12.1 hours a week! I am a bike commuter and weight lifter, and even I don't exercise that much. So forgive me if I'm a little skeptical of the idea that they aren't exercising enough to keep the weight off. 

The history of the Pima is a heart-wrenching story that has been repeated hundreds, perhaps thousands of times all over the world. Europeans bring in white flour, sugar and other processed food, it destroys a native populations' health, and then researchers either act like they don't understand why it happened, or give unsatisfying explanations for it.

The Pima are canaries in the coal mine, and we can learn a lot from them. Their health problems resemble those of other poor Americans (and wealthier ones also, to a lesser extent). This is because they are both eating similar types of things. The problem is creeping into society at large, however, as we rely more and more on processed wheat, corn, soy and sugar, and less on wholesome food. Obesity in the US has doubled in the past 30 years, and childhood obesity has tripled. Diabetes is following suit. Life expectancy has begun to diminish in some (poor) parts of the country. Meanwhile, our diet is looking increasingly like Pima reservation food. It's time to learn a lesson from their tragedy.

Water for the Pima

A few months ago, I published a post about the Pima Indians (Akimel O'odham) of Arizona. The Pima are one of the most heart-wrenching examples of the disease of civilization afflicting a society after a nutrition transition. Traditionally a healthy agricultural people, they now have some of the highest rates of obesity and diabetes in the world.

The trouble all started when their irrigation waters were diverted upstream in the late 19th century. Their traditional diet of corn, beans, squash, fish, game meats and gathered plant foods became impossible. They became dependent on government food programs, which provided them with white flour, sugar, lard and canned goods. Now they are the subjects of scientific research because of their staggering health problems.

I'm happy to report that after more than 30 years of activism, lawsuits and negotiation, the Pima and neighboring tribes have reached an agreement with the federal government that will restore a portion of their original water. Of the 2 million acre-feet of water the Pima were estimated to have used since before the 16th century, the settlement will restore 653,500. An acre-foot is approximately the personal water use of one household. The settlement also provides federal funds for reconstructing old irrigation canals.

Now we will see how the Pima will use it. Will they return to an agricultural lifestyle, perhaps with the advantages of modern technology? Or will they lease the water rights for money and continue to live off Western foods? Perhaps some of both. They are definitely aware that Western food is causing their health problems, and that they could regain their health by eating traditional foods. However, white flour "fry bread", sugar and canned meat have been around for so long they are also a cultural tradition at this point. Only time will tell which path they choose.

A New Toy

I bought a new toy the other day: a blood glucose meter. I was curious about my post-meal blood glucose after my HbA1c reading came back higher than I was expecting. A blood glucose meter is the only way to know what your blood sugar is doing in your normal setting.

"Glucose intolerance" is the inability to effectively control blood glucose as it enters the bloodstream from the digestive system. It results in elevated blood sugar after eating carbohydrate, which is not a good thing. In someone with normal glucose tolerance, insulin is secreted in sufficient amounts, and the tissues are sufficiently sensitive to it, that blood glucose is kept within a fairly tight range of concentrations.

Glucose tolerance is typically the first thing to deteriorate in the process leading to type II diabetes. By the time fasting glucose is elevated, glucose intolerance is usually well established. Jenny Ruhl talks about this in her wonderful book Blood Sugar 101. Unfortunately, fasting glucose is the most commonly administered glucose test. That's because the more telling one, the oral glucose tolerance test (OGTT), is more involved and more expensive.

An OGTT involves drinking a concentrated solution of glucose and monitoring blood glucose at one and two hours. Values of >140 mg/dL at one hour and >120 mg/dL at two hours are considered "normal". If you have access to a blood glucose meter, you can give yourself a makeshift OGTT. You eat 60-70 grams of quickly-digesting carbohydrate with no fat to slow down absorption and monitor your glucose.

I gave myself an OGTT tonight. I ate a medium-sized boiled potato and a large slice of white bread, totaling about 60g of carbohydrate. Potatoes and bread digest very quickly, resulting in a blood glucose spike similar to drinking concentrated glucose! You can see that in the graph below. I ate at time zero. By 15 minutes, my blood glucose had reached its peak at 106 mg/dL.


My numbers were 97 mg/dL at one hour, and 80 mg/dL at two hours; far below the cutoff for impaired glucose tolerance. I completely cleared the glucose by an hour and 45 minutes. My maximum value was 106 mg/dL, also quite good. That's despite the fact that I used more carbohydrate for the OGTT than I would typically eat in a sitting. I hope you like the graph; I had to prick my fingers 10 times to make it! I thought it would look good with a lot of data points.

I'm going to have fun with this glucose meter. I've already gotten some valuable information. For example, just as I suspected, fast-digesting carbohydrate is not a problem for someone with a well-functioning pancreas and insulin-sensitive tissues. This is consistent with what we see in the Kitavans, who eat a high-carbohydrate, high glycemic load diet, yet are extremely healthy. Of course, for someone with impaired glucose tolerance (very common in industrial societies), fast-digesting carbohydrates could be the kiss of death. The big question is, what causes the pancreas to deteriorate and the tissues to become insulin resistant? Considering certain non-industrial societies were eating plenty of carbohydrate with no problems, it must be something about the modern lifestyle: industrially processed grains (particularly wheat), industrial vegetable oils, refined sugar, lack of fat-soluble vitamins, toxic pollutants and inactivity come to mind. One could make a case for any of those factors contributing to the problem.

Paleolithic Diet Clinical Trials

If Dr. Ancel Keys (of diet-heart hypothesis fame) had been a proponent of "paleolithic nutrition", we would have numerous large intervention trials by now either confirming or denying its ability to prevent health problems. In this alternate reality, public health would probably be a lot better than it is today. Sadly, we have to settle for our current reality where the paleolithic diet has only been evaluated in two small trials, and medical research spends its (our) money repeatedly conducting failed attempts to link saturated fat to every ill you can think of. But let's at least take a look at what we have.

Both trials were conducted in Sweden. In the first one, lead by Dr. Per Wändell, 14 healthy participants (5 men, 9 women) completed a 3-week dietary intervention in which they were counseled to eat a "paleolithic diet". Calories were not restricted, only food categories were. Participants were told to eat as much as they wanted of fruit, vegetables, fish, lean meats, nuts, flax and canola oil, coffe and tea (without dairy). They were allowed restricted quantities of dried fruit, potatoes (2 medium/day) salted meat and fish, fat meat and honey. They were told not to eat dairy, grain products, canned food, sugar and salt.

After three weeks, the participants had:

• Decreased their caloric intake from 2,478 to 1,584 kcal
• Increased their percentage protein and fat, while decreasing carbohydrate
• Decreased saturated fat, increased dietary cholesterol, decreased sodium intake, increased potassium
• Lost 2.3 kg (5 lb)
• Decreased waist circumference, blood pressure and PAI-1

Not bad for a 3-week intervention on healthy subjects. This study suffered from some serious problems, however. #1 is the lack of a control group as a means for comparison. Ouch. #2 is the small study size and resulting lack of statistical power. I consider this one encouraging but by no means conclusive.

The second study was conducted by the author of the Kitava study, Dr. Staffan Lindeberg. The study design was very interesting. He randomly assigned 29 men with ischemic heart disease, plus type II diabetes or glucose intolerance, to either a "Mediterranean diet" or a "paleolithic diet". Neither diet was calorie-restricted. Here's the beauty of the study design: the Mediterranean diet was the control for the paleo diet. The reason that's so great is it completely eliminates the placebo effect. Both groups were told they were being assigned to a healthy diet to try to improve their health. Each group was educated on the health benefits of their diet but not the other one. It would have been nice to see a regular non-intervention control group as well, but this design was adequate to see some differences.

Participants eating the Mediterranean diet were counseled to focus on whole grains, low-fat dairy, potatoes, legumes, vegetables, fruit, fatty fish and vegetable oils rich in monounsaturated fats and alpha-linolenic acid (omega-3). I'm going to go on a little tangent here. This is truly a bizarre concept of what people eat in the Mediterranean region. It's a fantasy invented in the US to justify the mainstream concept of a healthy diet. My father is French and I spent many summers with my family in southern France. They ate white bread, full-fat dairy at every meal, legumes with fatty pork, sausages and lamb chops. In fact, full-fat dairy wasn't fat enough sometimes. Many of the yogurts and cheeses we ate were made from milk with extra cream added. 

The paleolithic group was counseled to eat lean meat, fish, fruit, leafy and cruciferous vegetables, root vegetables (including moderate amounts of potatoes), eggs and nuts. They were told to avoid dairy, grain products, processed food, sugar and beer.

Both groups were bordering on obese at the beginning of the study. All participants had cardiovascular disease and moderate to severe glucose intolerance (i.e. type II diabetes). After 12 weeks, both groups improved on several parameters. That includes fat mass and waist circumference. But the paleolithic diet trumped the Mediterranean diet in many ways:

• Greater fat loss in the the midsection and a trend toward greater weight loss
• Greater voluntary reduction in caloric intake (total intake paleo= 1,344 kcal; Med= 1,795)
• A remarkable improvement in glucose tolerance that did not occur significantly in the Mediterranean group
• A decrease in fasting glucose
• An increase in insulin sensitivity (HOMA-IR)

Overall, the paleolithic diet came out looking very good. But I haven't even gotten to the best part yet. At the beginning of the trial, 12 out of the 14 people in the paleo group had elevated fasting glucose. At the end, every single one had normal fasting glucose. In the Mediterranean group, 13 out of 15 began with elevated glucose and 8 out of 15 ended with it. This clearly shows that a paleolithic diet is an excellent way to restore glucose control to a person who still has beta cells in their pancreas.

This post is getting long, so I think I'll save the interpretation for the next post.

Paleolithic Diet Clinical Trials Part II

There were a number of remarkable changes in both trials. I'll focus mostly on Dr. Lindeberg's trial because it was longer and better designed. The first thing I noticed is that caloric intake dropped dramatically in both trials, -36% in the first trial and a large but undetermined amount in Dr Lindeberg's. The Mediterranean diet group ended up eating 1,795 calories per day, while the paleolithic dieters ate 1,344. In both studies, participants were allowed to eat as much as they wanted, so those reductions were purely voluntary.

This again agrees with the theory that certain neolithic or industrial foods promote hyperphagia, or excessive eating. It's the same thing you see in low-carbohydrate diet trials, such as this one, which also reduce grain intake. The participants in Lindeberg's study were borderline obese. When you're overweight and your body resets its fat mass set-point due to an improved diet, fatty acids come pouring out of fat tissue and you don't need as many calories to feel satisfied. Your diet is supplemented by generous quantities of lard. Your brain decreases your calorie intake until you approach your new set-point.

That's what I believe happened here. The paleolithic group supplemented their diet with 3.9 kg of their own rump fat over the course of 12 weeks, coming out to 30,000 additional calories, or 357 calories a day. Not quite so spartan when you think about it like that.

The most remarkable thing about Lindeberg's trial was the fact that the 14 people in the paleolithic group, 2 of which had moderately elevated fasting blood glucose and 10 of which had diabetic fasting glucose, all ended up with normal fasting glucose after 12 weeks. That is truly amazing. The mediterranean diet worked also, but only in half as many participants.

If you look at their glucose tolerance by an oral glocose tolerance test (OGTT), the paleolithic diet group improved dramatically. Their rise in blood sugar after the OGTT (fasting BG subtracted out) was 76% less at 2 hours. If you look at the graph, they were basically back to fasting glucose levels at 2 hours, whereas before the trial they had only dropped slightly from the peak at that timepoint. The mediterranean diet group saw no significant improvement in fasting blood glucose or the OGTT. Lindeberg is pretty modest about this finding, but he essentially cured type II diabetes and glucose intolerance in 100% of the paleolithic group.

Fasting insulin, the insulin response to the OGTT and insulin sensitivity improved in the paleolithic diet whereas only insulin sensitivity improved significantly in the Mediterranean diet. Fasting insulin didn't decrease as much as I would have thought, only 16% in the paleolithic group.

Another interesting thing is that the paleolithic group lost more belly fat than the Mediterranean group, as judged by waist circumference. This is the most dangerous type of fat, which is associated with, and contributes to, insulin resistance and the metabolic syndrome. Guess what food belly fat was associated with when they analyzed the data? The strongest association was with grain consumption (probably mostly wheat), and the association remained even after adjusting for carbohydrate intake. In other words, the carbohydrate content of grains does not explain their association with belly fat because "paleo carbs" didn't associate with it. The effect of the paleolithic diet on glucose tolerance was also not related to carbohydrate intake.

So in summary, the "Mediterranean diet" may be healthier than a typical Swedish diet, while a diet loosely modeled after a paleolithic diet kicks both of their butts around the block. My opinion is that it's probably due to eliminating wheat, substantially reducing refined vegetable oils and dumping the processed junk in favor of real, whole foods. Here's a zinger from the end of the paper that sums it up nicely (emphasis mine):

The larger improvement of glucose tolerance in the Paleolithic group was independent of energy intake and macronutrient composition, which suggests that avoiding Western foods is more important than counting calories, fat, carbohydrate or protein. The study adds to the notion that healthy diets based on whole-grain cereals and low-fat dairy products are only the second best choice in the prevention and treatment of type 2 diabetes.

One Last Thought

In Dr. Lindeberg's paleolithic diet trial, subjects began with ischemic heart disease, and glucose intolerance or type II diabetes. By the end of the 12-week study, on average their glucose control was approaching normal and every subject had normal fasting glucose. Glucose control and fasting glucose in subjects following the "Mediterranean diet" did not change significantly. He didn't report changes in cardiovascular risk factors.

Why was the paleolithic diet so effective at restoring glucose control, while the Mediterranean diet was not? I believe the reason is that the Mediterranean diet did not eliminate the foods that were causing the problem to begin with: processed grains, particularly wheat. The paleolithic diet was lower in carbohydrate than the Mediterranean diet (40% vs 52%), although not exceptionally so. The absolute difference was larger since the paleolithic dieters were eating fewer calories overall (134 g vs 231 g). When they analyzed the data, they found that "the effect of the paleolithic diet on glucose tolerance was independent of carbohydrate intake". In other words, paleolithic dieters saw an improvement in glucose tolerance even if they ate as much carbohydrate as the average for the Mediterranean group.

This study population is not representative of the general public. These are people who suffered from an extreme version of the "disease of civilization". But they are examples of a process that I believe applies to nearly all of us to some extent. This paper adds to the evidence that the modern diet is behind these diseases.

A quick note about grains. Some of you may have noticed a contradiction in how I bash grains and at the same time praise Nutrition and Physical Degeneration. I'm actually not against grains. I think they can be part of a healthy diet, but they have to be prepared correctly and used in moderation. Healthy non-industrial cultures almost invariably soaked, sprouted or sourdough-fermented their grains. These processes make grains much more nutritious and less irritating to the digestive tract, because they allow the seeds to naturally break down their own toxins such as phytic acid, trypsin inhibitors and lectins.

Gluten grains are a special case. 12% of the US public is though to be gluten sensitive, as judged by anti-gliadin antibodies in the bloodstream. Nearly a third have anti-gliadin antibodies in their feces [update- these two markers may or may not indicate gluten sensitivity. SJG 2011]. Roughly 1% have outright celiac disease, in which the gut lining degenerates in response to gluten. All forms of gluten sensitivity increase the risk of a staggering array of health problems. There's preliminary evidence that gluten may activate the innate immune system in many people even in the absence of antibodies. From an anthropological perspective, wherever wheat flour goes, so does the disease of civilization. Rice doesn't have the same effect. It's possible that properly prepared wheat, such as sourdough, might not cause the same problems, but I'm not taking my chances. I certainly don't recommend quick-rise bread, and that includes whole wheat. Whole wheat seemed to be enough to preserve glucose intolerance in Lindeberg's study...

Peripheral vs. Ectopic Fat

I went to an interesting presentation the other day by Dr. George Ioannou of the University of Washington, on obesity and liver disease. He made an interesting distinction between the health effects of two types of body fat. The first is called subcutaneous fat (or peripheral fat). It accumulates right under the skin and is evenly distributed over the body's surface area, including extremities. The second is called ectopic fat. Ectopic means "not where it's supposed to be". It accumulates in the abdominal region (beer belly), the liver, muscle tissue including the heart, the pancreas, and perhaps in lipid-rich deposits in the arteries. Subcutaneous fat can be measured by taking skinfold thickness in different places on the body, or sometimes by measuring arm or leg circumference. Ectopic fat can be measured by taking waist circumference.

It's an absolutely critical distinction, because ectopic fat associates with poor health outcomes while subcutaneous fat does not. In this recent study, waist circumference was associated with increased risk of death while arm and leg circumference were associated with a reduced risk of death. I think the limb circumference association in this particular study is probably confounded by muscle mass, but other studies have also shown a strong, consistent association between ectopic fat and risk of death, but not subcutaneous fat. The same goes for dementia and a number of other diseases. I think it's more than an epidemiological asssociation. Surgically removing the abdominal fat from mice prevents insulin resistance and prolongs their lifespan.

People with excess visceral fat are also much more likely to have fatty liver and cirrhosis. It makes sense if you think of them both as manifestations of ectopic fat. There's a spectrum of disorders that goes along with excess visceral fat and fatty liver: it's called the metabolic syndrome, and it affects a quarter of Americans (NHANES III). We already have a pretty good idea of what causes fatty liver, at least in lab animals: industrial vegetable oils and sugar. What's the most widely used animal model of metabolic syndrome? The sugar-fed rat. What are two of the main foods whose consumption has increased in recent decades? Vegetable oil and sugar. Hmm... Fatty liver is capable of causing insulin resistance and diabetes, according to a transgenic mouse that expresses a hepatitis C protein in its liver.

You want to keep your liver happy. All those blood tests they do in the doctor's office to see if you're healthy-- cholesterol levels, triglycerides, insulin, glucose-- reflect liver function to varying degrees.

Abdominal fat is a sign of ectopic fat distribution throughout the body, and its associated metabolic consequences. I think we know it's unhealthy on a subconscious level, because belly fat is not attractive whereas nicely distributed subcutaneous fat can be. If you have excess visceral fat, take it as a sign that your body does not like your current lifestyle. It might be time to think about changing your diet and exercise regime. Here are some ideas.

The Tokelau Island Migrant Study: Diabetes

This post will be short and sweet. Diabetes is a disease of civilization. As Tokelauans adopted Western industrial foods, their diabetes prevalence increased. At any given time point, age-standardized diabetes prevalence was higher in migrants to New Zealand than those who remained on Tokelau:


This is not a difference in diagnosis. Tokelauans were examined for diabetes by the same group of physicians, using the same criteria. It's also not a difference in average age, sice the numbers are age-standardized. On Tokelau, diabetes prevalence doubled in a decade. Migrants to New Zealand in 1981 had roughly three times the prevalence of diabetes that Tokelauans did in 1971. I can only imagine the prevalence is even higher in 2008.

We don't know what the prevalence was in Tokelauans when their diet was completely traditional, but I would expect it to be low like other traditional Pacific island societies. I'm looking at a table right now of age-standardized diabetes prevalence on 11 different Pacific islands. There is quite a bit of variation, but the pattern is clear: the more modernized, the higher the diabetes rate. In several cases, the table has placed two values side-by-side: one value for rural inhabitants of an island, and another for urban inhabitants of the same island. In every case, the prevalence of diabetes is higher in the urban group. In some cases, the difference is as large as four-fold.

The lowest value goes to the New Caledonians of Touho, who are also considered the least modernized on the table (although even their diet is not completely traditional). Men have an age-standardized diabetes prevalence of 1.8%, women 1.4%. At the other extreme are the Micronesians of Nauru, affluent due to phosphate resources, who have a prevalence of 33.4% for men and 32.1% for women. They subsist mostly on imported food and are extremely obese.

The same patterns can be seen in Africa, the Arctic and probably everywhere that has adopted processed Western foods. White rice alone (compared with the combination of wheat flour and sugar) does not seem to have this effect.

The data in this post are from the book Migration and Health in a Small Society: the Case of Tokelau.

The Tokelau Island Migrant Study: Background and Overview
The Tokelau Island Migrant Study: Dental Health
The Tokelau Island Migrant Study: Cholesterol and Cardiovascular Health
The Tokelau Island Migrant Study: Weight Gain

Paleolithic Diet Clinical Trials Part III

I'm happy to say, it's time for a new installment of the "Paleolithic Diet Clinical Trials" series. The latest study was recently published in the European Journal of Clinical Nutrition by Dr. Anthony Sebastian's group. Dr. Sebastian has collaborated with Drs. Loren Cordain and Boyd Eaton in the past.

This new trial has some major problems, but I believe it nevertheless adds to the weight of the evidence on "paleolithic"-type diets. The first problem is the lack of a control group. Participants were compared to themselves, before eating a paleolithic diet and after having eaten it for 10 days. Ideally, the paleolithic group would be compared to another group eating their typical diet during the same time period. This would control for effects due to getting poked and prodded in the hospital, weather, etc. The second major problem is the small sample size, only 9 participants. I suspect the investigators had a hard time finding enough funding to conduct a larger study, since the paleolithic approach is still on the fringe of nutrition science.

I think this study is best viewed as something intermediate between a clinical trial and 9 individual anecdotes.

Here's the study design: they recruited 9 sedentary, non-obese people with no known health problems. They were 6 males and 3 females, and they represented people of African, European and Asian descent. Participants ate their typical diets for three days while investigators collected baseline data. Then, they were put on a seven-day "ramp-up" diet higher in potassium and fiber, to prepare their digestive systems for the final phase. In the "paleolithic" phase, participants ate a diet of:

Meat, fish, poultry, eggs, fruits, vegetables, tree nuts, canola oil, mayonnaise, and honey... We excluded dairy products, legumes, cereals, grains, potatoes and products containing potassium chloride...

Mmm yes, canola oil and mayo were universally relished by hunter-gatherers. They liked to feed their animal fat and organs to the vultures, and slather mayo onto their lean muscle meats. Anyway, the paleo diet was higher in calories, protein and polyunsaturated fat (I assume with a better n-6 : n-3 ratio) than the participants' normal diet. It contained about the same amount of carbohydrate and less saturated fat.

There are a couple of twists to this study that make it more interesting. One is that the diets were completely controlled. The only food participants ate came from the experimental kitchen, so investigators knew the exact calorie intake and nutrient composition of what everyone was eating.

The other twist is that the investigators wanted to take weight loss out of the picture. They wanted to know if a paleolithic-style diet is capable of improving health independent of weight loss. So they adjusted participants' calorie intake to make sure they didn't lose weight. This is an interesting point. Investigators had to increase the participants' calorie intake by an average of 329 calories a day just to get them to maintain their weight on the paleo diet. Their bodies naturally wanted to shed fat on the new diet, so they had to be overfed to maintain weight.

On to the results. Participants, on average, saw large improvements in nearly every meaningful measure of health in just 10 days on the "paleolithic" diet. Remember, these people were supposedly healthy to begin with. Total cholesterol and LDL dropped. Triglycerides decreased by 35%. Fasting insulin plummeted by 68%. HOMA-IR, a measure of insulin resistance, decreased by 72%. Blood pressure decreased and blood vessel distensibility (a measure of vessel elasticity) increased. It's interesting to note that measures of glucose metabolism improved dramatically despite no change in carbohydrate intake. Some of these results were statistically significant, but not all of them. However, the authors note that:

In all these measured variables, either eight or all nine participants had identical directional responses when switched to paleolithic type diet, that is, near consistently improved status of circulatory, carbohydrate and lipid metabolism/physiology.

Translation: everyone improved. That's a very meaningful point, because even if the average improves, in many studies a certain percentage of people get worse. This study adds to the evidence that no matter what your gender or genetic background, a diet roughly consistent with our evolutionary past can bring major health benefits. Here's another way to say it: ditching certain modern foods can be immensely beneficial to health, even in people who already appear healthy. This is true regardless of whether or not one loses weight.

There's one last critical point I'll make about this study. In figure 2, the investigators graphed baseline insulin resistance vs. the change in insulin resistance during the course of the study for each participant. Participants who started with the most insulin resistance saw the largest improvements, while those with little insulin resistance to begin with changed less. There was a linear relationship between baseline IR and the change in IR, with a correlation of R=0.98, p less than 0.0001. In other words, to a highly significant degree, participants who needed the most improvement, saw the most improvement. Every participant with insulin resistance at the beginning of the study ended up with basically normal insulin sensitivity after 10 days. At the end of the study, all participants had a similar degree of insulin sensitivity. This is best illustrated by the standard deviation of the fasting insulin measurement, which decreased 9-fold over the course of the experiment.

Here's what this suggests: different people have different degrees of susceptibility to the damaging effects of the modern Western diet. This depends on genetic background, age, activity level and many other factors. When you remove damaging foods, peoples' metabolisms normalize, and most of the differences in health that were apparent under adverse conditions disappear. I believe our genetic differences apply more to how we react to adverse conditions than how we function optimally. The fundamental workings of our metabolisms are very similar, having been forged mostly in hunter-gatherer times. We're all the same species after all.

This study adds to the evidence that modern industrial food is behind our poor health, and that a return to time-honored foodways can have immense benefits for nearly anyone. A paleolithic-style diet may be an effective way to claim your genetic birthright to good health. 

Paleolithic Diet Clinical Trials
Paleolithic Diet Clinical Trials Part II
One Last Thought

Paleolithic Diet Clinical Trials Part IV

Dr. Staffan Lindeberg has published a new study using the "paleolithic diet" to treat type II diabetics (free full text). Type II diabetes, formerly known as late-onset diabetes until it began appearing in children, is typically thought to develop as a result of insulin resistance (a lowered tissue response to the glucose-clearing function of insulin). This is often followed by a decrease in insulin secretion due to degeneration of the insulin-secreting pancreatic beta cells.

After Dr. Lindeberg's wild success treating patients with type II diabetes or glucose intolerance, in which he normalized the glucose tolerance of all 14 of his volunteers in 12 weeks, he set out to replicate the experiment. This time, he began with 13 men and women who had been diagnosed with type II diabetes for an average of 9 years.

Patients were put on two different diets for 3 months each. The first was a "conventional diabetes diet". I read a previous draft of the paper in which I believe they stated it was based on American Diabetes Association guidelines, but I can't find that statement in the final draft. In any case, here are the guidelines from the methods section:

The information on the Diabetes diet stated that it should aim at evenly distributed meals with increased intake of vegetables, root vegetables, dietary fiber, whole-grain bread and other whole-grain cereal products, fruits and berries, and decreased intake of total fat with more unsaturated fat. The majority of dietary energy should come from carbohydrates from foods naturally rich in carbohydrate and dietary fiber. The concepts of glycemic index and varied meals through meal planning by the Plate Model were explained [18]. Salt intake was recommended to be kept below 6 g per day.

The investigators gave the paleolithic group the following advice:

The information on the Paleolithic diet stated that it should be based on lean meat, fish, fruit, leafy and cruciferous vegetables, root vegetables, eggs and nuts, while excluding dairy products, cereal grains, beans, refined fats, sugar, candy, soft drinks, beer and extra addition of salt. The following items were recommended in limited amounts for the Paleolithic diet: eggs (≤2 per day), nuts (preferentially walnuts), dried fruit, potatoes (≤1 medium-sized per day), rapeseed or olive oil (≤1 tablespoon per day), wine (≤1 glass per day). The intake of other foods was not restricted and no advice was given with regard to proportions of food categories (e.g. animal versus plant foods). The evolutionary rationale for a Paleolithic diet and potential benefits were explained.

Neither diet was restricted in calories. After comparing the effects of the two diets for 3 months, the investigators concluded that the paleolithic diet:

• Reduced HbA1c more than the diabetes diet (a measure of average blood glucose)
• Reduced weight, BMI and waist circumference more than the diabetes diet
• Lowered blood pressure more than the diabetes diet
  
• Reduced triglycerides more than the diabetes diet
• Increased HDL more than the diabetes diet

However, the paleolithic diet was not a cure-all. At the end of the trial, 8 out of 13 patents still had diabetic blood glucose after an oral glucose tolerance test (OGTT). This is compared to 9 out of 13 for the diabetes diet. Still, 5 out of 13 with "normal" OGTT after the paleolithic diet isn't bad. The paleolithic diet also significantly reduced insulin resistance and increased glucose tolerance, although it didn't do so more than the diabetes diet.

As has been reported in other studies, paleolithic dieters ate fewer total calories than the comparison group. This is part of the reason why I believe that something in the modern diet causes hyperphagia, or excessive eating. According to the paleolithic diet studies, this food or combination of foods is neolithic, and probably resides in grains, refined sugar and/or dairy. I have my money on wheat and sugar, with a probable long-term contribution from industrial vegetable oils as well.

Were the improvements on the paleolithic diet simply due to calorie restriction? Maybe, but keep in mind that neither group was told to restrict its caloric intake. The reduction in caloric intake occurred naturally, despite the participants presumably eating to fullness. I suspect that the paleolithic diet reset the dieters' body fat set-point, after which fat began pouring out of their fat tissue. They were supplementing their diets with body fat-- 13 pounds (6 kg) of it over 3 months.

The other notable difference between the two diets, besides food types, was carbohydrate intake. The diabetes diet group ate 56% more carbohydrate than the paleo diet group, with 42% of their calories coming from it. The paleolithic group ate 32% carbohydrate. Could this have been the reason for the better outcome of the paleolithic group? I'd be surprised if it wasn't a factor. Advising a diabetic to eat a high-carbohydrate diet is like asking someone who's allergic to bee stings to fetch you some honey from your bee hive. Diabetes is a disorder of glucose intolerance. Starch is a glucose polymer.

Although to be fair, participants on the diabetes diet did improve in a number of ways. There's something to be said for eating whole foods.

This trial was actually a bit of a disappointment for me. I was hoping for a slam dunk, similar to Lindeberg's previous study that "cured" all 14 patients of glucose intolerance in 3 months. In the current study, the paleolithic diet left 8 out of 13 patients diabetic after 3 months. What was the difference? For one thing, the patients in this study had well-established diabetes with an average duration of 9 years. As Jenny Ruhl explains in her book Blood Sugar 101, type II diabetes often progresses to beta cell loss, after which the pancreas can no longer secrete an adequate amount of insulin.

This may be the critical finding of Dr. Lindeberg's two studies: type II diabetes can be prevented when it's caught at an early stage, such as pre-diabetes, whereas prolonged diabetes may cause damage that cannot be completely reversed though diet. I think this is consistent with the experience of many diabetics who have seen an improvement but not a cure from changes in diet. Please add any relevant experiences to the comments.

Collectively, the evidence from clinical trials on the "paleolithic diet" indicate that it's a very effective treatment for modern metabolic dysfunction, including excess body fat, insulin resistance and glucose intolerance. Another way of saying this is that the modern industrial diet causes metabolic dysfunction.

Paleolithic Diet Clinical Trials
Paleolithic Diet Clinical Trials Part II
One Last Thought
Paleolithic Diet Clinical Trials Part III

Diabetics on a Low-carbohydrate Diet

Diabetes is a disorder of glucose intolerance. What happens when a diabetic eats a low-carbohydrate diet? Here's a graph of blood glucose over a 24 hour period, in type II diabetics on their usual diet (blue and grey triangles), and after 5 weeks on a 55% carbohydrate (yellow circles) or 20% carbohydrate (blue circles) diet:


The study in question describes these volunteers as having "mild, untreated diabetes." If 270 mg/dL of blood glucose is mild diabetes, I'd hate to see severe diabetes! In any case, the low-carbohydrate, high-fat diet brought blood glucose down to an acceptable level without requiring medication.

It's interesting to note in the graph above that fasting blood glucose (18-24 hours) also fell dramatically. This could reflect improved insulin sensitivity in the liver. The liver pumps glucose into the bloodstream when it's necessary, and insulin suppresses this. When the liver is insulin resistant, it doesn't respond to the normal signal that there's already sufficient glucose, so it releases more and increases fasting blood glucose. When other tissues are insulin resistant, they don't take up the extra glucose, also contributing to the problem.

Glycated hemoglobin (HbA1c), a measure of average blood glucose concentration over the preceding few weeks, also reflected a profound improvement in blood glucose levels in the low-carbohydrate group:

At 5 weeks, the low-carbohydrate group was still improving and headed toward normal HbA1c, while the high-carbohydrate group remained at a dangerously high level. Total cholesterol, LDL and HDL remained unchanged in both groups, while triglycerides fell dramatically in the low-carbohydrate group.

When glucose is poison, it's better to eat fat.

Graph #1 was reproduced from Volek et al. (2005), which re-plotted data from Gannon et al. (2004). Graph #2 was drawn directly from Gannon et al.

Diabetics on a Low-carbohydrate Diet, Part II

I just found another very interesting study performed in Japan by Dr. Hajime Haimoto and colleagues (free full text). They took severe diabetics with an HbA1c of 10.9% and put them on a low-carbohydrate diet:

The main principle of the CRD [carbohydrate-restricted diet] was to eliminate carbohydrate-rich food twice a day at breakfast and dinner, or eliminate it three times a day at breakfast, lunch and dinner... There were no other restrictions. Patients on the CRD were permitted to eat as much protein and fat as they wanted, including saturated fat.

What happened to their blood lipids after eating all that fat for 6 months, and increasing their saturated fat intake to that of the average American? LDL decreased and HDL increased, both statistically significant. Oops. But that's water under the bridge. What we really care about here is glucose control. The patients' HbA1c (glycated hemoglobin; a measure of average blood glucose over the past several weeks) declined from 10.9 to 7.4%.

Here's a graph showing the improvement in HbA1c. Each line represents one individual:

Every single patient improved, except the "dropout" who stopped following the diet advice after 3 months (the one line that shoots back up at 6 months). And now, an inspirational anecdote from the paper:

One female patient had an increased physical activity level during the study period in spite of our instructions. However, her increase in physical activity was no more than one hour of walking per day, four days a week. She had implemented an 11% carbohydrate diet without any antidiabetic drug, and her HbA1c level decreased from 14.4% at baseline to 6.1% after 3 months and had been maintained at 5.5% after 6 months.

That patient began with the highest HbA1c and ended with the lowest. Complete glucose control using only diet and exercise. It may not work for everyone, but it's effective in some cases. The study's conclusion:

...the 30%-carbohydrate diet over 6 months led to a remarkable reduction in HbA1c levels, even among outpatients with severe type 2 diabetes, without any insulin therapy, hospital care or increase in sulfonylureas. The effectiveness of the diet may be comparable to that of insulin therapy.

Diabetics on a Low-carbohydrate Diet
The Tokelau Island Migrant Study: Diabetes

What's the Ideal Fasting Insulin Level?

[2013 update.  I'm leaving this post up for informational purposes, but I think it's difficult to determine the "ideal" insulin level because it depends on a variety of factors including diet composition.  Also, insulin assays are not always comparable to one another, particularly the older assays, so it's difficult to compare between studies]

Insulin is an important hormone. Its canonical function is to signal cells to absorb glucose from the bloodstream, but it has many other effects. Chronically elevated insulin is a marker of metabolic dysfunction, and typically accompanies high fat mass, poor glucose tolerance (prediabetes) and blood lipid abnormalities. Measuring insulin first thing in the morning, before eating a meal, reflects fasting insulin. High fasting insulin is a marker of metabolic problems and may contribute to some of them as well.

Elevated fasting insulin is a hallmark of the metabolic syndrome, the quintessential modern metabolic disorder that affects 24% of Americans (NHANES III). The average insulin level in the U.S., according to the NHANES III survey, is 8.8 uIU/mL for men and 8.4 for women (2). Given the degree of metabolic dysfunction in this country, I think it's safe to say that the ideal level of fasting insulin is probably below 8.4 uIU/mL.

Let's dig deeper. What we really need is a healthy, non-industrial "negative control" group. Fortunately, Dr. Staffan Lindeberg and his team made detailed measurements of fasting insulin while they were visiting the isolated Melanesian island of Kitava (3). He compared his measurements to age-matched Swedish volunteers. In male and female Swedes, the average fasting insulin ranges from 4-11 uIU/mL, and increases with age. From age 60-74, the average insulin level is 7.3 uIU/mL.

In contrast, the range on Kitava is 3-6 uIU/mL, which does not increase with age. In the 60-74 age group, in both men and women, the average fasting insulin on Kitava is 3.5 uIU/mL. That's less than half the average level in Sweden and the U.S. Keep in mind that the Kitavans are lean and have an undetectable rate of heart attack and stroke.

Another example from the literature are the Shuar hunter-gatherers of the Amazon rainforest. Women in this group have an average fasting insulin concentration of 5.1 uIU/mL (4; no data was given for men).

I found a couple of studies from the early 1970s as well, indicating that African pygmies and San bushmen have rather high fasting insulin. Glucose tolerance was excellent in the pygmies and poor in the bushmen (5, 6, free full text). This may reflect differences in carbohydrate intake. San bushmen consume very little carbohydrate during certain seasons, and thus would likely have glucose intolerance during that period. There are three facts that make me doubt the insulin measurements in these older studies:

1. It's hard to be sure that they didn't eat anything prior to the blood draw.
2. From what I understand, insulin assays were variable and not standardized back then.
3. In the San study, their fasting insulin was 1/3 lower than the Caucasian control group (10 vs. 15 uIU/mL). I doubt these active Caucasian researchers really had an average fasting insulin level of 15 uIU/mL. Both sets of measurements are probably too high.

Now you know the conflicting evidence, so you're free to be skeptical if you'd like.

We also have data from a controlled trial in healthy urban people eating a "paleolithic"-type diet. On a paleolithic diet designed to maintain body weight (calorie intake had to be increased substantially to prevent fat loss during the diet), fasting insulin dropped from an average of 7.2 to 2.9 uIU/mL in just 10 days. This is despite a substantial intake of carbohydrate, including fruit and vegetable sugars.  The variation in insulin level between individuals decreased 9-fold, and by the end, all participants were close to the average value of 2.9 uIU/mL. This shows that high fasting insulin is correctable in people who haven't yet been permanently damaged by the industrial diet and lifestyle. The study included men and women of European, African and Asian descent (7).

One final data point. My own fasting insulin, earlier this year, was 2.3 uIU/mL. I believe it reflects a good diet, regular exercise, sufficient sleep, and a relatively healthy diet growing up. It does not reflect: carbohydrate restriction, fat restriction, or saturated fat restriction.

So what's the ideal fasting insulin level? My current feeling is that we can consider anything between 2 and 6 uIU/mL within our evolutionary template.