Magnesium and Insulin Sensitivity

From a paper based on US NHANES nutrition and health survey data (1):

During 1999–2000, the diet of a large proportion of the U.S. population did not contain adequate magnesium... Furthermore, racial or ethnic differences in magnesium persist and may contribute to some health disparities.... Because magnesium intake is low among many people in the United States and inadequate magnesium status is associated with increased risk of acute and chronic conditions, an urgent need exists to perform a current survey to assess the physiologic status of magnesium in the U.S. population.

Magnesium is an essential mineral that's slowly disappearing from the modern diet, as industrial agriculture and industrial food processing increasingly dominate our food choices. One of the many things it's necessary for in mammals is proper insulin sensitivity and glucose control. A loss of glucose control due to insulin resistance can eventually lead to diabetes and all its complications.

Magnesium status is associated with insulin sensitivity (2, 3), and a low magnesium intake predicts the development of type II diabetes in most studies (4, 5) but not all (6). Magnesium supplements largely prevent diabetes in a rat model* (7). Interestingly, excess blood glucose and insulin themselves seem to reduce magnesium status, possibly creating a vicious cycle.

In a 1993 trial, a low-magnesium diet reduced insulin sensitivity in healthy volunteers by 25% in just four weeks (8). It also increased urinary thromboxane concentration, a potential concern for cardiovascular health**.

At least three trials have shown that magnesium supplementation increases insulin sensitivity in insulin-resistant diabetics and non-diabetics (9, 10, 11). In some cases, the results were remarkable. In type II diabetics, 16 weeks of magnesium supplementation improved fasting glucose, calculated insulin sensitivity and HbA1c*** (12). HbA1c dropped by 22 percent.

In insulin resistant volunteers with low blood magnesium, magnesium supplementation for four months reduced estimated insulin resistance by 43 percent and decreased fasting insulin by 32 percent (13). This suggests to me that magnesium deficiency was probably one of the main reasons they were insulin resistant in the first place. But the study had another very interesting finding: magnesium improved the subjects' blood lipid profile remarkably. Total cholesterol decreased, LDL decreased, HDL increased and triglycerides decreased by a whopping 39 percent. The same thing had been reported in the medical literature decades earlier when doctors used magnesium injections to treat heart disease, and also in animals treated with magnesium. Magnesium supplementation also suppresses atherosclerosis (thickening and hardening of the arteries) in animal models, a fact that I may discuss in more detail at some point (14, 15).

In the previous study, participants were given 2.5 g magnesium chloride (MgCl2) per day. That's a bit more than the USDA recommended daily allowance (MgCl2 is mostly chloride by weight), in addition to what they were already getting from their diet. Most of a person's magnesium is in their bones, so correcting a deficiency by eating a nutritious diet may take a while.

Speaking of nutritious diets, how does one get magnesium? Good sources include halibut, leafy greens, chocolate and nuts. Bone broths are also an excellent source of highly absorbable magnesium. Whole grains and beans are also fairly good sources, while refined grains lack most of the magnesium in the whole grain. Organic foods, particularly artisanally produced foods from a farmer's market, are richer in magnesium because they grow on better soil and often use older varieties that are more nutritious.

The problem with seeds such as grains, beans and nuts is that they also contain phytic acid which prevents the absorption of magnesium and other minerals (16). Healthy non-industrial societies that relied on grains took great care in their preparation: they soaked them, often fermented them, and also frequently removed a portion of the bran before cooking (17). These steps all served to reduce the level of phytic acid and other anti-nutrients. I've posted a method for effectively reducing the amount of phytic acid in brown rice (18). Beans should ideally be soaked for 24 hours before cooking, preferably in warm water.

Industrial agriculture has systematically depleted our soil of many minerals, due to high-yield crop varieties and the fact that synthetic fertilizers only replace a few minerals. The mineral content of foods in the US, including magnesium, has dropped sharply in the last 50 years. The reason we need to use fertilizers in the first place is that we've broken the natural nutrient cycle in which minerals always return to the soil in the same place they were removed. In 21st century America, minerals are removed from the soil, pass through our toilets, and end up in the landfill or in waste water. This will continue until we find an acceptable way to return human feces and urine to agricultural soil, as many cultures do to this day****.

I believe that an adequate magnesium intake is critical for proper insulin sensitivity and overall health.


* Zucker rats that lack leptin signaling

** Thromboxane A2 is an omega-6 derived eicosanoid that potently constricts blood vessels and promotes blood clotting. It's interesting that magnesium has such a strong effect on it. It indicates that fatty acid balance is not the only major influence on eicosanoid production.

*** Glycated hemoglobin. A measure of the average blood glucose level over the past few weeks.

**** Anyone interested in further reading on this should look up The Humanure Handbook

Real Food XI: Sourdough Buckwheat Crepes

Buckwheat was domesticated in Southeast Asia roughly 6,000 years ago. Due to its unusual tolerance of cool growing conditions, poor soils and high altitudes, it spread throughout the Northern latitudes of Eurasia, becoming the staple crop in many regions. It's used to a lesser extent in countries closer to the equator. It was also a staple in the Northeastern US until it was supplanted by wheat and corn.

Buckwheat isn't a grain: it's a 'pseudograin' that comes from a broad-leaved plant. As such, it's not related to wheat and contains no allergenic gluten. Like quinoa, it has some unusual properties that make it a particularly nutritious food. It's about 16 percent protein by calories, ranking it among the highest protein grains. However, it has an advantage over grains: it contains complete protein, meaning it has a balance of essential amino acids similar to animal foods. Buckwheat is also an exceptional source of magnesium and copper, two important nutrients that may influence the risk of insulin resistance and cardiovascular disease (1, 2).

However, like all seeds (including grains and nuts), buckwheat is rich in phytic acid. Phyic acid complexes with certain minerals, preventing their absorption by the human digestive tract. This is one of the reasons why traditional cultures prepare their grains carefully (3). During soaking, and particularly fermentation of raw batters, an enzyme called phytase goes to work breaking down the phytic acid. Not all seeds are endowed with enough phytase to break down phytic acid in a short period of time. Buckwheat contains a lot of phytase, and consequently fermented buckwheat batters contain very little phytic acid (4, 5). It's also high in astringent tannins, but thorough soaking in a large volume of water removes them.

Buckwheat is fermented in a number of traditional cultures. In Bhutan, it's fermented to make flatbreads and alcoholic drinks (6). In Brittany (Bretagne; Northwestern France), sourdough buckwheat flour pancakes are traditional. Originally a poverty food, it is now considered a delicacy.

The following simple recipe is based on my own experimentation with buckwheat. It isn't traditional as far as I know, however it is based on traditional methods used to produce sourdough flatbreads in a number of cultures. I used the word 'crepe' to describe it, but I typically make something more akin to a savory pancake or uttapam. You can use it to make crepes if you wish, but this recipe is not for traditional French buckwheat crepes.

It's important that the buckwheat be raw and whole for this recipe. Raw buckwheat is light green to light brown (as in the photo above). Kasha is toasted buckwheat, and will not substitute properly. It's also important that the water be dechlorinated and the salt non-iodized, as both will interfere with fermentation.

For a fermentation starter, you can use leftover batter from a previous batch (although it doesn't keep very long), or rice soaking water from this method (7).

Ingredients and Materials

• 2-3 cups raw buckwheat groats
• Dechlorinated water (filtered, boiled, or rested uncovered overnight)
• Non-iodized salt (sea salt, pickling salt or kosher salt), 2/3 tsp per cup of buckwheat
  
• Fermentation starter (optional), 2 tablespoons
  
• Food processor or blender

Recipe

1. Cover buckwheat with a large amount of dechlorinated water and soak for 9-24 hours. Raw buckwheat is astringent due to water-soluble tannins. Soaking in a large volume of water and giving it a stir from time to time will minimize this. The soaking water will also get slimy. This is normal.
   
2. Pour off the soaking water and rinse the buckwheat thoroughly to get rid of the slime and residual tannins.
3. Blend the buckwheat, salt, dechlorinated water and fermentation starter in a food processor or blender. Add enough water so that it reaches the consistency of pancake batter. The smoother you get the batter, the better the final product will be.
4. Ferment for about 12 hours, a bit longer or shorter depending on the temperature and whether or not you used a starter. The batter may rise a little bit as the microorganisms get to work. The smell will mellow out. Refrigerate it after fermentation.
   
5. In a greased or non-stick skillet, cook the batter at whatever thickness and temperature you prefer. I like to cook a thick 'pancake' with the lid on, at very low heat, so that it steams gently.
   

Dig in! Its mild flavor goes with almost anything. Batter will keep for about four days in the fridge.

Thanks to Christaface for the CC licensed photo (Flickr).

Low Micronutrient Intake may Contribute to Obesity

Lower Micronutrient Status in the Obese

Investigators have noted repeatedly that obese people have a lower blood concentration of a number of nutrients, including vitamin A, vitamin D, vitamin K, several B vitamins, zinc and iron (1). Although there is evidence that some of these may influence fat mass in animals, the evidence for a cause-and-effect relationship in humans is generally slim. There is quite a bit of indirect evidence that vitamin D status influences the risk of obesity (2), although a large, well-controlled study found that high-dose vitamin D3 supplementation does not cause fat loss in overweight and obese volunteers over the course of a year (3). It may still have a preventive effect, or require a longer timescale, but that remains to be determined.

Hot off the Presses

A new study in the journal Obesity, by Y. Li and colleagues, showed that compared to a placebo, a low-dose multivitamin caused obese volunteers to lose 7 lb (3.2 kg) of fat mass in 6 months, mostly from the abdominal region (4). The supplement also reduced LDL by 27%, increased HDL by a whopping 40% and increased resting energy expenditure. Here's what the supplement contained:

Vitamin A(containing natural mixed b-carotene) 5000 IU
Vitamin D 400 IU
Vitamin E 30 IU
Thiamin 1.5 mg
Riboflavin 1.7 mg
Vitamin B6 2 mg
Vitamin C 60 mg
Vitamin B12 6 mcg
Vitamin K1 25 mcg
Biotin 30 mcg
Folic acid 400 mcg
Nicotinamide 20 mg
Pantothenic acid 10 mg
Calcium 162 mg
Phosphorus 125 mg
Chlorine 36.3 mg
Magnesium 100 mg
Iron 18 mg
Copper 2 mg
Zinc 15 mg
Manganese 2.5 mg
Iodine 150 mcg
Chromium 25 mcg
Molybdenum 25 mcg
Selenium 25 mcg
Nickel 5 mcg
Stannum 10 mcg
Silicon 10 mcg
Vanadium 10 mcg

Although the result needs to be repeated, if we take it at face value, it has some important implications:

• The nutrient density of a diet may influence obesity risk, as I speculated in my recent audio interview and related posts (5, 6, 7, 8, 9).
• Many nutrients act together to create health, and multiple insufficiencies may contribute to disease. This may be why single nutrient supplementation trials usually don't find much.
• Another possibility is that obesity can result from a number of different nutrient insufficiencies, and the cause is different in different people. This study may have seen a large effect because it corrected many different insufficiencies.
  
• This result, once again, kills the simplistic notion that body fat is determined exclusively by voluntary food consumption and exercise behaviors (sometimes called the "calories in, calories out" idea, or "gluttony and sloth"). In this case, a multivitamin was able to increase resting energy expenditure and cause fat loss without any voluntary changes in food intake or exercise, suggesting metabolic effects and a possible downward shift of the body fat "setpoint" due to improved nutrient status.
  

Practical Implications

Does this mean we should all take multivitamins to stay or become thin? No. There is no multivitamin that can match the completeness and balance of a nutrient-dense, whole food, omnivorous diet. Beef liver, leafy greens and sunlight are nature's vitamin pills. Avoiding refined foods instantly doubles the micronutrient content of the typical diet. Properly preparing whole grains by soaking and fermentation is equivalent to taking a multi-mineral along with conventionally prepared grains, as absorption of key minerals is increased by 50-300% (10). Or you can eat root vegetables instead of grains, and enjoy their naturally high mineral availability. Or both.

Traditional Preparation Methods Improve Grains' Nutritive Value

Soaking or Germinating Grains

The most basic method of preparing grains is prolonged soaking in water, followed by cooking. This combination reduces the level of water-soluble and heat-sensitive toxins and anti-nutrients such as tannins, saponins, digestive enzyme inhibitors and lectins, as well as flatulence factors. It also partially degrades phytic acid, which is a potent inhibitor of mineral absorption, an inhibitor of the digestive enzyme trypsin and an enemy of dental health (1). This improves the digestibility and nutritional value of grains as well as legumes.

I prefer to soak all grains and legumes for at least 12 hours in a warm location, preferably 24. This includes foods that most people don't soak, such as lentils. Soaking does not reduce phytic acid at all in grains that have been heat-treated, such as oats and kasha (technically not a grain), because they no longer contain the phytic acid-degrading enzyme phytase. Cooking without soaking first also does not have much effect on phytic acid.

The next level of grain preparation is germination. After soaking, rinse the grains twice per day for an additional day or two. This activates the grains' sprouting program and further increases their digestibility and vitamin content. When combined with cooking, it reduces phytic acid, although modestly. Therefore, most of the minerals in sprouted whole grains will continue to be inaccessible. Many raw sprouted grains and legumes are edible, but I wouldn't use them as a staple food because they retain most of their phytic acid as well as some heat-sensitive anti-nutrients (2).

Grinding and Fermenting Grains

Many cultures around the world have independently discovered fermentation as a way to greatly improve the digestibility and nutritive value of grains (3). Typically, grains are soaked, ground, and allowed to sour ferment for times ranging from 12 hours to several days. In some cases, a portion of the bran is removed before or after grinding.

In addition to the reduction in toxins and anti-nutrients afforded by soaking and cooking, grinding and fermentation goes much further. Grinding greatly increases the surface area of the grains and breaks up their cellular structure, releasing enzymes which are important for the transformation to come. Under the right conditions, which are easy to achieve, lactic acid bacteria rapidly acidify the batter. These bacteria are naturally present on grains, but adding a starter makes the process more efficient and reliable.

Due to some quirk of nature, grain phytase is maximally active at a pH of between 4.5 and 5.5, which is mildly acidic. This is why the Weston Price foundation recommends soaking grains in an acidic medium before cooking. The combination of grinding and sour fermentation causes grains to efficiently degrade their own phytic acid (as long as they haven't been heat treated first), making minerals much more available for absorption (4, 5, 6, 7). This transforms whole grains from a poor source of minerals into a good source.

The degree of phytic acid degradation depends on the starting amount of phytase in the grain. Corn, rice, oats and millet don't contain much phytase activity, so they require either a longer fermentation time, or the addition of high-phytase grains to the batter (8). Whole raw buckwheat, wheat, and particularly rye contain a large amount of phytase (9), although I feel wheat is problematic for other reasons.

As fermentation proceeds, bacteria secrete enzymes that begin digesting the protein, starch and other substances in the batter. Fermentation reduces lectin levels substantially, which are reduced further by cooking (10). Lectins are toxins that can interfere with digestion and may be involved in autoimmune disease, an idea championed by Dr. Loren Cordain. Grain lectins are generally heat-sensitive, but one notable exception is the nasty lectin wheat germ agglutinin (WGA). As its name suggests, WGA is found in wheat germ, and thus is mostly absent in white flour. WGA may have been another reason why DART participants who increased their wheat fiber intake had significantly more heart attacks than those who didn't. I don't know if fermentation degrades WGA.

One of the problems with grains is their poor protein quality. Besides containing a fairly low concentration of protein to begin with, they also don't contain a good balance of essential amino acids. This prevents their efficient use by the body, unless a separate source of certain amino acids is eaten along with them. The main limiting amino acid in grains is lysine. Legumes are rich in lysine, which is why cultures around the world pair them with grains. Bacterial fermentation produces lysine, often increasing its concentration by many fold and making grains nearly a "complete protein", i.e. one that contains the ideal balance of essential amino acids as do animal proteins (11, scroll down to see graph). Not very many plant foods can make that claim. Fermentation also increases the concentration of the amino acid methionine and certain vitamins.

Another problem with grain protein is it's poorly digested relative to animal protein. This means that a portion of it escapes digestion, leading to a lower nutritive value and a higher risk of allergy due to undigested protein hanging around in the digestive tract. Fermentation followed by cooking increases the digestibility of grain protein, bringing it nearly to the same level as meat (12, 13, 14, 15). This may relate to the destruction of protease inhibitors (trypsin inhibitors, phytic acid) and the partial pre-digestion of grain proteins by bacteria.

Once you delve into the research on traditional grain preparation methods, you begin to see why grain-eating cultures throughout the world have favored certain techniques. Proper grain processing transforms them from toxic to nutritious, from health-degrading to health-giving. Modern industrial grain processing has largely eschewed these time-honored techniques, replacing them with low-extraction milling, extrusion and quick-rise yeast strains.

Many people will not be willing to go through the trouble of grinding and fermentation to prepare grains. I can sympathize, although if you have the right tools, once you establish a routine it really isn't that much work. It just requires a bit of organization. In fact, it can even be downright convenient. I often keep a bowl of fermented dosa or buckwheat batter in the fridge, ready to make a tasty "pancake" at a moment's notice. In the next post, I'll describe a few recipes from different parts of the world.

Further reading:

How to Eat Grains
A Few Thoughts on Minerals, Milling, Grains and Tubers
Dietary Fiber and Mineral Availability
A New Way to Soak Brown Rice

Grains as Food: an Update

Improperly Prepared Grain Fiber can be Harmful

Last year, I published a post on the Diet and Reinfarction trial (DART), a controlled trial that increased grain fiber intake using whole wheat bread and wheat bran supplements, and reported long-term health outcomes in people who had previously suffered a heart attack (1). The initial paper found a trend toward increased heart attacks and deaths in the grain fiber-supplemented group at two years, which was not statistically significant.

What I didn't know at the time is that a follow-up study has been published. After mathematically "adjusting" for preexisting conditions and medication use, the result reached statistical significance: people who increased their grain fiber intake had more heart attacks than people who didn't during the two years of the controlled trial. Overall mortality was higher as well, but that didn't reach statistical significance. You have to get past the abstract of the paper to realize this, but fortunately it's free access (2).

Here's a description of what not to eat if you're a Westerner with established heart disease:

Those randomised to fibre advice were encouraged to eat at least six slices of wholemeal bread per day, or an equivalent amount of cereal fibre from a mixture of wholemeal bread, high-fibre breakfast cereals and wheat bran.

Characteristics of Grain Fiber

The term 'fiber' can refer to many different things. Dietary fiber is simply defined as an edible substance that doesn't get digested by the human body. It doesn't even necessarily come from plants. If you eat a shrimp with the shell on, and the shell comes out the other end (which it will), it was fiber.

Grain fiber is a particular class of dietary fiber that has specific characteristics. It's mostly cellulose (like wood; although some grains are rich in soluble fiber as well), and it contains a number of defensive substances and storage molecules that make it more difficult to eat. These may include phytic acid, protease inhibitors, amylase inhibitors, lectins, tannins, saponins, and goitrogens (3). Grain fiber is also a rich source of vitamins and minerals, although the minerals are mostly inaccessible due to grains' high phytic acid content (4, 5, 6).

Every plant food (and some animal foods) has its chemical defense strategy, and grains are no different*. It's just that grains are particularly good at it, and also happen to be one of our staple foods in the modern world. If you don't think grains are naturally inedible for humans, try eating a heaping bowl full of dry, raw whole wheat berries.

Human Ingenuity to the Rescue

Humans are clever creatures, and we've found ways to use grains as a food source, despite not being naturally adapted to eating them**. The most important is our ability to cook. Cooking deactivates many of the harmful substances found in grains and other plant foods. However, some are not deactivated by cooking. These require other strategies to remove or deactivate.

Healthy grain-based cultures don't prepare their grains haphazardly. Throughout the world, using a number of different grains, many have arrived at similar strategies for making grains edible and nutritious. The most common approach involves most or all of these steps:

• Soaking
  
• Grinding
• Removing 50-75% of the bran
  
• Sour fermentation
• Cooking
  

But wait, didn't all healthy traditional cultures eat whole grains? The idea might make us feel warm and fuzzy inside, but it doesn't quite hit the mark. A recent conversation with Ramiel Nagel, author of the book Cure Tooth Decay, disabused me of that notion. He pointed out that in my favorite resource on grain preparation in traditional societies, the Food and Agriculture Organization publication Fermented Cereals: a Global Perspective, many of the recipes call for removing a portion of the bran (7). Some of these recipes probably haven't changed in thousands of years. It's my impression that some traditional cultures eat whole grains, while others eat them partially de-branned.

In the next post, I'll explain why these processing steps greatly improve the nutritional value of grains, and I'll describe recipes from around the world to illustrate the point.


* Including tubers. For example, sweet potatoes contain goitrogens, oxalic acid, and protease inhibitors. Potatoes contain toxic glycoalkaloids. Taro contains oxalic acid and protease inhibitors. Cassava contains highly toxic cyanogens. Some of these substances are deactivated by cooking, others are not. Each food has an associated preparation method that minimizes its toxic qualities. Potatoes are peeled, removing the majority of the glycoalkaloids. Cassava is grated and dried or fermented to inactivate cyanogens. Some cultures ferment taro.

** As opposed to mice, for example, which can survive on raw whole grains.

Copper in Food

Sources of Copper

It isn't hard to get enough copper-- unless you live in an industrial nation. I've compiled a chart showing the copper content of various refined and unrefined foods to illustrate the point. The left side shows industrial staple foods, while the right side shows whole foods. I've incorporated a few that would have been typical of Polynesian and Melanesian cultures apparently free of cardiovascular disease. The serving sizes are what one might reasonably eat at a meal: roughly 200 calories for grains, tubers and whole coconut; 1/4 pound for animal products; 1/2 teaspoon for salt; 1 cup for raw kale; 1 oz for sugar.

Note that beef liver is off the chart at 488 percent of the USDA recommended daily allowance. I don't know if you'd want to sit down and eat a quarter pound of beef liver, but you get the picture. Beef liver is nature's multivitamin: hands down the Most Nutritious Food in the World. That's because it acts as a storage depot for a number of important micronutrients, as well as being a biochemical factory that requires a large amount of B vitamins to function. You can see that muscle tissue isn't a great source of copper compared to other organs, and this holds true for other micronutrients as well.

Beef liver is so full of micronutrients, it shouldn't be eaten every day. Think of it in terms of the composition of a cow's body. The edible carcass is mostly muscle, but a significant portion is liver. I think it makes sense to eat some form of liver about once per week.

Modern Agriculture Produces Micronutrient-poor Foods

The numbers in the graph above come from NutritionData, my main source of food nutrient composition. The problem with relying on this kind of information is it ignores the variability in micronutrient content due to plant strain, soil quality, et cetera.

The unfortunate fact is that micronutrient levels have declined substantially over the course of the 20th century, even in whole foods. Dr. Donald R. Davis has documented the substantial decline in copper and other micronutrients in American foods over the second half of the last century (1). An even more marked decrease has occurred in the UK (2), with similar trends worldwide. On average, the copper content of vegetables in the UK has declined 76 percent since 1940. Most of the decrease has taken place since 1978. Fruits are down 20 percent and meats are down 24 percent.

I find this extremely disturbing, as it will affect even people eating whole food diets. This is yet another reason to buy from artisanal producers, who are likely to use more traditional plant varieties and grow in richer soil. Grass-fed beef should be just as nutritious as it has always been. Some people may also wish to grow, hunt or fish their own food.

Copper and Cardiovascular Disease

In 1942, Dr. H. W. Bennetts dissected 21 cattle known to have died of "falling disease". This was the name given to the sudden, inexplicable death that struck herds of cattle in certain regions of Australia. Dr. Bennett believed the disease was linked to copper deficiency. He found that 19 of the 21 cattle had abnormal hearts, showing atrophy and abnormal connective tissue infiltration (fibrosis) of the heart muscle (1).

In 1963, Dr. W. F. Coulson and colleagues found that 22 of 33 experimental copper-deficient pigs died of cardiovascular disease. 11 of 33 died of coronary heart disease, the quintessential modern human cardiovascular disease. Pigs on a severely copper-deficient diet showed weakened and ruptured arteries (aneurysms), while moderately deficient pigs "survived with scarred vessels but demonstrated a tendency toward premature atherosclerosis" including foam cell accumulation (2). Also in 1963, Dr. C. R. Ball and colleagues published a paper describing blood clots in the heart and coronary arteries, heart muscle degeneration, ventricular calcification and early death in mice fed a lard-rich diet (3).

This is where Dr. Leslie M. Klevay enters the story. Dr. Klevay suspected that Ball's mice had suffered from copper deficiency, and decided to test the hypothesis. He replicated Ball's experiment to the letter, using the same strain of mice and the same diet. Like Ball, he observed abnormal clotting in the heart, degeneration and enlargement of the heart muscle, and early death. He also showed by electrocardiogram that the hearts of the copper-deficient mice were often contracting abnormally (arrhythmia).

But then the coup de grace: he prevented these symptoms by supplementing the drinking water of a second group of mice with copper (4). In the words of Dr. Klevay: "copper was an antidote to fat intoxication" (5). I believe this was his tongue-in-cheek way of saying that the symptoms had been misdiagnosed by Ball as due to dietary fat, when in fact they were due to a lack of copper.

Since this time, a number of papers have been published on the relationship between copper intake and cardiovascular disease in animals, including several showing that copper supplementation prevents atherosclerosis in one of the most commonly used animal models of cardiovascular disease (6, 7, 8). Copper supplementation also corrects abnormal heart enlargement-- called hypertrophic cardiomyopathy-- and heart failure due to high blood pressure in mice (9).

For more than three decades, Dr. Klevay has been a champion of the copper deficiency theory of cardiovascular disease. According to him, copper deficiency is the only single intervention that has caused the full spectrum of human cardiovascular disease in animals, including:

• Heart attacks (myocardial infarction)
  
• Blood clots in the coronary arteries and heart
• Fibrous atherosclerosis including smooth muscle proliferation
• Unstable blood vessel plaque
  
• Foam cell accumulation and fatty streaks
  
• Calcification of heart tissues
  
• Aneurysms (ruptured vessels)
• Abnormal electrocardiograms
• High cholesterol
• High blood pressure
  

If this theory is so important, why have most people never heard of it? I believe there are at least three reasons. The first is that the emergence of the copper deficiency theory coincided with the rise of the diet-heart hypothesis, whereby saturated fat causes heart attacks by raising blood cholesterol. Bolstered by some encouraging findings and zealous personalities, this theory took the Western medical world by storm, for decades dominating all other theories in the medical literature and public health efforts. My opinions on the diet-heart hypothesis aside, the two theories are not mutually exclusive.

The second reason you may not have heard of the theory is due to a lab assay called copper-mediated LDL oxidation. Researchers take LDL particles (from blood, the same ones the doctor measures as part of a cholesterol test) and expose them to a high concentration of copper in a test tube. Free copper ions are oxidants, and the researchers then measure the amount of time it takes the LDL to oxidize. I find this assay tiresome, because studies have shown that the amount of time it takes copper to oxidize LDL in a test tube doesn't predict how much oxidized LDL you'll actually find in the bloodstream of the person you took the LDL from (10, 11).

In other words, it's an assay that has little bearing on real life. But researchers like it because for some odd reason, feeding a person saturated fat causes their LDL to be oxidized more rapidly by copper in a test tube, even though that's not the case in the actual bloodstream (12). Guess which result got emphasized?

The fact that copper is such an efficient oxidant has led some researchers to propose that copper oxidizes LDL in human blood, and therefore dietary copper may contribute to heart disease (oxidized LDL is a central player in heart disease-- read more here). The problem with this theory is that there are virtually zero free copper ions in human serum. Then there's the fact that supplementing humans with copper actually reduces the susceptibility of red blood cells to oxidation (by copper in a test tube, unfortunately), which is difficult to reconcile with the idea that dietary copper increases oxidative stress in the blood (13).

The third reason you may never have heard of the theory is more problematic. Several studies have found that a higher level copper in the blood correlates with a higher risk of heart attack (14, 15). At this point, I could hang up my hat, and declare the animal experiments irrelevant to humans. But let's dig deeper.

Nutrient status is sometimes a slippery thing to measure. As it turns out, serum copper isn't a good marker of copper status. In a 4-month trial of copper depletion in humans, blood copper stayed stable, while the activity of copper-dependent enzymes in the blood declined (16). These include the important copper-dependent antioxidant, superoxide dismutase. As a side note, lysyl oxidase is another copper-dependent enzyme that cross-links the important structural proteins collagen and elastin in the artery wall, potentially explaining some of the vascular consequences of copper deficiency. Clotting factor VIII increased dramatically during copper depletion, perhaps predicting an increased tendency to clot. Even more troubling, three of the 12 women developed heart problems during the trial, which the authors felt was unusual:

We observed a significant increase over control values in the number of ventricular premature discharges (VPDs) in three women after 21, 63, and 91 d of consuming the low-copper diet; one was subsequently diagnosed as having a second-degree heart block.

In another human copper restriction trial, 11 weeks of modest copper restriction coincided with heart trouble in 4 out of 23 subjects, including one heart attack (17):

In the history of conducting numerous human studies at the Beltsville Human Nutrition Research Center involving participation by 337 subjects, there had previously been no instances of any health problem related to heart function. During the 11 wk of the present study in which the copper density of the diets fed the subjects was reduced from the pretest level of 0.57 mg/ 1000 kcal to 0.36 mg/1000 kcal, 4 out of 23 subjects were diagnosed as having heart-related abnormalities.

The other reason to be skeptical of the association between blood copper and heart attack risk is that inflammation increases copper in the blood (18, 19). Blood copper level correlates strongly with the marker of inflammation C-reactive protein (CRP) in humans, yet substantially increasing copper intake doesn't increase CRP (20, 21). This suggests that elevated blood copper is likely a symptom of inflammation, rather than its cause, and presents an explanation for the association between blood copper level and heart attack risk.

Only a few studies have looked at the relationship between more accurate markers of copper status and cardiovascular disease in humans. Leukocyte copper status, a marker of tissue status, is lower in people with cardiovascular disease (22, 23). People who die of heart attacks generally have less copper in their hearts than people who die of other causes, although this could be an effect rather than a cause of the heart attack (24). Overall, I find the human data lacking. I'd like to see more studies examining liver copper status in relation to cardiovascular disease, as the liver is the main storage organ for copper.

According to a 2001 study, the majority of Americans may have copper intakes below the USDA recommended daily allowance (25), many substantially so. This problem is exacerbated by the fact that copper levels in food have declined in industrial nations over the course of the 20th century, something I'll discuss in the next post.

Magnesium and Vitamin D Metabolism

Ted Hutchinson posted a link in the comments section of my last post, pointing to a page on the Vitamin D Council's website where Dr. John Cannell discusses cofactors required for proper vitamin D metabolism. It's actually the site's home page, highlighting how important he feels this matter is. In this case, 'cofactor' simply means another nutrient that's required for the efficient production and use of vitamin D. They include:

• Magnesium
• Zinc
• Vitamin K2
• Vitamin A
• Boron

And probably others we aren't yet aware of. On another page, Dr. Cannell links to two papers that review the critical interaction between magnesium status and vitamin D metabolism (1, 2). Here's a quote from the abstract of the second paper:

Magnesium... is essential for the normal function of the parathyroid glands, metabolism of vitamin D and adequate sensitivity of target tissues to [parathyroid hormone] and active vitamin D metabolites. Magnesium deficit is usually associated with hypoparathyroidism, low production of active vitamin D metabolites, in particular 1,25(OH)2 vitamin D3 and resistance to PTH and vitamin D. On the contrary, magnesium excess, similar to calcium, inhibits PTH secretion. Bone metabolism is impaired under positive as well as under negative magnesium balance.

Magnesium status is critical for normal vitamin D metabolism, insulin sensitivity, and overall health. Supplemental magnesium blocks atherosclerosis in multiple animal models (3, 4). Most Americans don't get enough magnesium (5).

The bottom line is that no nutrient acts in a vacuum. The effect of every part of one's diet and lifestyle is dependent on every other part. I often talk about single nutrients on this blog, but my core philosophy is that a proper diet focuses on Real Food, not nutrients. Tinkering with nutritional status using supplements is potentially problematic. Despite what some people might tell you, our understanding of nutrition and human health is currently rather crude-- so it's best to respect the accumulated wisdom of cultures that don't get the diseases we're trying to avoid.