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

New Saturated Fat Review Article by Dr. Ronald Krauss

I never thought I'd see the day when one of the most prominent lipid researchers in the world did an honest review of the observational studies evaluating the link between saturated fat and cardiovascular disease. Dr. Ronald Krauss's group has published a review article titled "Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease". As anyone with two eyes and access to the medical literature would conclude (including myself), they found no association whatsoever between saturated fat intake and heart disease or stroke:

A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD.

Bravo, Dr. Krauss. That was a brave move.

Thanks to Peter for pointing out this article.

Krauss's New Article on Saturated Fat Intervention Trials

Dr. Ronald Krauss's group just published another article in the American Journal of Clinical Nutrition, this time on the intervention trials examining the effectiveness of reducing saturated fat and/or replacing it with other nutrients, particularly carbohydrate or polyunsaturated seed oils. I don't agree with everything in this article. For example, they cite the Finnish Mental Hospital trial. They openly acknowledge some contradictory data, although they left out the Sydney diet-heart study and the Rose et al. corn oil study, both of which showed greatly increased mortality from replacing animal fats with polyunsaturated seed oils. Nevertheless, they get it right in the end:

Particularly given the differential effects of dietary saturated fats and carbohydrates on concentrations of larger and smaller LDL particles, respectively, dietary efforts to improve the increasing burden of CVD risk associated with atherogenic dyslipidemia should primarily emphasize the limitation of refined carbohydrate intakes and a reduction in excess adiposity.

This is really cool. Krauss is channeling Weston Price. If this keeps up, I may have no reason to blog anymore!

Rabbits on a High-Saturated Fat Diet Without Added Cholesterol

I just saw another study that supports my previous post Animal Models of Atherosclerosis: LDL. The hypothesis is that in the absence of excessive added dietary cholesterol, saturated fat does not influence LDL or atherosclerosis in animal models, relative to other fats (although omega-6 polyunsaturated oils do lower LDL in some animal models). This appears to be consistent with what we see in humans.

In this study, they fed four groups of rabbits different diets:

1. Regular low-fat rabbit chow
2. Regular low-fat rabbit chow plus 0.5 g cholesterol per day
3. High-fat diet with 30% calories as coconut oil (saturated) and no added cholesterol
   
4. High-fat diet with 30% calories as sunflower oil (polyunsaturated) and no added cholesterol
   

LDL at 6 months was the same in groups 1, 3 and 4, but was increased more than 20-fold in group 2. It's not the fat, it's the fact that they're overloading herbivores with dietary cholesterol!

Total cholesterol was also the same between all groups except the cholesterol-fed group. TBARS, a measure of lipid oxidation in the blood, was elevated in the cholesterol and sunflower oil groups but not in the chow or coconut groups. Oxidation of blood lipids is one of the major factors in atherosclerosis, the vascular disease that narrows arteries and increases the risk of having a heart attack. Serum vitamin C was lower in the cholesterol-fed groups but not the others.

This supports the idea that saturated fat does not inherently increase LDL, and in fact in most animals it does not. This appears to be the case in humans as well, where long-term trials have shown no difference in LDL between people eating more saturated fat and people eating less, on timescales of one year or more (some short trials show a modest LDL-raising effect, but even this appears to be due to an increase in particle size rather than particle number). Since these trials represent the average of many people, they may hide some individual variability: it may actually increase LDL in some people and decrease it in others.

Merry Christmas!

What's the Ideal Fasting Insulin Level?

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 prevents the escape of fat from fat tissue and causes a number of other metabolic disturbances.

Elevated fasting insulin is a hallmark of the metabolic syndrome, the quintessential modern metabolic disorder that affects 24% of Americans (NHANES III). Dr. Lamarche and colleagues found that having an insulin level of 13 uIU/mL in Canada correlated with an 8-fold higher heart attack risk than a level of 9.3 uIU/mL (1; thanks to NephroPal for the reference). So right away, we can put our upper limit at 9.3 uIU/mL. 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 as well.

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. However, their glucose tolerance was excellent (5, 6, free full text). 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. 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, a relatively healthy diet growing up, and the fact that I managed to come across the right information relatively young. It does not reflect: carbohydrate restriction, fat restriction, or saturated fat restriction. Neither does the low fasting insulin of healthy non-industrial cultures.

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, although the lower half of that range may be preferable.