The huge gap between glycemic loads of refined and unrefined carbohydrate-rich foods

I often refer to foods rich in refined carbohydrates in this blog as among the most disease-promoting agents of modern diets. Yet, when one looks at the glycemic indices of foods rich in refined and unrefined carbohydrates, they are not all that different.

The glycemic index of a carbohydrate-rich food reflects how quickly the food is digested and generate a blood glucose response. Technically, it is measured as the area under a two-hour blood glucose response curve following the consumption of a portion of the food with a fixed amount of carbohydrates.

A measure that reflects much better the underlying difference between foods rich in refined and unrefined carbohydrates is the glycemic load, which is the product of the glycemic index of a food by the carbohydrate content in a 100 g portion of the food.

The glycemic load is also the reason for one known fact among diabetics. If a diabetic person eats a very small amount of a high glycemic index food, he or she will have a relatively small increase in blood sugar. If that person consumes a large amount of the same food, the increase in blood sugar will be dramatic.

The table below (click on it to enlarge) shows the remarkable differences between the glycemic loads of foods rich in refined and unrefined carbohydrates. It was taken from an article co-authored by Loren Cordain, Michael R. Eades, and Mary D. Eades (full reference at the end of this post).

At the time of this post’s writing, the article from which the table above was taken had a solid number of citations to it; a total of 74 citations on Google Scholar’s database. It is an excellent article, which I highly recommend reading in full (the link to the online full text is at the end of this post).

What is the reason for the differences in glycemic loads?

The answer is that foods rich in unrefined carbohydrates, even those with a high glycemic index (such as potatoes), are also packed with a number of other things – e.g., micronutrients, fiber, water, and even some protein. An Irish (white) potato is 75 percent water. By comparison, cereal, without milk added, is about 1 percent water. You have to add a lot of whole milk to it to make it a bit healthier. And even unsweetened whole milk is about 5 percent sugar.

There was nothing even remotely similar to modern foods rich in refined carbohydrates in the diet of our Paleolithic ancestors. In fact, the types of food rich in refined carbohydrates shown on the table above are very recent, typically dating back to less than a hundred years ago. That is, they are so recent that it is unlikely that any of us have genetic adaptations to those types of food.

Once one’s glucose metabolism is seriously impaired, which seems to be associated with consumption over many years of refined carbohydrates and sugars (as well as some genetic predisposition, which may have evolved among some of our ancestors), then even the foods with high glycemic index and low glycemic load (e.g., potato) will lead to highly elevated glucose levels if eaten in more than very small amounts.

Insulin resistant individuals should avoid even foods with high glycemic index and low glycemic load, as well as any food that significantly increases their blood glucose levels after a meal, because highly elevated glucose levels are toxic to various tissues in the body. The longer those highly elevated serum glucose levels are maintained, the more damage is done; e.g., 2 hours as opposed to 30 minutes at 180 mg/dl. One reason why they are toxic is because they lead to high levels of protein glycation; this is a process whereby sugar binds to protein and “warps” it, impairing its functions.

Generally speaking, the more glycation is going on in our body, the more accelerated is the aging process.

Reference:

Loren Cordain, Michael R. Eades, Mary D. Eades (2003). Hyperinsulinemic diseases of civilization: More than just Syndrome X. Comparative Biochemistry and Physiology: Part A, 136, 95–112.

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.

Low fasting triglycerides: A marker for large-buoyant LDL particles

Small-dense LDL particles are particles that are significantly smaller than the gaps in the endothelium. The endothelium is a thin layer of cells that line the interior of arteries. Those gaps are about 25-26 nanometers (nm) in diameter. Small-dense LDL particles can contribute a lot more to the formation of atheromas (atherosclerotic plaques) in predisposed individuals than large-buoyant LDL particles.

Note that typically LDL particles are about 23-25 nm in diameter in most people, and yet not everybody develops atheromas. It is illogical to believe that evolution made LDL particles within those ranges of size to harm us, given the size of the gaps in the endothelium, unless you believe in something like this joke theory. There are underlying factors that make individuals much more prone to the development of atheromas than others.

One of those factors is chronic inflammation, which is caused by: chronic stress, excessive exercise (aerobic or anaerobic), and a diet rich in refined carbohydrates (e.g., white bread, pasta) and refined sugars (e.g., high fructose corn syrup, table sugar).

Can a standard lipid profile report tell me anything about my LDL particle pattern?

Yes, check you fasting triglycerides. If they are below 70 mg/dL, it is very likely that you have a predominance of large-buoyant LDL particles in your blood. That is, your LDL particle pattern is most likely Pattern A (see figure below, from: www.degomamd.com), the least atherogenic of the patterns identified by a Vertical Auto Profile (VAP) test. This test is more sophisticated than a standard lipid profile test, where the LDL cholesterol is typically calculated. For a discussion of a sample VAP test report, see this post.

So, you can get a rough idea about your LDL pattern type only by checking your fasting triglyceride levels on a standard lipid profile test report, if you cannot or do not want to have a VAP test done. The higher your fasting triglyceride levels are, above 70, the more likely it is that your LDL particle pattern is Pattern B, which is the most potentially atherogenic pattern.

Large-buoyant LDL particles often lead to high measured LDL cholesterol levels. This situation is analogous to that of water-filled balloons. If you have 10 balloons, each holding 0.5 L of water, then your total water amount is 5 L. If the same balloons are filled with 1 L of water each, then your total water amount is 10 L. That is, even though the number of LDL particles (analogous to the number of balloons) may be the same as that of a person with low LDL cholesterol, large-buoyant LDL particles have more cholesterol (water content in each balloon) in them, and lead to higher measured LDL cholesterol (total amount of water in the balloons) levels.

This leads to the counterintuitive situation where your LDL cholesterol levels go up, and your risk of developing cardiovascular disease actually goes down.

Also worth keeping in mind is that fasting triglyceride levels are strongly and negatively correlated with HDL cholesterol levels. The higher your fasting triglyceride levels are, usually the lower are your HDL cholesterol levels. The latter are also provided in standard lipid profile reports.

How do you decrease your fasting triglycerides?

A good way to start is to do some of the things that increase your HDL cholesterol.

References:

Elliott, W.H., & Elliott, D.C. (2009). Biochemistry and molecular biology. 4th Edition. New York: NY: Oxford University Press.

Lemanski, P.E. (2004). Beyond routine cholesterol testing: The role of LDL particle size assessment. CDPHP Medical Messenger, May 2004.

Genetic clustering of metabolic disorders: Meet your relatives

As noted in this post, it is possible for a food-related trait to evolve to fixation in an entire population in as little as 396 years; not the millions of years that some believe are necessary for mutations to spread.

Moreover, evolution through fixation can occur in the absence of any selective pressure. That is, traits that are neutral with respect to fitness may evolve by chance, particularly in small populations. (A group of 100 individuals who made it to the Americas after a long and grueling trek would fit the bill.) This rather counterintuitive phenomenon is known as genetic drift (Hartl & Clark, 2007; Maynard Smith, 1998).

Fast evolution of traits certainly applies to polygenic traits, such as traits associated with nutrient metabolism. Polygenic traits are traits that are influenced by multiple genes, with those genes acting together to influence the expression of the trait.

Moreover, a mutation in one single pleiotropic gene (a gene that influences various traits) can lead to dramatic changes in interconnected phenotypic traits. This includes traits associated with complex processes involving multiple body tissues, such as glucose and fat metabolism.

Some disagree, arguing that complex traits need much longer to evolve. I wish I could be convinced of that; it would make our understanding of health issues and related predictions a lot easier. For example, we could zero in on Homo erectus as our target for an ideal Paleolithic diet.

Unfortunately, when you look around, you see people with food allergies, metabolic disorders, and other food- and lifestyle-related complications; and those problems cluster among people who seem to share recent common ancestors. Interestingly, in many cases those people do not look alike, in spite of sharing common ancestors.

For example, here in South Texas, it is clear that people from Amerindian ancestry (like me, although mine is from South America) are a lot more predisposed to diabetes than others. There are exceptions, of course; we are talking about probabilities here. Especially common here in South Texas are people with South and Central American Indian ancestry; less common but also represented are descendants of North American Indian tribes such as the Kickapoos.

Very recent food inventions, such as refined carbohydrates, refined sugars, omega-6-rich vegetable oils, and hydrogenated fats are too new to have influenced the genetic makeup of anybody living today. So, chances are, they are bad for the vast majority of us. Sure, a small percentage of the population may not develop any hint of diseases of civilization after consuming them for years, but chances are they are not going to be as healthy as they could be.

Other not so recent food inventions, such as olive oil, certain types of bread, certain types of dairy etc. may be better, in terms of overall health effects, for some people than for others. In fact, they may be particularly health-promoting for certain groups of individuals. The reason may be found in inherited metabolic traits. Learning about your ancestors could be helpful in this respect. The problem is that many people's ancestry is quite mixed; again, I give myself as an example - South American Indian, German, Italian, Portuguese ... and who knows what else.

Another, easier and perhaps more effective, way to figure out what particular foods, and in what quantities, may be healthy for you is to keep in touch with close and distant biological relatives; e.g., grandparents, parents, siblings, cousins (family gathering photo below from: www.lega.co.uk). It is likely that you share genes with them. If several of them developed a particular disease, and they consumed a lot of a certain type of food prior to that, then maybe that food should not be part of your diet.

This may also help you avoid making serious mistakes regarding health issues by acting too fast in response to laboratory test results. Relatives may share some quirky metabolic responses, which could be indicative of a disease at first glance and actually have no negative long term effects, and perhaps some positive ones.

For example, let us assume that a person, let us call her Mary, is in her early 50s and has been consuming a diet rich in refined carbohydrates and sugars for her entire life. Her fasting blood glucose looks pretty good at around 82 mg/dL.

Mary then adopts a diet that includes only vegetables and animal fat and protein. This new diet induces mild ketosis. She then notices that her fasting blood sugar is now 113 mg/dL, much higher than the previous 82 mg/dL. Mary’s doctor tells her that she may be pre-diabetic.

Mary knows that the change in diet was associated with the increase in fasting blood sugar, and reverts back to her diet rich in refined carbohydrates and sugars. Her fasting blood sugar goes down to 82 mg/dL, and she is happy. Her doctor congratulates her. However, she becomes obese and develops the metabolic syndrome in her late 50s, and several related diseases soon after.

Let us now look at a different scenario. After getting the 113 mg/dL fasting blood sugar reading on a mildly ketogenic diet, Mary talks to as many of her living relatives as she can. She asks many questions and finds out that a few of them were big meat and veggie eaters and had the same metabolic response. They are in their 60s and 70s and have no hint of diabetes. In fact, they are relatively lean and fairly healthy. She then sticks to her diet of only vegetables and animal fat and protein for life, and never develops the metabolic syndrome.

This fictitious case is based on the idea that low carbohydrate diets that induce mild ketosis may also induce physiological (not pathological) insulin resistance, leading to a version of the much talked about dawn phenomenon. This phenomenon, in this context, seems to be related to our good friend, but much maligned, palmitic acid. Several bloggers discussed it in excellent posts. Peter at Hyperlipid blogged about it here and here; Stephan at Whole Health Source blogged about it here.

Now, going back to keeping in touch with close and distant relatives. It is important to check your relatives’ lifestyle patterns as well, because diet is not everything, even though it is a major contributor to health outcomes. By lifestyle patterns I mean things like level and type of physical activity, sunlight exposure (which strongly influences vitamin D levels), and frequency and quality of social interactions (which reduce stress).

Regarding social interactions, it is worth noting that humans are highly social beings, and social isolation is almost universally detrimental to both mental and physical health.

References:

Hartl, D.L., & Clark, A.G. (2007). Principles of population genetics. Sunderland, MA: Sinauer Associates.

Maynard Smith, J. (1998). Evolutionary genetics. New York, NY: Oxford University Press.

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.

Low Vitamin D: Cause or Result of Disease?

Don Matesz at Primal Wisdom put up a post a few days ago that I think is worth reading. It follows an e-mail discussion between us concerning a paper on magnesium restriction in rats (executive summary: moderate Mg restriction reduces the hormone form of vitamin D by half and promotes osteoporosis). In his post, Don cites several papers showing that vitamin D metabolism is influenced by more than just vitamin D intake from the diet and synthesis in the skin.

Celiac disease patients have low 25(OH)D3, the circulating storage form of vitamin D, which spontaneously corrects on a gluten-free diet. There are numerous suggestions in the medical literature that overweight and sickness cause low vitamin D, potentially confounding the interpretation of studies that find lower levels of illness among people with low vitamin D levels.

Don't get me wrong, I still think vitamin D is important in preventing disease. But it does lead me to question the idea that we should force down huge doses of supplemental vitamin D to get our 25(OH)D3 up to 60, 70 or even 80 ng/mL. When the dosage of supplemental D goes beyond what a tan Caucasian could conceivably make on a day at the beach (4,000 IU?), that's when I start becoming skeptical. Check out Don's post for more.

Body mass index and cancer deaths in various US states

Ancel Keys is often heavily criticized for allegedly originating the fat phobia that we see today in the US and other countries, perhaps with good reason. But he has also made many important contributions to the health sciences.

One of them was the index known as body mass index (BMI), calculated based on a person's weight and height. Unlike other measures, such as body fat percentage and body fat mass, BMI is very easy to calculate; divide your weight (kg) by your height (m) squared.

BMI is strongly correlated with body fat percentage, and body fat mass. Very muscular people are exceptions; they may have a high BMI and yet reduced body fat.

Excessive body fat mass leads to chronic inflammation, due in part to elevated circulating levels of pro-inflammatory hormones such as tumor necrosis factor-alpha (cute name eh?).

Chronic inflammation, in turn, leads to increased incidence of cancer.

Thus it should be no surprise that having a BMI above 30 (obesity level) is strongly correlated with cancer death rates; see graph below (click on it to enlarge), from: Florida, 2009 (full reference at the end of this post).

The correlation for the graph above is a high 0.702, calculated as the square-root of the R-squared value shown at the bottom-right. The R-squared is the percentage of explained variance for cancer deaths, meaning that nearly 50 percent of the cancer deaths are "explained", or caused, by the BMI percentages.

One more reason to bring body fat down to healthy levels.

How do you do that? A good way to start is to replace refined carbohydrates and sugars with natural sources of protein and fat in your diet; eggs included, no need to worry about dietary cholesterol.

Reference:

Florida, R. (2009). The geography of obesity. Creative Class, Nov. 25.