Understanding the role of vitamin K-dependent proteins in vascular calcification

What if the process of arterial calcification was regulated from within the cells of the blood vessels, and that it had nothing directly to do with what you ate and what circulated in the bloodstream because calcification takes place not anywhere near the surface but inside the blood vessel wall?

What if the process of arterial calcification was actually a process by which muscle is transformed into bone, a process by which vascular smooth muscle cells transform themselves into bone cells which then actually build bone tissue within the blood vessel wall?

And what if apoptosis preceded calcification, what if cell death was what triggered the process of calcification, and it was the apoptotic bodies of dead vascular smooth muscle cells within the blood vessel wall that served as the nodes around which calcium crystals formed?

Would you not find this shocking? Find it incredible that any of these could be true, let alone all of them? It’s entirely not at all what we’ve been told by “health experts” and “health authorities” for more than half a century!

All of these statements are hard to believe. It is especially unbelievable that muscle cells can change into bone-building cells, and begin to grow bone tissue within the artery wall. It sounds surreal, kind of like science fiction. But it isn’t. All of it is true. All of this has been observed.

Interesting, you may think, but what does any of this have to do vitamin K? Everything! It has everything to do with vitamin K.

How clever we are

The sophistication and precision of biochemical reactions and processes in animals and humans are mind blowing. Understanding how they work is a wonderfully noble endeavour that is certainly very fulfilling in its own right. In some cases though, it can be a matter of life and death. And in the case of the processes related to and regulated by vitamin K dependent proteins it definitely is.

This is not an exaggeration to push you to read on. It’s a statement of fact. And you’ll see how this is true by the time we finish. I believe it is essential, for each one of us to understand the details of how things in our body work and how they are related and connected in order to appreciate their significance and their importance.

We are so clever. We can figure out such complicated things when we put our minds to it. Things like complex biochemical pathways, or long chains of enzymatic reactions that, one step at a time, transform molecules from one form into another. And it is this kind of cleverness that has enabled us to develop the hundreds of different types of medications we can find today in drug stores.

We have designed medications to address basically every symptom we can think of. If it’s a symptom we’ve had, it’s most likely a symptom that many others have or have had. And if many have the same or a similar symptom, we can be sure that at least one pharmaceutical company will have made a drug for it.

Warfarin was developed in the 1950s to prevent or at least suppress coagulation, and in so doing help prevent or at least reduce the number of strokes and heart attacks. Because so many people either suffer from, are susceptible to, or are at risk of cardiovascular disease, many people take warfarin.

And what I mean by many in this case is between 20 and 30 million prescriptions per year in the United States alone. The number went up to 35 million in 2010 and dropped back to 20 million in 2015. That’s a lot of warfarin pills! You can see the stats here (http://clincalc.com/DrugStats/Drugs/Warfarin). Warfarin is in the top 50 drugs. It’s 42nd down the list. Just below aspirin at 39, insulin at 36, and ibuprofen at 34, as you can see here (http://clincalc.com/DrugStats/Top200Drugs.aspx).

Surely close to every household in the western world will have somewhere in a bathroom cupboard or drawer a bottle of aspirin or ibuprofen. Given how close to warfarin they are in popularity of usage, there’s clearly no need to even say that this anti-coagulant drug is in broad and widespread use.

Isn’t this great, though? Millions of people at risk of having blood clots that would possibly cause them a stroke or heart attack, protected by taking a little warfarin every day? Yes, I suppose in some ways, it is, if these people are actually at risk. But, unfortunately, with a drug like that, we can be pretty sure that most are taking it preventatively, as in, just in case. And this is a problem.

Warfarin works by disrupting the process that leads to the activation of coagulation factors. The blood’s ability to form clots quickly is one of its most vital functions, because without it we would just bleed to death from a flesh wound. Evolutionarily, we simply would not have made it to here without this protection mechanism that ensured that when we were wounded, the blood would immediately thicken to stop it bleeding out of our body by forming clots at the surface of the open wound as fast as possible. The special proteins responsible for regulating coagulation are vitamin K-dependent proteins (VKDPs).

It has taken a long time to understand, first of all, that there wasn’t just vitamin K, but in fact two different kinds of vitamin K. It is also true that it has taken a long time to identify the major vitamin K-dependent proteins and figure out how they work. We are talking about 40 years from the 1950s to the 1990s. So, you really shouldn’t be surprised if you haven’t read or heard about this before.

But today, a lot has been understood through in vitro and in vivo observations, trials and studies both in animal models and in humans. And even though we will inevitably continue to deepen our understanding of the subtleties of the molecular mechanisms, the species, and the interactions involved in the life of cells and proteins in how they affect the state of our blood vessels and organs, this is a sketch of the picture we have at this stage.

Vitamin K dependent proteins

There are about twenty identified VKDPs belonging to two classes: hepatic—those produced by the liver, and extra-hepatic—those produced in other tissues. Those from the first class are the most well-known and well-studied. They are the coagulation factors (II, VII, IX, and X) manufactured by the liver and activated within it before being pushed into the bloodstream and circulated throughout the body to maintain a healthy coagulation response in case it is ever needed. These are the ones targeted by warfarin. Naturally, since that drug has been around since the 1950s, the role and function of these vitamin-K dependent coagulation factors have also been known at least since that time.

The second class is less known and less studied but has—luckily for us—gained much more attention in the last two decades. It includes three very important proteins whose functions are essential in maintaining healthy blood vessels. But unlike the coagulation factors produced in the liver, these proteins are instead produced by the vascular smooth muscle cells and activated there locally in the vasculature. These vascular health factors, we call them that in analogy to but to distinguish them from the coagulation factors, were identified much more recently in the 1980s and 1990s. All are proteins that contain gamma-carboxyglutamic acid abbreviated Gla.

Some important ones for us here are osteocalcin, for which it took 30 years to be identified as an inhibitor of calcification when it was discovered in vitro to prevent the precipitation of crystals in a supersaturated calcium solution. This means that without it, calcium crystals would have inevitably formed spontaneously in the solution. Osteocalcin is also called bone Gla protein. Growth arrest specific protein 6 is involved in the regulation of cell proliferation, and seems to inhibit premature cell death. And the most important one in relation to soft tissue calcification, matrix Gla protein abbreviated MGP.

Matrix Gla protein was originally isolated from bone, but it has been found to be expressed in several other tissues including kidney, lung, heart, and—most critically—vascular smooth muscle cells or VSMCs. It is now known to be the most potent inhibitor of calcification of blood vessels, and even though the liver does produce and secrete MGP into the bloodstream, only the MGP produced in the vasculature inhibits calcification.

Besides being produced in different tissues, another important difference between the two classes of VKDPs is that the liver-produced coagulation factors are phylloquinone—or vitamin K1-dependent, whereas the vascular smooth muscle cell-produced proteins are menaquinone—or vitamin K2-dependent. In light of the fact that it is rather hard to find vitamin K1 insufficiency with a diet that contains at least some green plant foods, while the exact opposite is true for vitamin K2 of which the western diet is practically devoid, this difference is highly significant.

Both vitamin K1 and K2 are absorbed in the second and third portions of the small intestine, the jejunum and ileum, K1 is delivered to the liver, whereas K2 is transported via LDL and HDL to other organs. K1 is mainly found in the liver, whereas K2 is preferentially stored in peripheral tissues, with the highest levels in the brain, aorta, pancreas, and fat tissues. This obviously attests to the importance of these essential vitamins.

While vitamin K1 and K2 are really two different vitamins with different functions, transport mechanisms, and distribution in the tissues, and while there are several differences between the vitamin K1-dependent and the vitamin K2-dependent proteins, these have one essential thing in common. This is, as their name says, that they are vitamin K-dependent. What this means is that all these proteins share the same enzymatic chain of activation—whether it mediated by K1 or K2—that transforms them into their biologically active form, the form they need to have in order to do the things they are meant to do.

All VKDPs must be carboxylated in order to be activated. The process is complicated and not yet completely understood. We know that it is targeted to the glutamic acid (Glu) residues on the protein that must be made into gamma-carboxylglutamic acid (Gla). We also know that the process is mediated by the enzyme gamma-glutanyl carboxylase (GGC), and that vitamin K is the main co-factor that enables the enzyme to perform the activation. In the end, the process leads to the addition of a carbon dioxide molecule to the gamma-carbon of Glu, which transforms it into Gla. However, it is the reduced form of vitamin K that is required.

Vitamin K, whether it is the plant-based phylloquinone (K1) or the animal-based menaquinone (K2), enters the body through the diet in its non-reduced form. Reduction involves the addition of hydrogen in molecular form, H2, to make KH2. Transformations of this kind are generally always done by enzymes, and so is this one. In this case the enzyme is vitamin K epoxide reductase (VKOR). Its action is essential because it is the reduced form KH2 that acts as the co-factor in the process of carboxylation.

The energy released by the oxidation of KH2 drives the addition of the carboxyl group unto the glutamic acid residues. But the oxidised form of vitamin K, KO, can subsequently be reduced again to KH2. Thus vitamin K is first reduced, then oxidised to help push the carboxyl group unto the glutamic residue, and then reduced once more to start the whole cycle again. This cycle is called the vitamin K epoxide reductase or VKOR cycle.

For this class of proteins, the VKDPs, activation through carboxylation means for them to acquire the structure and properties needed to bind calcium in order to transport it. You may recall from a previous chapter in the story of vitamin K2, matrix Gla protein generally transports calcium out of soft tissues in order to prevent calcification, and bone Gla protein generally transports it into bones and teeth to prevent osteopenia, osteoporosis, and tooth decay.

The big red flag

Now you understand why it is that when, in our remarkable cleverness, we understood that the main coagulation factors depended on the action of these enzymes to be activated and rendered functional, we naturally concluded that the best way to prevent clot formation would be to prevent coagulation, and that this could be achieved by blocking these enzymes from doing what they are intended to in a healthy organism. This is precisely what warfarin does.

And it does it well. Otherwise it wouldn’t have become as commonly used as it is. And we can be certain it has saved a lot of people much of the pain and possibly life-threatening conditions that a blood clot could have caused them. The problem is that the vascular health factors so critical for maintaining healthy blood vessels, depend on the same enzymes for activation as do the coagulation factors. Preventing the carboxylation of coagulation factors, prevents, in exactly the same way, the carboxylation of the vascular health factors.

This was only understood to be a major problem relatively recently. We first had to understand that there isn’t just one kind of vitamin K, but that there are two, and that they are very different in their functions. We had to understand that both vitamin K1 and vitamin K2-dependent proteins rely on the same enzymes to get activated. We had to understand the carboxylation process by which they are activated. And we had to understand that MGP, BGP, and Gas 6 are vitamin K-dependent proteins, that they are specifically vitamin K2-dependent, how they are activated, what they actually do in our veins and arteries, and what happens if they can’t do what they are designed to do.

A major red flag about anticoagulants and warfarin came up from what was seen in mice. The first part of the study was with MGP-knockout mice, (mice in which the MGP-encoding gene was deactivated). They were observed to have stunted growth from the premature calcification of the epiphysis—the part at the end of bones and at the junction with the cartilage of the joint which allows the bone to grow longer. As as soon as the epiphysis calcifies, longitudinal growth stops. But this was the least severe of the problems that were observed.

The MGP-knockout mice very quickly developed severe arterial calcification, and died highly prematurely, within 6 to 8 weeks, of strokes, heart attacks, and rupture of the aorta. Normal lab mice live 2 to 3 years and some even up to 4 years. So, in the least extreme case, a MGP-knockout mouse dying from aortic rupture at 2 months instead of living a relatively short normal life of only 2 years, would be equivalent for a human that would normally live to the age of 72 to die at the age of 6!

Here is what severe coronary calcification looks like in humans:

severe_coronary_calcification

Severe coronary calcification in a patient with end-stage renal disease. We can see that these blood vessels are basically filled with bone tissue that appears bright white. (https://www.bmj.com/content/362/bmj.k3887)

It was also observed that although the liver did produce and release MGP into the bloodstream, it had no effect on the arteries. Only the tissue-specific, locally-produced MGP within the vascular smooth muscle cells was able to inhibit calcification.

To check these conclusions, a similar study was done on normal mice that were given vitamin K1 to ensure proper liver function and healthy coagulation, and warfarin to block all extra-hepatic MGP action in tissues. The result? Stunted growth, pervasive arterial calcification, and premature death from stroke, heart attack, and aortic rupture.

The conclusions were solid: matrix Gla protein is the organism’s primary protection against soft tissue and arterial calcification; liver MGP has no protective effect on arteries, and only VSMCs-produced MGP can inhibit calcification in the arteries; both vitamin K deficiency and disruptions of the action of the enzymes that activate MGP cause extensive soft tissue calcification; and only vitamin K2, not vitamin K1, can inhibit warfarin-induced calcification.

Going further

When this was understood, more attention began to be paid to matrix Gla protein. Many other details were elucidated through further investigations. It was found that MGP is an 84-amino acid protein with five Gla residues. That all of these Gla residues are produced by gamma-carboxylation, which is mediated by the enzyme gamma-carboxylase that requires vitamin K2 as a cofactor, and that until now, the only known function of Gla residues is to bind calcium ions and crystals (calcium apatite). It was discovered that the concentration of calcium and phosphate in extracellular fluids is high enough to trigger and sustain growth of crystals, but that MGP and BGP prevent this from happening. That MGP is required by VSMCs to maintain their elastic and contractile nature. And not just that.

MGP actually inhibits the transformation of VSMCs into bone cells by antagonising the action of Bone Morphogenic Protein 2 (BMP2). It turns out that the muscle cells of the blood vessels have in them the potential to either stay smooth elastic contractile muscle cells, or turn into osteoblast-like bone building cells. BMP2 triggers that osteogenetic gene expression in the VSMCs: it tells muscle cells of the blood vessels to transform into bone-building cells.  And as if this wasn’t enough, BMP2 also induces apoptosis: it tells blood vessel muscle cells to commit suicide, which is certainly to help in the process given that once dead, they can be used as seeds for calcium crystal formation, and thus promote a faster and more efficient calcification.

What induces expression of BMP2 in cells? Probably several things that we haven’t yet identified. But for now we know that BMP2 is stimulated by oxidative stress, chronic inflammation, and high blood sugar levels. The good news is that MGP protects against all of these effects by antagonising BMP2. So if there is enough MGP and enough vitamin K2, if there are no disruptions to the action of the vitamin K dependent enzymes by anticoagulants like warfarin, and if oxidative stress, inflammation, and blood sugar are kept low, then there is protection against calcification of the arteries and other soft tissues like the liver, kidneys, and heart.

Recap

Here we have it. We have now understood the role of vitamin K dependent proteins in vascular calcification. And although it was a little long and maybe somewhat arduous, all the details are clear. It is complicated. I won’t deny that. But I have strived to make it all as accessible as I could without diluting the mechanisms of action and relationship between the different players. Let’s recap to make sure you are left with the essential elements in mind.

Vitamin K dependent proteins can either be vitamin K1 or vitamin K2 dependent. The dependence comes from the fact that vitamin K is required to activate the protein. This activation is the carboxylation in which a carbon dioxide is added to the glutamic acid residues along the protein. Carboxylation is mediated by carboxylase (GGC) that requires the reduced form of vitamin K in order to oxidise it and get the energy to push the carbon dioxide molecule onto the glutamic acid residue. Vitamin K is reduced by reductase (VKOR) which can do it over and over again in what is called the VKOR cycle.

Vitamin K1 dependent proteins are mostly liver based coagulation factors. Vitamin K2 dependent proteins are mostly outside the liver and generally involved in inhibiting soft tissue calcification. The most important calcification-inhibiting VKDP is matrix Gla (MGP), which performs a wide range of tasks to maintain elastic, flexible, calcium-free blood vessel walls.

Calcification is triggered by the death of vascular smooth muscle cells. These dead muscle cells act at seeds for calcium apatite crystals to form. VSMCs can be induced to become osteoblast bone-building like cells that then go on to stimulate the growth of bone tissue within the artery walls. This process is stimulated by bone morphogenic protein 2 (BMP2), which is expressed under conditions of oxidative stress, inflammation, and hyperglycaemia.

To prevent and reverse calcification the most important is to provide a good supply of vitamin K2 through diet and supplementation. Because it is essential in the activation of Gla proteins but only through its role in the VKOR cycle, the amount of K2 is the rate limiting factor. Hence more is better than less, and excess will simply remain unused but will not cause harm.

Naturally, matrix Gla protein needs to be available. Cells of tissues where calcification occurs (kidney, liver, heart, and blood vessels) secrete MGP. An interesting evolutionary self-protection adaptation mechanism. And here’s another: the amount of MGP that is produced by a cell depends on at least two factors that have been identified. One is the amount of calcium; the other is the amount of vitamin D3. In both cases, the more there is, the more MGP is produced.

So, vitamin D3 has the role of making calcium available but at the same time stimulates the production of MGP in order for the calcium to be available to the bones and not to the soft tissues. But for this, it relies on vitamin K2. This is why vitamin D3 without vitamin K2 leads to calcification: because MGP and BGP remain inactive and incapable of binding to the calcium ions to move them into bones and out of tissues. On the other hand, plenty of vitamin K2 would indeed activate the available MGP, but without enough vitamin D3 there might not be enough MGP to confer proper protection against calcification. This is a perfect example of the complementarity of action and function in essential micronutrients. There are certainly many more, but this one is particularly remarkable.

Final thoughts

I want to close on a final consideration. It is so easy and seems so natural for us to think in terms of this and that, good and bad, for and against, that our tendency is to look at everything in these terms. This is also true when we look at biochemical processes like the ones we have described and explored here. We naturally lean towards looking at the calcification inhibiting mechanisms as protective, and those that promote calcification and apoptosis as destructive.

But the reality is that cells, proteins, and enzymes don’t behave in these terms, they don’t think in these terms simply because they don’t think. They react biochemically to what they are exposed to, to the molecules and chemical messengers they encounter, to the quality of the liquids in which they bathe, to the characteristics of the environment in which they live, microsecond after microsecond, without any forethought or concern for the microsecond that will follow. The only guiding principle that can be used to lead us to understand why things happen the way they do is evolutionary adaptation to survive.

Having recognised this, we immediately see that the mechanisms that promote apoptosis of VSMCs, their subsequent transformation to osteoblast-like cells, and the growth of bone tissue within the artery walls that we refer to as arterial calcification, can only be a protection mechanism. A mechanism to protect the tissues and cells from the damaging effects of exposure to free radicals, inflammatory molecules, and glucose. Because, as we have seen, the process is reversible, it would be perfectly natural to undergo periods of calcification followed by periods during which the bone tissue is broken down and removed from our arteries and other soft tissues and organs when the circumstances allow it. Actually, we should say when the circumstances dictate it, because no matter what happens, it is always the circumstances—the environment—that dictate what is to happen.

What we can do, with the knowledge of what we have understood, is make choices about what we eat and drink, when and how much we eat, and how we live, sleep, and exercise. Choices that will shape or reshape, define or redefine the makeup of this internal environment of the body to always move us in the direction of optimal biochemistry, optimal physiology, optimal metabolism, and optimal health.

Everything that we explore together is always about just this. But sometimes the corrective action requires effort, sometimes even a lot of effort. In this case, however, it is as simple as can be, because it only requires us to supplement with vitamin K2 and possibly also D3. Of course, the last thing we want is a lifestyle that promotes the expression of BMP2 and the growth of bone tissue within our arteries. But supplementing with K2 and D3 together will in general bring only benefits. I know it was a very long-winded way to get to this, but now you understand why. That was—and is—the whole point of this blog, after all. I hope you enjoyed reading.

 

The information in this article comes primarily from the following papers: Molecular Mechanisms Mediating Vascular Calcification by Proudfoot and Shanahan (2006); Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification by Danziger (2008); The Role of Vitamin K in Soft Tissue Calcification by Theuwissen, Smit, and Vermeer (2012).

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Insulin and Triglycerides

Every time I review someone’s blood test results, and then discuss with them what they mean and what they should do to improve their numbers, there’s something I almost always have to explain. And this was the relationship between fasting insulin and triglyceride levels.

Take a look at this plot:

trigs_vs_insulin_gb

Plot showing ten pairs of measurements of insulin and triglycerides, made from the same blood samples. They were collected between 2011 and 2017, and all are from my own blood tests.

It shows measurements of insulin concentration on the horizontal axis in mili units per millilitre (mIU/ml), and triglyceride levels on the vertical axis in milligrammes per decilitre (mg/dl). This is a correlation plot in which independent measurements of one variable are plotted against independent measurements of another in an attempt to see if there is a relationship between them.

Is there an order in the way the dots are organized? They are clearly not randomly distributed as a circular cloud of dots—it would mean that there is no relationship. Instead, we see what looks like a linear relationship in which lower values of insulin correspond to lower values of triglycerides, and higher values of insulin correspond to higher values of triglycerides. It’s not a straight line, but it’s definitely a clear linear relationship, and the value of the correlation coefficient, which quantifies how tight the relationship actually is, of just under 0.9 is pretty close to 1. In other words, it’s a pretty tight linear relationship.

Triglyceride is a fancy word for fat or lipid, because fat molecules are composed of three fatty acids held together by a glycerol structure. This is what triglyceride refers to. The amount of fat in the blood is affected by the amount of fat we eat, and the amount of body fat we have. Naturally, after a fatty meal, triglyceride levels will increase as the fat goes from the digestive system into the blood, they will reach a maximum, and then start to go down. The longer we wait before we eat again, the lower they will go. But there’s a few complications.

The first is that depending on the amount of insulin, one of whose jobs it is to transport nutrients into cells, whatever is circulating in the blood—and this includes glucose, of course, but also protein and fat—will in general be stored away faster if insulin is higher, and slower if insulin is lower. This means that if you eat fat together with sugar or starch, the whole lot will be packed away, and mostly as fat, minus the little bit of glucose your muscles and liver have room to store up as glycogen.

The second is that depending on the state of insulin sensitivity—the fundamental parameter that determines how well or poorly cells can use fat for fuel—triglycerides will in general be used up faster if we are more insulin sensitive and slower if we are more insulin resistant. This means that in the morning, twelve to fourteen hours after having had the exact same meal, the more insulin sensitive person will have lower triglyceride levels than the more insulin resistant.

And in fact, no matter if we have a measure of fasting insulin or not, and no matter how little we know about the person’s overall health, fasting triglyceride concentration is probably the best general marker of insulin sensitivity. Nevertheless, because their levels fluctuate quite a lot over the course of each day as a function of what we eat and drink, it is true for triglyceride levels as it is true for many other blood tests that are affected by the kind and amount of food and drink we’ve had over the last days, and most importantly by the amount of sweet or starchy carbohydrates.

Now, take a look at this second plot:

trigs_vs_insulin_final

Plot showing, in addition to the 10 points shown in the first plot (in red), another 20 pairs of measurements of insulin and triglycerides, also all from the same blood samples, but from seven other persons.

It shows the same 10 data points shown in the first plot from my own results, but with another 20 pairs of measurements taken from other people that I’ve coached and helped with the interpretation of their results. You can see that the relationship is better defined because of the additional points that now together cover a wider range of values on both axes.

However, you can also see that, the relationship is not as tight. In particular, there are a few points that are quite far off the main trend—mostly those at the top of the plot with high triglyceride and low insulin values. We see how these off-trend points affect the tightness of the relationship seen in the initial data set when we compare the values of the correlation coefficients. These off-trend points lead us to the third complication I wanted to bring up.

But first, please take a minute to consider the matter: What could lead to having low insulin and at the same time high triglycerides? What could be the cause of the difference between my numbers, which did contain some very low insulin levels, but all of which were paired with equally low triglyceride values, and this other person’s numbers? What causes insulin to go down? What happens when insulin is low? What could cause triglycerides to go up while insulin is low?

Insulin, no matter how high it is, will start to go down when we stop eating. The longer we fast, the lower it will go. Each person’s baseline will be a little different depending mainly on their metabolic health and their body fat stores. The more efficient the metabolism is at using fat for fuel—the more insulin sensitive, the lower insulin will go. But also the lower the body fat stores are, the lower insulin will go. On the flip side, the more insulin resistant and the fatter we are, the longer it will take for insulin to drop and the higher it will stay at baseline.

This is pretty shitty. I mean, as we develop insulin resistance, average insulin levels will become higher and higher. As a result we’ll store calories into our growing fat cells more and more easily, and will therefore become fatter and fatter, faster and faster. But fat cells also secrete insulin! So, the more fat cells there are, the higher the insulin levels will be, and the harder it will be to lower our basal insulin. To burn fat, we need to lower insulin levels. The fatter we are, the higher the insulin levels will tend to be. And the fatter we are, the harder it will be to lower insulin levels.

It’s a bit of a catch, but in the end, it’s not such a big deal because basically everyone who is overweight and who starts to fast and restrict carbohydrates melts their fat stores away very well. It works incrementally: insulin goes down a little, insulin resistance is reduced a little, fat-burning starts; insulin goes down a little lower, insulin resistance is further reduced, fat-burning increases; and on it goes, until we have lost all those extra kilos of fat that we were carrying on our body, be it 5, 15, 20, 35, 60 or even 100 kg of fat! It’s just a matter of time.

Now, after this little tangent on insulin and fat stores, we can come back to those anomalous points in the plot, the most conspicuous of which is the one just below 120 mg/dl of triglycerides but only 3 mUI/ml of insulin. Have you come up with an explanation? Here it mine:

That point is from one of my wife’s blood tests. It is unusual because it was done after 24 hours of fasting. My 24-hour fasting blood test done a number of weeks before, and my numbers were 41 for trigs at 2.3 for insulin. The difference between her and I was that I was already very lean, whereas she wasn’t. Therefore, as she fasted, her insulin levels dropped very low, and then the body started releasing its fat stores into the bloodstream in high gear. This is why her triglyceride levels were this high while her insulin was that low. It’s almost certainly the same for the other two points up there with trigs at 110 and 90 with insulin around 4 and 2.5 (the latter one of which is also my wife’s).

Since we did many of our blood tests around the same time, there are 9 data points from her on the plot. Several are in the centre of the main trend at insulin values between 6 and 7, but I’d like draw your attention to her lowest insulin value that was measured at 1.8, and at which time her trigs were at 57, and her lowest triglyceride level of 48, at which time her insulin was at 2.2. This shows that on average her values are a little further along the trend than mine are because of the small difference in body fat, but that she has good insulin sensitivity, and a well-functioning metabolism that can efficiently use fat for fuel.

The other off-trend point, but in the other direction on the right hand side, with insulin just above 10 and trigs around 65, is from my mother’s first blood test which I ordered and included insulin and trigs, before I got her off carbs. She was 82 at the time, eating a regular kind of diet, but not a very nutritious or varied diet with plenty of bread and cheese, because she had serious problems moving around and taking care of herself while still living alone. And so, it’s just the result of being older, having plenty of carbs, but not being highly insulin resistant nor highly overweight. Her baseline insulin levels were just generally higher because of her age and diet, but her trigs weren’t excessively high.

However, after just four days of intermittent fasting on a very low carb regime with most calories coming coconut oil spiked green juices and coconut milk smoothies, her insulin went from 10.3 to 4.7, and she lost 5 kilos, which, of course, were mostly from the release of water that the body was retaining to counter the effects of the chronic inflammation that immediately went down with the very-low carb regime and fasting.

Later, having sustained this strict green healing protocol for about 6 weeks, her numbers were at 2.9 for insulin and 56 for trigs. And by then she had lost another 5 kg, but this was now mostly fat. She had, at that point, recovered full insulin sensitivity, had lost most of her body fat stores, and overhauled her metabolism. She was 83 at that time, which shows that this sort of resetting of the metabolism can work at any age.

On this note, let’s conclude with these take-home messages:

First, the next time you get a blood test, request that insulin and triglycerides be measured, because it’s the only way to know what your fasting insulin actually is, and because it is very telling of your level of insulin resistance or sensitivity, overall metabolic health, as well as your average rate of ageing as we’ve seen in a previous post on insulin and the genetics of longevity.

Second, when you get the results back, you will be able to tell from your triglycerides concentration, in light of your insulin level, either how well the body is using fat for fuel—in the case you are already lean, or how fast you are burning your fat stores—in the case you still have excess body fat to burn through.

And third, resetting metabolic health can be done at any time and at any age, and is yet another thing that shows us how incredible our body is—the more we learn generally or individually, the more amazing it reveals itself to be.

Rejecting the lipid hypothesis with a cholesterol of 278 mg/dl and a smile

When it comes to evaluating how likely you are to have a heart attack, the most accurate diagnostic—the gold standard—is the calcium score. The reason why it’s the most accurate is because it’s calculated from an actual 3D image of the heart and the blood vessels around it. A computerised tomography (CT) scan is done, and from it the amount of plaque buildup in all the places where it appears because of the high density of the calcium it contains is measured and summed to give the total calcium score.

3d_image_of_my_heart

3D volume rendering of my heart seen from the top.

This is the closest thing we have to a direct measurement of the amount of plaque in the network of arteries around the heart. From doing this to thousands of people, we know that plaque usually begins to accumulate after the age of 35. Why isn’t the calcium score test done systematically on everyone above 40 in order to assess their immediate risk, but also to track their individual cardiovascular evolution, showing, with a reliable reference each year, how quickly or slowly arterial plaque is growing? Because it’s too expensive. Therefore, it’s only prescribed to people who are deemed to be at high risk based on other so-called “risk factors”. You know the list: overweight, sedentary, smoking, stressed, etc. But the clincher in this list of risk factors, the one factor that has pretty much eclipsed all the other ones, at least for the past few decades, is high cholesterol.

The focus on cholesterol was, over time, shifted to LDL, the “bad” cholesterol, and later on the ratio between it and HDL, the “good” cholesterol, terms introduced by the pharmaceutical industry to convince us that there is a battle between a good guy and a villain that must be stopped, which they can help with by providing us cholesterol lowering statins, even if with each passing year, the evidence exonerating cholesterol and lipoproteins from any wrong-doing in the genesis and progression of cardiovascular disease has been accumulating. Still, for people and for doctors, it’s really hard to overcome the several decades of conditioning we’ve suffered holding cholesterol as the main culprit for heart disease.

Fortunately, this knowledge and information have been shared and available for as long as the first experiments that set us on this damning direction in thinking and mindset. For my part, I first read a clear expose on the function of cholesterol and lipoproteins from Ron Rosedale over 10 years ago. Then I read it from Uffe Ravnskov, then from Anthony Colpo, then from Malcolm Kendrick who has and to this day continues to investigate the topic and share his findings on his blog, and then from Gary Taubes. All of this has taught me that cholesterol, HDL, and LDL, are not only not dangerous, but that they are essential and crucial for optimal health. This, I shared with you in late 2011 in But what about cholesterol? and shaped my diet to maintain good healthy levels: I restricted carbohydrates and polyunsaturated oils, and have gotten most of my calories from minimally processed saturated fats from grass fed animals fats, coconut oil, butter, and olive oil. In this endeavour to maintain strong cholesterol and lipoprotein levels, as you can see below, I have succeeded.

The following plot shows all the measurements of total cholesterol I have ever gotten made from blood tests over the past decade. What you can see is that in late 2007—a time before which I ate mostly complex carbohydrates and polyunsaturated seed oils while avoiding animal and saturated fats—my total cholesterol was below 150 mg/dl. Since then, it has been generally around or above 200 mg/dl with a slight upward trend over the years.

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My own total cholesterol levels in mg/dl measured from late 2007 to mid 2018.

If we look at the concentration of low and high density lipoproteins LDL and HDL, we also see consistently high levels, with LDL typically 10-30 mg/dl higher than HDL levels. Unsurprisingly, the same general shape and trend are is seen in these measurements as are seen in those of the total cholesterol.

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My own LDL and HDL levels in mg/dl measured from late 2007 to mid 2018.

Many of you have been reading this blog for a while, and I trust that you have therefore also known for a while that cholesterol is good for you, and that we should strive to have robust levels of HDL, LDL, and total cholesterol. Whether you have managed to overcome the conditioning we have all been subject to over our lifetimes about the purported but never-substantiated dangers of cholesterol and saturated fats, I cannot know. But I hope that I have at least helped a little in that respect.

In any case, I have for several years, every since I first read about the calcium score, wanted to get this test done, and see where I actually stood on the arterial calcification scale. I’ve never had fears or apprehension about it because even when I first read about it, I felt that I had a pretty good idea of the process by which cardiovascular disease evolved, and was following a regime that I knew would minimise the likelihood of atherosclerosis. But still, there is a big difference between having confidence that something is the case, and actually knowing that it is by seeing observational, quantitative, measured evidence for it. Finally, this spring, I was able to get a calcium score done.

I was very lucky to be referred to a young (45), well-informed, and open-minded cardiologist who also does research and has led trials on a group of several thousands of people who work at the Santander Bank campus near Madrid. He also happens to be the head of the cardiology imaging unit of the Clinical Hospital San Carlos in Madrid, a post he has held for more than 6 years now. So, he’s not just any cardiologist: he’s one of the best, and most importantly, one of the very best in cardiology imaging, which was exactly the purpose of consulting with him in the first place. I could not have been in better hands.

On our first appointment, after the initial conversation and questions regarding medical and health history, his assistant helped do an ECG, which looked “perfectly normal”, he said. Then he did the ultrasound with Doppler imaging that allows to see the heart pumping and the blood flowing with a colour coding of red and blue for the blood flowing away and towards the probe. To the trained eye of the imaging cardiologist, the Doppler ultrasound shows how the heart moves, how the cross-sections of the arteries pulsate with the heart beats, how the valves open and close, how flexible the tissues are, and how impeded or unimpeded the flow is. After a thorough examination, from one side and then from the other, he said everything looked very good.

At the end of the appointment he wrote a prescription for the CT scan to be able to get my calcium score, and another for a set of blood tests to which he willingly allowed me to request any additional one I wanted to have done. Before leaving the clinic, the assistant was able to arrange to have the blood test and the scan on the same day one week later: the blood test would be done in house first thing in the morning, and the scan would be done afterwards at the best medical imaging facility in the city.

The day before the scan, I read up on the test, how it’s done, how the measurements are made, and what the score means. I found out that, first, that the measuring of the amount of plaque buildup was done by eye, meaning that the experience and know-how of the cardiologist doing it was quite important. Second, I found out that the scale was not normalised like a scale from 1 to 10 or 0 to 100; that it was from 0 to whatever, which could be 400, 1000 or 4000. Although I was surprised and a little disappointed at first—we all love to get a score that can be immediately compared to everyone else’s, and gives us a sense of where we stand with respect to the rest of the population—I quickly realised that this made good sense given that it is not a relative but instead an absolute measure of plaque buildup in the arteries: naturally, this can go from no plaque to a little bit, to a lot, and to a ton of plaque. One could imagine estimating a maximum amount—say the amount needed to completely fill up the arteries—and use that as the normalising factor representative of 100%, and expressing every other result with respect to this. For now, this hasn’t been done, and the guidelines for interpreting your calcium score suggest values as follows:

  • 0 — No identifiable plaque. Risk: Very low, generally less than 5 percent.
  • 1 – 10 — Minimal identifiable plaque. Risk: Very unlikely, less than 10 percent.
  • 11 – 100 — Definite, at least mild atherosclerotic plaque. Risk: Mild or minimal coronary narrowing likely.
  • 101 – 400 — Definite, at least moderate atherosclerotic plaque. Risk: Mild coronary artery disease highly likely, significant narrowings possible.
  • 401 or Higher — Extensive atherosclerotic plaque. Risk: High likelihood of at least one significant coronary narrowing.

I got the blood test results back before the calcium score: everything looked good. Because most of my blood markers have been stable for years, especially the metabolic markers related to glucose and fat metabolism, the ones I am most interested in are those I need to monitor: things like B12, folate, homocysteine, and D, all of which need to be controlled and their levels adjusted with supplements; those that show my hormonal status, especially for the thyroid and sex hormones; and finally the markers of systemic inflammation which should always be as low as possible. The cholesterol panel is the one that for me has the least importance. But we are here considering cholesterol and lipoproteins in relation to cardiovascular risk assessed by means of the calcium score. So, these were the measured values: total cholesterol was 278 mg/dl, HDL was 122 mg/dl, LDL was 145 mg/dl, VLDL was 11 mg/dl (ref: <40), lipoprotein(a) was 4.40 mg/dl (ref: <30), and the ratios of total/HDL and LDL/HDL labelled atherogenesis indices were 2.28 (ref: <4.5) and 1.19 (ref: <3.55), values which are all deemed very good, of course.

A few days later I got my calcium score back. What do you think it was? You know I’m currently 45 and that calcification begins to grow after the age of 30-35, and has definitely progressed by the age of 40. You also know that—from what we are told by most doctors and health authorities—that plaque buildup and calcification is an inevitable part of ageing, that no matter what we do or eat or not eat, even if we might be able do things to slow it down, plaque accumulates and calcification progresses in only one direction: upward and onward. With this in mind, what would you guess my calcium score was?

My calcium score—based on 3D imaging of the heart and the region around it, and calculated by the one of best imaging cardiologist in Spain—was 0. It wasn’t 10 or 20. It wasn’t even 1, or 2, or 3. It was zero.

In our scientific training we learn that theories can never be proven—that they can only be disproven, and that hypotheses can never of accepted—that they can only be rejected. We also learn that to disprove or reject a theory or hypothesis, what is needed is a single contradicting piece of evidence, a single contradicting observation. The lipid hypothesis—that elevated blood cholesterol leads to atherosclerosis of the arteries, and that therefore decreasing blood cholesterol concentration significantly reduces cardiovascular risk—has been ingrained into our psyche more solidly than almost anything else that we collectively believe. But faced with this evidence, even if it is from one person only, of having maintained “elevated” fasting cholesterol levels consistently for a decade while in spite of this having gotten a perfect calcium score at the age of 45, the hypothesis must surely be rejected.

Even if we didn’t have any other evidence at all, according to the scientific principle that one contradicting piece of evidence is sufficient to reject a hypothesis, this single instance of my history of high total cholesterol together with a calcium score of zero is enough to reject the hypothesis that having elevated blood cholesterol levels over a long time leads to atherosclerosis and therefore to cardiovascular disease.

And we can be sure I’m not the only one. In fact, I’m willing to bet anything that most people in the low carb community who have been low carbers for as long as I have will have high cholesterol levels and low calcium scores. But still, to change the mindset of several generations of doctors, journalists, and people everywhere—hundreds of millions of educated people conditioned from decades of misinformation—will take years, probably decades. That’s how we are as social animals: stubborn in our beliefs.

In any case, I hope you, at least are, if you weren’t already, are now convinced that having high cholesterol does not cause atherosclerosis. Are you now curious to find out what your calcium score is? If you do get it done, please share.

For my part, I feel even more confident than I did. Even if I assured you more than five years ago in the spring of 2013 in At the heart of heart disease that you could be entirely free from cardiovascular disease by following some basic guidelines I listed regarding our eating, drinking, and living habits, there is nothing like observational evidence. And now we have it.

Case study: B12 deficiency, rapid weight loss, protein in the urine, osteoarthritis, elevated vitamin D

Just last week, a friend of mine wrote me this:

My mom has not been well.  Not eating well, massive head ache, lost a lot of weight.  Blood test results yesterday showed that she’s B12 deficient;  urine, however, has too much protein.  Any idea why?

I suppose, since he asked me, it most likely meant her MD didn’t offer an explanation for the test results.  One this is sure, neither she nor he knew what to do.  My feeling is that he asked just in case I knew anything that could help. And I did. So, I did.

Let’s go through the analysis together:

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Is it normal to have protein in the urine?  What is supposed to be excreted in the urine?  What organ regulates what goes and what doesn’t go into the urine?  Under what circumstances would protein end up in the urine?

From a biological standpoint protein is precious.  From an evolutionary standpoint protein is hard to come by and hence relatively rare.  Therefore, the body has evolved to use and keep as much protein as it can.  The urine is intended to excrete uric acid, which is the main acid produced by metabolic processes.  Urine is excreted through the urethra, it is stored in the bladder, and it is produced by the kidneys, which filter the acids out of the blood.  The kidneys try to prevent large molecules like amino acids and glucose from going through into the urine.  The solids in the blood are separated from the water, the acid is filtered out of it, and depending on the state of hydration, more or less water is used to make urine or returned back to the blood.  The only circumstances under which protein would end up in the urine are 1) that the kidneys are not working properly, and unable to filter the protein out of the blood, 2) that there is a serious excess of protein in the blood, or 3) that there is both kidney dysfunction and excess amino acids in the blood.  We’ve explored kidney function in great detail before in The kidney: evolutionary marvel, and this understanding comes from there.

This means we already know that his mom either has kidney disease, that there is too much protein in the blood, or both.  But he wrote that she had lost a lot of weight.  Losing weight can be due to fat loss, muscle loss, or both.  Usually, very rapid weight loss in the elderly is not voluntary, and almost always means rapid loss of fat and muscle.  Therefore, for sure, the protein in the urine was the result of a the fast weight loss with rapid breakdown of muscle tissue.

But why?  Why would she all of a sudden start losing weight so fast?  What could have happened or triggered this?

Well, he also wrote that she was found to be B12 deficient.  And if this was recognized by the conventional MD who ordered the tests, you can be sure B12 levels were very low: surely below 200 pg/ml.

Do we become B12 deficient all of a sudden?  Or do B12 levels decrease slowly and gradually over the years?  Can we even become B12 deficient all of a sudden?  Why do we become B12 deficient in the first place?  And why is B12 important and relevant in this case?

It is possible to become B12 deficient all of a sudden.  This happens when our levels are marginally acceptable to start, and we receive a large dose of an anesthetic, before a surgery, for example.  Anaesthetic drugs deplete B12; and the larger the dose, the more severe the depletion.  But this is certainly not the majority of cases.

Most of the time, B12 levels decrease slowly and gradually over the years,  either from inadequate intake, or from compromised digestion.  In the younger population, it is usually from inadequate intake—as is the case for vegans and vegetarians.  In older adults, it is usually from compromised digestion—as is the case from the middle aged to the elderly, generally from a damaged gut and stomach cells that do not produce enough hydrochloric acid needed to break down the protein we eat.

As some of you will remember, we’ve also explored the importance and functions of vitamin B12 in B12: your life depends on it and more recently in Case Study: Homocysteine, B12, and folate.  Vitamin B12 is most important for its role in the nervous system: for healthy nerves and proper brain function.  But it is also an important anabolic nutrient essential in building and preserving muscle tissue.  Bodybuilders everywhere have been taking B12 supplements for at least 4 decades, exactly because it’s a potent natural anabolic.

Therefore, here is where our analysis leads us:

The most probable explanation is that his mother has been growing more and more deficient over the years, a B12 deficiency developed over several decades that just recently reached critically low levels. This triggered rapid weight loss that caused both the loss of body fat stores and the breakdown of muscle tissue.  The fat loss released streams of toxins that have been accumulating in the fat cells over years and years, and which caused the massive head aches from which she was complaining.  The muscle loss, the rapid breakdown of muscle tissue due to the extreme B12 deficiency, caused the kidneys to be overwhelmed and become unable to keep all these amino acids in circulation, and the protein therefore spilled into the urine.

My recommendation: B12 shots of 1 mg once a week for 10 weeks, and then of 5 mg once a month for the rest of her life.

 

The story doesn’t end here.  It turns out that she has osteoarthritis and she’s in pain.  Some time ago some friends of hers recommended taking vitamin D supplements, and so she did.  When she got her blood test done, her 25-OH-D was through the roof at 127 ng/ml.  If you’ve read our last post on vitamin K2 you will know that this is possibly the worst thing that someone with arthritis can do: high levels of D without correspondingly high levels of K2 will accelerate soft tissue calcification.  And since osteoarthritis is a disease of calcification, it will make everything much worse than it already is.  Naturally, I immediately recommend she stop taking vitamin D and start taking large doses of vitamin K2 as soon as possible, before something more serious like a stroke or a heart attack happens.

He sent me the blood tests, which I examined to get a better picture.  Interestingly, few markers were out of the reference ranges.  This is probably why nobody said anything other than to point out the obvious abnormalities: low B12, high D, and protein in the urine.

But in addition, what could be seen was that both urea and creatinine were near the top of their range, which is expected from rapid weight (muscle) loss, and the eGFR (the estimated glomerular filtration rate) was at the low end of the reference range, which is expected from compromised kidney function given the protein in the urine.  C-reactive protein was high but not super high.  This signals system inflammation, and is naturally excepted for someone with arthritis, as we also have seen together in the past (https://healthfully.net/category/arthritis/).  Lastly, calcium was also high, but nevertheless within the reference range, something we would expected for someone with high D and not enough K2.

 

I asked if she was taking medications, and she was.  Several different drugs among which were a statin drug to lower cholesterol, a malaria drug used to treat symptoms of arthritis, and a couple of high blood pressure drugs one that is a diuretic and forces the kidneys to excrete more water, and the other that is an angiotensin antagonist that blocks the hormone which tells the kidneys to retain water when hydration is inadequate.  I replayed my view that drugs typically always attempt to block some pathway, and prevent the body from doing something that it naturally does to protect itself.  And in this case, she should wean herself off all of these over a few weeks.

I also explained that one of the most serious side effects of statin drugs is that they cause muscle wasting, promoting muscle tissue breakdown.  Statins do this in everyone, but in the elderly who already have accelerated muscle breakdown, it can be very serious.

My final recommendations, beside coming off the various drugs gradually to avoid a shock to the body, were as simple as possible for an old woman to follow: high dose B12 shots, high dose K2 pills, and high dose Mg as L-threonate, plenty of water and salt each day, a low carb diet rich in animal fats and green veggies, and sodium bicarbonate in water first thing in the morning on an empty stomach.  We’ll see what happens.

 

Blood tests can be used very effectively as a window onto the inner environment of the body.  MDs tend to only pay attention to the markers outside the reference range that appear in bold on the print outs.  But the reference range is derived from the blood tests of the whole population, and the population is far from being optimally healthy, that’s for sure.  What we need are not reference ranges derived from a sickly population, but an understanding of how the body works, what its organs and systems are trying to do, and with that understanding, of what our blood markers should be … ideally. What they should be in the best possible case.

That’s what we have to aim for.  And that’s what we have to learn to do, because we certainly can’t rely on your average MD to help us in this.  If you are an MD, and you are reading this, you already know that you are not your average MD, and I’m pretty confident you also know that your patients are lucky to have you.

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Reversing calcification and the miracle of vitamin K2

Vitamin K2 is the only known substance that can stop and reverse soft tissue calcification.

If you didn’t stop at the end of that sentence to say Wow to yourself, you should keep reading.

Soft tissue calcification is one of the most serious health problems we face as individuals, as modern societies, and, on a global scale, as a species.  Cardiovascular disease—which leads to heart attacks and strokes, and accounts for nearly half of all deaths in industrialised countries—is a disease of soft tissue calcification: the calcification of our arteries.

Arthritis, of which basically everyone past the age of 40 suffers, and increasingly more with time and with age, is a disease of soft tissue calcification.  It is caused by the calcification of the cartilage in the joints:  the joints of the knees, but also of the shoulders; the joints of the hips, but also of the wrists; the joints of the elbows, but also of the feet and the toes; the cartilage between the vertebrae of the neck and the spine all the way down the back, but also of the hands and of the fingers.

Soft tissue calcification also causes kidney stones and kidney disease.  How many people above the age of 60 don’t have kidney problems?  Hardly any.  And how many young men and women in their 20s and 30s already have kidney stones and kidney dysfunction?  More and more every year.

Every one of the processes generally associated with ageing, from heart disease and stroke, to Alzheimer’s and dementia, to arthritis and kidney disease, to stiffness in the joints and muscles, but also to the wrinkling of the skin, is intimately linked to soft tissue calcification.

And now, let me repeat the sentence with which we opened:  Vitamin K2 is the only known substance that can stop and reverse soft tissue calcification.  It is really remarkable.

Maybe you didn’t know about calcification.  And so, maybe you are wondering why it is such a major and widespread problem, why it affects everyone no matter where we are or what we do.  It’s a good question.  But because we know that only vitamin K2 can prevent this from happening, we already have our answer:  soft tissue calcification is a major and widespread problem because our intake of vitamin K2 is inadequate to provide protection from calcification.

Naturally, the next question is why?  Why is our intake of vitamin K2 so inadequate?  If it is such a crucial essential nutrient, we would surely not be here as a species if intake had always been so inadequate.  Looking at things the other way around, if we are so dependent on adequate K2 intake for staying healthy, this must necessarily mean that we evolved having plenty of it in our food supply.  What’s so different now?

To answer this question with some level of detail—meaning with an explanation more extensive than just saying that it’s industrialisation that stripped our food supply of vitamin K2 as it has for all the essential nutrients to a greater or lesser extent—we have to understand what K2 is, how it’s made, and where it’s found in food.

The short answer is that K2 is found in the fat of pastured animals that graze on fresh green grass, and produced from vitamin K1 by certain kinds of bacteria in their gut.

The longer answer is that vitamin K2 is a family of compounds called menaquinones, ranging from MK-4 to MK-13 depending on their molecular structure.  These compounds are derived from the plant analog, the sister compound, vitamin K1, called phylloquinone, and found in chlorophyll-rich plant foods.  Phylloquinone is consumed by the pastured animal, it makes its way into their intestines, and there it is transformed by the bacteria of the animal’s intestinal flora.  The resulting menaquinone is then stored in the fat cells of the animal as well as in the fat of their milk if they are milk-producing.  Consuming these animal fats in which vitamin K2 has been concentrated will provide this precious essential micronutrient.

If the grazing animal does not feed on green grass, they get no vitamin K1.  If they get no vitamin K1, their gut flora is not only compromised and negatively altered with respect to what it should be if they were consuming the grass they have evolved eating, but it produces no vitamin K2.  If their gut flora produces no vitamin K2, their fat and milk will contain no vitamin K2, and neither their offspring nor any person consuming products derived from the animal will get any vitamin K2.  Hence, no grass feeding, no vitamin K2 in the animal’s fat.

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It is most natural that grass-eating animals should be grazing on fresh green grass in open pastures.  And yet, it is rather rare.  But without green grass, there is no vitamin K1.  And without vitamin K1 there can be no vitamin K2.

Maybe you’ve already thought ahead, and wondered since it is bacteria that produces vitamin K2 from vitamin K1 in the guts of grazing animals, can’t we make vitamin K2 without the need for grass-fed animals to do it for us?  Yes, it is possible.  Fermented vegetables and dairy products like cheese can also contain vitamin K2.  In fact, in the case of cheese, there is a lot more in the finished hard cheese than in the milk used to make it.  The amount varies widely because it depends on the kind of bacteria.  For dairy products, hard cheeses like Gouda have the most, and for plant foods, even if fermented veggies have a little, the Japanese fermented soybean snack natto is the ultimate source of K2.

As we all know, pastured meat and dairy is not easy to come by in our modern world.  It’s actually quite hard to find.  Our supermarkets and food stores are flooded with industrially produced meat and dairy from animals that have never seen a blade of grass—grass-grazing animals living their entire lives indoors, in stalls, fed and fattened exclusively on grains, corn, and soybeans.  This is how we have stripped our food supply of vitamin K2, and this is why is this a modern phenomenon—most of our grand-parents were still eating pastured meats and animal foods.

And if this wasn’t enough of a blow to vitamin K2 status, trans-fats, which are formed when vegetable oils are hydrogenated to be made saturated and stable (for long shelf life), and which most of us consume in great quantities, contain a K2 analog called DHP (dihydrophylloquinone) that displaces the little K2 that might has found its way into our diet.

It is for all these reasons that soft tissue calcification is so widespread.  And you have at this point what you need to know in order to first stop the process by which your soft tissues are getting increasingly calcified, and then, in time, to remove the accumulated calcium from these tissues.  It’s simple: healthy grass-fed animals produce yellow butter, yellow yolks, and yellowish fat;  you need to eat plenty of pastured animal foods, making sure you eat the fat in which vitamin K2 is concentrated, and, to be sure you have enough to reverse the already present calcification, take K2 supplements.  And this might be enough for you.

If it is, you can head to your browser to find and order some K2 supplements (I currently get mine, it’s a 500 mcg per tablet, from Phoenix Nutrition).  Also, we need to know that the two main forms of K2 are MK-4 (with four double bonds) and MK-7 (with seven).  The first is the one generally found in animal fats that haven’t been fermented, while the second is the product of bacterial fermentation.  Hence, meat and butter contain mostly MK-4, whereas natto, sauerkraut, and cheese contain mostly MK-7.

There is an important difference between these two forms of K2 in terms of their effects inside the body which has to do with their half-life, not in the sense of radioactivity, but in the sense of duration of biological activity in the body.  MK-4 will be in circulation at therapeutic doses for a number of hours, while MK-7 remains in circulation between 24 and 48 hours.  Therefore, to be safe, we need to eat grass fed meat and butter, and take MK-7 supplements (I take 1000 mcg), always after a meal with plenty of fat to maximize absorption.

If you are curious to find out more, if you want to know how menaquinone does this, how vitamin K2 does its miracles inside the body, then we need to take a closer look at the biochemistry of calcium metabolism.

There are three proteins found in bone matrix that undergo gamma-carboxylation via Vitamin K-dependent enzymes: matrix-gla-protein (MGP) (Price et al., 1983), osteocalcin (bone gla-protein, BGP) (Price et al., 1976), both of which are made by bone cells, and protein S (made primarily in the liver but also made by osteogenic cells) (Maillard et al., 1992) (Table V).  The presence of di-carboxylic glutamyl (gla) residues confers calcium-binding properties to these proteins.

MGP is found in many connective tissues and is highly expressed in cartilage.  It appears that the physiological role of MGP is to act as an inhibitor of mineral deposition.  MGP-deficient mice develop calcification in extraskeletal sites such as in the aorta (Luo et al., 1997).  Interestingly, the vascular calcification proceeds via transition of vascular smooth muscle cells into chondrocytes, which subsequently hypertrophy (El-Maadawy et al., 2003).  In humans, mutations in MGP have been also been associated with excessive cartilage calcification (Keutel syndrome, OMIM 245150).

Whereas MGP is broadly expressed, osteocalcin is somewhat bone specific, although messenger RNA (mRNA) has been found in platelets and megakaryocytes (Thiede et al., 1994).  Osteocalcin-deficient mice are reported to have increased bone mineral density compared with normal (Ducy et al., 1996).  In human bone, it is concentrated in osteocytes, and its release may be a signal in the bone-turnover cascade (Kasai et al., 1994).  Osteocalcin measurements in serum have proved valuable as a marker of bone turnover in metabolic disease states.  Interestingly, it has been recently suggested that osteocalcin also acts as a hormone that influences energy metabolism by regulating insulin secretion, beta-cell proliferation, and serum triglyceride (Lee et al., 2007).

These are the first three paragraphs of the chapter Noncollagenous Bone Matrix Proteins in Principles of Bone Biology (3rd ed.) which I found it on the web when I was searching for more info on the biochemical action of menaquinone.

And now, here is my simple explanation of how things work:

The players are the fat-soluble vitamins A, D, and K2;  three special proteins called osteocalcin, matrix gla protein, and protein S;  and an enzyme called vitamin K-dependent carboxylase.

First, vitamin D makes calcium available by allowing its absorption from the intestines into the bloodstream.  This is vital for life and health.  You know that severe vitamin D deficiency is extremely dangerous and develops into the disease that deforms bones called rickets.  Milder forms of vitamin D deficiency are much harder to detect without a blood test, but can and do lead to a huge spectrum of disorders and health problems.  However, without vitamin K2, ample or even just adequate levels of vitamin D will inevitably lead to increased soft tissue calcification.

Vitamins A and D make bone-building cells (osteoblasts) and teeth-building cells (odontoblasts) produce osteocalcin (also known as bone gla protein or BGP) and matrix gla protein (or MGP).  This is key because it is these proteins that will transport the calcium.

Vitamin K2, through the action of the vitamin K-dependent carboxylase enzyme, activates bone and matrix gla proteins by changing their molecular structure which then allows them to bind and transport calcium.

Once activated, bone gla protein brings calcium (and other minerals) into the bones;  and matrix gla protein takes calcium out of the soft tissues like smooth muscle cells of arteries, but also organs, cartilage, skeletal muscles, and skin.  Without this K2-dependent activation, BGP and MGP remain inactive, and the calcium accumulates in soft tissues all over the body.

What completes the act, is that vitamin K2 activates protein S which oversees and helps the immune system clear out the stuff of arterial plaques that remains once the calcium making the plaques structurally stable has been taken out.  And, amazingly, protein S does this without triggering a large inflammatory response.

Even though it is quite straight forward when explained in this way, this understanding of vitamin K2 and its action in the body is really quite recent: in the last 20 years or so.  For one thing, it was only 10 years ago that Chris Masterjohn solved the 60-year old mystery of Weston A. Price’s X-Factor, correctly identifying it for the first time as vitamin K2. (You can read that for yourself here.)  And although some laboratory studies and experiments on vitamin K were done several decades ago, the majority are from the last 10 years (take a look at the references in Masterjohn’s paper.)

We’ll stop here for now.  But we’ll come back to vitamin K2 because there are so many other amazing things it does for our health.

This article was inspired by Dr. Kate Rheaume-Bleue’s book entitled Vitamin K2 and the Calcium Paradox.  If you think it could be useful to others, please Like and Share it.

Ten years of carbohydrate restriction: here’s why

It was almost exactly ten years ago, in March 2008, that I read Ron Rosedale’s Insulin and Its Metabolic Effects.  I now know that this is surely the one thing I’ve read that has had the most impact on my life. Rosedale’s presentation was a total revelation to me:  I had never read anything about insulin before, and his explanations of the biochemical and physiological functions and effects of insulin on the body all made perfect sense in and of themselves, but also appealed to my appreciation and reliance on complete explanations that are consistent with the facts we can observe about them.  I eliminated insulin-stimulating carbohydrates from my diet overnight.  That was that.

We were then still vegetarian at home.  Hence, the family breakfast, following Mercola’s example, became smoothies made of raw, local, pastured eggs with berries and stevia.  That lasted quite a while.  I always travelled with my hand blender and stevia, brought eggs if it was for short trip, or scouted out places to get good ones when the trip was longer.  Throughout a summer trip along the American west coast, I made our raw egg smoothies every day, in hotel rooms and campgrounds.

At one point, I discovered coconut oil and coconut milk.  The breakfast smoothies evolved to being made of eggs and coconut milk with berries, and eventually only coconut milk, berries and stevia.  This period lasted several years until we moved on to cold pressed green juice with coconut milk; it was two thirds juice and one third milk.  We also did this for several years until about two years ago when our son left for university, at which point we dropped having breakfast entirely to allow for a daily overnight fasting period of about 16 hours from after dinner to lunchtime.

 

Food intolerance testing in 2014 showed that all three of us were intolerant to eggs; we removed them from our diet.  My wife and I had the most and our son the least intolerances; this was not surprising given we were a lot older than him.  It also showed my wife and I were intolerant to most dairy products; we removed them from our diet.  We were also intolerant to grains: both highly intolerant to wheat, and then I, in addition, somewhat less so to barley, malt, and quinoa—we ate quinoa almost daily for years as our son was growing up.  He, although not intolerant to dairy or wheat, was intolerant to almonds, pistachios, and brazil nuts. (Here are my test results, if you’re interested.)

Imagine: vegetarian for 20 years, with a diet during these two decades from teenage hood to middle adult hood consisting primarily of wheat and grain products, beans, cheese and yogurt, eggs and nuts.  Of course, also plenty of sweet fruit, starchy vegetables, and salads, as with is true for most vegetarians.  But the bulk, both in volume and in calories, was from grain products, cheese, and eggs.  The shocker for me was that the food intolerance test painted the profile of a meat-eater:  if you remove grains, dairy, and eggs, what is left is animal flesh, vegetables and fruits.

If now, in addition, you remove fruit and starchy vegetables to avoid insulin-stimulating carbohydrates, all that is left is animal flesh and green vegetables.  That’s just how it is.  We also used to eat almonds—the richest in magnesium, and brazil nuts—the richest in selenium, almost daily.  But because our son was intolerant to both and I was intolerant to brazil nuts, we removed those from our diet as well.

IMG_2275

 

These were all food intolerances; they were not allergies.  But they were nonetheless intolerances, some stronger, some weaker.  If you are concerned about health in the sense of being in the best state of health you can, then obviously you must not eat foods to which you are intolerant.  Otherwise, your immune system is triggered each time the offending molecules in those foods enter the gut and bloodstream.  This gradually but inevitably makes the intolerance greater, your system weaker, and body sicker.

Over these ten years, I’ve read quite a few books, articles, blog posts, and detailed discussions about health-related matters.  I’ve also experimented quite a bit with my own diet, and learned a great deal from that.  The other thing I’ve done a lot of, is have conversations with people about diet, nutrition, diseases, and the metabolic effects of different foods and of insulin.

My position—which has only grown stronger with time—is that the first and most fundamental pillar of optimal health is having a metabolism that runs on fat.  And this means keeping insulin levels low by restricting sugars and starches.  Not necessarily always, but most of the time, as in almost always.

The first question that people ask when they find out is why: Why do you not eat bread? Bread has forever been essential to humans.  I simply couldn’t live without bread.  Or, why don’t you eat potatoes, or rice, or pasta?  They’re so good!  I simply couldn’t live without potatoes and pasta.  And, you don’t even eat fruit? But isn’t fruit full of vitamins and minerals?

The way I have answered has depended on a lot of things: the setting, the atmosphere, the company, the time available, but most importantly on the person.  Some people are actually interested to find out, and maybe even learn something.  Most, however, are not.  Consequently, I have made the answer shorter and shorter over the years.  Now, I even sometimes say: well, just because, and smile.

Maybe you have wondered, or even still wonder why.  Maybe although you’ve read so many times in my writings that I think everyone seeking to improve their health should restrict insulin-stimulating carbohydrates, you still wonder what the main reason is, what the most fundamental reason for which I don’t eat sugars and starches.  Here’s why:

 

It’s not primarily because carbs and insulin make us fat by promoting storage and preventing the release of energy from the ever larger reserves of fat in our body: I am lean and always have been.

It’s not primarily because carbs and insulin lead to insulin resistance, metabolic syndrome, and diabetes; inflammation, dyslipidemia, water retention, and high blood pressure; kidney dysfunction, pancreatic dysfunction, and liver dysfunction: my fasting glucose, insulin, and triglycerides have been around 85 mg, 3 mili units, and 40 mg per dl for years; my blood pressure is 110/70 mg Hg, glomerular filtration rate is high, and all pancreatic and liver markers are optimal.

It’s not primarily because carbs and insulin promote cancer growth since cancer cells fuel their activity and rapid reproduction by developing some 10 times the number of insulin receptors as normal cells to capture all the glucose they can, fermenting it without oxygen to produce a little energy and tons of lactic acid, further acidifying the anaerobic environment in which they thrive.  My insulin levels are always low, and my metabolism has been running on fat in a highly oxygenated alkaline environment for a decade.

It’s not primarily because carbs and insulin promote atherosclerosis, heart disease and stroke by triggering hundreds of inflammatory pathways that compound into chronic inflammation and damage to the blood vessels, which then leads to plaque formation and accumulation, restriction of blood flow, and eventually to heart attack and stroke: my sedimentation rate, interleukin-6, C-reactive protein, and Apolipoprotein-A are all very low.

It’s not primarily because carbs and insulin promote the deterioration of the brain, dementia, and Alzheimer’s, both through the damage to blood vessels around and in the brain itself, and insulin resistance of brain cells, which together lead to restricted blood flow, energy and nutrient deficiency, and accumulation of damaging reactive oxygen species and toxins in the cells, and, unsurprisingly, eventually to dysfunction that just grows in time: because my metabolism runs on fat, this means that my brain runs on ketones, and is therefore free of excessive insulin or glucose exposure.

It isn’t primarily for any of these reasons, which, I believe, are each sufficient to motivate avoiding sugars and starches in order to keep tissue exposure to glucose and insulin as low as possible.

 

My main reason is that, at the cellular level, in its action on the nucleus and on gene expression, insulin is the primary regulator of the rate of ageing.

Insulin is essential for life: without insulin, cells starve and die. It is essential for growth: without insulin cells don’t reproduce, and there can be no growth.  This is why at that most fundamental level, insulin regulate growth in immature individuals.  But in mature individuals, once we have stopped growing, insulin is the primary regulator of the rate of ageing, both in terms of its effect in suppressing the production of antioxidants and cleansing and repair mechanisms within the cell, but also in stimulating cellular reproduction. And the more reproduction cycles, the greater accumulation of DNA transcription defects, the faster the shortening of telomeres, and the faster the ageing.

This is a fundamental fact that appears to be true for all living organisms.  It is as true for yeasts and worms, as it is for mice and rats, as it is for dogs and humans.  And the rate of ageing is the rate of degeneration, of growing dysfunction, of more damage and less repair, of lower metabolic efficiency and less energy, of increased cell death and senescence.  I personally wish to be as healthy, energetic, strong, and sharp as possible for as long as possible.  This is why I avoid sugars and starches.  This is why I restrict insulin-stimulating carbohydrates.

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How much water do you lose during a bath?

Have you ever wondered how much water you sweat out during a bath? Well, I often did. A few years ago, I had a very regular schedule in the morning because my wife and son had to leave early to make it to school in time.  I got up early to make the green juice for the three of us, but after they left at 7:30, I had plenty of time before going to work.

For a couple months during the winter, I had a bath twice a week.  They were therapeutic baths: I was correcting a long-standing whole body magnesium deficiency from decades of intense physical exercise without ever supplementing with Mg, or anything else for that matter.  I was curious to know, and so I tried to remember to weigh myself before and after each bath, and write that down.  I did it for a while, but I forgot everything about it.

A couple of days ago I did a complete cleanup of my closet, and found the little piece of paper on which I had written all the measurements.  I thought it would be fun to share that with you.

I tried to stick to the same conditions in terms of drinking and peeing, but I wouldn’t call it a tightly constrained scientific experiment. I made 15 measurements of my weight before and after soaking in the bath at about 45-47 C for approximately 45 minutes, and calculated the difference:

  1. 59.6  58.9  0.7
  2. 59.5  58.9  0.6
  3. 59.6  58.8  0.8
  4. 60.3  59.8  0.5
  5. 59.6  58.8  0.8
  6. 60.1  59.5  0.6
  7. 59.6  58.9  0.7
  8. 60.0  59.4  0.6
  9. 60.4  59.6  0.8
  10. 59.4  58.9  0.5
  11. 59.9  59.3  0.6
  12. 60.9  60.3  0.6
  13. 60.6  60.1  0.5
  14. 60.6  60.0  0.6
  15. 60.5  59.9  0.6

This is what the distribution of the differences looks like:

histo-diff

Frequency distribution of difference in body weight before and after bath. (The digital scale had one digit, and assuming the precision on each measurement is half that (0.05 kg), this would make the combined uncertainty on each calculated difference the square root of twice the square of that, and hence 0.07 kg.)

Given that there are various trends in our weight from day to day that depend on a wide range of factors, only the difference between the weight before and after the baths is important for us here. But because they all have the same uncertainty, it has no effect on the mean, which turns out to be 0.63 (9.5/15); the variance, which turns out to 0.01; and the error on the mean, which turns out to be 0.03. Hence the mean difference in weight before and after is 0.63 +/- 0.03 kg.

There would have certainly been variations in the temperature of the water, which could account for the variations in the before and after differences ranging between 0.5 and 0.8 kg. We could say that the hottest baths resulted in a water loss of 800 ml, whereas the more moderate temperatures caused a loss of 500 ml. In any case, as we said, the average of the 15 measurements is 0.63 kg, and this equates to 0.63 litres or 630 ml of water.

I think it is reasonable to consider this is in terms of the fraction of water loss with respect to body weight, which for me at the time would have been equivalent to about 1% of body weight. This is probably not precisely the case, but a good guideline to follow: if you weighed 80 kg, you should consider that a 45 minute bath would cause you to lose about 800 ml of water; if you were 100 kg it would cause you to sweat out a full litre.

And so, that’s it. The answer to the question of how much water we lose during a bath—or actually more specifically, during a bath in which the water is around 45 C, and in which we soak for 45 minutes, and in which we have dissolved 1 cup of baking soda and 1 cup of magnesium chloride—is about 1% of our body weight.  Very easy to remember.

Therefore, ideally, we would be sipping cool alkaline water throughout the bath to make up for that loss and minimize the dehydrating effects of that much sweating.

Have you ever done this on your own: weighed yourself before and after a bath to see how much water you lost? If you have, I’d be very curious to know what you found. If you haven’t but are intrigued, and want to do it, please go ahead and let us know.

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