If you're like most people, you spend your entire day at a desk and 3-4 hours a week at a gym trying to combat the negative effects associated with sitting at that desk. As time has gone on, you've probably also noticed a reduced ability to maintain your body weight as well as increased risk markers for cardiovascular disease and other chronic diseases. Even when you double up the amount of time you exercise per week for your New Years' resolution your results get worse each year, leading to year over year increases in fat mass. The reason this happens is not because you don't exercise enough, it's because you spend too much time sitting. Sedentary behavior leads to modified genetic expression that promotes fat gain and cardiovascular disease, and no amount of exercise at a gym will prevent that. When you look at the grand scheme of things, even if you exercise intensely for 16 hours a week that still leaves 152 hours per week where the wrong genes are turned on. Don't believe it? Let's take a look at some of the research.
High levels of sedentary behavior are associated with the metabolic syndrome, independent of other factors related to the metabolic syndrome including moderate to vigorous physical activity(Alcohol intake, smoking status, age, gender, diabetes and heart disease)(1, 2). This means that getting physical activity via exercise did not compensate for the amount of time spent being sedentary. The amount of sedentary time also has a strong positive relationship with triglyceride levels as well as waist circumference and waist to hip ratio. High levels of sedentary time also lead to higher circulating levels of insulin(3, 4, 5, 6, 7, 8), impaired glucose clearance(3, 7, 8) and impaired fatty acid metabolism(5, 7, 8). While a couple of these studies were done with people on multiple days of bed rest and therefore not directly comparable to people sitting at a desk day in and day out, most of these changes with insulin action and glucose appear to be a result of changes in localized gene expression due to a lack of muscular contraction(7). In fact, as discussed in Part 2a of my 3 part series "Myths, Metabolism, and Appetite" (Part 2a), it may actually be whether or not the leg is loaded, regardless of muscular contraction. Unloading one leg while still allowing movement of that leg for 48 hours leads to altered genetic expression that increases protein breakdown and anti-oxidant pathways (Indicating increased oxidative stress) while reducing mitochondrial metabolism with no change in gene expression in the other leg(9). This reduction is mitochondrial metabolism is probably the mechanism by which fatty acid metabolism is reduced during sedentary periods. These changes persisted even after 24 hours of reloading the leg.
When we look at who is most affected negatively by sedentary behavior from an insulin sensitivity perspective, it appears that healthy people are more negatively impacted than people prone to Type 2 Diabetes (T2D). In a study that looked at bed rest and changes in insulin sensitivity with healthy people as well as people with first degree relatives with T2D (FDR)and those with low birth weight, two risk factors for T2D, the healthy subjects experienced a greater drop in insulin sensitivity (5). The authors hypothesize that this effect is due to the other two groups already having some degree of insulin resistance. In another study comparing insulin sensitivity changes in healthy subjects to FDR, whole body insulin sensitivity declined in both groups but hepatic (Liver) insulin sensitivity declined only in the FDR group. This is interesting because as discussed in "Myths, Metabolism, and Appetite", people who are prone to T2D and FDR of T2D have fewer type I fibers and a higher proportion of type IIx muscle fibers. This is, in part, a gene environment interaction.
While the more oxidative (Fat burning) type I fibers have not been shown to convert to other fiber types, the more glycolytic (Glucose burning) type IIa and IIx fibers tend to convert back and forth based on recruitment of said fibers. Lack of use causes IIa fibers to convert to IIx fibers which are more insulin resistant while regular recruitment of IIx fibers causes them to convert to IIa fibers. In people with a higher percentage of type II vs. type I muscle fiber types that also do not recruit these fibers regularly, most will become insulin resistant as more of their musculature converts to the insulin resistant type IIx fibers. People with this genotype probably have to participate in regular strength training to recruit the insulin resistant IIx fibers enough so that they convert to the less insulin resistant IIa fibers, particularly if they intend to consume a high carbohydrate diet. Coincidentally, converting IIx fibers to IIa fibers allows these people to store more muscle glycogen. Emptying out these glycogen stores with regular, intense strength training will provide a larger storage compartment for ingested carbohydrate and delay hepatic insulin resistance. Ironically enough, people with this genotype tend to be the better power sport athletes so it seems that modern life is just not compatible with this genotype. My guess is they would also have been the best hunters which could indicate why such a high percentage of the population is prone to T2D from an evolutionary perspective.
Another interesting aspect of sedentary behavior is it's effects on lipoprotein lipase(LPL) activity. LPL is an enzyme responsible for triglyceride breakdown. Reduced LPL activity leads to higher blood triglycerides via a reduced ability to metabolize fat. Obviously conditions that lead to a reduction in LPL activity are not ideal, especially if one of your goals is to reduce body fat. Sedentary behavior has been shown to dramatically lower LPL activity (6, 7) in the muscles of the leg and reducing sedentary behavior has been shown to have a greater effect on increasing LPL activity than does adding vigorous physical activity (7). This increase in LPL activity makes sense because the muscle fiber type associated with physical activity of lower intensities is the type I fibers that tend to rely more on fat as a substrate. As the intensity of your exercise increases, so does the utilization of glucose as fuel to power the type II fiber types during that activity. During both active and passive recovery there appears to be a switch to the type I fibers and a greater reliance on fat as fuel, perhaps to spare glucose for future intense activity.
Other genes and pathways associated with health are positively affected by breaking up periods of inactivity. One study identified 75 different genes differentially expressed during periods of inactivity vs. periods of activity used to break up inactive periods (8). Many of these genes are involved in processes that are known risk factors for cardiovascular disease. Breaking up periods of inactivity with periods of physical activity for 2 minutes every 20 minutes positively affected the expression of genes associated with carbohydrate metabolism, antioxidant pathways and anti-inflammatory pathways. Another study found breaking up periods of inactivity improved postprandial insulin and glucose concentrations when compared to a completely sedentary condition(9). While we have focused much of our attention on the localized effect of sedentary behavior on muscles and to a lesser extent the liver, there also appears to be a significant negative impact on the brain.
Increased sympathetic nervous system activity is a widely known symptom of obesity and T2D. The autonomic nervous system is in charge of regulating mostly involuntary processes and has two branches. The parasympathetic branch is responsible for rest and digest while the sympathetic nervous system is responsible for the fight or flight response. People with increased sympathetic nervous system activity have a problem getting out of stress mode, in other words they are in a constant state of stress. Research indicates that this increased sympathetic activity may be mediated by dysfunction in a part of the brain called the rostral ventrolateral medulla (RVLM)(10). The RVLM is the primary part of the brain involved in regulating sympathetic nervous system activity. Physical inactivity may have wide-ranging negative effects on the RVLM and this could explain the detrimental effects of sedentary behavior on measures of cardiovascular disease regulated by the autonomic nervous system such as hypertension. It is not known at this point if the difference between sedentary and active people is due to a negative effect of being sedentary, a positive effect of being active, or a combined effect of the two.
As you can see, being in a seated position for prolonged periods is a significant factor in poor health and an inability to metabolize fat. While insulin sensitivity and blood glucose utilization are two big factors impacting both, these are not the only considerations. The data suggests that sitting for long periods of time is terrible for your health and no amount of exercise at the gym can attenuate the bad effects of sitting. These effects may expand beyond the physical changes happening in the muscles and more than likely has deleterious effects on the brain.
EDIT: After I wrote this I found a new randomized clinical trial that looked at 3 groups (sedentary, sedentary+1 hour of intense exercise, and a group that spent half the time being sedentary and the other half standing or doing low intensity activity). Guess who "won". :)
Check it out.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055542
Thursday, February 14, 2013
Tuesday, February 12, 2013
Cholesterol Screening: A cost to benefit analysis
As more and more employers realize the importance of maintaining a healthy working staff, the number of companies participating in cholesterol screening as part of a risk assessment protocol has increased. There are obvious financial and ethical benefits to having happy, healthy workers. A happier worker is more productive and tends to cost less from a health insurance standpoint. The problem is, will cholesterol screening actually achieve that stated goal? In other words, if I put my worker bees through a cholesterol screening, will this save me some scratch? Let's explore this a little further.
The point of putting workers through a cholesterol screen is to identify those who are at risk for heart disease and/or future coronary events. Once identified, these people will be put on the appropriate therapy to ensure that they avoid experiencing the big one and needing the higher medical costs of dealing with the problem as it arises. In other words, we can all agree that an ounce of prevention is worth a pound of cure. However, let's see if that is actually what we are accomplishing.
Unless you have been hiding under a rock for the past several decades you have heard of statin drugs. Statin drugs are currently the standard of care for treating people with heart disease, despite there being no real evidence that they prevent heart attacks in anyone other than middle aged men who have already had a heart attack. In this very small sample of people, cholesterol screenings are unnecessary because these men are already on statins. For the remainder, let's take a look at what you are buying in to.
Let's say I have a large business with 1000 employees who are not currently on statins and they all sign up for cholesterol screening. The criteria for high cholesterol puts approximately 1 in 3 people in this group, so let's say 333 of your employees are diagnosed with high cholesterol. Most physicians will not prescribe a statin based solely on high cholesterol, so let's assume only 200 of your employees are recommended to take statin drugs. What can we expect to see in terms of results?
If you listen to the way these drugs are marketed, you would realize that statins reduce heart attack risk by 36%, but what does this mean in a way that is pertinent to our discussion? Probably the most clear cut way would be to look at a number that gives you the risk to benefit ratio. In the pharmaceutical world, this is referred to as the number needed to treat (NNT). The NNT is the number of people you would need to treat with the drug in order to prevent 1 person from experiencing the adverse event you are trying to prevent. In other words, in the case of statins, the NNT is the number of people you would need to treat to prevent 1 heart attack. When we look at this number, we get a much clearer picture of what we are getting. The NNT to prevent 1 heart attack varies between 70-250 people depending on the study you look at. When you take in to consideration that this NNT also includes people who have already had a coronary event, the NNT for people that will be undergoing cholesterol screening is closer to 1 in 250. In other words, 249 of the people you are treating with this drug are not benefiting from taking it. Furthermore, you would need to treat all 250 of these people for 5 years with the drug before you would prevent that 1 heart attack.
It is highly likely that every one of the 200 employees you have identified as candidates for statin therapy will receive no benefit from the drug, and you as well as they get to pay for that therapy. In addition, recent research has shown that statin therapy induces diabetes in 1 out of 200 people taking the drugs. So, while you have prevented zero heart attacks you have actually increased your healthcare costs by adding a diabetic to the payroll. By the way, people with Type 2 Diabetes have the same risk of heart attack or dying from heart disease as people who have already had a heart attack. Framed in that context, does that cholesterol screening really sound like something that is going to prove beneficial to your organization or does it seem more like a way to sell you something that is not really going to benefit you at all?
There is, of course, very large healthcare costs associated with someone experiencing a heart attack. You may even hear that spending all of that money treating people with a drug that is not benefiting them in any way may make sense when you look at the cost savings of preventing a heart attack. Ethical considerations aside, this benefit does not exist. High cholesterol isn't even a good indicator of future heart disease. The actual data shows that 50% of the people who die of heart disease have normal cholesterol. In other words, you are financing a screen that has the same likelihood of predicting a heart attack as a coin flip, and investing a large sum of money in it's ability to do that.
The point of putting workers through a cholesterol screen is to identify those who are at risk for heart disease and/or future coronary events. Once identified, these people will be put on the appropriate therapy to ensure that they avoid experiencing the big one and needing the higher medical costs of dealing with the problem as it arises. In other words, we can all agree that an ounce of prevention is worth a pound of cure. However, let's see if that is actually what we are accomplishing.
Unless you have been hiding under a rock for the past several decades you have heard of statin drugs. Statin drugs are currently the standard of care for treating people with heart disease, despite there being no real evidence that they prevent heart attacks in anyone other than middle aged men who have already had a heart attack. In this very small sample of people, cholesterol screenings are unnecessary because these men are already on statins. For the remainder, let's take a look at what you are buying in to.
Let's say I have a large business with 1000 employees who are not currently on statins and they all sign up for cholesterol screening. The criteria for high cholesterol puts approximately 1 in 3 people in this group, so let's say 333 of your employees are diagnosed with high cholesterol. Most physicians will not prescribe a statin based solely on high cholesterol, so let's assume only 200 of your employees are recommended to take statin drugs. What can we expect to see in terms of results?
If you listen to the way these drugs are marketed, you would realize that statins reduce heart attack risk by 36%, but what does this mean in a way that is pertinent to our discussion? Probably the most clear cut way would be to look at a number that gives you the risk to benefit ratio. In the pharmaceutical world, this is referred to as the number needed to treat (NNT). The NNT is the number of people you would need to treat with the drug in order to prevent 1 person from experiencing the adverse event you are trying to prevent. In other words, in the case of statins, the NNT is the number of people you would need to treat to prevent 1 heart attack. When we look at this number, we get a much clearer picture of what we are getting. The NNT to prevent 1 heart attack varies between 70-250 people depending on the study you look at. When you take in to consideration that this NNT also includes people who have already had a coronary event, the NNT for people that will be undergoing cholesterol screening is closer to 1 in 250. In other words, 249 of the people you are treating with this drug are not benefiting from taking it. Furthermore, you would need to treat all 250 of these people for 5 years with the drug before you would prevent that 1 heart attack.
It is highly likely that every one of the 200 employees you have identified as candidates for statin therapy will receive no benefit from the drug, and you as well as they get to pay for that therapy. In addition, recent research has shown that statin therapy induces diabetes in 1 out of 200 people taking the drugs. So, while you have prevented zero heart attacks you have actually increased your healthcare costs by adding a diabetic to the payroll. By the way, people with Type 2 Diabetes have the same risk of heart attack or dying from heart disease as people who have already had a heart attack. Framed in that context, does that cholesterol screening really sound like something that is going to prove beneficial to your organization or does it seem more like a way to sell you something that is not really going to benefit you at all?
There is, of course, very large healthcare costs associated with someone experiencing a heart attack. You may even hear that spending all of that money treating people with a drug that is not benefiting them in any way may make sense when you look at the cost savings of preventing a heart attack. Ethical considerations aside, this benefit does not exist. High cholesterol isn't even a good indicator of future heart disease. The actual data shows that 50% of the people who die of heart disease have normal cholesterol. In other words, you are financing a screen that has the same likelihood of predicting a heart attack as a coin flip, and investing a large sum of money in it's ability to do that.
Tuesday, January 22, 2013
Paleo and your microbiome
My guess is that most of you reading this blog realize how dramatically your life can change by switching to a Paleo Diet. Having worked in the fitness industry for 17 years I have not seen anything quite like it. Not only do people tend to lose a boatload of weight doing the diet, but many of the minor health maladies/aches and pains they have attributed to just getting old tend to fade away as well. What most people fail to realize is that these 2 improvements are not separate issues. They are also not mechanical in nature, you don't ache less because you have less weight to lug around. The reason for both are tied to the inner ecosystem known as your gut microbiome.
This past year has been a gigantic leap forward in human health. Epigenetics is picking up steam and being realized as one of the most important discoveries in human health ever while potentially revolutionizing the way we look at evolution. However, if this past year has had an MVP for health research, it is the gut microbiome hands down. From autism to autoimmunity to obesity to insulin resistance, changes in the gut seem to be dramatically affecting the way the human organism works. Whether we are talking about the gut environment itself or the bacterial species that inhabit it, having a healthy gut is crucial to human health. In fact, the gut is where most of your immune system lies and those bacterial species ferment the food you eat in order to provide your body with nutrients. So, what is the gut microbiome?
The gut microbiome refers to the make up of the bacteria in your gut. What most people don't realize is that you are more bacteria than human, about 10 times more bacteria than human. If you look at the number of genes a human has in relation to the number of genes contained in the bacteria that inhabit one, the microbiome contains 100x more. Given that the genes are what actually accomplish biological functions, the microbiome is pretty important stuff.
As we find out more about the way our bodies work, the way we approach certain things changes. New research as well as research that has been around for decades indicates that weight gain/loss isn't solely regulated by calories in vs calories out, also known as energy balance. For one, the magnitude of both calories in and calories out is highly variable based on what you eat, what you do, your genetic make up and you microbiome. Another issue is that in the absence of Lipopolysaccharide (LPS) induced sepsis, animals fed high fat or high calories diets don't tend to gain weight. Ironically enough, what you eat seems to be the most important factor here, both in terms of maintaining the integrity of the intestinal barrier as well as providing the bacterial diversity that is necessary for optimal health. In my opinion, the gut microbiome will help explain a lot of the things we don't currently understand in human health. Chief among them is weight loss.
When someone comes to me because they are having trouble losing weight on a Paleo diet, the first thing I look for is nutrients that may be compromising the gut lining either directly by causing inflammation or indirectly by changing the gut microbiome. Obviously I need to find out if this person is work week Paleo or 7 days a week Paleo. The problem with being work week Paleo is that every Friday after 5 through Sunday night they undo most of the healing they had done to their gut over the course of the previous 4.5 days. It would basically be like popping the stitches on a wound every 5 days, certainly not a winning strategy for wound treatment.
The next step is to look at the composition of their diet, specifically what veggies they are eating. One group of people that I red flag are those people who are Atkins circa 2002 Paleo. These people eat nothing but meat and often neglect both bone broth and organ meats, both necessary components of doing it that way. This is a problem because high fat diets tend to cause significant amounts of gut inflammation by changing the gut microbiome, something we are trying to avoid. However, it appears that it is not the high fat diet per se, but an absence of plant matter in the diet. Here is a rundown of that topic...
Human Food Project: An eater's guide to a healthy microbiome
Before we get in to how this may happen we should go over how bacteria spread in an environment such as your gut. If I have 2 petri dishes full of the same ratio of a diverse array of bacteria and introduce different fuel sources in to each they will quickly become drastically different from one another. This is because the bacterial species that consume the fuel source I introduce will multiply while the others will die off and be replaced with bacteria that can use that fuel. So, if I put a plant in one and meat in the other, we would eventually have completely different bacterial communities. Your gut operates in the same way. When you eat a purely meat diet, some of the beneficial bacteria that ferments plant material and heals your gut lining reduce in numbers, making it difficult to heal an already damaged gut. In addition, eating a diet devoid of plant material slows down the transit time of what you are consuming, allowing it to fester in your intestines long enough to cause some serious inflammation. The prescription...More plants in the diet.
Now that I have gone through all of that, I would like to announce that my Synergy Wellness Paleo Challenge Group will be participating in a challenge within the challenge. That's right, I plan on making next week Microbiome Diversity week with the ultimate goal of eating a minimum of 40 different vegetables during the week. If you are interested in getting involved, let me know. You don't have to do the challenge to be in the group, most people just use it as a way to get recipes and tricks to help them follow the diet.
This past year has been a gigantic leap forward in human health. Epigenetics is picking up steam and being realized as one of the most important discoveries in human health ever while potentially revolutionizing the way we look at evolution. However, if this past year has had an MVP for health research, it is the gut microbiome hands down. From autism to autoimmunity to obesity to insulin resistance, changes in the gut seem to be dramatically affecting the way the human organism works. Whether we are talking about the gut environment itself or the bacterial species that inhabit it, having a healthy gut is crucial to human health. In fact, the gut is where most of your immune system lies and those bacterial species ferment the food you eat in order to provide your body with nutrients. So, what is the gut microbiome?
The gut microbiome refers to the make up of the bacteria in your gut. What most people don't realize is that you are more bacteria than human, about 10 times more bacteria than human. If you look at the number of genes a human has in relation to the number of genes contained in the bacteria that inhabit one, the microbiome contains 100x more. Given that the genes are what actually accomplish biological functions, the microbiome is pretty important stuff.
As we find out more about the way our bodies work, the way we approach certain things changes. New research as well as research that has been around for decades indicates that weight gain/loss isn't solely regulated by calories in vs calories out, also known as energy balance. For one, the magnitude of both calories in and calories out is highly variable based on what you eat, what you do, your genetic make up and you microbiome. Another issue is that in the absence of Lipopolysaccharide (LPS) induced sepsis, animals fed high fat or high calories diets don't tend to gain weight. Ironically enough, what you eat seems to be the most important factor here, both in terms of maintaining the integrity of the intestinal barrier as well as providing the bacterial diversity that is necessary for optimal health. In my opinion, the gut microbiome will help explain a lot of the things we don't currently understand in human health. Chief among them is weight loss.
When someone comes to me because they are having trouble losing weight on a Paleo diet, the first thing I look for is nutrients that may be compromising the gut lining either directly by causing inflammation or indirectly by changing the gut microbiome. Obviously I need to find out if this person is work week Paleo or 7 days a week Paleo. The problem with being work week Paleo is that every Friday after 5 through Sunday night they undo most of the healing they had done to their gut over the course of the previous 4.5 days. It would basically be like popping the stitches on a wound every 5 days, certainly not a winning strategy for wound treatment.
The next step is to look at the composition of their diet, specifically what veggies they are eating. One group of people that I red flag are those people who are Atkins circa 2002 Paleo. These people eat nothing but meat and often neglect both bone broth and organ meats, both necessary components of doing it that way. This is a problem because high fat diets tend to cause significant amounts of gut inflammation by changing the gut microbiome, something we are trying to avoid. However, it appears that it is not the high fat diet per se, but an absence of plant matter in the diet. Here is a rundown of that topic...
Human Food Project: An eater's guide to a healthy microbiome
Before we get in to how this may happen we should go over how bacteria spread in an environment such as your gut. If I have 2 petri dishes full of the same ratio of a diverse array of bacteria and introduce different fuel sources in to each they will quickly become drastically different from one another. This is because the bacterial species that consume the fuel source I introduce will multiply while the others will die off and be replaced with bacteria that can use that fuel. So, if I put a plant in one and meat in the other, we would eventually have completely different bacterial communities. Your gut operates in the same way. When you eat a purely meat diet, some of the beneficial bacteria that ferments plant material and heals your gut lining reduce in numbers, making it difficult to heal an already damaged gut. In addition, eating a diet devoid of plant material slows down the transit time of what you are consuming, allowing it to fester in your intestines long enough to cause some serious inflammation. The prescription...More plants in the diet.
Now that I have gone through all of that, I would like to announce that my Synergy Wellness Paleo Challenge Group will be participating in a challenge within the challenge. That's right, I plan on making next week Microbiome Diversity week with the ultimate goal of eating a minimum of 40 different vegetables during the week. If you are interested in getting involved, let me know. You don't have to do the challenge to be in the group, most people just use it as a way to get recipes and tricks to help them follow the diet.
Monday, January 14, 2013
Magnesium Part 3: The wrath of histamine
In the first 2 parts of this blog series we went over the importance of magnesium to the metabolic syndrome and lifestyle factors that contribute to magnesium wasting. If you haven't read those two blogs they can be found here and here. If you remember from part 1, one of the important functions of magnesium is to help create the histamine metabolizing enzyme Diamine Oxidase (DAO). In magnesium deficient rats, DAO activity is decreased to 50% after 8 days of magnesium deficiency and it returns to baseline once magnesium is reintroduced back in to the diet(1). In addition, histidine decarboxylase (HDC) activity is increased in some of the tissues of the magnesium deficient rats, particularly the spleen and peritoneum but not the skin(2). HDC is an enzyme that makes histamine from histidine, an amino acid. It is this conversion as well as certain foods that contain and/or liberate histamine that can be potentially problematic for someone with an existing magnesium deficiency.
Histamine intolerance is a condition where histamine accumulates in the body as a result of defective histamine metabolism(3). This occurs as a result of reduced DAO activity, something that is made worse by a magnesium deficiency as referenced in the above study. In addition, HDC activity increases which increases the conversion of histidine to histamine in the gut and circulation. Histidine can be found in most high protein foods and is an essential amino acid. As histamine accumulates in the body, numerous symptoms related to allergic reactions can occur including rash, GI symptoms, headache, hypotension, heart arrythmia, and a host of other symptoms. Below is a flow chart of symptoms taken from reference #(3).
It becomes important for a person experiencing these symptoms to do a good job of managing histamine levels. To do this, one should avoid foods that contain histamine, foods that liberate histamine from mast cells, and foods that block DAO activity. Foods that contain histamine include alcohol, any food that has undergone microbial fermentation including cheeses, meats, pickled foods/sauerkraut, beans, pulses, nuts, chocolate, wheat based products, shellfish, canned foods, and smoked meats(4). Leftovers should be strictly avoided as bacteria act on the histidine in foods quickly, converting it in to histamine even in the refrigerator. Foods that are known to liberate histamine from mast cells include citrus fruits, chocolate, nuts, papaya, beans/pulses, tomatoes, strawberries, pork, spinach,wheat germ, undercooked egg whites, and food additives(3,4). Finally, foods that are known to block DAO activity include alcohol, green/black/mate teas, and energy drinks(4).
In addition to minimizing foods that can increase histamine levels in the body, it is a good idea to increase magnesium levels to help support DAO levels and reduce HDC levels. Another nutrient that appears to be important in supporting DAO levels is Vitamin B6(5,6). There is also evidence that vitamin B6 may help transport magnesium in to cells, possibly by forming a complex between the two(7). As far as foods to support DAO activity, one interesting finding is that fat is the only macronutrient that increases DAO levels in the lymphatic system, protein appears to only increase DAO levels in the intestinal lumen while carbohydrate seems to have no effect on DAO levels(8). Therefore, DAO only enters the circulation in the presence of fat. If you are experiencing systemic symptoms of histamine intolerance, increasing fat intake may be something you want to look at. Just make sure you take any oral magnesium supplement away from high fat meals as there is evidence that fat negatively impacts magnesium absorption(9). However, if the reduction of magnesium absorption is due to utilizing more magnesium for DAO production, this may be a positive effect.
Most of you who have been "enjoying" the paleo autoimmune protocol are probably jumping for joy that you get to eliminate a bunch of other foods. Ironically enough, some of the foods that are known to negatively impact histamine levels are also FODMAPS. The point here is that if you are experiencing autoimmune symptoms you should be keeping a strict food journal to identify foods that are triggering responses so that you can compare those foods to foods that are known to cause negative reactions in the body to establish mechanism. If these foods seem to match up to foods known to negatively impact histamine levels, try that route. If it's FODMAPS that tend to be causing the problems, remove those foods. If there doesn't seem to be any rhyme or reason to the reactions and you eat a lot of leftovers, something people who eat a paleo diet do often, try eating only fresh food. If you want to find out if histamine is a problem, try antihistamines for a couple of days to find out if that ameliorates some of the symptoms. I wouldn't use that as your solution since it's not a solution, it's a band-aid, but improvement from antihistamines infers that histamine may be a problem.
If you do identify histamine as being the culprit, it is probably a dose/response issue. What I mean by that is you should find your tolerable dose of histamine and attempt to limit exposure to foods that increase histamine to below that dose. The absolute fastest way to remedy the situation would be to eliminate those foods altogether, but that doesn't really leave much left if you are already on a paleo diet. In any case, you may also want to increase magnesium and Vitamin B6 intake to both increase DAO production and reduce HDC production. It seems fairly apparent that one of the underlying issues in the whole situation is a magnesium deficiency. My best guess is that correcting the magnesium deficiency corrects the histamine intolerance. In this situation I would recommend both oral and topical magnesium supplementation to make sure both the gut and your cells are getting their fair share of magnesium.
Histamine intolerance is a condition where histamine accumulates in the body as a result of defective histamine metabolism(3). This occurs as a result of reduced DAO activity, something that is made worse by a magnesium deficiency as referenced in the above study. In addition, HDC activity increases which increases the conversion of histidine to histamine in the gut and circulation. Histidine can be found in most high protein foods and is an essential amino acid. As histamine accumulates in the body, numerous symptoms related to allergic reactions can occur including rash, GI symptoms, headache, hypotension, heart arrythmia, and a host of other symptoms. Below is a flow chart of symptoms taken from reference #(3).
It becomes important for a person experiencing these symptoms to do a good job of managing histamine levels. To do this, one should avoid foods that contain histamine, foods that liberate histamine from mast cells, and foods that block DAO activity. Foods that contain histamine include alcohol, any food that has undergone microbial fermentation including cheeses, meats, pickled foods/sauerkraut, beans, pulses, nuts, chocolate, wheat based products, shellfish, canned foods, and smoked meats(4). Leftovers should be strictly avoided as bacteria act on the histidine in foods quickly, converting it in to histamine even in the refrigerator. Foods that are known to liberate histamine from mast cells include citrus fruits, chocolate, nuts, papaya, beans/pulses, tomatoes, strawberries, pork, spinach,wheat germ, undercooked egg whites, and food additives(3,4). Finally, foods that are known to block DAO activity include alcohol, green/black/mate teas, and energy drinks(4).
In addition to minimizing foods that can increase histamine levels in the body, it is a good idea to increase magnesium levels to help support DAO levels and reduce HDC levels. Another nutrient that appears to be important in supporting DAO levels is Vitamin B6(5,6). There is also evidence that vitamin B6 may help transport magnesium in to cells, possibly by forming a complex between the two(7). As far as foods to support DAO activity, one interesting finding is that fat is the only macronutrient that increases DAO levels in the lymphatic system, protein appears to only increase DAO levels in the intestinal lumen while carbohydrate seems to have no effect on DAO levels(8). Therefore, DAO only enters the circulation in the presence of fat. If you are experiencing systemic symptoms of histamine intolerance, increasing fat intake may be something you want to look at. Just make sure you take any oral magnesium supplement away from high fat meals as there is evidence that fat negatively impacts magnesium absorption(9). However, if the reduction of magnesium absorption is due to utilizing more magnesium for DAO production, this may be a positive effect.
Most of you who have been "enjoying" the paleo autoimmune protocol are probably jumping for joy that you get to eliminate a bunch of other foods. Ironically enough, some of the foods that are known to negatively impact histamine levels are also FODMAPS. The point here is that if you are experiencing autoimmune symptoms you should be keeping a strict food journal to identify foods that are triggering responses so that you can compare those foods to foods that are known to cause negative reactions in the body to establish mechanism. If these foods seem to match up to foods known to negatively impact histamine levels, try that route. If it's FODMAPS that tend to be causing the problems, remove those foods. If there doesn't seem to be any rhyme or reason to the reactions and you eat a lot of leftovers, something people who eat a paleo diet do often, try eating only fresh food. If you want to find out if histamine is a problem, try antihistamines for a couple of days to find out if that ameliorates some of the symptoms. I wouldn't use that as your solution since it's not a solution, it's a band-aid, but improvement from antihistamines infers that histamine may be a problem.
If you do identify histamine as being the culprit, it is probably a dose/response issue. What I mean by that is you should find your tolerable dose of histamine and attempt to limit exposure to foods that increase histamine to below that dose. The absolute fastest way to remedy the situation would be to eliminate those foods altogether, but that doesn't really leave much left if you are already on a paleo diet. In any case, you may also want to increase magnesium and Vitamin B6 intake to both increase DAO production and reduce HDC production. It seems fairly apparent that one of the underlying issues in the whole situation is a magnesium deficiency. My best guess is that correcting the magnesium deficiency corrects the histamine intolerance. In this situation I would recommend both oral and topical magnesium supplementation to make sure both the gut and your cells are getting their fair share of magnesium.
Wednesday, January 9, 2013
Hardwired for failure...
http://www.sciencedaily.com/releases/2012/06/120612115812.htm
http://www.newstrackindia.com/newsdetails/2012/12/20/205-Gut-bacteria-may-be-making-you-hungry.html
The articles above illustrate something I try to get clients to understand every day. While they are busy concerning themselves with how many calories they consume and trying to burn as many as possible, something I tell them not to do, they ignore the fact that what they choose to eat is actually changing their operating system. The reason I recommend a paleo diet is that the paleo diet actually repairs this operating system. It's not only the software our systems have run on forever, it's the software our systems are optimized for.
When you choose to follow the diet for a couple of days and then go off the rails and eat something you shouldn't, you undo a significant amount of the progress you made because you begin to re-feed the bacteria you have been trying to do away with for the last couple of days. Think of it as sending supplies to the enemies you are at war with, why would you do that? Obviously if you are further along on the diet and have re-established your operating system you have a lot more leeway than someone who has been on the diet for a little while.
One of the hardest things to do is to get someone to change their diet. I can't tell you how many clients who I've told to eliminate grains, legumes, and dairy who tell me they have done just that only to find out they are eating greek yogurt and granola for breakfast. Granola has grain in the first 4 letters and who doesn't understand yogurt is dairy? It's not that they are stupid people, it's that in a metabolically deranged individual they will always look for workarounds, it's what their body tells them to do. Given the multiple body systems, and non-body systems in the instance of gut bugs, involved in driving them towards what they eventually end up eating, stupid isn't the proper term. I prefer the term hardwired for failure, and until they fix this issue that's what they'll continue to be. While they may be able to lose a little weight here and there and maintain it for a few months, they will always go back to the status quo because they never fix the problem. Eating the way a standard American eats changes the operating system, changes appetite, and drives people to make poor food choices. It is also one of the primary drivers of the obesity and heart disease epidemics.
http://www.newstrackindia.com/newsdetails/2012/12/20/205-Gut-bacteria-may-be-making-you-hungry.html
The articles above illustrate something I try to get clients to understand every day. While they are busy concerning themselves with how many calories they consume and trying to burn as many as possible, something I tell them not to do, they ignore the fact that what they choose to eat is actually changing their operating system. The reason I recommend a paleo diet is that the paleo diet actually repairs this operating system. It's not only the software our systems have run on forever, it's the software our systems are optimized for.
When you choose to follow the diet for a couple of days and then go off the rails and eat something you shouldn't, you undo a significant amount of the progress you made because you begin to re-feed the bacteria you have been trying to do away with for the last couple of days. Think of it as sending supplies to the enemies you are at war with, why would you do that? Obviously if you are further along on the diet and have re-established your operating system you have a lot more leeway than someone who has been on the diet for a little while.
One of the hardest things to do is to get someone to change their diet. I can't tell you how many clients who I've told to eliminate grains, legumes, and dairy who tell me they have done just that only to find out they are eating greek yogurt and granola for breakfast. Granola has grain in the first 4 letters and who doesn't understand yogurt is dairy? It's not that they are stupid people, it's that in a metabolically deranged individual they will always look for workarounds, it's what their body tells them to do. Given the multiple body systems, and non-body systems in the instance of gut bugs, involved in driving them towards what they eventually end up eating, stupid isn't the proper term. I prefer the term hardwired for failure, and until they fix this issue that's what they'll continue to be. While they may be able to lose a little weight here and there and maintain it for a few months, they will always go back to the status quo because they never fix the problem. Eating the way a standard American eats changes the operating system, changes appetite, and drives people to make poor food choices. It is also one of the primary drivers of the obesity and heart disease epidemics.
Monday, January 7, 2013
Factors in improving magnesium status
In my last blog found here I went over the importance of magnesium in the metabolic syndrome. In this blog I will go over some of the things I feel are important in maintaining an adequate magnesium status. While digging through the research I found a lot more than what I originally bargained for so it appears we may have a part 3, but more on that later.
To recap, when your intestine becomes permeable, an endotoxin known as LPS enters your blood circulation. This sepsis leads to your cells not responding to insulin, leading to high blood glucose levels which cause an even greater secretion of insulin which leads to conversion of glucose to fat and storage in your fat tissue. In addition, the release of histamine in response to this sepsis increases your need for DAO, an enzyme used to decrease histamine levels. Since all of the above require magnesium in order to perform these processes, magnesium deficiency appears to be a central player in the metabolic syndrome. The question now becomes how can we manage our magnesium levels to prevent these issues?
Judging by the way this country operates, my guess is that most of the people who read part 1 came to the conclusion that they need to start supplementing with magnesium. While magnesium supplementation is a good idea given the mineral depleted status of our soil and de-mineralized status of most water sources, just shoving magnesium supplements in to your mouth is probably not sufficient. We need to pay attention to multiple factors here including whether or not the magnesium we ingest makes it's way in to cells, if it stays there, as well as how much magnesium we use on a daily basis.
The RDA for magnesium is set at 320mg for women and 420mg for men while actual intake in North America is 228mg and 323mg, respectively(1). According to Carolyn Dean, MD, author of The Magnesium Miracle, research over the past 20 years shows that 300mg is required per day just to offset daily losses under ideal conditions(2). When you add in stress, lack of sleep, a high sugar diet, diuretics such as caffeine and alcohol, and other things known to affect magnesium status, this number increases dramatically. Let's take a look at each one and see what the research shows.
Stress and sleep deprivation are so intertwined that it is difficult to separate the two. If there is any relationship that underscores the fact that you cannot separate the mental state from the physical it's the relationship between sleep and stress. Magnesium appears to be a huge player here. In a study performed on students during finals week, students who were under stress and had 80% of the sleep they were accustomed to saw a decrease in erythrocyte magnesium levels(3). This study confirmed the results of a previous study by the same principal investigator that showed 4 weeks of sleep deprivation increased catecholamine levels (Stress hormones) and decreased intracellular magnesium levels and heart rate variability (HRV)(4). Heart rate variability is a measure of autonomic function/stress where lower heart rate variability indicates increased stress load.
One of the problems one experiences with magnesium deficiency and sleep is that reduction in the quality and quantity of sleep increases magnesium wasting while a magnesium deficiency reduces the quality and quantity of sleep, making the problem worse. One of the primary roles of magnesium in the body is to calm down the nervous system. In a small study with people who experience restless leg syndrome, 10 subjects were given an oral magnesium supplement in the evenings. The number of arousals per hour experienced by the subjects due to leg movements was reduced from 17 to 7, sleep efficiency improved from 75% to 85%, and 7 of the subjects stated that their sleep had improved on oral magnesium supplementation(5). In another study on rats, 9 weeks of a magnesium restricted diet increased wakefulness by 50%, with a reduction of slow wave sleep by week 7. When magnesium was reintroduced back in to the diet, the rats' sleep patterns returned to baseline(6). Because of it's ability to improve sleep quality, it is probably a good idea to dose any magnesium supplementation just prior to bed in people who have poor sleep quality that may be caused by magnesium deficiency. This will help end the vicious cycle of low magnesium decreasing sleep quality which in turn decreases magnesium levels.
One form of stress that people expect to see positive benefits from is exercise. The results of exercise on magnesium balance have been mixed with most studies showing a shift from the plasma to erythrocytes (intracellular space) with an increase in urinary output on the same day based on the intensity of the exercise(7,8). In 1 study, the amount of magnesium lost in the urine was positively correlated to post-exercise blood lactate levels and oxygen consumption indicating that exercise modalities that rely more on the anaerobic energy pathways are likely to induce greater losses of magnesium than aerobic activities(7). This information should be of practical use to people pounding themselves in to the ground with 5 times a week crossfit and p90x style workouts as well as overweight people who begin with exercise that is too intense for their needs on January 1st.
As stated in part 1, magnesium is required to not only secrete insulin but also for cells to take in glucose once insulin has attached to the receptor on the cell membrane. It makes sense that as you increase the amount of carbohydrate you eat you would also need to increase the amount of magnesium you get in order to process the higher amount of glucose being manufactured from that carbohydrate. It would seem that this is a problem of relying on insulin as the primary modality of increasing glucose transport in to cells. While a person who uses physical activity as their primary method of transporting glucose in to cells may not need to worry about magnesium needs via insulin action, the fact that ATP must be bound to magnesium in order to be active shows that there is really no way of getting around the greater need for magnesium in a higher carbohydrate diet, whether you exercise or sit on your keister.
As far as diuretics go, caffeine and alcohol are by far the most frequently used diuretics given their ease of availability. Since both increase water loss, they can both have an impact on magnesium status. Alcoholics tend to have lower levels of magnesium and some of the clinical symptoms of alcoholism such as hypertension, sleep problems, and the withdrawal symptoms after ceasing alcohol use appear to be from low magnesium levels(9,10). Alcohol negatively impacts magnesium by drastically increasing urinary losses(9). Interestingly enough, this appears to be dose dependent as a study looking at the effects of light beer consumption (330mL/day for 30 days)showed an increase in plasma magnesium status with the ingestion of beer when compared to a control drink containing mineral water with similar mineral content(11). (Mmmm, beer) However, we do not know if this is a shift out of cells and in to the plasma or a result of a response to the alcohol and magnesium combination.
Caffeine appears to have the same effect on magnesium as alcohol in that it increases urinary loss of magnesium. The urinary loss of magnesium appears to be dose related and tends to occur around the time of caffeine consumption, tapering off as time from ingestion increases(12,13,14). The average intake of magnesium is nowhere near sufficient in people who drink alcohol or coffee/caffeinated beverages, get poor sleep, are chronically stressed, exercise intensely, and eat high sugar diets. I would even make the argument that the RDA is insufficient for people who do more than one of these things on a regular basis.
Up until this point we have discussed lifestyle factors that increase the need for magnesium. The next logical step is to increase magnesium intake via supplementation or foods high in magnesium. The problem is, this simplistic way of looking at it can be problematic. Many gastrointestinal issues can prevent magnesium from being absorbed. Since magnesium requires stomach acid to separate the elemental magnesium from whatever it is bound to, people with low stomach acid tend to have a problem absorbing magnesium(2). In addition, those with a leaky gut will also have a problem absorbing magnesium because some of the magnesium channels are located in the tight junctions between enterocytes. In fact, 80-90% of the magnesium absorbed from the intestine uses these tight junction channels, illustrating why a healthy gut is critical in making sure magnesium is getting in to the blood so it can make it's way to cells(15).
In 2 studies performed on rats, animals that were induced with intestinal permeability to either 5 or 10 fold greater than baseline levels saw permeability return to baseline upon rinsing the lumen with magnesium or calcium at lower permeability and only magnesium at higher permeability(16,17). In this instance ingesting oral magnesium may prove beneficial to healing your leaky gut, but if you continue to enjoy weekly gluten and alcohol bombs on Friday through Sunday very little magnesium will ever make it in to your cells so you wouldn't really be fixing the problem. It would be like trying to heal a cut on your hand that has 5 stitches by popping the stitches every few days, it's never going to heal that way. Take a couple of months to fix the problem and then return to enjoying your life, it will be worth it in the end. Obviously a couple of rat studies proves nothing but they certainly make you think, especially with so much other evidence pointing to a positive effect of magnesium on health.
Let's say you are doing everything you can to heal your leaky gut and you would like to speed up the process. You like the idea of taking oral magnesium and you are doing everything in your power to avoid things that may perforate your intestinal lining. Is there something we can do to also get magnesium directly to cells? In his book transdermal magnesium therapy, Dr. Mark Sircus goes over, in detail, the benefits of transdermal magnesium therapy. There appears to be multiple ways to use magnesium transdermally, and while there is not a lot of studies supporting the use of it that way, there are thousands of anecdotal reports of success on the internet. In my opinion, the best way would be to enjoy dips in sea water as often as possible, but since a lot of us are landlocked, I will go over the other routes of administration.
Magnesium sulfate (Epsom salt) baths-Putting magnesium sulfate in to a bath or a foot soak is one potential way of getting magnesium transdermally. I find this way to be less than ideal from a cost perspective because you have to use a ton of epsom salts. However, I've done the baths with just 2 cups of epsom salts and when you are finished I cannot think of ever being in a more relaxed state. I also add in an equal amount of baking soda as a sort of detox bath. Foot baths are also a good option and require less epsom salts.
Magnesium chloride oil-A few companies make a magnesium preparation from sea brine that can be effective for delivering magnesium while bypassing the gut. It's not really an oil, but it kind of feels that way. This was how I did it when I was having problems sleeping and oral magnesium glycinate didn't seem to help. I was out like a light on the first night and my wife commented I was not my normal tossing and turning self. Obviously I cannot rule out placebo effect but when you can't sleep any effect is welcome.
Personally, I use magnesium oil transdermally and it was initially my preferred modality because even high oral doses of magnesium glycinate did nothing. It turns out this was because I had a leaky gut and the magnesium wasn't making it's way in to my cells. As the leaky gut improved I no longer needed to take it in this manner so now I just take periodic baths and a small oral dose. It took a while for me to fix the issue because I initially went at it alone and didn't completely fix my diet. I eventually contacted a functional medicine doctor to help address the issue, something I will be discussing in an upcoming blog series. I do continue to use the oil as a deodorant/anti-perspirant because it works better than anything else I have ever tried. I will not go over how much I took to resolve my issue because it is higher than the RDA and I'm not a doctor, I will only say that I did a lot of digging on this site and followed his instructions:
http://drsircus.com/medicine/magnesium
FYI, at high doses the oil burns. As far as oral magnesium goes, I like dimagnesium malate and magnesium oxide. If you search around the internet enough you will find plenty of evidence that magnesium oxide isn't absorbed well from the intestine. This may not be a bad thing if you have significant issues in your gut and are taking transdermal magnesium with it. The functional medicine doctor I use told me that in his clinical experience the magnesium oxide he prescribes seems to work better than anything else. My guess is that since it doesn't get absorbed well from the gut it probably works better for fixing issues in the gut. As for dosage, this will be specific to the individual and requires a bit of tinkering. You'll know if you take too much orally because your stools will become loose. As an example, I took about 4x times the RDA and still didn't experience diarrhea. As long as you have properly functioning kidneys you don't really need to worry about overdoing it, but consult your doctor just to make sure.
So where do we go from here? In researching for this second part I actually came upon something very interesting with regard to the histamine part of the magnesium picture but it would have made this blog too long. In the final part of this blog series on magnesium I will explore the interplay between histamine and magnesium and how you may be unknowingly botching your efforts to improve magnesium status by eating those leftovers.
If you have any questions about magnesium feel free to post them in the comments.
To recap, when your intestine becomes permeable, an endotoxin known as LPS enters your blood circulation. This sepsis leads to your cells not responding to insulin, leading to high blood glucose levels which cause an even greater secretion of insulin which leads to conversion of glucose to fat and storage in your fat tissue. In addition, the release of histamine in response to this sepsis increases your need for DAO, an enzyme used to decrease histamine levels. Since all of the above require magnesium in order to perform these processes, magnesium deficiency appears to be a central player in the metabolic syndrome. The question now becomes how can we manage our magnesium levels to prevent these issues?
Judging by the way this country operates, my guess is that most of the people who read part 1 came to the conclusion that they need to start supplementing with magnesium. While magnesium supplementation is a good idea given the mineral depleted status of our soil and de-mineralized status of most water sources, just shoving magnesium supplements in to your mouth is probably not sufficient. We need to pay attention to multiple factors here including whether or not the magnesium we ingest makes it's way in to cells, if it stays there, as well as how much magnesium we use on a daily basis.
The RDA for magnesium is set at 320mg for women and 420mg for men while actual intake in North America is 228mg and 323mg, respectively(1). According to Carolyn Dean, MD, author of The Magnesium Miracle, research over the past 20 years shows that 300mg is required per day just to offset daily losses under ideal conditions(2). When you add in stress, lack of sleep, a high sugar diet, diuretics such as caffeine and alcohol, and other things known to affect magnesium status, this number increases dramatically. Let's take a look at each one and see what the research shows.
Stress and sleep deprivation are so intertwined that it is difficult to separate the two. If there is any relationship that underscores the fact that you cannot separate the mental state from the physical it's the relationship between sleep and stress. Magnesium appears to be a huge player here. In a study performed on students during finals week, students who were under stress and had 80% of the sleep they were accustomed to saw a decrease in erythrocyte magnesium levels(3). This study confirmed the results of a previous study by the same principal investigator that showed 4 weeks of sleep deprivation increased catecholamine levels (Stress hormones) and decreased intracellular magnesium levels and heart rate variability (HRV)(4). Heart rate variability is a measure of autonomic function/stress where lower heart rate variability indicates increased stress load.
One of the problems one experiences with magnesium deficiency and sleep is that reduction in the quality and quantity of sleep increases magnesium wasting while a magnesium deficiency reduces the quality and quantity of sleep, making the problem worse. One of the primary roles of magnesium in the body is to calm down the nervous system. In a small study with people who experience restless leg syndrome, 10 subjects were given an oral magnesium supplement in the evenings. The number of arousals per hour experienced by the subjects due to leg movements was reduced from 17 to 7, sleep efficiency improved from 75% to 85%, and 7 of the subjects stated that their sleep had improved on oral magnesium supplementation(5). In another study on rats, 9 weeks of a magnesium restricted diet increased wakefulness by 50%, with a reduction of slow wave sleep by week 7. When magnesium was reintroduced back in to the diet, the rats' sleep patterns returned to baseline(6). Because of it's ability to improve sleep quality, it is probably a good idea to dose any magnesium supplementation just prior to bed in people who have poor sleep quality that may be caused by magnesium deficiency. This will help end the vicious cycle of low magnesium decreasing sleep quality which in turn decreases magnesium levels.
One form of stress that people expect to see positive benefits from is exercise. The results of exercise on magnesium balance have been mixed with most studies showing a shift from the plasma to erythrocytes (intracellular space) with an increase in urinary output on the same day based on the intensity of the exercise(7,8). In 1 study, the amount of magnesium lost in the urine was positively correlated to post-exercise blood lactate levels and oxygen consumption indicating that exercise modalities that rely more on the anaerobic energy pathways are likely to induce greater losses of magnesium than aerobic activities(7). This information should be of practical use to people pounding themselves in to the ground with 5 times a week crossfit and p90x style workouts as well as overweight people who begin with exercise that is too intense for their needs on January 1st.
As stated in part 1, magnesium is required to not only secrete insulin but also for cells to take in glucose once insulin has attached to the receptor on the cell membrane. It makes sense that as you increase the amount of carbohydrate you eat you would also need to increase the amount of magnesium you get in order to process the higher amount of glucose being manufactured from that carbohydrate. It would seem that this is a problem of relying on insulin as the primary modality of increasing glucose transport in to cells. While a person who uses physical activity as their primary method of transporting glucose in to cells may not need to worry about magnesium needs via insulin action, the fact that ATP must be bound to magnesium in order to be active shows that there is really no way of getting around the greater need for magnesium in a higher carbohydrate diet, whether you exercise or sit on your keister.
As far as diuretics go, caffeine and alcohol are by far the most frequently used diuretics given their ease of availability. Since both increase water loss, they can both have an impact on magnesium status. Alcoholics tend to have lower levels of magnesium and some of the clinical symptoms of alcoholism such as hypertension, sleep problems, and the withdrawal symptoms after ceasing alcohol use appear to be from low magnesium levels(9,10). Alcohol negatively impacts magnesium by drastically increasing urinary losses(9). Interestingly enough, this appears to be dose dependent as a study looking at the effects of light beer consumption (330mL/day for 30 days)showed an increase in plasma magnesium status with the ingestion of beer when compared to a control drink containing mineral water with similar mineral content(11). (Mmmm, beer) However, we do not know if this is a shift out of cells and in to the plasma or a result of a response to the alcohol and magnesium combination.
Caffeine appears to have the same effect on magnesium as alcohol in that it increases urinary loss of magnesium. The urinary loss of magnesium appears to be dose related and tends to occur around the time of caffeine consumption, tapering off as time from ingestion increases(12,13,14). The average intake of magnesium is nowhere near sufficient in people who drink alcohol or coffee/caffeinated beverages, get poor sleep, are chronically stressed, exercise intensely, and eat high sugar diets. I would even make the argument that the RDA is insufficient for people who do more than one of these things on a regular basis.
Up until this point we have discussed lifestyle factors that increase the need for magnesium. The next logical step is to increase magnesium intake via supplementation or foods high in magnesium. The problem is, this simplistic way of looking at it can be problematic. Many gastrointestinal issues can prevent magnesium from being absorbed. Since magnesium requires stomach acid to separate the elemental magnesium from whatever it is bound to, people with low stomach acid tend to have a problem absorbing magnesium(2). In addition, those with a leaky gut will also have a problem absorbing magnesium because some of the magnesium channels are located in the tight junctions between enterocytes. In fact, 80-90% of the magnesium absorbed from the intestine uses these tight junction channels, illustrating why a healthy gut is critical in making sure magnesium is getting in to the blood so it can make it's way to cells(15).
In 2 studies performed on rats, animals that were induced with intestinal permeability to either 5 or 10 fold greater than baseline levels saw permeability return to baseline upon rinsing the lumen with magnesium or calcium at lower permeability and only magnesium at higher permeability(16,17). In this instance ingesting oral magnesium may prove beneficial to healing your leaky gut, but if you continue to enjoy weekly gluten and alcohol bombs on Friday through Sunday very little magnesium will ever make it in to your cells so you wouldn't really be fixing the problem. It would be like trying to heal a cut on your hand that has 5 stitches by popping the stitches every few days, it's never going to heal that way. Take a couple of months to fix the problem and then return to enjoying your life, it will be worth it in the end. Obviously a couple of rat studies proves nothing but they certainly make you think, especially with so much other evidence pointing to a positive effect of magnesium on health.
Let's say you are doing everything you can to heal your leaky gut and you would like to speed up the process. You like the idea of taking oral magnesium and you are doing everything in your power to avoid things that may perforate your intestinal lining. Is there something we can do to also get magnesium directly to cells? In his book transdermal magnesium therapy, Dr. Mark Sircus goes over, in detail, the benefits of transdermal magnesium therapy. There appears to be multiple ways to use magnesium transdermally, and while there is not a lot of studies supporting the use of it that way, there are thousands of anecdotal reports of success on the internet. In my opinion, the best way would be to enjoy dips in sea water as often as possible, but since a lot of us are landlocked, I will go over the other routes of administration.
Magnesium sulfate (Epsom salt) baths-Putting magnesium sulfate in to a bath or a foot soak is one potential way of getting magnesium transdermally. I find this way to be less than ideal from a cost perspective because you have to use a ton of epsom salts. However, I've done the baths with just 2 cups of epsom salts and when you are finished I cannot think of ever being in a more relaxed state. I also add in an equal amount of baking soda as a sort of detox bath. Foot baths are also a good option and require less epsom salts.
Magnesium chloride oil-A few companies make a magnesium preparation from sea brine that can be effective for delivering magnesium while bypassing the gut. It's not really an oil, but it kind of feels that way. This was how I did it when I was having problems sleeping and oral magnesium glycinate didn't seem to help. I was out like a light on the first night and my wife commented I was not my normal tossing and turning self. Obviously I cannot rule out placebo effect but when you can't sleep any effect is welcome.
Personally, I use magnesium oil transdermally and it was initially my preferred modality because even high oral doses of magnesium glycinate did nothing. It turns out this was because I had a leaky gut and the magnesium wasn't making it's way in to my cells. As the leaky gut improved I no longer needed to take it in this manner so now I just take periodic baths and a small oral dose. It took a while for me to fix the issue because I initially went at it alone and didn't completely fix my diet. I eventually contacted a functional medicine doctor to help address the issue, something I will be discussing in an upcoming blog series. I do continue to use the oil as a deodorant/anti-perspirant because it works better than anything else I have ever tried. I will not go over how much I took to resolve my issue because it is higher than the RDA and I'm not a doctor, I will only say that I did a lot of digging on this site and followed his instructions:
http://drsircus.com/medicine/magnesium
FYI, at high doses the oil burns. As far as oral magnesium goes, I like dimagnesium malate and magnesium oxide. If you search around the internet enough you will find plenty of evidence that magnesium oxide isn't absorbed well from the intestine. This may not be a bad thing if you have significant issues in your gut and are taking transdermal magnesium with it. The functional medicine doctor I use told me that in his clinical experience the magnesium oxide he prescribes seems to work better than anything else. My guess is that since it doesn't get absorbed well from the gut it probably works better for fixing issues in the gut. As for dosage, this will be specific to the individual and requires a bit of tinkering. You'll know if you take too much orally because your stools will become loose. As an example, I took about 4x times the RDA and still didn't experience diarrhea. As long as you have properly functioning kidneys you don't really need to worry about overdoing it, but consult your doctor just to make sure.
So where do we go from here? In researching for this second part I actually came upon something very interesting with regard to the histamine part of the magnesium picture but it would have made this blog too long. In the final part of this blog series on magnesium I will explore the interplay between histamine and magnesium and how you may be unknowingly botching your efforts to improve magnesium status by eating those leftovers.
If you have any questions about magnesium feel free to post them in the comments.
Wednesday, December 26, 2012
Magnesium-A central player in obesity
Robb Wolf-Blast from the Past
The above video is a presentation that Robb Wolf gave at SUNY New Paltz in 2012. There are a ton of nuggets on why an ancestral diet is the best choice for human health, but there is one particular construct I would like to focus on for this blog. At 52:50 in the presentation Robb discusses the relationship between sepsis and insulin resistance. The basic gist is that obesity is caused via sepsis induced insulin resistance. Lipopolysaccharide (LPS) enters the blood via a leaky gut caused by the dissolution of the tight junctions between enterocytes (Cells of the intestinal wall). This basically poisons the blood which, in turn, induces insulin resistance which progresses to both diabetes and the metabolic syndrome. According to Robb, this is to spare glucose for the brain. If you think about it, given the fact that most of our ancestors died of some sort of infection, it would make sense that when infection of the blood occurs there is an evolutionary advantage conferred to the host by sparing glucose for the brain. However what is the mechanism that causes this advantage and is there any way to exploit it?
Interestingly enough, you don't even need to dig too deep in to the literature to find some pretty strong relationships in this scenario of sepsis-induced insulin resistance. In fact, when we look at these relationships, one thing seems to contribute to insulin resistance, diabetes, obesity, sepsis, and even early death due to sepsis. I am talking about the 4th most abundant mineral in the body and one that has gotten little play from scientists up until recently, magnesium.
Magnesium is critically important in over 300 enzymatic reactions in your body. Both the secretion of and effectiveness of insulin are dependent on adequate magnesium. In the presence of insulin, cells require magnesium in order to take in glucose from the bloodstream(1). In children, serum magnesium has been shown to be lower in obese children than lean controls(2). In adults, lowering serum and intracellular magnesium via a diet low in magnesium has been shown to reduce insulin sensitivity. Evidence from the study suggests this was via reduced insulin action(3). Oral magnesium intake has also been shown to improve insulin sensitivity, even in people who have normal magnesium levels(4). This could be due to the fact that serum magnesium is a terrible indicator for magnesium status given that magnesium is primarily an intracellular cation and serum magnesium levels are tightly controlled. If they weren't you would die with the slightest variation outside of the normal range. When compared to normal controls, people with the metabolic syndrome tend to have lower intakes of magnesium(5). Mirroring the results of this study, a prospective study performed in 2012 found an inverse relationship between the intake of magnesium and incidence of diabetes. What makes this study more interesting than the others is the fact that they also found an inverse relationship between magnesium intake/serum magnesium and markers of inflammation(6). It is widely known that chronic inflammation is correlated with diabetes and metabolic syndrome, the fact that both magnesium intake and serum magnesium levels correlated with the level of chronic inflammation in this study strengthens that notion. It is even possible that this relationship could be stronger if intracellular magnesium was measured. But how does a magnesium deficiency lead to chronic inflammation?
When we look at the effects of sepsis on insulin sensitivity, the strength of the relationship between the 2 is as strong as the relationship between magnesium deficiency and insulin resistance. In a study on rats, progressive magnesium deficiency increased the rate of mortality in rats induced with endotoxemia(7). The longer the rats were magnesium deficient the more likely they were to die from endotoxemia. In addition, rats that were treated with magnesium had a 300% increased likelihood of survival compared with control rats. In another study on rats, sepsis induced a drop in magnesium over time that eventually recovered during the later part of sepsis(8). In a study in humans, 52% of patients entering the ICU unit had hypomagnesemia. Patients with hypomagnesemia were almost twice as likely to die (58% vs 32%), required more care, and were twice as likely to experience sepsis (38% vs 19%)(9). As menioned above, one of the problems with measuring serum magnesium is that it is tightly controlled in the body, if it gets too out of whack you die. Since magnesium is primarily found within cells, Red Blood Cell magnesium seems to be a better indicator of magnesium status. In studies that have measured RBC magnesium instead of serum, the incidence of hypomagnesemia in critically ill patients is much higher which may confound the results(9).
Given that hypomagnesemia leads to both an increased risk of sepsis as well as poorer outcomes, there must be some mechanism by which magnesium inhibits sepsis. In a study examining rabbits rendered endotoxemic with LPS, histamine levels quickly increased to 50x greater than baseline values and remained that high throughout the 6 hour study period(10). A study on humans performed in 1996 found multiple relationships between sepsis and histamine levels. None of the patients with low histamine levels as determined by criteria in the study experienced sepsis while 45% of the patients with sepsis had high histamine levels. Of the patients with sepsis, the non-survivors had higher plasma histamine levels than survivors and all of the subjects with a high sepsis score AND high plasma histamine levels died(11). All of this begs the question, is there some relationship between histamine and magnesium?
Two studies in humans have shown a decrease in intracellular magnesium levels during increased histamine levels in asthmatic patients(12,13). In the first study, magnesium and histamine levels were measured during asthma attack. When compared to asymptomatic levels as well as control subjects, histamine levels increased during asthma attack while plasma and intracellular magnesium levels dropped(12). In the second study, patients were given histamine to induce an asthma attack. While plasma magnesium didn't change, there was a significant decrease in intracellular magnesium levels(13). One of the likely mechanisms by which histamine reduces magnesium levels is via Diamine oxidase (DAO) production. DAO is an enzyme secreted by cells of the intestinal mucosa that enters the circulation via the lymphatic system. DAO inactivates histamine and is dependent on magnesium for production. Therefore, when histamine levels increase, magnesium is used to create DAO to metabolize the histamine. As magnesium levels drop due to sustained histamine release, DAO levels drop and histamine levels increase. In a study performed on rats, rats fed a magnesium deficient diet for 8 days had a decrease in duodenal DAO activity which led to an increase in blood histamine levels. Feeding the rats a diet high in magnesium for 2 days decreased blood histamine levels to that of controls(14).
The relationship between histamine levels and magnesium appears to be multi-faceted. In another study on rats, magnesium deficiency led to an initial increase of histamine levels reaching a maximum of 5x the control level by 14 days on a magnesium restricted diet with a subsequent decline to control levels as the magnesium deficiency continued(15). The mast cells (cells that secret histamine) that remained or were produced after magnesium deficiency had a reduced capacity to store and secrete histamine. This implies that magnesium is necessary for the manufacture and secretion of histamine as well as the inactivation of it. Judging from the results of both experiments, priority is given to histamine production over histamine metabolism. This underscores the importance of histamine release to the immune response.
One hormonal player in the obesity/insulin resistance game that we have yet to discuss is leptin. Leptin is an inflammatory hormone secreted by fat tissue that suppresses appetite. Basically, you eat food and when you start making body fat, leptin is secreted by fat cells to tell the brain that you are in a fed state. In obesity and the metabolic syndrome, people become resistant to the effects of leptin. This causes them to never receive the fed signal which causes them to overeat. While there is no good evidence linking leptin to magnesium, there is very strong evidence linking leptin to histamine in mice. In a study on rats, the administration of leptin caused an increase in hypothalamic histamine that lasted 4 hours in anesthetized rats(16). The same dosage of leptin given to non-anesthetized rats significantly reduced food intake. In another study, mice treated with leptin had an 84% reduction in food intake when compared to controls 24 hours after being treated(17). In mice treated with FMH(an inhibitor of histamine) prior to leptin, appetite was not significantly different. In a study using mice bred to lack the histamine H1 receptor(H1KO), injection of leptin did not significantly change appetite in comparison to control mice. These findings were confirmed in another study on rats(18). Finally, in a study that looked directly at the effect of histamine on feeding behavior and fat deposition, injecting leptin resistant obese and diabetic mice with histamine reduced food intake and bodyweight(19). In addition, histamine treatment in the experimental group reduced body fat, ob gene expression, and leptin levels to a greater degree than that seen in pair-fed controls. The histamine treated H1KO mice also saw greater improvements in blood glucose and insulin sensitivity than pair-fed controls. Interestingly enough, the effect on body fat reduction was only significant in visceral fat, the type of body fat associated with insulin resistance and the metabolic syndrome.
The sum of all of the evidence discussed above points to very strong relationships between sepsis, insulin resistance, histamine, and leptin. It seems as though control of sepsis may be given priority over blood glucose control and magnesium may mediate this. Since both biological functions are dependent on magnesium for proper function, preference has to be given to one function over the other. Over the course of evolution, natural selection would have favored those animals that gave precedence to control of sepsis over blood glucose control since infection was the primary cause of mortality and blood glucose levels were controlled by the availability of food and energy required to attain it. In addition, system-wide insulin resistance during sepsis would confer an advantage to the host via conserving blood glucose for the brain. It appears there is a very strong relationship between magnesium intake and levels, histamine levels, sepsis, and insulin resistance. One potential idea is that a diet high in foods that increase intestinal permeability and blood levels of LPS increase the body's need for magnesium to both produce and metabolize histamine. Since the body naturally gives precedence to control of sepsis over that of blood glucose, people who experience endotoxemia from LPS will have reduced magnesium availability to both produce insulin and allow glucose uptake by cells. If magnesium deficiency reaches the point of negatively impacting the production of DAO, histamine levels will increase. At some point, either histamine levels decrease, possibly due to magnesium deficiency, or histamine receptors downregulate and become resistant to histamine in the brain. This reduces leptin signaling and leads to an inability to control appetite. These could be the initial stages of insulin resistance that eventually progress to Type 2 Diabetes and the metabolic syndrome.
It appears that special care should be taken to manage magnesium status both by increasing intake as well as limiting lifestyle activities that increase magnesium depletion to prevent the metabolic syndrome. Examples of lifestyle activities that are known to deplete magnesium are poor sleep, high carbohydrate diets, smoking, alcohol intake, excess stress, and eating foods that increase intestinal permeability and blood levels of LPS (1). Interestingly enough, all of these activities have been shown to be correlated with the metabolic syndrome. This is not to say that magnesium is the sole cause of the entire problem, only that it is a major player in it and a potential target for therapy. This also presents a competing paradigm that contrasts with the energy balance paradigm for weight management.
In my next blog I will explain this in plain English and give actionable steps to improve the metabolic syndrome and how those steps contribute to a healthy magnesium status. Here's a hint, it involves a lot more than taking magnesium supplements.
REFERENCES
1)Magnesium miracle
2)http://www.ncbi.nlm.nih.gov/pubmed/15855585
3)http://hyper.ahajournals.org/content/21/6_Pt_2/1024.short
4)http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2010.01332.x/abstract;jsessionid=8F71CE49763637EE8FA0805916869F81.d04t02?deniedAccessCustomisedMessage=&userIsAuthenticated=false
5)http://onlinelibrary.wiley.com/doi/10.1038/oby.2007.628/full
6)http://care.diabetesjournals.org/content/33/12/2604.short
7)http://journals.lww.com/ccmjournal/Abstract/1995/01000/Progressive_magnesium_deficiency_increases.19.aspx
8)http://link.springer.com/article/10.1186%2F2110-5820-1-53?LI=true#page-1
9)http://www.japi.org/january_2011/oa_%20hoyponagnesemia.pdf
10)http://link.springer.com/article/10.1007%2Fs00210-002-0651-x?LI=true
11)http://journals.lww.com/ccmjournal/Abstract/1996/10000/Histamine_release_in_sepsis__A_prospective,.12.aspx
12)http://europepmc.org/abstract/MED/749826
13)http://erj.ersjournals.com/content/16/4/621.short
14)http://www.ncbi.nlm.nih.gov/pubmed/3111814
15)http://jn.nutrition.org/content/110/5/851.full.pdf
16)http://www.sciencedirect.com/science/article/pii/S0006899300023258
17)http://cat.inist.fr/?aModele=afficheN&cpsidt=1201182
18)http://diabetes.diabetesjournals.org/content/48/12/2286.short
19)http://diabetes.diabetesjournals.org/content/50/2/376.short
The above video is a presentation that Robb Wolf gave at SUNY New Paltz in 2012. There are a ton of nuggets on why an ancestral diet is the best choice for human health, but there is one particular construct I would like to focus on for this blog. At 52:50 in the presentation Robb discusses the relationship between sepsis and insulin resistance. The basic gist is that obesity is caused via sepsis induced insulin resistance. Lipopolysaccharide (LPS) enters the blood via a leaky gut caused by the dissolution of the tight junctions between enterocytes (Cells of the intestinal wall). This basically poisons the blood which, in turn, induces insulin resistance which progresses to both diabetes and the metabolic syndrome. According to Robb, this is to spare glucose for the brain. If you think about it, given the fact that most of our ancestors died of some sort of infection, it would make sense that when infection of the blood occurs there is an evolutionary advantage conferred to the host by sparing glucose for the brain. However what is the mechanism that causes this advantage and is there any way to exploit it?
Interestingly enough, you don't even need to dig too deep in to the literature to find some pretty strong relationships in this scenario of sepsis-induced insulin resistance. In fact, when we look at these relationships, one thing seems to contribute to insulin resistance, diabetes, obesity, sepsis, and even early death due to sepsis. I am talking about the 4th most abundant mineral in the body and one that has gotten little play from scientists up until recently, magnesium.
Magnesium is critically important in over 300 enzymatic reactions in your body. Both the secretion of and effectiveness of insulin are dependent on adequate magnesium. In the presence of insulin, cells require magnesium in order to take in glucose from the bloodstream(1). In children, serum magnesium has been shown to be lower in obese children than lean controls(2). In adults, lowering serum and intracellular magnesium via a diet low in magnesium has been shown to reduce insulin sensitivity. Evidence from the study suggests this was via reduced insulin action(3). Oral magnesium intake has also been shown to improve insulin sensitivity, even in people who have normal magnesium levels(4). This could be due to the fact that serum magnesium is a terrible indicator for magnesium status given that magnesium is primarily an intracellular cation and serum magnesium levels are tightly controlled. If they weren't you would die with the slightest variation outside of the normal range. When compared to normal controls, people with the metabolic syndrome tend to have lower intakes of magnesium(5). Mirroring the results of this study, a prospective study performed in 2012 found an inverse relationship between the intake of magnesium and incidence of diabetes. What makes this study more interesting than the others is the fact that they also found an inverse relationship between magnesium intake/serum magnesium and markers of inflammation(6). It is widely known that chronic inflammation is correlated with diabetes and metabolic syndrome, the fact that both magnesium intake and serum magnesium levels correlated with the level of chronic inflammation in this study strengthens that notion. It is even possible that this relationship could be stronger if intracellular magnesium was measured. But how does a magnesium deficiency lead to chronic inflammation?
When we look at the effects of sepsis on insulin sensitivity, the strength of the relationship between the 2 is as strong as the relationship between magnesium deficiency and insulin resistance. In a study on rats, progressive magnesium deficiency increased the rate of mortality in rats induced with endotoxemia(7). The longer the rats were magnesium deficient the more likely they were to die from endotoxemia. In addition, rats that were treated with magnesium had a 300% increased likelihood of survival compared with control rats. In another study on rats, sepsis induced a drop in magnesium over time that eventually recovered during the later part of sepsis(8). In a study in humans, 52% of patients entering the ICU unit had hypomagnesemia. Patients with hypomagnesemia were almost twice as likely to die (58% vs 32%), required more care, and were twice as likely to experience sepsis (38% vs 19%)(9). As menioned above, one of the problems with measuring serum magnesium is that it is tightly controlled in the body, if it gets too out of whack you die. Since magnesium is primarily found within cells, Red Blood Cell magnesium seems to be a better indicator of magnesium status. In studies that have measured RBC magnesium instead of serum, the incidence of hypomagnesemia in critically ill patients is much higher which may confound the results(9).
Given that hypomagnesemia leads to both an increased risk of sepsis as well as poorer outcomes, there must be some mechanism by which magnesium inhibits sepsis. In a study examining rabbits rendered endotoxemic with LPS, histamine levels quickly increased to 50x greater than baseline values and remained that high throughout the 6 hour study period(10). A study on humans performed in 1996 found multiple relationships between sepsis and histamine levels. None of the patients with low histamine levels as determined by criteria in the study experienced sepsis while 45% of the patients with sepsis had high histamine levels. Of the patients with sepsis, the non-survivors had higher plasma histamine levels than survivors and all of the subjects with a high sepsis score AND high plasma histamine levels died(11). All of this begs the question, is there some relationship between histamine and magnesium?
Two studies in humans have shown a decrease in intracellular magnesium levels during increased histamine levels in asthmatic patients(12,13). In the first study, magnesium and histamine levels were measured during asthma attack. When compared to asymptomatic levels as well as control subjects, histamine levels increased during asthma attack while plasma and intracellular magnesium levels dropped(12). In the second study, patients were given histamine to induce an asthma attack. While plasma magnesium didn't change, there was a significant decrease in intracellular magnesium levels(13). One of the likely mechanisms by which histamine reduces magnesium levels is via Diamine oxidase (DAO) production. DAO is an enzyme secreted by cells of the intestinal mucosa that enters the circulation via the lymphatic system. DAO inactivates histamine and is dependent on magnesium for production. Therefore, when histamine levels increase, magnesium is used to create DAO to metabolize the histamine. As magnesium levels drop due to sustained histamine release, DAO levels drop and histamine levels increase. In a study performed on rats, rats fed a magnesium deficient diet for 8 days had a decrease in duodenal DAO activity which led to an increase in blood histamine levels. Feeding the rats a diet high in magnesium for 2 days decreased blood histamine levels to that of controls(14).
The relationship between histamine levels and magnesium appears to be multi-faceted. In another study on rats, magnesium deficiency led to an initial increase of histamine levels reaching a maximum of 5x the control level by 14 days on a magnesium restricted diet with a subsequent decline to control levels as the magnesium deficiency continued(15). The mast cells (cells that secret histamine) that remained or were produced after magnesium deficiency had a reduced capacity to store and secrete histamine. This implies that magnesium is necessary for the manufacture and secretion of histamine as well as the inactivation of it. Judging from the results of both experiments, priority is given to histamine production over histamine metabolism. This underscores the importance of histamine release to the immune response.
One hormonal player in the obesity/insulin resistance game that we have yet to discuss is leptin. Leptin is an inflammatory hormone secreted by fat tissue that suppresses appetite. Basically, you eat food and when you start making body fat, leptin is secreted by fat cells to tell the brain that you are in a fed state. In obesity and the metabolic syndrome, people become resistant to the effects of leptin. This causes them to never receive the fed signal which causes them to overeat. While there is no good evidence linking leptin to magnesium, there is very strong evidence linking leptin to histamine in mice. In a study on rats, the administration of leptin caused an increase in hypothalamic histamine that lasted 4 hours in anesthetized rats(16). The same dosage of leptin given to non-anesthetized rats significantly reduced food intake. In another study, mice treated with leptin had an 84% reduction in food intake when compared to controls 24 hours after being treated(17). In mice treated with FMH(an inhibitor of histamine) prior to leptin, appetite was not significantly different. In a study using mice bred to lack the histamine H1 receptor(H1KO), injection of leptin did not significantly change appetite in comparison to control mice. These findings were confirmed in another study on rats(18). Finally, in a study that looked directly at the effect of histamine on feeding behavior and fat deposition, injecting leptin resistant obese and diabetic mice with histamine reduced food intake and bodyweight(19). In addition, histamine treatment in the experimental group reduced body fat, ob gene expression, and leptin levels to a greater degree than that seen in pair-fed controls. The histamine treated H1KO mice also saw greater improvements in blood glucose and insulin sensitivity than pair-fed controls. Interestingly enough, the effect on body fat reduction was only significant in visceral fat, the type of body fat associated with insulin resistance and the metabolic syndrome.
The sum of all of the evidence discussed above points to very strong relationships between sepsis, insulin resistance, histamine, and leptin. It seems as though control of sepsis may be given priority over blood glucose control and magnesium may mediate this. Since both biological functions are dependent on magnesium for proper function, preference has to be given to one function over the other. Over the course of evolution, natural selection would have favored those animals that gave precedence to control of sepsis over blood glucose control since infection was the primary cause of mortality and blood glucose levels were controlled by the availability of food and energy required to attain it. In addition, system-wide insulin resistance during sepsis would confer an advantage to the host via conserving blood glucose for the brain. It appears there is a very strong relationship between magnesium intake and levels, histamine levels, sepsis, and insulin resistance. One potential idea is that a diet high in foods that increase intestinal permeability and blood levels of LPS increase the body's need for magnesium to both produce and metabolize histamine. Since the body naturally gives precedence to control of sepsis over that of blood glucose, people who experience endotoxemia from LPS will have reduced magnesium availability to both produce insulin and allow glucose uptake by cells. If magnesium deficiency reaches the point of negatively impacting the production of DAO, histamine levels will increase. At some point, either histamine levels decrease, possibly due to magnesium deficiency, or histamine receptors downregulate and become resistant to histamine in the brain. This reduces leptin signaling and leads to an inability to control appetite. These could be the initial stages of insulin resistance that eventually progress to Type 2 Diabetes and the metabolic syndrome.
It appears that special care should be taken to manage magnesium status both by increasing intake as well as limiting lifestyle activities that increase magnesium depletion to prevent the metabolic syndrome. Examples of lifestyle activities that are known to deplete magnesium are poor sleep, high carbohydrate diets, smoking, alcohol intake, excess stress, and eating foods that increase intestinal permeability and blood levels of LPS (1). Interestingly enough, all of these activities have been shown to be correlated with the metabolic syndrome. This is not to say that magnesium is the sole cause of the entire problem, only that it is a major player in it and a potential target for therapy. This also presents a competing paradigm that contrasts with the energy balance paradigm for weight management.
In my next blog I will explain this in plain English and give actionable steps to improve the metabolic syndrome and how those steps contribute to a healthy magnesium status. Here's a hint, it involves a lot more than taking magnesium supplements.
REFERENCES
1)Magnesium miracle
2)http://www.ncbi.nlm.nih.gov/pubmed/15855585
3)http://hyper.ahajournals.org/content/21/6_Pt_2/1024.short
4)http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2010.01332.x/abstract;jsessionid=8F71CE49763637EE8FA0805916869F81.d04t02?deniedAccessCustomisedMessage=&userIsAuthenticated=false
5)http://onlinelibrary.wiley.com/doi/10.1038/oby.2007.628/full
6)http://care.diabetesjournals.org/content/33/12/2604.short
7)http://journals.lww.com/ccmjournal/Abstract/1995/01000/Progressive_magnesium_deficiency_increases.19.aspx
8)http://link.springer.com/article/10.1186%2F2110-5820-1-53?LI=true#page-1
9)http://www.japi.org/january_2011/oa_%20hoyponagnesemia.pdf
10)http://link.springer.com/article/10.1007%2Fs00210-002-0651-x?LI=true
11)http://journals.lww.com/ccmjournal/Abstract/1996/10000/Histamine_release_in_sepsis__A_prospective,.12.aspx
12)http://europepmc.org/abstract/MED/749826
13)http://erj.ersjournals.com/content/16/4/621.short
14)http://www.ncbi.nlm.nih.gov/pubmed/3111814
15)http://jn.nutrition.org/content/110/5/851.full.pdf
16)http://www.sciencedirect.com/science/article/pii/S0006899300023258
17)http://cat.inist.fr/?aModele=afficheN&cpsidt=1201182
18)http://diabetes.diabetesjournals.org/content/48/12/2286.short
19)http://diabetes.diabetesjournals.org/content/50/2/376.short
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