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.