Let's say you've gone to your doctor for your annual check-up. The Dr. comes in and tells you that he sees something in your bloodwork that is troubling to him, and he'd like to put you on a drug. At this point the vast majority of people will just take the drug, but a few may question the Dr. more, as they should. Let's just assume you are one of those people, and the conversation carries on.
"Well, I'm a little concerned about your bloodwork. You have an elevated risk for cardiovascular disease, I'd like to put you on one of 2 drugs. The first one will reduce your future risk of death from cardiovascular disease by 30%, and the second will only prevent death for 1 out of 30 people."
As the shock sets in, you begin to think about the prospects of having to take a drug for the rest of your life. Of course, cardiovascular disease has always been on your mind. Your father had a heart attack at 55. You've done your best to get regular exercise and eat a healthy diet, and at 45 years of age feel 10 years younger. Despite feeling well and never having had a heart attack, you decide it's likely in your best interest to take a drug.
Which drug would you take? Assuming that you are generally good at math, most people would choose the first one. The problem is, the first and the second drug are the same drug. Of course clinical research studies often have different outcomes depending on how they are designed, but this data is not only for the same drug it's from the same study, I just worded the outcome differently(1). This illustrates an important point; when research results are worded in a way that inflates the results, people are more likely to take a drug.
When you look at the "30% decreased risk", that is something termed
relative risk. This is used often despite the fact that it presents the
data in a deceptive way that makes you more likely to take the drug. Let's say you perform a study with 100 people
in the treatment group and 100 people in the placebo group. Of the
people who received the treatment only 1 person died, while in the group
not receiving the treatment 2 people died. This would seem to be a
very small effect since the absolute difference is only 1. However,
stated in relative risk terms, the treatment reduced the risk of death
by 50%. This is where numbers like the number needed to treat(NNT) come
in handy. In this fake study, the NNT is 100. In other words, you
need to treat 100 people with the drug to prevent one death, the other 99 who are
taking it will not live any longer with or without the drug. Yay!
This is problematic for many reasons, not the least of which being that most pharmaceutical drugs have a laundry list of side effects that could affect the 29 out of 30 people not experiencing a benefit from the drug. For statins, this means an increased risk of neurological problems, muscle pain, an increased risk for Type 2 diabetes, liver damage, and more. Another reason this is problematic is that they have recently revised the guidelines for prescribing statin drugs which would increase the number of people eligible to take the drugs to 56 million. This would potentially prevent 1.87 million deaths over the course of 5-6 years, while 54.13 million would be taking the drug with no benefit from a mortality standpoint. The interesting part is that these numbers are for people who have had a previous heart attack, if you've never had a heart attack, the picture is worse.
For primary prevention, the NNT is a lot worse. Primary prevention essentially means using statins to prevent a heart attack or stroke in someone who has never had one before. The NNT in these people is 1 in 60 to prevent a heart attack and 1 in 268 to prevent a stroke. Side effects, on the other hand were seen in 1 in 50 people(Type 2 diabetes) or 1 in 10(muscle damage)(2). The NNT to prevent 1 death from cardiovascular disease in primary prevention trials fluctuates but is typically around 1 in 120. Taken together, this means that in 600 people you would prevent 10 heart attacks and prevent 5 deaths, while
creating 12 new cases of diabetes, which increases your risk for a heart
attack. In fact, people with Type 2 diabetes have the same risk of experiencing a heart attack as someone who has had a heart attack before and are twice as likely to die from a heart attack than non-diabetics(3). So, of the 600 people who took the drug, 10 will prevent a heart attack and 12 will substantially increase their risk for one. Does that sound like something you would sign up for?
When you look at the data this way, it makes the decision on whether or not to take something like a statin a lot more difficult. I can't tell a person whether or not they should take a drug, that's between that person and their doctor. Looking at the total picture from a numbers standpoint makes the decision a lot more difficult than, "You're the DR, whatever you say". On top of the numbers issue, they are finding new therapeutic effects from these drugs every day and so many of the results conflict with one another. Recent evidence has shown that statins may be protective against cancer when taken for 4 years(4), but they may also double a woman's risk of breast cancer when taken for over 10 years(5).
While many of the researchers who come to positive findings on these drugs hail them, one has to wonder how they know the drugs are totally safe when they are finding new ways to use them every day. If you are looking for therapeutic uses for a drug and are just now finding new ones, how can you get a complete handle on the total range of side effects when they are more of an afterthought and may not pop up until 10 years down the road? The point of this is not to prevent you from taking pharmaceutical drugs, the point is that you should ask more questions, research these drugs, and weigh the pros and cons before you decide that's the route you're going to take. Just for the sake of comparison, 300 minutes of exercise per week for the use of primary prevention of heart disease can reduce your risk by 20%(6) and regular exercise for secondary prevention can reduce the risk of death from heart disease by 27%(7).
Showing posts with label Heart Disease. Show all posts
Showing posts with label Heart Disease. Show all posts
Thursday, September 4, 2014
Wednesday, May 14, 2014
L-Carnitine, red meat, and heart disease
In a recent article that hit most every newsroom last week, red meat kills people again. Here is a link to one of the articles (1) and here is a link to the actual study (2). The headlines that hit the newsstands were along the line of, "Red meat increases heart disease!" and things along that nature. If the rate that nutritional information does a flip flop doesn't normally give you vertigo, it will today. In an article published less than a week later, researchers note that an increase in L-Carnitine is protective in people who have just experienced a heart attack (3). Before I show you why you should not rely on the news media to dictate your lifestyle choices, let's look at what each study showed.
In the first study, researchers compared the effect of L-Carnitine supplementation between meat eaters to non-meat eaters. In meat eaters, bacteria in the gut fermented L-Carnitine in to TMAO, a chemical known to accelerate atherosclerosis while this effect was non-existent in non-meat eaters. Since L-Carnitine is high in red meat, researchers believed that constant red meat consumption led to changes in gut flora that promotes an environment beneficial to creation of TMAO. So, excessive red meat consumption leads to higher levels of bacteria that convert Carnitine to TMAO and this can increase atherosclerosis. Check!
The second study was a meta analysis (Large study evaluating many studies) and found that using L-Carnitine was beneficial in the recovery from a heart attack. People who used L-Carnitine were less likely to die from any cause, were less likely to experience arrythmia, less likely to experience angina, and had smaller infarct size than those who did not use L-Carnitine. So, Carnitine conveyed a benefit to the person using it, specifically for heart health.
These 2 contradictory studies highlight a couple of problems. First, the headlines that state, "Red meat increases heart disease" are wrong. Having a specific type of gut flora that may be found in meat eaters would indicate you shouldn't take L-Carnitine supplements. If you don't eat tons of red meat you are unlikely to have gut flora indicative of the people in this study that had a problem with TMAO. Next, by looking at the study we can find the limitations of what the study can say. One thing of note was that this study did not control for veggie intake. What if the benefit of being vegan wasn't that you are not eating red meat, but that vegetable intake is high? A meat eater that eats a lot of vegetables would have very different gut flora than a meat eater who eats none. Maybe the vegan diet is beneficial because of the high vegetable intake, not because of a lack of meat. This is one of the reasons the Synergy Wellness Program recommends a large diversity of foods. A larger diversity of foods allows the bacteria in your gut to be diverse, preventing pathogenic bacteria from being able to grow to a capacity that could impact your health.
One of the problems with getting your science information from the popular press is that they seem to ignore what a study shows as well as the limitations study design put on what you can extract from a study. When you see an article that one week shows coffee to be bad for you, then the following week find one that says it's bad for you, more often than not the problem isn't that the data is conflicting it's that people are ignoring the fact that certain types of data are not appropriate for drawing conclusions. Even when the data is appropriate, the title of the article is meant to grab your attention, not be scientifically accurate. Keep this in mind whenever you are looking at "science" in the popular press.
In the first study, researchers compared the effect of L-Carnitine supplementation between meat eaters to non-meat eaters. In meat eaters, bacteria in the gut fermented L-Carnitine in to TMAO, a chemical known to accelerate atherosclerosis while this effect was non-existent in non-meat eaters. Since L-Carnitine is high in red meat, researchers believed that constant red meat consumption led to changes in gut flora that promotes an environment beneficial to creation of TMAO. So, excessive red meat consumption leads to higher levels of bacteria that convert Carnitine to TMAO and this can increase atherosclerosis. Check!
The second study was a meta analysis (Large study evaluating many studies) and found that using L-Carnitine was beneficial in the recovery from a heart attack. People who used L-Carnitine were less likely to die from any cause, were less likely to experience arrythmia, less likely to experience angina, and had smaller infarct size than those who did not use L-Carnitine. So, Carnitine conveyed a benefit to the person using it, specifically for heart health.
These 2 contradictory studies highlight a couple of problems. First, the headlines that state, "Red meat increases heart disease" are wrong. Having a specific type of gut flora that may be found in meat eaters would indicate you shouldn't take L-Carnitine supplements. If you don't eat tons of red meat you are unlikely to have gut flora indicative of the people in this study that had a problem with TMAO. Next, by looking at the study we can find the limitations of what the study can say. One thing of note was that this study did not control for veggie intake. What if the benefit of being vegan wasn't that you are not eating red meat, but that vegetable intake is high? A meat eater that eats a lot of vegetables would have very different gut flora than a meat eater who eats none. Maybe the vegan diet is beneficial because of the high vegetable intake, not because of a lack of meat. This is one of the reasons the Synergy Wellness Program recommends a large diversity of foods. A larger diversity of foods allows the bacteria in your gut to be diverse, preventing pathogenic bacteria from being able to grow to a capacity that could impact your health.
One of the problems with getting your science information from the popular press is that they seem to ignore what a study shows as well as the limitations study design put on what you can extract from a study. When you see an article that one week shows coffee to be bad for you, then the following week find one that says it's bad for you, more often than not the problem isn't that the data is conflicting it's that people are ignoring the fact that certain types of data are not appropriate for drawing conclusions. Even when the data is appropriate, the title of the article is meant to grab your attention, not be scientifically accurate. Keep this in mind whenever you are looking at "science" in the popular press.
Thursday, May 8, 2014
New study sheds light on the connection between stress and heart disease
A new study in the journal Biological Psychiatry has identified a link between chronic stress and heart disease, and you may not be surprised to learn that this link is inflammation. The study looked at activity in a part of the brain that helps to regulate emotion called the dorsal anterior cingulate cortex(dACC) and levels of inflammation in the body. The researchers found that increased activation of the dACC led to higher levels of the inflammatory molecule IL-6 and these higher levels of IL-6 corresponded with more plaque accumulation on artery walls. Let's take a look at what all of this means.
To fully understand what this means, we first have to discuss something that is regulated by the dACC called cognitive reappraisal. Cognitive reappraisal is a method of regulating the emotional response to stimuli. If this sounds familiar, it's very similar to what one tries to achieve while practicing mindfulness meditation. The problem is, cognitive reappraisal can be either positive or negative. If a stimulus causes enhanced activation of the dACC but this emotion does not make it to the amygdala to generate an emotional response, that's a positive thing. If a stimulus continually activates the dACC but also activates the amygdala constantly, that leads to a constant emotional response and chronic stress.
In this study, they found that constantly reappraising a stressful situation caused increased activity in the dACC which increased inflammation. Since this area of the brain helps control many autonomic processes, it's not surprising that activation of this area of the brain can modulate the immune response. Furthermore, the dACC is associated with anxiety and OCD-type behaviors in so much that severing the area has been shown to benefit people with OCD not responsive to medications(1).
Obviously you shouldn't severe your dACC, but this study points to the importance of reducing stress and letting things go to reduce heart disease risk. The increased level of IL-6, an inflammatory cytokine highly associated with heart disease and Type 2 diabetes, is likely a large player in the relationship between stress and health. In my next blog, I'll go over some of the physical warning signs that you may be experiencing chronic stress.
Thursday, August 8, 2013
The popular media. misinformation, and heart disease.
During a routine physical, former President George W. Bush discovered he had a blocked artery in his heart earlier this week. The following day, he had a stent placed in the artery to open the blockage. Watching the NBC Nightly News' description of the event, I found myself to be dumbfounded. Below is a list of key points from the news broadcast.
This certainly adds to the confusion I get when I tell people they don't really need to concern themselves with the amount of cholesterol they eat unless they have a genetic condition called familial hypercholesterolemia. Familial hypercholesterolemia is found in 1 out of every 500 people so it is certainly not a common condition. It will also be interesting to see whether or not the former President is put on statins, despite having normal cholesterol levels. People with familial hypercholesterolemia and people with a previous heart attack are the only people I would recommend take a statin, but that's just what the research shows and I'm not a doctor. That makes the point moot.
A more common problem with dietary research isn't with how the research is conducted so much as the way it is reported. The popular media loves to report results from epidemiological research as fact. These types of studies cannot prove cause and effect, they can only identify relationships that can be further studied with better research. The primary problem lies within the fact that most people get their information from the popular news media and not from peer reviewed journals. When the media reports this stuff, it sticks because everyone has heard it and it becomes established fact even though it has never been proven scientifically. Then, physicians get on television and keep the BS rolling. Is it any wonder how we are so misinformed on diet?
- President Bush is an avid exerciser
- He exercises 5 times a week for at least 30 minutes
- His cholesterol is normal
- Eating a low fat, "heart healthy" diet is your best protection
What you believe about nutrition could be wrong
The medical correspondent, Nancy Snyderman, MD, as well as host Lester Holt bantered about how even someone living a seemingly healthy lifestyle is not immune to the ravages of heart disease. What struck me as strange is that the notion that the recommendations for heart health are pretty much bogus never entered anybody's mind. Of course there is a huge genetic factor involved here as well as the stress involved with leading the free world for 8 years. After all, his father has heart disease and held the same job for 4 years. I have no problem with this fact. However, I do take issue with the recommendations being untouchable, especially if someone can pretty much follow them word by word and still get a blockage.Exercise-Not the cat's meow
For one, exercise is great and is something everyone should do for a multitude of reasons. As for reducing your risk for heart disease, reducing the amount of time spent being sedentary is far more important than exercising. This should be common sense, but to put some numbers behind it, 30 minutes of exercise performed 5 days a week is 2.5 hours out of a total of 168 hours in the week. That's 1.4% of the week, it doesn't even seem plausible that this amount of time could counteract being a slouch on the couch for the other 98.6%.High cholesterol is an overrated risk factor
The fact that his cholesterol is normal is also interesting for most people, but isn't very surprising. Approximately 50% of heart attacks occur in people with normal or low cholesterol. That didn't prevent Dr. Snyderman from referring to the blockage as a cholesterol blockage. I wonder why they don't refer to them as calcifications since the plaques that form the blockages are 50% calcium and only 3% cholesterol.This certainly adds to the confusion I get when I tell people they don't really need to concern themselves with the amount of cholesterol they eat unless they have a genetic condition called familial hypercholesterolemia. Familial hypercholesterolemia is found in 1 out of every 500 people so it is certainly not a common condition. It will also be interesting to see whether or not the former President is put on statins, despite having normal cholesterol levels. People with familial hypercholesterolemia and people with a previous heart attack are the only people I would recommend take a statin, but that's just what the research shows and I'm not a doctor. That makes the point moot.
Low fat does not mean low risk
The notion that the low fat heart healthy diet isn't actually healthy to the heart has been unraveling over the course of the last 5 years. Not only has it been determined that saturated fat and cholesterol are not that bad for you, replacing these foods with processed, low fat foods high in carbohydrate is worse. This has been the de facto dietary advice for a healthy heart for more than 40 years. Talk about digging yourself deeper in to a hole.Science works best when done properly
All of this brings up an excellent point that most people need to understand about science. Science doesn't make truths, it identifies them. When funding for science primarily comes from companies with financial interests in the outcomes of that science, you cannot expect to get unbiased results. A recent article looked at the likelihood of finding positive outcomes in both industry funded and government funded studies, specifically with the pharmaceutical industry. Oddly enough, government funded studies tend to get positive outcomes around 50% of the time while industry funded studies tend to find positive results around 85% of the time. Part of this problem is certainly due to the fact that industry is not required to report results from all of their studies, so they just don't report the negative ones. This is more of a pharmaceutical industry problem, but who do you think is pushing the low fat, low cholesterol BS? I'd go with the folks making the anti-cholesterol drugs.A more common problem with dietary research isn't with how the research is conducted so much as the way it is reported. The popular media loves to report results from epidemiological research as fact. These types of studies cannot prove cause and effect, they can only identify relationships that can be further studied with better research. The primary problem lies within the fact that most people get their information from the popular news media and not from peer reviewed journals. When the media reports this stuff, it sticks because everyone has heard it and it becomes established fact even though it has never been proven scientifically. Then, physicians get on television and keep the BS rolling. Is it any wonder how we are so misinformed on diet?
Wednesday, May 15, 2013
A new understanding of Type 2 Diabetes and Cardiovascular disease
A new discovery by scientists at the Harvard School of Public Health has brought us closer to understanding Type 2 Diabetes and the metabolic syndrome. Adipose Protein 2(aP2), a carrier protein found in adipocytes and macrophages, appears to also act as a signaling molecule that adipocytes secrete to increase glucose production in the liver(1). This is not the first study showing aP2 to be a contributing factor to Type 2 Diabetes and the metabolic syndrome. Let's look take a look at some of the other data.
In a study in 1999, disrupting the aP2 gene in mice lead to a 40% drop in basal lipolysis and a 300% increase in the amount of non-esterified fatty acids stored within the fat cells of the mice with aP2 disrupted(2). This indicates aP2 as a significant, if not the sole, contributor to the increase in fatty acid release from fat cells found in insulin resistance and the metabolic syndrome. Within fat cells, it appears aP2 is the signal that says, "Enough, no more fat!" Recall that Lipopolysaccharide (LPS) causes system-wide insulin resistance when it is introduced in to the body. A recent study showed that injecting LPS in to the leg of humans lead to muscle insulin resistance and increased lipolysis in fat cells; causing them to leak palmitate, one of the primary fatty acids stored in humans(3). It is likely that the palmitate was shuttled from the adipocyte by aP2 as aP2 has a 2-3x greater affinity for palmitic acid than does KLBP, the other lipid binding protein found in adipocytes(4). It appears LPS induced endotexemia is an integral step in the development of Type 2 Diabetes leading to not only muscle and fat cell insulin resistance, but also increased glucose production in the liver. In addition, blocking aP2 expression in macrophages and adipocytes has been shown to both decrease inflammation as well as protect against insulin resistance(5). The role of aP2 in the metabolic syndrome does not end there.
The gene for aP2 is also expressed in macrophages, cells of the immune system that engulf invaders in order to neutralize them Recall from the last LPS blog found here that when LPS attaches to the cell membrane of macrophages that macrophages switch from metabolizing fatty acids to metabolizing glucose. A byproduct from this switch, succinate, causes the secretion of IL-1Beta which induces insulin resistance in muscle cells and adipocytes. When exposed to oxidized LDL, macrophages become foam cells and contribute to the accumulation of plaque on blood vessel walls as aP2 becomes the most upregulated gene(6, 7) and macrophages that are aP2 deficient show a reduced capacity to form foam cells(8). In addition, it is IL-1Beta that signals muscle and fat cells to become insulin resistant and it is this insulin resistance that increases lipolysis in the fat cell and causes it to dump fatty acids, and potentially aP2, in to the bloodstream.
If all of this were not bad enough, high blood glucose causes an increase in monocyte production by bone marrow. These monocytes move to blood vessel walls and prevent the removal of plaque deposits, which over time would increase plaque accumulation on blood vessel walls. Reducing blood glucose levels prevents this increased production of monocytes and blood levels of the signaling molecule that causes this over-production of monocytes coincides with the level of coronary artery disease seen in Type 1 Diabetics(9). This entire story could potentially be the vicious cycle that leads to cardiovasular disease. Having a liver that over-secretes glucose because it thinks your fighting an infection cannot possibly help attenuate the situation.
When looking at this issue from an evolutionary biology perspective, it seems odd that an immune response would get so out of whack that it would cause these issues in an organism. When we look at in the proper context, it is absolutely a beneficial trait. In the vast majority of our time here, fasting blood glucose levels were probably between 80-90mg/dL. A mild to moderate elevation in a blood glucose level that low is probably not going to lead to sufficient plaque accumulation, certainly not in comparison to the 125mg/dL+ fasting blood glucose seen in Type 2 Diabetics. In addition, there was probably still sufficient physical activity during infection to prevent major rises in blood and glucose. A muscle that is insulin resistant is not incapable of burning glucose, it is incapable of using insulin to store it. Physical activity would still cause translocation of GLUT4 to the muscle cell membrane to take in glucose, the priority is not to prevent muscle from burning glucose it's to prevent circulating glucose from being stored in muscle tissue as it is needed for the immune system. This would allow the organism to flee in the case of immediate danger while healing from an infection. Once the infection is healed, it is unlikely that blood glucose levels would rise enough to prevent healing of plaque on blood vessel walls when a person has to actively go out and hunt or gather their food.
In a pretty thorough discussion of Otzi, the well preserved mummy of a 45 year old man who lived approximately 5400 years ago, Dr. Stephan Guyenet identifies a few health issues that Otzi experienced. In addition to having a few of his major arteries calcified, Otzi had several signs of infectious disease including intestinal parasties, Lyme's disease, and an "unknown illness that occurred three times in the four months prior to his death." Otzi also consumed significant amounts of grain, as evidenced by the belly full of wheat found in his stomach. We will never know the specifics of Otzi's health, but the fact that there was significant infectious disease prior to his death as well as significant atherosclerosis points to a potential relationship. Were the calcifications in his arteries accumulated over time or was his level of calcification a snapshot of his poor health at the time of his death? Evidence points to atherosclerosis being a part of the human condition, is that role as collateral damage from an overactive immune system? We certainly cannot ignore the effect intestinal parasites may have had on the composition of his gut flora as well.
One of the theories currently being kicked around for our chronic disease epidemic, and the basis for the Paleo diet, is that the storage proteins in grains and legumes as well as the casein found in dairy can cause a molecule called zonulin to open the tight junctions between cells of the intestinal wall. This allows LPS in to the bloodstream, potentially initiating the above events to fight an infection that doesn't really exist. There is clinical evidence that the Paleo diet leads to better cardiovascular profiles when compared to a Mediterranean diet(10, 11) as well as better glucose tolerance(12). The chief difference between the 2 diets is that the Mediterranean diet allows the consumption of grains, legumes, and dairy. Zonulin is a huge problem for people with Celiac disease because they tend to have high levels of it and the ingestion of gluten causes even higher levels. Gluten causes the same response in people without Celiac disease, but to a much smaller degree. In someone with a more robust immune system or who only gets minor doses of these offending proteins, it probably does no significant permanent damage. This could change with age, however, as the immune system becomes less effective and potential changes in gut flora manifest themselves after decades of eating foods that may not be suited to a healthy gut
If the triggers do turn out to be the proteins in grains, legumes and dairy; Western civilization is in trouble. Processed foods are loaded with this stuff; just try to find one without grains (Wheat, corn), legumes (Soy, peanuts), or dairy (Milk, cheeses). Another potential route for LPS to make it's way in to the bloodstream is via bacterial overgrowth in to the small intestine. The type of bacteria you need to worry about primarily consume sugars. Given that the average American eats about 130lbs of sugar annually, it is not unlikely that some of it may feed bacteria that could pose a problem. At the very least, dumping that amount of sugar in to your bloodstream will negatively impact your ability to remove accumulated plaque from your blood vessel walls. Over the course of 40-50 years, this could ultimately lead to your demise.
While this new discovery helps give us a mechanistic look at how blood glucose regulation and plaque accumulation on blood vessel walls may go awry in some instances, it still leaves quite a few questions to be answered. Is this the most common way this process happens? How do food reward and leptin fit in here? Why is our brain wired so that we overconsume foods that are bad for us healthwise? How is the gut flora involved? Are these issues causes or effects? None of this changes the fact that overconsumption will more than likely cause the same problems, but is it via the same mechanism or a different one? Does food overconsumption eventually lead to reaching your genetic capacity to store fat and leaching of fatty acids, and aP2, in to the bloodstream to initiate the same process? As you can see, whenever we find one answer, 20 more questions pop up.
In a study in 1999, disrupting the aP2 gene in mice lead to a 40% drop in basal lipolysis and a 300% increase in the amount of non-esterified fatty acids stored within the fat cells of the mice with aP2 disrupted(2). This indicates aP2 as a significant, if not the sole, contributor to the increase in fatty acid release from fat cells found in insulin resistance and the metabolic syndrome. Within fat cells, it appears aP2 is the signal that says, "Enough, no more fat!" Recall that Lipopolysaccharide (LPS) causes system-wide insulin resistance when it is introduced in to the body. A recent study showed that injecting LPS in to the leg of humans lead to muscle insulin resistance and increased lipolysis in fat cells; causing them to leak palmitate, one of the primary fatty acids stored in humans(3). It is likely that the palmitate was shuttled from the adipocyte by aP2 as aP2 has a 2-3x greater affinity for palmitic acid than does KLBP, the other lipid binding protein found in adipocytes(4). It appears LPS induced endotexemia is an integral step in the development of Type 2 Diabetes leading to not only muscle and fat cell insulin resistance, but also increased glucose production in the liver. In addition, blocking aP2 expression in macrophages and adipocytes has been shown to both decrease inflammation as well as protect against insulin resistance(5). The role of aP2 in the metabolic syndrome does not end there.
The gene for aP2 is also expressed in macrophages, cells of the immune system that engulf invaders in order to neutralize them Recall from the last LPS blog found here that when LPS attaches to the cell membrane of macrophages that macrophages switch from metabolizing fatty acids to metabolizing glucose. A byproduct from this switch, succinate, causes the secretion of IL-1Beta which induces insulin resistance in muscle cells and adipocytes. When exposed to oxidized LDL, macrophages become foam cells and contribute to the accumulation of plaque on blood vessel walls as aP2 becomes the most upregulated gene(6, 7) and macrophages that are aP2 deficient show a reduced capacity to form foam cells(8). In addition, it is IL-1Beta that signals muscle and fat cells to become insulin resistant and it is this insulin resistance that increases lipolysis in the fat cell and causes it to dump fatty acids, and potentially aP2, in to the bloodstream.
If all of this were not bad enough, high blood glucose causes an increase in monocyte production by bone marrow. These monocytes move to blood vessel walls and prevent the removal of plaque deposits, which over time would increase plaque accumulation on blood vessel walls. Reducing blood glucose levels prevents this increased production of monocytes and blood levels of the signaling molecule that causes this over-production of monocytes coincides with the level of coronary artery disease seen in Type 1 Diabetics(9). This entire story could potentially be the vicious cycle that leads to cardiovasular disease. Having a liver that over-secretes glucose because it thinks your fighting an infection cannot possibly help attenuate the situation.
When looking at this issue from an evolutionary biology perspective, it seems odd that an immune response would get so out of whack that it would cause these issues in an organism. When we look at in the proper context, it is absolutely a beneficial trait. In the vast majority of our time here, fasting blood glucose levels were probably between 80-90mg/dL. A mild to moderate elevation in a blood glucose level that low is probably not going to lead to sufficient plaque accumulation, certainly not in comparison to the 125mg/dL+ fasting blood glucose seen in Type 2 Diabetics. In addition, there was probably still sufficient physical activity during infection to prevent major rises in blood and glucose. A muscle that is insulin resistant is not incapable of burning glucose, it is incapable of using insulin to store it. Physical activity would still cause translocation of GLUT4 to the muscle cell membrane to take in glucose, the priority is not to prevent muscle from burning glucose it's to prevent circulating glucose from being stored in muscle tissue as it is needed for the immune system. This would allow the organism to flee in the case of immediate danger while healing from an infection. Once the infection is healed, it is unlikely that blood glucose levels would rise enough to prevent healing of plaque on blood vessel walls when a person has to actively go out and hunt or gather their food.
In a pretty thorough discussion of Otzi, the well preserved mummy of a 45 year old man who lived approximately 5400 years ago, Dr. Stephan Guyenet identifies a few health issues that Otzi experienced. In addition to having a few of his major arteries calcified, Otzi had several signs of infectious disease including intestinal parasties, Lyme's disease, and an "unknown illness that occurred three times in the four months prior to his death." Otzi also consumed significant amounts of grain, as evidenced by the belly full of wheat found in his stomach. We will never know the specifics of Otzi's health, but the fact that there was significant infectious disease prior to his death as well as significant atherosclerosis points to a potential relationship. Were the calcifications in his arteries accumulated over time or was his level of calcification a snapshot of his poor health at the time of his death? Evidence points to atherosclerosis being a part of the human condition, is that role as collateral damage from an overactive immune system? We certainly cannot ignore the effect intestinal parasites may have had on the composition of his gut flora as well.
One of the theories currently being kicked around for our chronic disease epidemic, and the basis for the Paleo diet, is that the storage proteins in grains and legumes as well as the casein found in dairy can cause a molecule called zonulin to open the tight junctions between cells of the intestinal wall. This allows LPS in to the bloodstream, potentially initiating the above events to fight an infection that doesn't really exist. There is clinical evidence that the Paleo diet leads to better cardiovascular profiles when compared to a Mediterranean diet(10, 11) as well as better glucose tolerance(12). The chief difference between the 2 diets is that the Mediterranean diet allows the consumption of grains, legumes, and dairy. Zonulin is a huge problem for people with Celiac disease because they tend to have high levels of it and the ingestion of gluten causes even higher levels. Gluten causes the same response in people without Celiac disease, but to a much smaller degree. In someone with a more robust immune system or who only gets minor doses of these offending proteins, it probably does no significant permanent damage. This could change with age, however, as the immune system becomes less effective and potential changes in gut flora manifest themselves after decades of eating foods that may not be suited to a healthy gut
If the triggers do turn out to be the proteins in grains, legumes and dairy; Western civilization is in trouble. Processed foods are loaded with this stuff; just try to find one without grains (Wheat, corn), legumes (Soy, peanuts), or dairy (Milk, cheeses). Another potential route for LPS to make it's way in to the bloodstream is via bacterial overgrowth in to the small intestine. The type of bacteria you need to worry about primarily consume sugars. Given that the average American eats about 130lbs of sugar annually, it is not unlikely that some of it may feed bacteria that could pose a problem. At the very least, dumping that amount of sugar in to your bloodstream will negatively impact your ability to remove accumulated plaque from your blood vessel walls. Over the course of 40-50 years, this could ultimately lead to your demise.
Conclusion
While this new discovery helps give us a mechanistic look at how blood glucose regulation and plaque accumulation on blood vessel walls may go awry in some instances, it still leaves quite a few questions to be answered. Is this the most common way this process happens? How do food reward and leptin fit in here? Why is our brain wired so that we overconsume foods that are bad for us healthwise? How is the gut flora involved? Are these issues causes or effects? None of this changes the fact that overconsumption will more than likely cause the same problems, but is it via the same mechanism or a different one? Does food overconsumption eventually lead to reaching your genetic capacity to store fat and leaching of fatty acids, and aP2, in to the bloodstream to initiate the same process? As you can see, whenever we find one answer, 20 more questions pop up.
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