No free lunch: No calorie sweeteners shown to cause gut changes that induce glucose intolerance

No-calorie sweeteners have proven to be relatively useless in the fight against obesity, despite what the food industry may tell you.  In a new study published in Nature, researchers provide evidence that no-calorie sweeteners can induce metabolic changes that lead to glucose intolerance in both mice and humans.  This study found that the changes in glucose tolerance come about from shifts in gut bacteria.

The mouse arm of this study started by feeding mice a 10% solution of either saccharin, aspartame, or sucralose in place of drinking water and comparing their glucose tolerance to control mice given either water alone or a 10% glucose solution.  After 11 weeks, the glucose tolerance in the mice given the artificial sweetener was worse than the mice given water or even glucose.  Previous research has shown that certain no calorie sweeteners can alter the gut microbiome, so the researchers gave mice a 4 week course of antibiotics to wipe out the microbiome.  The result...Glucose tolerance returned to normal.

To make certain that the effects were due strictly to changes in the gut microbiome, researchers transplanted feces from the mice given saccharin in to germ-free mice who had not had the sweetener.  Within a week, the germ-free mice had the same changes in glucose tolerance as those who consumed the no-calorie sweetener.  Looking at the fecal samples, researchers found changes in the microbiome that mirrored changes in the microbiome of humans that eat no-calorie sweeteners.  Furthermore, a follow-up with 7 humans with no history of using no-calorie sweeteners who were fed saccharin at the maximum daily limit allowed by the FDA found that 4 of the subjects had poorer glucose tolerance after 7 days and an altered gut microbiome that, when transplanted in to mice, resembled the one seen in mice fed saccharin.

This study brings up a few important points.  While the dosage of no-calorie sweetener was high, it was within FDA limits.  So while you may not consume these sweeteners at the level seen in these studies, the point is that they aren't entirely benign.  Furthermore, relying on these sweeteners as a crutch to kick a sweet tooth may not be in your best interest, especially if you are diabetic.  Secondly, some people did not respond negatively to the no-calorie sweetener.  An important question to answer would be whether or not Type 2 diabetics, who have poor glycemic control in the first place, are more likely to be susceptible to poorer glycemic control from these sweeteners due to their microbiome.  I would be willing to bet that people with Type 2 diabetes are more likely to rely on no-calorie sweeteners because they "have no direct effect on blood glucose".  Unfortunately, they apparently have an indirect effect on blood glucose that is just as bad as a direct one.

Finally, even though the people who weren't affected by the artificial sweeteners were in the minority, the fact that their glucose tolerance wasn't affected, nor was their microbiome, points to no-calorie sweeteners being benign for them.  As is a frequent topic in this blog, an individualized approach to health and diet is always the best approach.

Evolution and diabetes part 2: Blood glucose regulation by ancestral humans

In my last blog I went over a study that casts some doubt on the notion that the liver is critical for blood glucose control.  In this study, they found that mice who had their liver blocked from contributing to blood glucose control adapted by shifting that duty over to the kidneys and intestine(1).  The assumption that the liver is king as far as blood glucose control is a fairly widely held concept due to the fact that it can store 100g of glucose and produce glucose from non-carbohydrate sources.  The problem arises when you take in to account that easy access to carbohydrates is a fairly recent phenomenon.  Taken together with other scientific evidence, it appears that the intestine should likely play a larger role in blood glucose regulation than it does today, and the modern diet prevents this from happening.

In this study the kidneys took on a much larger role in blood glucose regulation during times of fasting as the gene crucial for blood glucose regulation increased in expression.  The intestine also saw an increase in expression of this gene, but the total expression of this gene was 50x greater in the kidney.  These results may understate the importance of the intestine in blood glucose regulation, especially in the non-fasted state.

When you compare the diet of ancestral, pre-agricultural humans to that of today, one glaring difference is the fiber content of the diet.  Today, the average human diet contains less than 20g of fiber per day.  In his book The Story of the Human Body, Dr. Dan Lieberman's assessment of the literature points to the consumption of 100-150g of fiber per day by pre-agricultural humans.  This number is in line with what previous research has shown(2) as well as Jeff Leach's experience living with modern day hunter gatherers.  While the difference in fiber intake may not seem important when you consider humans don't absorb fiber, when you look at what it does to the microbiome and the effect it has on blood glucose regulation you can see that it is likely very important.

When bacteria in the intestine break down fiber, they make short-chain fatty acids(SCFAs), specifically butyrate and propionate.  Both of these SCFAs promote intestinal gluconeogensis in complementary ways(3).  Gluconeogenesis is the generation of blood glucose from non-carbohydrate sources and it allows the intestine to participate in blood glucose regulation through the fermentation of fiber by bacteria in the gut.  Interesingly, when gluconeogenesis is shut off in the intestine, all of the metabolic benefits of a high fiber diet are lost despite having a similar microbiome.  So, in a population where people consume low amounts of fiber, the intestine likely has a negligible role in regulating blood glucose.  Ironically, in this population, blood glucose tends to run high.  In a population where fiber is consumed in large quantities, the intestine likely takes on a much larger role in regulating blood glucose.  In this population, blood glucose tends to remain low.  This is not the only piece of the puzzle, however.

There is another issue that arises when bacteria in the intestine don't ferment fiber in to butyrate.  Butyrate is the fuel of choice for cells of the colon(4), but they are able to metabolize glucose as well.  A problem occurs when there isn't enough butyrate for the cells of the colon(Colonocytes), they must rely on glucose as a source of energy(4, 5).  When colonocytes are provided enough butyrate, they break it down in to the ketone beta-hydroxybutyrate which can be further broken down for energy.  When there isn't enough butyrate, they are forced to metabolize glucose which colonocytes break down in to lactate.  Colonocytes cannot metabolize lactate so it is sent to the liver to undergo gluconeogenesis.  In a mouse model of colitis, this is how colonocytes metabolize energy(5).  Unfortunately, glucose is unable to provide enough energy for efficient  gastrointestinal function in this manner(4).

In addition to having an effect on gluconeogenesis by the intestine, SCFAs also stimulate secretion of a hormone called glucagon-like peptide 1(GLP-1)(6).  GLP-1 has several roles in the body, but of interest to our discussion is it's role in insulin and glucagon secretion.  Insulin lowers blood glucose by causing cells to take it in while glucagon causes blood glucose to increase by increasing gluconeogenesis in the liver, kidney and intestine as well as causing those organs to release glucose.  GLP-1 stimulates insulin secretion in a glucose dependent manner, when glucose levels are high GLP-1 stimulates more insulin than when glucose levels are low while it causes glucagon levels to fall independent of glucose levels.  It is worthy to note that carbohydrate consumption also causes GLP-1 to be secreted, but since carbohydrate consumption will cause blood glucose levels to rise, it will cause more insulin secretion than one would see going the fiber route.

People with Type 2 diabetes tend to have a large amount of insulin in their blood, but their cells don't respond to it because they have become resistant.  This causes their blood glucose to run high because insulin can't do it's job of lowering blood glucose.  Since glucagon increases blood glucose and runs high in Type 2 diabetics, it is believed that lowering glucagon levels can help correct the high blood glucose levels associated with the disease.  Metformin, the Type 2 diabetes medicine of choice, works by causing the liver to make less glucose, which causes the same effect as lowering glucagon.  GLP-1 and drugs that mimic it accomplish the same thing, are being used as pharmaceutical therapies, and the result is lower blood glucose levels(7, 8).

The positive effect of administering GLP-1 to improve blood glucose regulation brings up a few interesting questions.  Is the intestine a more important component of blood glucose regulation than we give it credit for?  Is bacterial fermentation of fiber in to butyrate the first step in blood glucose regulation given how important it likely was for blood glucose regulation in ancestral humans?  Finally, is administering pharmaceutical GLP-1 merely restoring an ancient signal from the intestine to the liver saying, "I have your back" with regard to gluconeogenesis and blood glucose regulation?  While we are unlikely to find answers to these questions any time soon, it is very interesting that higher fiber intake is very protective against Type 2 diabetes (9, 10, 11, 12).  Furthermore, people with Type diabetes tend to have more disturbances within the digestive tract than healthy people(13, 14) with the most common disturbance being constipation.

Between the evidence provided above and comparisons of the ancestral diet to our modern one, it seems likely that the modern diet may be presenting an environment that causes blood glucose to be regulated in a way that is not efficient for humans.  Our long history of high fiber consumption likely selected for people who were good at using the fermentation of fiber by resident bacteria as the first step of blood glucose regulation that involved the intestine to a much larger degree than it does today.  The modern diet puts a much larger burden on the liver to make and regulate blood glucose due to the high carbohydrate and low fiber content of the diet.  This provides less fuel to allow the intestine to participate in blood glucose regulation and may be a contributing factor to Type 2 diabetes and the increased occurrence of GI disorders associated with the disease.

Evolution, diabetes, and blood glucose regulation

When practiced appropriately, science can shed a lot of light on some pretty powerful concepts in human health.  To date we have unlocked the human genome, developed some novel pharmaceutical interventions for diseases that were once taking a large toll on society, and begun to understand that we are carrying along an exponentially larger number of bacteria that have a dramatic impact on the way we function.  However, many of the health concerns we see today are not being addressed in the appropriate manner.  Comparing the use of a pharmaceutical drug to no treatment, or placebo, makes perfect sense when you are dealing with a bacterial or viral pathogen, but does it really make sense when the true problem is a poor lifestyle?

When performing science, you are not really trying to prove anything, you are trying to disprove the null hypothesis.  The null hypothesis is the default position, and in the instance of a pharmaceutical intervention against a pathogen it typically means giving some of the subjects a placebo pill to simulate not doing anything.  The problem is, at this point, there is a very large lifestyle component to the vast majority of diseases we are seeing today.  This includes cardiovascular disease, some types of cancer, Alzheimer's, and the topic of this blog, Type 2 diabetes.  If we know that a poor lifestyle largely contributes to these diseases, should the default position be taking a placebo pill and calling it a day, or would it make more sense to have the default condition be changing those lifestyle habits that cause the disease?  I suppose that depends on how you look at what the pharmaceutical intervention is trying to accomplish.

Let's be honest, I've worked in the health and wellness field for 18 years.  When someone is told they need to change their lifestyle or a disease they have is going to progress and they choose not to, they really aren't looking for a solution.  What they are looking for is something that will allow them to continue their poor lifestyle while preventing the damage that their lifestyle causes.  If this is what we are testing for with pharmaceutical interventions for these lifestyle diseases, it only makes sense to have the null hypothesis be the condition where the damage stops.  In other words, the null hypothesis should be the lifestyle that causes no more damage.  That way, when we compare the pharmaceutical intervention to the proper lifestyle group, we have an idea to what extent the drug is actually subsidizing the poor behavior.  When you compare the pharmaceutical drug to doing absolutely nothing other than taking a sugar pill, what would you expect to happen?  The drug will come out looking like it's the cure for something that it's not, which gives the false impression that the person has nothing to worry about.

So what lifestyle should be this default position?  Since these lifestyle diseases are prevalent in Western society, it makes no sense to have the null hypothesis be based on the lifestyle of Westerners.  However, these diseases are not at all prevalent in modern day hunter gatherers who live a lifestyle more in line with the one we spent most of our time evolving under.  This has led many to believe that the null hypothesis, the default lifestyle condition to test against, should be identical to the one we evolved under.

This poses a major problem.  The vast majority of our science has been conducted during a time when the Western lifestyle has been the default condition because that has been the default condition since clinical research has become prominent.  An easy way to understand this is that we have come up with RDAs for nutrients in human health, but these RDAs are only relevant under a Western lifestyle because a Western lifestyle is the condition under which they were tested.  So it is improper to say that the RDA for Vitamin C is the amount of Vitamin C one needs to prevent scurvy.  The proper way to phrase what the science actually shows is that the RDA for Vitamin C is the amount of Vitamin C one living a Western lifestyle during the time of testing needs to prevent scurvy.

Assuming the way we currently do things as it pertains to lifestyle is the default condition can also lead us down the wrong path when we are looking at how our body works.  It has been assumed that the liver is the primary site of blood glucose regulation.  However, this may not actually be the case, it could be that the liver is the primary site of blood glucose regulation in those living a Western lifestyle.  A study looking at blood glucose regulation in mice has shed some light on why this may be the case.

In order to better understand how blood glucose is regulated, researchers studied mice who were unable to regulate blood glucose via the liver.  The liver is considered to be critical in blood glucose regulation, without it we cannot stabilize blood glucose.  As the story goes, we eat carbohydrates that turn in to glucose, the liver stores that glucose and releases it during fasting, and when we are completely fasted, the liver makes glucose from non-carbohydrate food sources.

In the fed state during the study, blood glucose levels were identical between normal mice and mice that were unable to use their liver to regulate blood glucose.  During the fasted state, blood glucose levels dropped initially and ketones went up, but within 30 hours both groups of mice had the same blood glucose level as genetic expression changed in the kidneys and intestine to favor blood glucose regulation by those organs in the absence of the liver(1).  It is important to note that while blood glucose levels were lower in the mice who relied on the kidneys and intestines for glucose production, blood glucose never reached a critical state as the kidneys and intestines utilized ketones for approximately 50% of their energy and were able to provide enough glucose for survival.  In addition, this study found that the kidneys and intestine make glucose out of the amino acid glutamine while the liver uses alanine and lactate.

While it may not seem like this study has any real world relevance since most humans have functioning livers, it does highlight that the liver is not absolutely necessary for blood glucose regulation.  The liver is certainly a large player in blood glucose regulation as it can store approximately 100g of glucose and is capable of making glucose from other sources, but the assumption that the optimal way to regulate blood glucose is through consumption of carbohydrate and storage in the liver is flawed.  At this point we really don't know for sure how to optimally regulate blood glucose, but if we look at some key aspects of the ancestral diet some doubt creeps in.

In my next blog we'll take a look at how blood glucose may have been regulated by ancestral humans and how the drastic change in the way we regulate blood glucose now may be contributing to the increased prevalence of Type 2 diabetes.

Part 2

Proper management of Type 2 Diabetes: Don't focus on calories and exercise

Type 2 diabetes is extremely prevalent in modern society.  Despite spending decades trying to get people to exercise more and eat less, the problem has only gotten worse.  Thirty years ago Type 2 diabetes was called adult-onset diabetes because people only developed it when they became adults.  The theory behind this is that people would go from an active lifestyle of playing with friends, playing sports, partaking in gym class, and walking from class to class when they were in school to jockeying a desk for forty hours a week once they started work.  In an effort to combat the problem, more people began counting calories and going to the gym to ward off to the disease.  It hasn't worked.

When you look at how Type 2 diabetes has changed, it is most certainly for the worse.  Not only are more people getting it, even children are being diagnosed with it.  Currently, proper management of Type 2 diabetes involves eating fewer calories and burning more calories through exercise. While most people would certainly be better off doing both, they shouldn't be where most of your attention is focused.  Most people would be better served taking the following advice first:

• Eat more fruits and vegetables
• Limit or eliminate all processed foods
• Spend as little time as possible sitting
• Get 10,000 steps per day
• Get 8 hours of quality sleep every night

Eat more fruits and vegetables

Eating more fruits and vegetables helps on a few levels.  First, both are more nutrient dense than they are energy dense which means they have fewer calories per unit of volume.  By eating more fruits and vegetables, you will feel fuller on less food because they take up more room in the stomach.  Both are also good sources of fiber which will cause food to move more quickly through the digestive tract.  Soluble fiber also helps feed the beneficial bacteria in your gut that helps heal damage to your intestinal lining.  People with Type 2 Diabetes tend to consume fewer fruits and vegetables as well as fiber.

Limit processed food

Limiting or eliminating processed foods is important because processed foods tend to be more energy dense. This means you have to eat more to feel full because they tend to carry more calories per unit volume.  Most processed foods also tend to be very inflammatory to your intestinal lining.  Obesity and Type 2 diabetes are often referred to as inflammatory conditions so lowering the amount of inflammation you experience is a good idea.  Gluten, which is found in most processed foods, is bad because it can cause an immune reaction that causes blood glucose to run high because glucose gets conserved for the immune system.  This causes your body to increase insulin production and can damage the pancreas, a hallmark of Type 2 Diabetes.  For more of the science on this process, click here.

Reduce sitting time

Spending as little time siting as possible helps on a couple of fronts with Type 2 Diabetes management.  First, it helps you burn off some of the carbohydrates you eat and lowers your blood glucose.  Secondly, for as long as we have been studying the effects of sedentary behavior(hundreds of years), scientists have noted that sedentary behavior slows down the movement of food from your gastorintestinal tract.  The longer food stays in your GI tract, the more calories you will be able to extract from it.  In addition, being in a seated position for long periods of time causes poor genetic expression that increases the risk for Type 2 Diabetes as well as other poor health outcomes. For more of the science on this check out this blog.

Get 10,000 steps

Getting 10,000 steps a day is a general recommendation for good health put out by many health organizations including the American Heart Association as well as the American Medical Association.  It helps in basically the same way that reducing sitting time works.  I recommend people spread out their steps through the day and a recent study showed taking a 15 minute walk after very meal helped people with Type 2 Diabetes manage their blood glucose better than a single 45 minute walk.

Get 8 hours of quality sleep

Getting 8 hours of quality sleep per night is also a very important habit to have to manage Type 2 Diabetes.    Poor sleep can lead to poor blood glucose control and disturb many hormonal systems by disrupting circadian rhythms.  Even just a week of getting 6 hours or less of sleep per night can disrupt these rhythms, which is common for many people.  This article does a pretty good job of discussing the science behind this.

Conclusion

The purpose of this article is not to give you the impression that calories are not important or that you shouldn't exercise.  Calories are significant, but that doesn't mean counting them is an effective tool for managing Type 2 diabetes.  Exercise is an important component of any comprehensive health program, but you have to realize that your priorities should lie with the other 6 factors first.  Once you have successfully implemented those strategies, you can add exercise in to boost your results.  As for calorie counting...You can count calories if you choose, but if you are following the other 6 factors listed above, you probably won't have to.

Conquering Type 2 diabetes: Exercise and Supplements

Over the last 2 blogs we have discussed how you can manipulate diet and lifestyle to help prevent or reverse Type 2 diabetes.  The reason hose two blogs came first is because that is where most of your efforts should lie.  Unfortunately, mot people first look to supplements and exercise to beat Type 2 diabetes and this is a mistake.  It is simply not possible to reverse the damage from an inappropriate diet and lifestyle with exercise and supplements no matter what your condition is, especially Type 2 diabetes.  The sooner people realize this, the sooner they can attain optimal health, wellbeing, and an ideal physique.  However, this does not mean exercise and supplements are of no value.  In fact, once you get the other two factors in line, exercise and supplements can be a good way to have a little more flexibility in your diet and help mitigate the damage you can cause if you go nuts on the weekend.  Let's take a look at the research.

Exercise for Type 2 diabetes

I have written extensively on this blog about the different muscle types and how they help ictate what a person with Type 2 diabetes should do for exercise.  Rather than hash out all of the research again, you can find the article that cite all of the references here and here.  Now, let's just get the crib notes version of all of that.

You have two major types of muscle fibers, Type I and Type II.  Type II fibers can be further broken down in to Type IIa and Type IIx fibers.  See the chart below of the characteristics of each fiber type.  Please note that IIx and IIb are used interchangeably to denote the fastest twitch muscle fibers so on this chart the IIx fibers are referred to as IIb fibers.

 .

Taken from http://general.utpb.edu/fac/eldridge_j/kine3350/chapte19n.jpg

The important thing to realize about these muscle fiber types is that the IIa and IIx fibers can more or less convert to one another depending on training status.  When a person begins exercising, over time the IIx fibers convert to IIa fibers while Type I fibers just increase their fat storing ability.  When a person stops exercising, eventually the IIa fibers convert back to IIx fibers.  This is important for Type 2 diabetes because people prone to Type 2 diabetes have a higher proportion of Type II muscle fibers.  People with Type 2 diabetes have a very high percentage of IIx fibers.  It is easy to see that the higher proportion of IIx fibers is obviously a result of not partaking in regular exercise.

As a long term adaptation to exercise, muscle fibers begin to store more energy in the form of glucose and fat.  Type I fibers use primarily fat to recharge their energy stores while the Type II fiber types tend to store more glucose, or glycogen.  Type IIx fibers store less glycogen than IIa fibers and as an adaptation to continued exercise, they begin to increase glycogen stores and convert to IIa fibers.  This has a couple of positive benefits with regard to blood glucose control.  First, by actively using the glycogen stored within the muscle, the muscle is able to take in more glucose when you eat carbohydrates and store it as glycogen.  In addition, this increases the amount of glycogen the muscle fiber can store, giving you more leeway when you decide to consume excessive carbohydrates before they begin turning to fat or accumulating in your bloodstream.

In order to get the Type IIx fibers to convert to IIa fibers, you need to activate them.  Type II fiber types are activated during high force movements such as lifting weights or performing the explosive movements common in most sports.  They are not typically activated by activities that are long and slow in duration, these activities recruit primarily Type I muscle fibers.  In addition, you want to use a full range of motion in whatever activity you are doing or you won't activate all of the muscle fibers from the muscle group you are using.  Unfortunately, most people begin jogging or biking in an attempt to help combat Type 2 diabetes.  This is a mistake because most people do not do them at an intensity sufficient to activate the Type II muscle fiber types, few people use a full range of motion when they run, and running and biking do little for the upper body.

The best bang for your buck to beat Type 2 diabetes exercise-wise is to either play a sport or strength train.  Any sport will do provided it is not an endurance event such as high mileage running or biking,  You could even do short sprints which I highly recommend provided you are doing something for your upper body as well.  My personal preference is strength training because you can do it in 30 minutes and you can get away with only doing it twice a week if you lift heavy enough weights.  You will want to work mostly compound movements such as lunges, pull ups, push ups/bench press, shoulder press, rows, and deadlifts.  Technique is important so using an experienced strength coach or personal trainer is a good idea.  In my experience, sticking to 3 sets of 12 reps for the first month to break yourself in and gradually working towards 3 sets or 4-8 reps per exercise is the best exercise option for fighting Type 2 diabetes.

Supplements for Type 2 diabetes

There are a few supplements that are beneficial for people with Type 2 diabetes.  These include:

Magnesium

Magnesium is critically important for proper blood glucose control.  Not only is it necessary for insulin secretion, it's also necessary for glucose to move from your blood in to cells once insulin has attached to the cell to let glucose in.  For a thorough discussion on magnesium, click here.  The problem with supplementing magnesium is that you want a type of magnesium that is time released so that it doesn't cause loose stool.  Magnesium oxide, the form of magnesium most typically found in supplements is poorly absorbed and normally causes loose stool.  I personally use Jigsaw Magnesium w/SRT but you can also use any brand of magnesium glycinate or citrate.

You want approximately 420mg or elemental magnesium a day as a maintenance dose.  If you are deficient in magnesium, as most people are(Especially people with Type 2 diabetes), you may need much more to become sufficient in magnesium.  You can request an RBC magnesium test from an integrative medicine doctor to determine if you have adequate magnesium levels.  In addition, if you have low stomach acid, gut dysbiosis, or leaky gut you may want to try transdermal magnesium in the form of magnesium oil or epsom salt baths as you will have problems absorbing it.  Since magnesium is water soluble, excess magnesium is simply excreted in the urine.  If you have kidney issues you should speak with your doctor before beginning magnesium supplementation.  I do not have kidney problems and have gone as high as 1500mg per day between oral (800mg) and transdermal(700mg) for a month with no issue.  However, the oil burns and you may need to dilute it with distilled water before applying.  If you have problems sleeping, this is your go to supplement.

Iodine

There is some epidemiological evidence that Type 2 diabetics take in too little iodine(1) and people with Type 2 diabetes are at an increased risk for hypothyroidism(2).  This data is certainly not a scorching endorsement for iodine in Type 2 diabetes, but in my opinion most people who don't eat sea vegetables, or ample amounts of fish are probably deficient in iodine.  In addition, high consumption of goitrogenic foods such as the cruciferous vegetables(Broccoli, spinach, cauliflower, kale) and using refined sea salt instead of iodized salt also make you more likely to be deficient in iodine.  In the body, iodine is used to make thyroid hormones which regulate metabolism in every cell.  If you are not sure if you are deficient in iodine, there is a test called the 24 hour iodine loading test which can show you whether or not you need to supplement with iodine.  For more information on supplementing with iodine, click here.

Resistant starch

Resistant starch is a hot topic in the Paleo community.  Like soluble fiber, resistant starch is fermented in to short chain fatty acids in your large intestine which are used to heal gut damage.  Studies have shown resistant starch to lower blood glucose and impove insulin sensitivity in healthy subjects (3,4,5,6) and subjects with Type 2 diabetes(7,8).  The structure of resistant starch prevents it from being digested in the small intestine, allowing it to make it to the large intestine where it can feed good bacteria that help improve blood glucose regulation(For more on how this works click here).  There are supplements that contain resistant starch such as Hi-maize corn starch, but the most readily available form of resistant starch is unmodified potato starch which contains 7.8g of resistant starch per tbsp.  You can use it as a thickener in shakes or put it in water and drink it.  Just be sure not to heat it as heating it changes the starch in to a more digestible form.  Two tbsp per day seems to be a sufficient dose, but once you improve your gut function and blood glucose control you only really need to use it as damage control when you decide to go nuts and eat crazy.  It is best to start with a lower dose and spread it out throughout the day to prevent gas.  I have a future blog post planned on resistant starch that will go in to more detail as there is a ton of research on it.

Conclusion

So there you have it.  Over the last 3 blogs we've gone over everything you need to know about diet, lifestyle, exercise, and supplements to prevent or reverse Type 2 diabetes.  For the vast majority of people with insulin resistance or full blown Type 2 diabetes, this is more than enough to fix blood glucose control and prevent the damage caused by elevated glucose levels.  If you have done sufficient damage to your pancreas you may be dependent on some level of insulin injections for life, but this protocol will allow you to minimize the amount of insulin you need to inject and live a happier, healthier life.

Conquering Type 2 Diabetes: Lifestyle

When trying to overcome Type 2 diabetes, lifestyle modification trumps medicine most of the time.  If you have done so much damage that there are not enough beta cells in your pancreas to make insulin you may be dependent on insulin for life, but you can still limit the amount of insulin you need via lifestyle modification.  In the previous blog on diet we went over why you should avoid processed foods and eat plenty of fruits and vegetables to help promote good gut bacteria and a healthy intestinal lining.  In this blog we will cover other lifestyle factors that impact blood glucose control.  These factors can be broken down in to three primary categories: Sleep, physical activity, and stress management.

Sleep

Sleep is incredibly important for human health and insufficient sleep duration and/or quality can have a major impact on your health.  A study published in 2013 found that insufficient sleep affected the expression of 711 genes that help modulate the stress response, immune system, and metabolism(1).  The study found that 1 week of sleep restriction of slightly less than 6 hours per night lead to a host of problems at the genetic level including increased oxidative stress, altered circadian rhythm, and altered energy metabolism, three hallmarks of many of the chronic diseases we see today including Type 2 diabetes.  This study is a fairly good representation of the sleep habits of many Americans as a good chunk of the population gets less than 6 hours per night(2).  Other studies have found that restricted sleep lead to changes in glucose regulation, insulin sensitivity, and leptin sensitivity(3, 4).  These changes begin to occur in as little as 2 nights of restricted sleep and a single night of no sleep(Hear that night shifters?).  Typically, the progression of Type 2 diabetes begins with leptin resistance followed by insulin resistance.  Over time, blood glucose regulation becomes permanently affected and Type 2 diabetes ensues.  The research on sleep and Type 2 diabetes is pretty much settled at this point, not getting good quality sleep for 8 hours dramatically increases your risk for Type 2 diabetes(4).

Physical Activity

When most people think of physical activity they think of exercise.  This is a mistake, because an hour of exercise per day cannot make up for prolonged sedentary time in helping prevent Type 2 diabetes and the metabolic syndrome(5, 6, 7).  Even just breaking up prolonged periods of sitting with 2 minutes of physical activity every 20 minutes helps improve glucose metabolism(8).  Most of the data points to spending as little time per day sitting being more important than exercising.  Certainly exercise is also important, but try standing more throughout the day first.

Next, walking more throughout the day is also something that is very beneficial in preventing and reversing Type 2 diabetes.  Aside from the benefits of not being sedentary, taking a 15 minute walk after each meal has been shown to decrease the risk of Type 2 diabetes(9).  Furthermore, people who maintain their daily step count over 5 years have been shown to maintain their insulin sensitivity better than people whose daily step count decreased over that time(10).  A good goal to shoot for and the recommendation by the American Heart Association is 10,000 steps per day.  The average American tends to get about 6600, quite a bit lower than the recommended number.  Just taking a 15 minute walk after each meal will give you 4500 steps, so it's not that difficult to accomplish.

Stress

Physical inactivity can also lead to changes in the brain that can modulate the stress response in a negative way(11).  In addition, sleep restriction can cause an overactive stress response(1).  To complete the circle, sleep restriction in the face of physical inactivity has been shown to negatively impact insulin sensitivity and blood glucose regulation(12).  All three of the factors we have discussed today are interrelated when it comes to the risk of Type 2 diabetes.  While it may be easy to put yourself to bed early or make sure you get enough daily steps in, managing stress is a completely different ballgame. Fortunately, doing the other two usually helps with the third.

It's very easy to see the importance of the stress response when it comes to physical stress.  When you are out in the jungle and about to become a lion's lunch, the stress response springs in to action to partition your resources for fight or flight.  This puts all non-essential processes on hold and floods the body with stress hormones.  The stress response begins and ends in the hypothalamus.  In what is basically a game of hormonal telephone, the hypothalamus tells the pituitary gland to tell the adrenal glands to make stress hormones.  These hormones help mobilize energy, particularly glucose, to provide the body with fast acting energy.  Over time, these hormones act on the hypothalamus and tell it to cools it's jets.  Obviously mobilizing energy is key to fighting or fleeing, the problem is that there is a direct line from the amygdala to the hypothalamus and that can turn on the stress response in the face of a perceived threat.

The amygdala is the emotional center of the brain.  Under the proper circumstances, the amygdala can tell the hypothalamus to initiate the stress response.  The problem is that in today's society, there are so many psychological stressors that can initiate the stress response.  How am I going to pay the mortgage?  What if my wife divorces me?  I have a big deadline that I need to make.  Any sort of situation that we deem as stressful has the potential to initiate the stress response.  The problem is, what do you need energy for to flee an emotional stressor?  Furthermore, can you ever really flee an emotional stressor?  Even if you do, there is typically another one right behind it.  As these stress hormones and glucose enter your bloodstream, there really is no need for them because it's not energy that you need.  What you need is to stop processing this information through your amygdala.  This is the goal of mindfulness.

The reason you have been hearing so much about mindfulness and mindfulness meditation is because mindfulness is a way to alter your thought processing so that you avoid generating an emotional response to psychological stress.  Many companies have begun mindfulness meditation programs as a way to help reduce stress for their employees and top executives tout it's benefits in helping them deal with stress.  How does this relate to Type 2 diabetes?  People with Type 2 diabetes have increased sympathetic nervous system activity(13).  This basically means that their stress response is activated more often and more easily than a normal person.  This flood of stress hormones and blood glucose is not good when it isn't needed.  Just to get a firm grasp on how important the stress response is in Type 2 diabetes, one of the ways that the stress response increases blood glucose is by causing the liver to produce more of it.  One of the primary pharmaceuticals used in Type 2 diabetes is metformin and it's mode of action is...It causes the liver to make less glucose.

Developing good stress management tools is key to helping prevent or reverse Type 2 diabetes.  Mindfulness is probably the best tool out there and can provide a one-two punch combined with proper sleep to help manage stress and help prevent or reverse Type 2 diabetes.  Add in a little physical activity to make you tired, and you have a pretty good jump start on living a healthier, Type 2 diabetes-free life.

Conclusion

There is tons of research on the aspects of lifestyle that will negatively impact blood glucose regulation and increase your risk for Type 2 diabetes.  Getting enough sleep, partaking in  regular physical activity, and managing stress are all important in preventing Type 2 diabetes as well as managing your blood glucose if you have it.  Making an effort to get 8 hours of sleep every night, getting at least 10,000 steps a day, spending as little time as possible being seated/sedentary, and utilizing stress management strategies such as yoga and practicing mindfulness should be on your to-do list if you want to live a long, healthy, happy life free of Type 2 diabetes.

Part 1-Overview
Part 2-Diet

Conquering Type 2 Diabetes: Diet

In the first blog in this series we went over the basic outline for this series.  In this first part of the series we discuss dietary changes.  Most of the books that deal with treating Type 2 diabetes with diet tend to recommend eating basically the same types of food but in smaller quantities.  I don't mean that these books don't recommend changes, they do.  What I mean is that rather than regular bread they tell you to eat whole grain bread.  Rather than white rice they tell you to eat brown rice.  Rather than white pasta you should eat whole grain pasta.  The problem is, there really is no significant difference between any of these switches.  While they may have a minor effect on your blood glucose level, they really aren't getting at the problem.  When you are looking to repair your metabolism you need to look at food from a completely different perspective.  Not only do you need to be concerned with he sustenance you are providing to yourself, you need to look at how what you eat affects the inhabitants of your gut.  I am talking about the gut bacteria that make up your gut microbiota.

Research in to the microbiota

Clinical research tends to go in waves and currently clinical research seems to be swarming in on an area of research that was once thought to be the ramblings of charlatans and quacks.  Ten years ago you could fit all of the research studies on gut dysbiosis and gut bacteria in to a small binder, now there are thousands of ongoing research projects every year discovering more and more about the link between the inhabitants of our gut and health conditions ranging from autism to Type 2 diabetes.  There is a very strong link between Type 2 diabetes and the inhabitants of your gut.  It's so strong that within a few days of having gastric bypass surgery, patients' blood glucose control normalizes and this effect is thought to partially mediated by a rapid change in the gut microbiota(1).  Since this area of research is in it's infancy, there are certainly no hard rules written in stone but we can see some trends

How a leaky gut contributes to Type 2 Diabetes

I have discussed the relationship between a leaky gut and Type 2 diabetes multiple times on this blog.  Rather than rehash it all, you can go here to see the pathology behind how a leaky gut contributes to Type 2 diabetes.  When your intestinal barrier is compromised, LPS leaks in to the bloodstream and causes insulin resistance.  In addition, sometimes overeating certain types of foods can cause pathogenic bacteria who have LPS as a part of their plasma membrane to overgrow in the gut.  LPS shouldn't be in the bloodstream so it is up to your immune system to take care of the invader.  In the meantime, repairing the gut lining will close off the supply of LPS and take some of the burden off of the immune system.  The best way to repair the gut lining is to commission some of your friends in the microbiota to do the job, a group of friends called bifidobacteria.

Bifidobacteria are a species of bacteria in your gut that provide quite a service to you.  In exchange for a little bit of fiber, they ferment that fiber in to a short chained fatty acid called butyric acid(2).  Butyric acid is used by the cells of your intestines to heal damage to the gut lining.  While most people look to take probiotics to re-inoculate their gut, your best bet is to provide prebiotics.  Probiotics are the actual strains of bacteria while prebiotics are the substrate these bacteria ferment, aka their food.  Whether or not the probiotics make it through the acidic contents of the stomach is up for debate while the prebiotics are indigestible by humans so they most certainly do.  In addition, just dumping strains of bacteria will do nothing if they don't have food.  Not only will they not survive and just be flushed out in your feces, they'll have no way of making butyric acid and, therefore, no way of healing your gut lining.

The best dietary approach to healing your gut

Healing your gut is an important step in conquering Type 2 diabetes.  Most people go on a very low carbohydrate diet which can yield some results, but this is normally an indirect relationship.    When most people reduce carbohydrates, they accomplish this by eliminating processed foods.  Processed foods are typically high in sugar or other refined carbohydrates.  I would even consider whole grain breads, cereals and pastas in this group because the limited fiber content in the whole grain varieties don't even come close to making up for everything else that's in them.  Your goal should be to eliminate all processed foods for a couple of months and to eat lots of plants in the form of fruits and vegetables.  This will provide lots of fiber for the good bacteria to ferment and heal your gut while at the same time eliminating the sugar that tends to feed the bad bacteria.  This is by far the best and fastest way to turn the ship around with Type 2 diabetes and re-establish proper blood glucose regulation.

Even if you decide that this approach is too extreme, you should increase the amount of vegetables you eat and limit processed foods as much as possible.  Look at your gut as a battle ground with two opposing sides waging war.  On the one side you have the troops who are helping you by manufacturing nutrients and repairing your gut lining and on the other you have the troops who are trying to wreak havoc in your digestive tract and trying to gain access to your bloodstream.  You want to provide more reinforcements/food to the good guys so that they can win the war and help maintain your health and avoid Type 2 diabetes.

Is this change for life? 

While avoiding processed foods is a good practice, once you fix a leaky gut and restore a proper balance of good bacteria in your gut you should be able to indulge in some processed foods provided you are also getting gut healing veggies in as well.  There is probably a tolerable dose of processed foods you can get away with eating that won't immediately impair your blood glucose control and return you to the land of Type 2 diabetes.  This dose is probably specific to the individual and will depend on how robust your immune system is, how good your digestion is, and on your age as it affects the other factors.  There is also a genetic component as well.

Conclusion

In the war against Type 2 diabetes, you should focus on what goes in to your mouth as reinforcements for the battle.  If you focus on providing more reinforcements to the bacteria that provide a benefit to you and less to the bacteria that can cause problems, you should be able to win the war.  Once you fix your gut lining and establish a good balance of good bacteria that is beneficial to you, you may be able to indulge in foods that previously threw your blood glucose out of whack provided you maintain a constant supply of reinforcements for the good guys.

Part 1 -Overview
Part -Lifestyle

Conquering Type 2 Diabetes: What the research shows part 1

Unless you live under a rock or are part of some hunter-gatherer tribe that has a computer lab you know someone with pre-diabetes or Type 2 diabetes.  In modern Western society, Type 2 diabetes is as ubiquitous as McDonald's and pharmacies, two establishments that see their fair share of Type 2 diabetics.  The sad part about this is that there seems to be enough research available to the general population that Type 2 diabetes should be completely avoidable.  It is my belief that if that vast majority of people took the research and used it to their advantage, most Type 2 diabetics could reverse the disease and everyone else could avoid it altogether.  That is not to say that this can help everyone, some people have done so much damage to their pancreas that they may be stuck taking diabetes drugs forever.  In other instances, people just aren't willing to change their lifestyle in a way that will prevent this largely reversible metabolic state.  For those people willing to put in the time and effort, this blog series should provide everything you need to know to conquer Type 2 Diabetes.  In this first part, we will provide a general overview of the plan.

What is Type 2 diabetes?

Type 2 diabetes is a metabolic disorder where high blood glucose is accompanied by high levels of insulin and cellular insulin resistance.  People with Type 2 diabetes tend to have an exaggerated blood glucose response to foods, particularly foods high in carbohydrate.  Over time, consistently high blood glucose levels cause damage to the organs and tissues of the body.  This can lead to blindness, neuropathy(Nerve pain), heart disease, and Alzheimer's to name only a few.

Type 2 diabetes is diagnosed in a couple of ways.  It used to be primarily diagnosed with fasting blood glucose levels, which is a test of your blood glucose level after not eating for 8 hours.  A fasting blood glucose level between 100 and 124mg/dL is considered pre-diabetic and fasting blood glucose above 125mg/dL is considered diabetic.  The problem with using fasting blood glucose levels as the primary means of diagnosing Type 2 diabetes is that you can have a normal fasting blood glucose reading but still have an abnormal blood glucose response to food, called the postprandial glucose response.  The more appropriate test given now is called your A1c, or hemoglobn A1c.  Your A1c is basically a 3 month average of your blood glucose levels determined by your level of glycated hemoglobin, hemoglobin damaged by sugars in the body.  An A1c below 7% is considered in the healthy range.

Once diagnosed with Type 2 diabetes, the best means for controlling progression of the disorder is via lifestyle intervention.  I believe very few people know this and the ones that do are not given enough of a slap upside the head to realize it's serious business.  A good portion of people are also looking for the easy way out and immediately go the pharmaceutical route rather than change what they are doing, which is more than likely causing the problem in the first place.  Whatever the reason, one of the dumbest things you can do health-wise is to go after the symptoms rather than the root causes of the problem.  This can be broken down in to 3 steps and will be covered in three separate blogs.

Fixing your gut

Of every step you are going to need to take to win the battle of Type 2 Diabetes, this one is the toughest.  Not only will it require you to avoid many of the foods you love to eat, it will require you to change your entire approach toward food.  Most of us look at what we eat as a way to provide energy and resources to our body.  While this is certainly a big part of it, the research also shows we need to consider the inhabitants of our guts as well., aka your gut bacteria.  These little guys aren't just freeloaders along for the ride, they provide many useful functions that we are dependent on for optimal health.  In addition, people with Type 2 Diabetes almost have a signature microbiota, another name for the inner society of bacteria that reside in your gut.  This signature microbiota can lead to a greater energy harvest from your food, gut inflammation, an inability to repair gut damage, and a host of other problems seen in Type 2 diabetes.

Most people who try to tackle Type 2 diabetes go immediately to a low carbohydrate diet.  While it may be a good idea to reduce carbohydrate intake initially while your mechanism to control blood sugar is faulty, realize this is merely a symptom.  We want to reduce carbohydrate to prevent your blood glucose from skyrocketing, but going to low on carbohydrates can actually make the problem worse.  Instead, you want to focus on eating the right types of carbohydrates to heal your gut, establish a healthy gut microbiota, and give you long lasting energy throughout the day.  Once you do this it may be possible to eat small amounts of foods that once caused major blood glucose fluctuations without any problem.  To what extent this is possible is more than likely individual and dependent on how much damage you've done.

Lifestyle factors

There are many lifestyle factors that can push your blood glucose and insulin levels high.  Most of these lifestyle issues will have a negative impact on your stress response.  One of the major roles of your stress response is to mobilize glucose to provide your muscles with energy to fight or flee.  Study after study has shown that people with Type 2 diabetes have higher levels of stress hormones in their body than people with normal blood glucose control.  This is because their stress response becomes altered in a way that always puts them in flight or flight mode.  In the lifestyle factors section we will discuss the effects of each factor on blood glucose control as well as techniques you can use to get yourself moving in the right direction.  It is important to note that we will cover physical activity in this section but exercise in the next.  Physical activity and exercise are two separate things and should be viewed in that way.  Most people get all of their physical activity in the form of exercise at the gym which is completely inadequate.

Exercise/Supplements

There are many benefits to exercise.  In Type 2 diabetes, exercise can be used as a "condiment" that allows you to speed up progress as well as have a little more flexibility in your diet.  In the same way, certain supplements can be used to improve nutritional deficiencies that are common in Type 2 diabetics. However, most people put most of their effort in to these two areas, treating them as if they are the main course rather than a condiment.  Putting most of your efforts in to the main dish(Diet and lifestyle) while using the condiments to optimize your results is the best approach to battling Type 2 diabetes.  In this section we will look at the best types of exercise to perform as well as supplements you may need to take to beat Type 2 diabetes.

Conclusion

Over the course of the next 3 blogs we will use research as our guide to learn how to fight Type 2 diabetes.  The vast majority of people who follow this advice will get their blood glucose levels in check if they are out of whack or will avoid Type 2 diabetes altogether if they are just looking to be healthy.  Whether you have Type 2 diabetes or not, this will more than likely be a significant lifestyle change, so let's get started.

Part 2: Diet 
Part 3: Lifestyle

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.

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.

LPS, insulin resistance, and obesity...An update

A new study in the journal Nature has opened up a new understanding in the relationship between obesity, inflammation and insulin resistance that could also have a larger impact on how we view weight loss, and more importantly health and well being.  The study, published in Nature in March of 2013, has lead to a shift in my line of thinking.  Recall from this blog that when Lipopolysaccharide (LPS) manages to find it's way in to your bloodstream via a leaky gut, it induces system-wide insulin resistance.  It seemed as though this would be a good strategy to conserve glucose for the brain, but this new study in Nature implies a different reason.

LPS, fuel selection, and cellular communication

The study, located here, identifies a metabolite called succinate as a signaling molecule in immune cells called macrophages that causes them to increase secretion of the inflammatory molecule IL-1B(1).  Succinate levels increase because macrophages shift their metabolism from oxidative phosphorylation (Fat burning) to aerobic glycolysis (Sugar burning) when LPS attaches to receptors on the plasma membrane.  This would increase macrophage activity as glycolysis produces energy much more rapidly than oxidative phosphorylation, something you want when a foreign invader enters you bloodstream.  Theoretically speaking, when succinate increases IL-1B, it is telling the rest of your cells that glucose is needed to fight the infection rather than for being stored for later muscular contraction.  Perhaps the relationship between inflammation and insulin resistance is simply communication between body systems (Immune and musculoskeletal) to partition resources(glucose) to the more pressing need(fighting an infection). 

This doesn't prevent muscles from burning glucose as physical activity causes glucose transporters to bring in glucose to muscles cells.  What it does is block insulin from increasing glucose uptake in to resting muscles as insulin's primary function is to store glucose as glycogen for later use.  Basically, it shouldn't directly impact the use of glucose by muscles, but it will indirectly impact the use of glucose in muscle by preventing the storage glucose for later use during recovery.  Click here for a not-as-sciencey rundown of this. This is not to say there is no benefit to the brain in this scenario, but since the signal originates from the immune system we should focus there.

When the scientists blocked succinate production with the anti-epilepsy drug vigabatrin, they were able to inhibit expression of IL-1B, cutting down the level of inflammation.  High IL-1B levels are seen in many diseases including diabetes.  Let's take a look at some of my older blogs and see where this all fit's in to the obesity/diabetes discussion.

Previous Type 2 diabetes discussion

Recall from here and here that Type 2 diabetics and people prone to obesity tend to have a higher percentage of Type IIx muscle fibers and a lower percentage of Type I fibers. There are 3 basic muscle fiber types: Type I, Type IIa, and Type IIx.  The type I fibers burn primarily fat, the IIa fibers burn primarily glycogen, and the IIx fibers burn primarily ATP as they do not tend to store much energy in the form of fat or glycogen to recharge ATP.  However, the Type II muscle fiber types can convert in to one another with physical activity or a lack of it.  When a person becomes sedentary over long periods of time, the IIa fibers begin converting to IIx fibers as their need to store glycogen to recharge ATP stores is not needed because they are not used.  When a person begins using the IIx fibers more with physical activity, they convert in to the IIa fibers as they begin to store more glycogen.  This leaves them with more room to store glycogen which gives the glucose from excess carbohydrate consumption a place to go.  However, this point is moot if LPS is inducing system-wide insulin resistance by partitioning glucose to the immune system and away from muscle cells.

This causes a double-edged sword scenario.  On the one hand, having a higher percentage of Type II muscle fiber types means a larger portion of your musculature uses glucose as a fuel supply.  In a trained state this is beneficial but in an untrained state you have a larger percentage of muscle fibers that don't use energy.  The problem is, as discussed in the first blog mentioned in the above paragraph, high insulin levels are what cause the IIa fibers to convert to IIx fibers.  Since the IIx fibers are the most insulin resistant of the muscle fibers, LPS induced system-wide insulin resistance can force adaptation in a way that will just make you progressively more insulin resistant, even when you are no longer directly dealing with LPS in the blood. As such, high levels of LPS need to be dealt with and avoided altogether if fixing insulin resistance is your goal.  However, we still have the other edge of that sword to deal with.

Since people who are prone to diabetes and obesity have a higher percentage of Type II muscle fibers, this means they also have a lower percentage of Type I muscle fibers.  Recall that the Type I muscle fibers burn primarily fat.  If LPS is inducing insulin resistance to spare glucose for the immune system, this means muscle is going to have to metabolize fat.  The problem here is that a lower proportion of Type I muscle fibers means a reduced ability to metabolize fat.  This effect, coupled with a decreased ability to suppress fatty acid release from adipose tissue(2) could be why we see something that is common in people with Type 2 diabetes, high levels of triglycerides in the blood.  We also see an accumulation of triglycerides in tissues that should not have high triglyceride levels such as muscle and liver tissue(2).  In people with a higher percentage of Type I muscle fibers, this may not be a concern as they are more equipped to metabolize fat and the Type I fibers are the most sensitive to insulin. This could help explain why they are less likely to contract Type 2 diabetes.

Conclusion

As you can see, having LPS in your bloodstream is far from an ideal scenario.  It has been hypothesized that the consumption of grains and dairy can increase the likelihood of LPS making it's way in to the bloodstream via a leaky gut.  This could potentially be one of the reasons a Paleo diet has been shown to improve glycemic control at a rapid rate, much faster than a Mediterranean diet (Paleo lowered FBG by 23 mg/dL in 10 days vs 0mg/dL for Mediterranean diet)(3).  The primary difference between these 2 diets is that the Paleo diet is grain, legume and dairy free while the Mediterranean diet is not.  In this particular study, they did not measure IL-1B levels and in other studies they measured CRP levels with no significant change (4).  Given the results of the recent study in Nature, perhaps measuring IL-1B  in a study comparing the Paleo diet with the Mediterranean diet can give us an answer to these questions and bring us closer to understanding more of the mechanisms that underlie insulin resistance and Type 2 diabetes.

Feel fat, depressed and unhealthy? Get off your tookus!

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

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