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Metabolic Syndrome: A Useless Construct?

Birds of a feather flock together. As they investigated the risk factors for cardiovascular disease and diabetes, medical detectives observed that the usual suspects liked to hang out together. Obesity, high blood pressure, abnormal blood lipids, and elevated blood sugars regularly appeared together in the same patient. It looked like a syndrome that might boil down to one underlying cause. They called it “metabolic syndrome” and started applying the concept to clinical practice.

It seemed like a good idea at the time, but now skeptical scientists are expressing their doubts.

What Is Metabolic Syndrome?

A “syndrome” is defined as a group of symptoms and signs that together are characteristic of a specific disorder or disease. All syndromes are not created equal. Some syndromes are well-defined, with known causes, such as Down syndrome, a specific constellation of congenital abnormalities that can be confirmed by genetic tests demonstrating the presence of an extra chromosome (or related chromosomal abnormalities). Others are less well defined, like chronic fatigue syndrome, which consists of fatigue in association with a variable list of symptoms and signs like pain and enlarged lymph nodes. There is no lab test for it, the cause is not known, and the diagnosis itself is controversial.

Metabolic syndrome is a combination of factors that increase the risk of cardiovascular disease and diabetes. It’s also known by other names including syndrome X and insulin resistance syndrome. It has gotten a lot of press in recent decades, but some scientists have questioned whether it really exists. We know many risk factors for cardiovascular disease and diabetes, but when does a group of risk factors become a “syndrome” and when does it become useful for diagnosis, prevention, or treatment?

Metabolic syndrome is differently defined by different organizations. The worldwide consensus definition of the International Diabetes Federation requires central obesity plus any two of: raised triglycerides, reduced HDL cholesterol, elevated blood pressure, and increased fasting blood sugar. The World Health Organization requires diabetes or impaired glucose tolerance along with two of the following: HBP, dyslipidemia, central obesity, and microalbuminemia. The US National Cholesterol Education Program requires three of: central obesity, elevated triglycerides, decreased HDL cholesterol, elevated blood pressure, and elevated fasting blood sugar. The key feature is central obesity in one definition and diabetes in another, but neither is required at all in the third. This is disturbing, to say the least. A patient with elevated blood pressure, low HDL, and elevated triglycerides who is not obese or diabetic would be classified as having metabolic syndrome by the NCEP, but not by the IDF or the WHO!

And so the prevalence of this syndrome varies considerably depending on which definition is used. The overall prevalence of metabolic syndrome is around 25% in the US population. It varies by age and race, and is over 43% for those older than 65.

A New Study

A new study found that metabolic syndrome was associated with a two- to three-fold increased risk of MI, but the same risk was conferred by having either hypertension or diabetes alone. The authors said,

People who advocate for the metabolic syndrome concept believe that when the component risk factors occur together this would have an additive or greater effect on risk, and therefore it is important to identify these individuals. But we didn’t find that. So our study adds to the evidence that a diagnosis of metabolic syndrome is not useful. It is better just to treat the actual risk factors.

They pointed out that there is a dose-response relationship between risk-factor severity and MI risk and that a standard definition of metabolic syndrome loses information because it converts continuous variables into categorical variables. And there are other significant risk factors that metabolic syndrome fails to consider, like sedentary life style and smoking. It would make more sense to replace the categorical definition of metabolic syndrome with a scoring system that assigns a weight based on the level of each risk factor and that uses a regression formula.

A Joint Statement

This is not a new concern. Five years ago, the American Diabetes Association and the European Association for the Study of Diabetes issued a joint statement entitled “The Metabolic Syndrome: Time for a Critical Appraisal.” They reviewed the literature and concluded that

the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a “syndrome.” Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the “metabolic syndrome.

They acknowledged that the metabolic syndrome had been a useful paradigm for drawing attention to the fact that some CVD risk factors tend to cluster in patients. But now it is time for a

…serious examination of whether medical science is doing any good by drawing attention to and labeling millions of people with a presumed disease that does not stand on firm ground.

Conclusion

The concept of a metabolic syndrome originally seemed promising: it carried the hope of better identifying patients at risk, contributing to establishing an etiology related to insulin resistance, and determining better routes to prevention and treatment. These ideas haven’t panned out. It is still unclear whether obesity causes the associated findings or whether an underlying condition causes the obesity along with the other findings or whether something else is going on. It is becoming increasingly clear that identifying and managing individual risk factors is the way to go.

Should the concept of metabolic syndrome be abandoned? Probably. But human nature makes us reluctant to abandon any idea after it has rooted itself in our consciousness. The metabolic syndrome has become so well established in the popular medical mind that it will not go without a struggle.

Posted in: Science and Medicine

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33 thoughts on “Metabolic Syndrome: A Useless Construct?

  1. BillyJoe says:

    I have never met anyone in Australia with “The Metabolic Syndrome”.
    Perhaps it’s a cultural thing.

    More specifically, I have two sibs who fit the “definition” but have never been given that label. Both are obese, smoke, have high cholesterol, central obesity, and diabetes, and never exercise.
    Both had heart attacks in their forties.

    (I, however, do not resemble them in any way shape or form :))

  2. alison says:

    It’ll be interesting to see whether this filters down into veterinary medicine, as Equine Metabolic Syndrome is the currently fashionable diagnosis for horses who are prone to diseases as a result of being overweight, underexercised and insulin resistant.

  3. lynnandevelyn says:

    I have some of these symptoms but your conclusion doesn’t make sense to me.
    I totally agree that just lumping symptoms into a “syndrome” doesn’t really accomplish anything; and that the best outcome would be to ” establish an etiology related to insulin resistance, and determine better routes to prevention and treatment.”
    However, I don’t see how this leads to ” It is becoming increasingly clear that identifying and managing individual risk factors is the way to go.”
    It seems to me that it would be more important to find the reasons for insulin resistance than to “manage” my elevated blood sugar by throwing more insulin at it and further increasing my insulin resistance.

  4. lhaber says:

    Lumpers v. splitters. It’s an age-old debate.

    From a patient education standpoint, the all-encompassing “syndrome” might be more valuable. Since obesity predisposes to everything else, and everything else seems tied to obesity, it could be very useful to pull everything together into one construct that a patient can understand, rather than attacking cholesterol, weight, and insulin-axis impairment as separate entities.

    But if we’re going to do studies, we at least all have to agree on a definition, or we’re studying apples and oranges.

  5. Harriet Hall says:

    Of course it’s more important to figure out the underlying causes, but so far the concept of metabolic syndrome has not contributed to that.

    Meanwhile, we are stuck trying to treat individual patients as best we can. lhaber suggests that the concept of metabolic syndrome might be motivational for patients, but I don’t see how it would help them understand any better than looking at tables of all the risk factors and showing how each affects cardiac mortality and how they interact.

    The real point is that metabolic syndrome is being used to identify patients at risk of cardiovascular disease and to target them for preventive efforts. If we select high-risk patients just on the basis of the metabolic syndrome, we are losing information and failing to identify other high-risk patients.

  6. trrll says:

    It seems to me that if these symptoms do indeed intend to cluster, that is sufficient to refer to it as a “syndrome.” Any theory of etiology must explain this clustering. The fact that no generally accepted explanation has yet emerged does not invalidate the concept. Whether or not the concept is diagnostically useful seems a quite separate question.

  7. Draal says:

    How do experiments on rats on a high calorie diet factor it? The work by David Sinclair et al. showed that obese rats supplemented with resveratrol did not suffer from “metabolic syndrome” and mimicked calorie restriction compared to the control group. It seems to support the idea of metabolic syndrome.

    And does the “French Paradox” provide any support to the metabolic syndrome idea?

  8. daedalus2u says:

    I have written this before, but I see the metabolic syndrome as the natural consequence of a low basal NO level. It reflects normal physiological compensation for low basal NO and the perturbations to physiology that low NO causes. The physiological changes observed in the metabolic syndrome are “features” to cope with the consequences of low NO.

    Low NO causes several things, lower capillary density (NO is what regulates capillary spacing), lower mitochondria number (NO is what triggers mitochondria biogenesis), reduced liver metabolic capacity (fewer liver mitochondria mean reduced metabolic capacity), reduced liver perfusion (reduced capillary spacing in the liver means reduced blood/liver exchange capacity), reduced flow mediated vasodilatation (flow mediated vasodilatation is due to NO generated via shear, low NO requires more shear to produce the same vasodilatation), lower ATP (sGC sensitivity to NO depends on ATP, NO and ATP go up and down in sync).

    The reduced capillary density (resulting in hypoxia) and reduced mitochondria number divert more ATP production to glycolysis. Glycolysis requires 19 times more glucose to produce the same ATP than does oxidative phosphorylation. Glucose demand of cells increases just as capillary exchange capacity is decreasing. The vasculature can’t deliver enough glucose, so physiology produces hyperglycemia.

    The important glucose concentration is not in bulk blood, but in the fluid adjacent to cells that are taking up glucose. Cells don’t get glucose from blood, they get glucose from the plasma that is perfusing the extravascular space where it is in contact with the cells that are taking it up. As the plasma moves from the capillary to cells away from the capillary, cells take up glucose and insulin, so there is less glucose and insulin available as the plasma moves away from the capillary. If the cells “too far” from a capillary don’t get enough glucose, then physiology can increase blood glucose levels. This is the hyperglycemia of the metabolic syndrome and also of diabetes type 1.

    The glucose uptake of cells is only active, through GLUT transporters. Only having active glucose transport allows the cells close to the capillary to saturate, so they cannot take up any more glucose and so they leave glucose for the cells farther from the capillary. This is what happens in hyperglycemia, or “glucose resistance”. The concentration of GLUT transporters is regulated by insulin, more insulin causes more GLUT transporters to be expressed on the cell surface so the cell takes up more glucose. At some level the effect of insulin “saturates”, that is it doesn’t get taken up. This “insulin resistance” allows for cells to not take up insulin, so that insulin is left for cells farther from the capillary. Insulin resistance is a feature that allows cells farther from a capillary to get more insulin. When cells far from a capillary still don’t get enough glucose, they send out starvation signals compelling hyperglycemia and compelling the consumption of carbohydrate rich foods.

    When cells make ATP via glycolysis they produce lactate. Lactate can be oxidized by cells and is the preferred substrate for the brain. When muscle produces lactate during metabolism above the aerobic threshold, the brain can consume the lactate, consuming the reducing equivalents that muscle is producing. This increases maximal muscle metabolic output by using brain mitochondria to consume reducing equivalents produced by the muscles. When the lactate level gets higher than what can be utilized by the brain, the excess is recycled into glucose by the liver in the Cori cycle. However, this takes mitochondria in the liver to consume the reducing equivalents and perfusion capacity of the liver to do the necessary exchange. If the liver doesn’t have the metabolic capacity to do this, then the lactate can’t be converted back into glucose.

    The body doesn’t have the ability to excrete lactate, and it cannot be stored as lactate (the way that some turtles can, in their shells which allow them to operate anoxically long term (months)). Each cell can use lactate (except for red blood cells which only do glycolysis), but normal metabolic needs of most cells are small compared to the quantity of lactate needed to be gotten rid of because cells are already doing as much oxidative phosphorylation as they can, this excess lactate is from some of the ATP normally generated by oxidative phosphorylation being generated by glycolysis instead. To oxidize the lactate produced along with one molecule of ATP requires the generation of 18 molecules of ATP via oxidation of that lactate.

    There isn’t enough ATP demand to consume all of that lactate and there are also reducing equivalents than must be consumed also. What each cell can do is turn lactate into fat. In the early stages the fat is generated as depot fat, first subcutaneously, then viscerally (reason why visceral fat is bad and correlates with severity). Then fat is deposited in the liver and in other ectopic places. Eventually it starts showing up in skeletal muscle and heart muscle. The ectopic fat is deposited where ever there are extra mitochondria that can be used to convert the excess lactate into fat. The more places it shows up, and the more there is, the worse everything gets. This ectopic fat is more of a symptom, but ectopic fat does reduce NO levels because NO is more soluble in lipid.

    The poor glucose tolerance is due to the inability of the liver to rapidly take up excess glucose. That is from a combination of reduced metabolic capacity and reduced perfusion due to capillary rarefaction.

    The hypertension is from capillary rarefaction, to force the same volume of blood (necessary to supply sufficient O2), through the vascular cross section reduced by capillary rarefaction requires a higher pressure drop. Higher pressure drop across vascular beds is a “feature” because it increases the extravascular flow of plasma necessary to deliver glucose to cells. The metabolic demand is actually increased because with fewer mitochondria, they are operating at a higher potential where there is more “slip”, that is it takes more substrate (reducing equivalents and O2) to generate the same ATP. This increased mitochondrial slip is the reason for the increased metabolic rate observed in the metabolic syndrome and obesity. The amount of ATP needed is about the same, but the amount of O2 needed to make the same ATP is increased due to mitochondria operating at a higher potential.

    Myocardial infarctions are more common because the heart muscle has less reserve mitochondria, it is operating more on the “edge”. When it does that, it generates more superoxide, lowering NO levels still more, causing more capillary rarefaction. The heart muscle still needs to do the same amount of work, but it doesn’t have the blood supply to do so because the capillary spacing is too high, so the heart gets bigger (dilative cardiomyopathy). There isn’t enough blood supply to support strong healthy tissue, so the tissue gets filled up with metabolically inert fibrotic tissue.

    Cells too far from a capillary don’t get enough glucose or O2, so they are in a perpetual state of ischemia, and some of them die one at a time, with the cells furthest from the capillaries dying first. They die one at a time, so there is no observable lesion, but the necrotic or apoptotic cell debris causes systemic inflammation as the cell debris is cleared. This is one source of many of the autoimmune antibodies that accompany many of the degenerative diseases, anti-mitochondrial antibodies in primary biliary cirrhosis, anti-nuclear DNA antibodies, antibodies against glutamic acid decarboxylase in stiff person syndrome (although some of his is due to reduced efficiency of autophagy due to increased oxidative stress, the HV-ATPase that makes the lysosome acidic is inhibited by oxidative stress and the pH gradient drives the rate and efficiency of autophagy, this disrupts downstream signaling from the lysosome). The increased turn-over of cells in a tissue compartment also accelerates senescence by shortening telomeres.

    Low ATP from low NO also increases the rate of senescence. When there is insufficient ATP, the first pathways that get turned off are the longest term pathways, those associated with repairing the repair pathways. Repairing the repair pathways is always second order with respect to urgency compared to using repair pathways to repair life-critical functions. However as the repair pathways degrade, the damage is irreversible and is what leads ultimately to organism senescence.

    Chronic high blood glucose causes accumulation of glycated proteins; advanced glycation end products (AGEs). These are a good measure of integrated blood glucose levels and are used to monitor long term averages of blood glucose, especially on hemoglobin. These tend to generate more superoxide, which is a “feature” in that it causes local reductions in NO which increases local constriction, increasing pressure drop and driving more plasma though the extravascular space. The lower NO levels also reduce inhibition of cytochrome c oxidase by NO and so decrease the O2 level at which mitochondria can consume O2, increasing the driving force for O2 diffusion to mitochondria.

    In summary, all the symptoms of the metabolic syndrome look (to me) like good regulation around a bad setpoint. The bad setpoint is due to low NO, and physiology is just trying to compensate the best it can.

  9. daedalus2u says:

    Draal, my hypothesis of the “French Paradox” is that it is due to bathing practices, not diet or wine consumption.

  10. weing says:

    I don’t think we should, and I do not, select high-risk patients just on the basis of the metabolic syndrome. I do use it to identify high-risk patients that don’t have other risk factors and will continue to do so. I also use it to motivate them to adopt lifestyle changes to prevent diabetes.

  11. Diane Jacobs says:

    @ daedalus2u (or anyone, really..)

    I want to pick your physiologically-astute brain for a moment, if I may.. (I’ve been reading about stress, glucocorticoids, allostatic load, allostasis, differences between stress, stress response, stressor.. cortisol, cytokines, etcetc.. so my questions are related to these topics..)

    1. How does what you discuss in your post (NO deficiency) relate to overabundance of glucocorticoid receptors, say on the hippocampus, (or pick any brain part) which we could call overabundance of exogenous stress, maybe, plus exercise deficiency?

    2. Also, what tissue are you talking about? Is it structural tissue (name your favorite mesodermal derivative – 98% of the body) or is it signaling tissue (name your favorite ectodermal derivative – brain, spinal cord, peripheral neurons, ANS, ENS, epidermis, adrenal cortex)? I ask because (I’ve read) the brain uses glucose at a rate 10 times higher than regular structural tissue (nervous system is only 2% of body but uses 20% of available metabolic energy, just to remain ready for those action potentials). So… implications?

    Seems to me that the brain has to put on its own oxygen mask (metaphorically speaking) first, and would be the first to perceive some sort of lack of groceries/glucose supply, even if the organism it runs is obese. That would be a “stressor” wouldn’t it? Feeling like it couldn’t get enough glucose? Also, exercise seems paradoxically to stress the structural stuff while enhancing/de-stressing brain function and regular physiology, helps reverse so-called metabolic syndrome. So… would an appropriate frame for “metabolic syndrome” possibly be stress overload (endogenous or exogenous – many brain parts can’t really tell the difference) plus exercise deficiency, more a functional problem and not really a disease, at least usually not yet.. more a verb than a noun?
    Thanks,
    Diane

  12. daedalus2u says:

    Diane, I am not sure I understand the question. All of those systems are extremely complex and are coupled, and are not well understood. There has to be system(s) of automatic gain control, by that I mean systems that regulate how many receptors are present in which tissue compartments and in which cells and what is the down stream effect of a certain level of signaling molecule. Something has to regulate that automatic gain, and I think NO is a large part of that automatic gain control and relates to recycling of endocytosed receptors and signaling during autophagy which I suspect regulates transcription of specific receptor proteins.

    Glucocorticoids are substrates and products of cytochrome P450 enzymes. Those enzymes are inhibited by NO, and those enzymes produce superoxide which lowers the NO level local to the enzyme, so the effect of NO on glucocorticoids and on glucocorticoid signaling is complex and exhibits feedback (positive and negative) and hysteresis.

    I think a better way of saying that there is an “over abundance” of glucocorticoid receptors is to say that there is a fault in the system of automatic regulation of glucotocorticoid receptor number. The same way not enough mitochondria resulting in exercise intolerance is better described as insufficient mitochondria rather than exercise deficiency leading to deconditioning because exercise does not always increase mitochondria number (as during chronic fatigue for example). There are times when exercise can reduce mitochondria number (as when exercising during acute illness).

    I am talking all tissues. I think the brain perceiving it does not have enough glucose is what makes people with the metabolic syndrome eat even when they have abundant depot fat, and why they crave carbohydrates. When you go into ketosis some of that craving goes away I think because ketone bodies don’t use the same GLUT transporters. Cells still need glucose for glycolysis but with ketone bodies floating around, there isn’t as much need for insulin resistance to get substrates to cells far from capillaries.

  13. criticalist says:

    Diane, if you are interested in the relationship bewteen cortisol and the metabolic syndrome, you may wish to look at some of the work by Mark Cooper and Paul Stewart (JCEM Dec 2009 4645-4654 for a good review.) They have investiagted the role of the intracellelular enzyme system the 11-beta -hydroxysteroid dehydrogenase (11-b-HSD) which interconverts cortisol and cortisone within the cell. There does seem to be evidence that upregulation of 11-b HSD-1 leads to increased intracellular cortisol generation in some tissues and can predispose to the metabolic syndrome (if it exists!).

  14. icarus4me says:

    Hmm, it seems to me that the problem is low global cAMP levels. Since a lack of cAMP is the one true cause of all disease, this would make sense. Raising global cAMP would no doubt alleviate this syndrome in a precise and specific way, just as it does for depression or Alzheimer’s. The drug companies trying to target specific receptors are going about this in a sadly discredited and very non-holistic way- why target receptors at all, when cAMP regulates everything?

  15. BillyJoe says:

    lynnandevelyn,

    “It seems to me that it would be more important to find the reasons for insulin resistance than to “manage” my elevated blood sugar by throwing more insulin at it and further increasing my insulin resistance.”

    I would have thought that both are important.
    Otherwise either you, lynn, or you, evelyn, may die of hyperglycaemia. Or do both of you have diabetes?

  16. icarus4me -

    cAMP? You mean like, the world needs more flamingo lawn figures, clocks made of tree trunk sections and paint-by-numbers of the old mill creek?

    Well, I agree. But, I’m not sure what it has to do with blood sugar levels or obesity.

  17. daedalus2u says:

    BillyJoe, the problem isn’t “insulin resistance” per se, the problem is not enough glucose getting to cells that are too far from a capillary. When those cells don’t get enough glucose, physiology pulls the only lever it has to try and fix it, physiology raises blood sugar.

    The reason that insulin works to lower blood sugar is that insulin causes more GLUT receptors on cells so that cells take up more glucose. When those cells have sufficient glucose, they don’t send out starvation signals that cause physiology to raise blood glucose, so blood glucose goes down. The path by which insulin lowers blood sugar is not via increased removal of glucose by cells, it is by cells becoming replete with glucose so they don’t send out the starvation signals that raise blood sugar.

    This is a subtle point that most doctors and researchers don’t appreciate how important it is even though they know it is correct. They know it is correct but they don’t know how to fix it.

    The role that insulin plays is not to remove glucose from the blood, but rather to trigger cells to express more GLUT receptors so that they take up more glucose. Insulin resistance is a feature to allow insulin to get to cells farther from a capillary so they can express more GLUT receptors and take up more glucose because they are not getting enough. Blood sugar will only go down when those cells are getting enough. The glucose level that “matters” (and matters a lot), is not the level in the blood, but rather the level that is adjacent to cells that are taking up that glucose. If that glucose level drops below a certain level, those cells experience ischemia. If the glucose level is low enough, those cells will die, no matter what the glucose level is in the blood stream.

  18. daedalus2u says:

    Just to add another point. The reason that blood sugar gets super high, is that physiology is calling for it to get super high. That means that despite this super high blood sugar, there are regions of the body that are not getting enough glucose.

    The adverse effects observed to correlate with a super high blood glucose level may not be from the super high blood glucose, they might be from the very low glucose levels in some tissue compartments that are triggering physiology to produce a super high blood glucose.

    Correlation is not causation. That some adverse effects correlate with high blood glucose does not necessarily mean that high blood glucose is causing them. The high blood glucose and the adverse effects may have a common cause, low glucose in specific tissue compartments.

  19. Diane Jacobs says:

    Thanks for the responses, folks; now I would like to know what GLUT stands for, and what a GLUT transporter is/might be. My guess is glutamate but for all I know there might be fifty different non-nervous system related things that GLUT stands for, so therefore the (dumb) question.
    Thank you for your patience as I try to follow along,
    Diane

  20. Anthro says:

    I’ll take your word for it that Metabolic Syndrome is not a helpful construct in general, but it helped me to reverse my own slide into heart disease and diabetes. I am an “apple”-shaped 60 yr. old who had very high BP at 40 (family history of early-onset heart disease), low HDL, high triglycerides, elevated glucose and a stent by 50. I was about 40 lbs overweight since having a baby at 37. by 57 I had crossed the line for glucose and was declared diabetic–had been on metformin for five years for “pre-diabetes”. Something clicked.

    I lost 45 lbs and have maintained it for over three years. I have always exercised and continue to do so. BP, HDL, Triglycerides have all greatly improved and medications decreased or discontinued. Glucose is completely normal. I always ate well, just too much.

    The concept of Metabolic Syndrome helped me to see a constellation of symptoms that, while they seemed genetically generated, were causing serious problems. When I realized that the underlying uniting principle was FAT, I realized I could change that. I still have an apple shape, but it is no longer as pronounced or obvious. My upper body is now more balanced with my thinner limbs.

    I know this is an anecdote, but one that I think is useful to anyone who has most or all of the factors of metabolic syndrome. No doc ever said that I had Metabolic Syndrome, but I read about it repeatedly and came to see that the only way to deal with it was to get rid of the mid and upper body fat, so I think it is a useful idea for the lay person. Also, I should add that no doctor ever told me to lose weight and since I lost the weight and moved I have a new doctor who never mentions it as she never saw me overweight. My old doctor was very supportive of what I had achieved and it really helped–the new doctor seems uninterested and I feel all on my own, which is okay, but I miss the support of the old clinic who cheered me on at each weigh-in.

  21. Harriet Hall says:

    Anthro,

    Doctors can and should do better. What if your doctor had sat down with you and gone over a statistical table listing each risk factor and showing how much each increased the probability that you would have a heart attack or die in the next 10 years? Then made a list of which of those factors were modifiable and how many years of life you could gain by modifying them? And also discussed how some of the risk factors interacted with others? And gave you feedback at each visit on how much your life expectancy had been statistically improved by your current progress? I used to have a whole book with tables for calculating those things for men/women in each age group, and now we have on-line risk prediction tools. Much of this could be computerized and made efficient enough not to take too much of the doctor’s time. What if we thought in terms of “all modifiable cardiac risk factors”instead of “metabolic syndrome”? Don’t you think that would be at least as useful and perhaps even more motivating?

  22. daedalus2u says:

    Here is a paper on GLUT transporters, they are glucose transporters.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435356/?tool=pubmed

    It is GLUT 4 that is regulated by insulin. What is “active” about the GLUT 4 transporters is that the number in the cell is regulated by the insulin level and the number of GLUT 4 transporters is limited so that they are “saturated”, that is the amount of glucose they take up is limited by the number of GLUT 4 transporters (which is regulated by insulin), not by the concentration of glucose in the fluid adjacent to the cell. It is the cells closest to the capillary, which contact the extravascular fluid first that become “saturated” so as to allow glucose to pass to cells down stream.

  23. Diane Jacobs says:

    daedalus2u, thank you so much for the additional info. After a once-over of that paper, looks like GLUT1 is the one most expressed in brain tissue. So many different GLUTs to learn about. Each tissue has its own preferred GLUT, kind of like each bird species has a unique beak shape.. OK, I’m way off topic, so thanks again.

    Another 60ish apple-shaped person who lost a bunch of weight, thanks to HH’s recommendation in a long-ago post to keep a food diary :^)
    Diane

  24. bakven says:

    Funny, anyone remembers the INTER HEART study some years ago

  25. BillyJoe says:

    Diane,

    “So many different GLUTs to learn about. ”

    Well, Daedalus could learn a little from you as well…
    He would have said GLUT transporters which comes out as Glucose transporter transporters. ;)

    ——————————

    Daedalus,

    Interesting take on the problem not being insulin resistance but intracellular glucose deficiency causing increases in blood glucose levels in an attempt to overcome the intracellular deficiency. And also that it is the low intracelluar glucose that cause the damage, not high blood glucose levels.

  26. daedalus2u says:

    BillyJoe, very high glucose levels ae not benign, but very low glucose levels are a lot worse. They do go together, so sorting out which is doing what adverse effect is difficult and there has not been a lot of research on this because it is experimentally challenging and is counter to the current paradigm.

  27. daedalus2u says:

    Billy Joe, I want to point out that the only reason that measuring blood sugar is a good method of telling when more insulin is needed is because blood sugar is still under excellent control. When the cells in what ever tissues are not getting enough glucose physiology raises blood glucose to compensate. That increase in blood glucose can be detected and insulin given to increase glucose delivery to cells, which then causes physiology to lower blood glucose. It is not the insulin that lowers blood glucose, it is physiology compensating for the cells having enough glucose getting inside.

  28. BillyJoe says:

    daedalus,

    Yes, I got your point:
    decreased intracellular glucose -> increased blood glucose levels -> increased insulin levels -> increased intracellular glucose -> decreased blood glucose levels.

    Also, yes, low blood sugar levels and high blood sugar levels can cause coma and death, but are you saying that high blood glucose levels have other adverse affects?

  29. daedalus2u says:

    High blood glucose does cause generation of superoxide. I think that is a “feature” to cause local low NO, local vasococonstriction, and local high pressure drop to increase extravascular flow of plasma.

    High blood glucose causes proteins to become glycosated and those glycosated proteins tend to increase superoxide too, I suspect that is a long time constant adaptation to increase extravascular flow while the vasculature remodels (but under low NO conditions the vasculature can’t remodel appropriately).

  30. BillyJoe says:

    Okay, as David Gorski is famous for saying:
    “It’s a bit more complicated than that!” :)

  31. Chris says:

    BillyJoe, I thought that was what Ben Goldacre says.

  32. BillyJoe says:

    Hmmm…I think you’re right.
    I’ve heard David use it, though, so perhaps he stole it from Ben.

  33. The Blind Watchmaker says:

    It is Ben Goldacre’s. Want to buy the tee shirt?

    http://badscience2.spreadshirt.co.uk/i-think-you-ll-find-it-s-a-bit-more-complicated-than-that-A8097896/customize/color/1

    I haven’t used metabolic syndrome much in practice. As an ICD-9 code, it never flies well with third party payers.

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