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Doves, Diplomats, and Diabetes

In the past I have criticized evolutionary medicine for its tendency to rely on unverifiable “Just-So Stories,” but a new book has helped me appreciate what the best kind of evolutionary thinking can contribute to our understanding of medicine. Doves, Diplomats, and Diabetes: A Darwinian Interpretation of Type 2 Diabetes and Related Disorders by Milind Watve investigates diabetes from an evolutionary perspective, suggesting how it might have originated, why it persisted, and how it is related to survival advantages. Watve develops well-reasoned hypotheses that can be tested by examining their expected consequences. He believes it is impossible to understand metabolism without understanding behavioral ecology, and he makes a good case.

A reassessment of the evidence concerning Type II diabetes (T2D) reveals a number of paradoxes. Elevated blood glucose is the defining feature of T2D but controlling it doesn’t prevent all the complications of diabetes, and it doesn’t appear that elevated blood sugar could produce all the pathological changes of diabetes.  Insulin resistance is believed to be central to a cluster of deadly diseases in humans, but in other animals it has no adverse effects on health and even increases lifespan. Studying diabetes from an evolutionary perspective can shed light on such paradoxes.

Insulin resistance leads to type II diabetes and coronary heart disease. It is associated with obesity and is thought to have developed as a response to periodic starvation, but a close examination of the evidence really doesn’t support that interpretation. Instead, it may be a socio-ecological adaptation that mediates (1) a transition in reproductive strategy to a smaller number of offspring with larger investment in each, and (2) a transition from a relatively more muscle-dependent lifestyle to a more brain-dependent lifestyle (stronger to smarter, soldier to diplomat).

There is a mass of complex information in this book that I can’t hope to master. It runs 428 pages and is exhaustively referenced. I hesitated to write about it because I don’t think I can do it justice. I can only hope to present a simplified summary to whet the appetite of interested readers.

Old paradigm: Type I diabetes is a primary deficiency of insulin. Type II diabetes is a relative insulin deficiency.  It begins with insulin resistance that leads to increased production of insulin (hyperinsulinemia); eventually the pancreatic beta cells wear out and can no longer produce enough insulin to compensate for the increased insulin resistance. Then blood sugar rises and that causes inflammatory changes with damage to blood vessels, eyes, kidneys, and heart.  Obesity is thought to be a primary cause (along with a genetic predisposition), and as the incidence of obesity has increased, the incidence of diabetes has increased.

New paradigm:

  1. A plurality of behavioral strategies can exist in a population of animals, and a prominent dichotomy is between the hawks and the doves, between the soldier (physical strength and aggression) and the diplomat (cognitive abilities and social manipulation). The number of individuals following each strategy varies with environmental and social conditions.
  2. Behavior affects physiology. Numerous physiological adaptations support the different behavioral repertoires, and the diplomat option is accompanied by a divestment from muscle, an increase in visceral fat, elevated cholesterol, elevated insulin, and insulin resistance.
  3. Increased levels of insulin, cholesterol, leptin, and cortisol produce aggression suppression, physical risk aversion, and enhanced cognitive functions.
  4. Aggression anticipates injuries, and the soldier’s body prepares for wound healing; the diplomat’s body puts its resources elsewhere, and therefore becomes more susceptible to factors that tend to impair wound healing such as low-grade chronic inflammation and deficiency of many growth factors.
  5. Crowding in a population affects reproductive strategies, aggressive behavior, etc.
  6. Most of the complications of diabetes are due to growth factor deficiency, changes in immune response, oxidative stress, and angiogenesis dysfunction. Hyperglycemia aggravates these effects but is not the underlying cause.
  7. Beta cell degeneration is not due to the pancreas “wearing out” but to factors that may be reversible. Other body functions increase their response in the face of increased demand; they don’t “wear out” and stop responding. Something is going on here that we don’t understand.
  8. Insulin resistance can be decoupled from the mechanisms listed in 6, and it can promote health and longevity. It is not central to the pathology of diabetes.
  9. The rate of glucose transport from the brain capillaries affects plasma glucose levels. The key to glucose homeostasis is most likely to be found in the brain.
  10. Obesity is not central to T2D but is only a risk factor. It is associated with suppression of soldier behaviors, with two-way causality.
  11. Insulin sensitivity and insulin secretion respond to a large number of signaling molecules including sex hormones, endorphins, myokines, and many others. It’s fiendishly complicated.
  12. T2D is not primarily or mainly about insulin and glucose homeostasis.
  13. Glycemic control is not sufficient to prevent all the complications of diabetes.
  14. The pathophysiology of T2D originates from brain and behavior rather than from diet and energy imbalance.
  15. T2D is potentially curable.

What about obesity? Fat has multiple functions in the body. Obesity is an adaptation that favors survival through various mechanisms rather than the simplistic explanation of energy storage to buffer against periods of starvation.  Rather than obesity causing insulin resistance or insulin resistance causing obesity, there is likely a behavioral syndrome that precedes both; neuroendocrine processes driven by specific behavioral strategies may initiate pathways leading to obesity and T2D and the associated pathologies. Relative obesity is more important than absolute obesity: in countries where obesity is less prevalent, people become diabetic at lower BMI.

Watve introduces the concept of “behavioral deficiencies,” for instance of aggression, agility and rapid action, adventure, injury proneness, exposures to sun, weather, plants, microbes, and animals. He suggests that such behavioral deficiencies contribute to various diseases including cancer, skin disorders, hormonal dysfunctions, osteoporosis, chronic fatigue syndrome, depression, and various inflammatory conditions. He suggests that the typical exercise prescriptions are grossly inadequate, and that exercises should be designed specifically to supplement specific behavioral deficiencies.  Competitive sports probably do more good than treadmills.

Unfortunately the book is very expensive and is not likely to reach many of those who would benefit from it. The list price is $209, and $159 for the eBook version.  I didn’t know it or its author even existed until Watve e-mailed me out of the blue and kindly sent me the pdf. Its extensive references cover a broad gamut of scientific disciplines. I don’t feel qualified to judge how credible his hypotheses are, and I wish experts in the various fields could read the book, all put their heads together, and critique it more intelligently than I could hope to. I would love to see some of his research proposals carried out.

I wrote an article on “Bad Books” where I said:

There are two kinds of science book: one aims to educate the public by explaining the current state of evidence and the consensus of the scientific community. The other has an agenda: it uses (and mis-uses) science to persuade readers to believe something that the authors believe but that the scientific community as a whole has rejected.

This book doesn’t fall into either category. I don’t know whether its conclusions are correct, but I do know that its approach is unimpeachable. It epitomizes the best of scientific thinking. It doesn’t go beyond the evidence. It recognizes where the evidence is insufficient and how better evidence could be obtained by the proposed studies.

Watve is a professor of biology at the Indian Institute of Science Education and Research in Pune, India.  His home page says:

I specialize in not specializing. I used research more as a tool in education and tried to motivate undergraduates to identify novel problems and use a variety of tools to handle them including modeling, simulations, observations, surveys, meta-analysis, field experiments as well as lab experiments…there is a common theme that runs through all the work, the connecting thread being evolutionary biology.

He challenges his students to question everything they read in their textbooks and to examine the evidence behind the accepted wisdom. In the case of diabetes, the underlying evidence was marked by a number of flaws, paradoxes, anomalies, and contradictions. That eventually led to the present book. He located thousands of published studies from various fields and tried to evaluate the data with a fresh eye. He also had access to data from many unpublished studies. He located some fascinating evidence that directly contradicts the standard textbook story of T2D.

The best thing about this book is its humility. Instead of bragging that he has found “the answer,” he raises more questions. He suggests hypotheses that might better explain the known facts, and proposes specific experiments to test those hypotheses. He says the new paradigm answers more questions than the old one but is far from complete. He begs researchers to carry out the necessary experiments. He invites criticism from readers. He even includes an epilogue entitled “I May be Wrong After All!!” He is interested in finding the truth rather than vindicating his own ideas.

He says:

I keep the possibility open that I have actually got into a thinking trap from where it is really difficult to get out. But I would like someone to try and convince me that it is so. I tried doing it myself and it did not work…the possibility remains that I have made erroneous arguments out of inadequate knowledge of the field. I would be glad to correct myself if anyone points out specific problems in my way of thinking.

These are the words of a true scientist and a wise man. Whether or not you agree with his ideas, you have to respect Milind Watve’s approach. He sets a stellar example for every scientist and critical thinker to follow.

Posted in: Basic Science, Book & movie reviews, Evolution

Leave a Comment (38) ↓

38 thoughts on “Doves, Diplomats, and Diabetes

  1. rmgw says:

    “In other animals it has no adverse effects on health”…isn’t it related to Laminitis in horses?

  2. goodnightirene says:

    I hope you will give us an update if you learn more about these ideas. Does the price of this book indicate that it is basically a textbook?

    As someone who has controlled (cured?) T2D through weight loss, I am particularly intrigued by these ideas–in as far as I could follow the summary. I’m not sure I am either a diplomat or a soldier and although I realize many women are now soldiers, I wonder if there isn’t a better analogy for women?

  3. daedalus2u says:

    This idea of T2D is also wrong. Animals can and do get the metabolic syndrome, not just horses but elephants get it. One of the leading causes of death in captive elephants is foot rot, infections of the feet just like what people with T1D and T2D get.

    The way that cells get glucose is through GLUT transporters from fluid that is outside the cell. This fluid is not blood, but is the lymph. Blood is confined to the vasculature, it is the lymph that “leaks” out and passes by every cell and transports everything except O2 and CO2 that is carried by the blood. Those gases diffuse through the intervening cells, where large molecules such as glucose, insulin and albumin can’t. Those large molecules must be conveyed via convection in lymph to the cell surface so they can be taken in through specialized transporters.

    Blood can have a constant glucose level because blood is well mixed. It circulates around and because there are different path lengths, it becomes well mixed and uniform, subject to the regulatory and counter-regulatory pathways. Blood glucose level is a global parameter, it requires global control. Cell glucose uptake is local, it requires local control.

    Blood circulation is fast, on the order of a minute. Plasma circulation takes about 10x longer, on the order of 10 minutes (but this is more variable). Blood delivers O2, and there is a significant artery-vein gradient in O2 levels. Lymph delivers glucose, there must be a significant gradient in glucose levels between the inlet and the outlet of the lymph compartment. This gradient times flow must equal the glucose consumed by the cells that remove glucose from the lymph compartment.

    Because the time constant for lymph circulation is long compared to that for blood circulation (10 min vs 1 min), to deliver sufficient glucose to high metabolic demand tissues can be difficult. Heart muscle can increase its metabolic rate about 10x. If there is increased glucose demand, it necessarily takes some time for the glucose to be put into the blood stream by the liver, transported to the capillary bed, and then conveyed from the blood to the cells by the lymph. That time can be reduced if the glucose concentration of the blood is increased beyond nominal levels.

    What happens if muscles are consuming glucose faster than it is being conveyed to them? The glucose concentration drops. How far can it drop? It can only drop until cells are unable to take it up and then cells are starved for glucose and will die. Before that happens, cells send “I am starving” signals to the CNS which triggers release of glucose by the liver, but that glucose takes some time to get to he proper site, into the extravascular space and into the cells that are “starving”.

    If many cells are “starving”, the first cells the glucose hits will take up all of it, leaving nothing for the cells farther downstream. To prevent this, it is necessary to prevent those first cells from taking up all the glucose, the cells need to be made “glucose resistant” such that they can take up some glucose but leave some for cells downstream. A way to do this is by limiting the maximum number of GLUT transporters. Cells with fewer GLUT transporters require a higher external glucose concentration to achieve the same glucose flux as cells with more GLUT transporters. But using that control scheme requires that the number of GLUT transporters be regulated independently in each cell. A way to do this is to use a hormone that diffuses along with glucose but which triggers the expression of GLUT transporters in cells. A hormone such as insulin.

    However, insulin is also consumed by cells, how to ensure that the first cells don’t consume all the insulin in the lymph? One way would be to make cells insulin resistant, such that they no longer take up insulin and increased insulin no longer causes increased GLUT expression. Having a maximum number of insulin receptors would accomplish this.

    The delivery of glucose to cells using the combination of blood and lymph requires there to be ways to limit glucose consumption by cells so that the glucose delivered by the common systems of blood and lymph can be shared by cells that take the glucose out at different concentrations (the concentrations are different because glucose in consumed and so the concentration in lymph drops.

    What could cause such a system to get out of whack? Glucose is mostly used to make ATP, either through glycolysis or through oxidative phosphorylation. Oxidative phosphorylation makes 19x more ATP per molecule of glucose, but it also requires O2. Glycolysis doesn’t require O2 but does require more glucose.

    What if there was insufficient O2 delivery? Cells would shift to more glycolysis. If O2 delivery was reduced by 5%, then 5% of the ATP made through oxidative phosphorylation would need to be made by glycolysis instead. That 5% would take as much glucose as the 95% being made by oxidative phosphorylation or about twice as much. Can the vasculature deliver twice as much glucose? Only by increasing the product of flow rate times concentration by 2x. Since the volumetric output of the heart is limited, and the cross section available for flow is limited, there can be slight increases in flow rate by inducing increased lymph flow via increased pressure drop across capillary beds (hypertension).

    How is O2 delivery regulated? Blood is oxygenated in the lungs, pumped by the heart, deoxygenated in the peripheral tissues, pumped by the heart through the lungs again. Arteriole blood is already at ~100% saturation, the only way to deliver more O2 is by pumping more blood. But the heart has only a limited capacity to pump blood. The way blood flow is regulated is by dilating vessels supplying tissue compartments to receive more blood and constricting vessels supplying tissue compartments to be denied blood.

    The O2 passively diffuses down the chemical potential gradient from the red blood cells to the mitochondria where it is consumed. To a first approximation the diffusion resistance is proportional to the surface area of the capillaries in the capillary bed. That depends mostly on the number of capillaries because they all have a minimum diameter that can let a blood cell travel through it and their length. This is characterized by the number of capillaries per unit area. A reduction in capillaries per unit area is known as capillary rarefaction and is known to occur in hypertension, systemic sclerosis, Raynaud’s, neurodegenerative diseases and some others.

    What sets capillary spacing? Obviously it must be regulated by physiology. Capillaries are “well formed”, that is there are not too few and not too many. This regulation requires both positive and negative regulation; angiogenesis when there are not enough and capillary ablation when there are too much. Wounds heal and generate well formed capillary beds, infants at birth have well formed capillary beds. Physiology must use a diffusible signal to “measure” the proximity of cells to oxyhemoglobin (the source of O2 and the sink of CO2).

    Could physiology use O2 as the diffusible signal? No, it can’t because the maximum O2 level is 100% saturation. There is no signal if capillaries are too close together. O2 gradients in utero are very different than post-birth because the infant is breathing air with a high O2 level, not getting meager amounts of O2 through the umbilical cord.

    A signal that could be used is nitric oxide, NO. Oxyhemoglobin is the sink for NO, and NO has essentially identical diffusion properties to O2. Being diffusively close to oxyHb could be measured with NO but with no difficulties at both the high end and low end. Using NO instead of O2 allows O2 gradients to be used to modulate O2 delivery while maintaining O2 consumption at high levels.

    Conveniently NO is already used to regulate vascular tone. High NO levels cause vasodilation and increase blood flow. If high NO also decreased capillary spacing, it would result in stable control. If capillaries are too far apart, then O2 levels go down, there are a number of nitrite reductases (xanthine oxidoreductase, deoxyhemoglobin, deoxymyoglobin, other heme enzymes) that increase NO levels. NO is anti-apoptotic. NO is also what inhibits cytochrome c oxidase and prevents O2 binding. To increase O2 consumption and decrease the k of O2 binding, the NO level needs to be lowered at mitochondria. Generating superoxide by having a reduced respiration chain does this. O2 picks up electrons from complex I and complex 3, generates superoxide, that reacts with NO at diffusion limited kinetics, the NO level goes down, cytochrome c oxidase becomes disinhibited, O2 binds, gets reduced to H2O, and electrons move off the respiration chain so it becomes more oxidizing.

    Regulation of capillary spacing could be a stable mechanism that is compatible with other uses of NO in regulating vascular tone.

    However, if the background NO level is low for any reason, physiology would interpret that as cells being closer to O2Hb than they really are, and then increase capillary spacing more than it should be increased.

  4. Harriet Hall says:

    @rmgw,
    ““In other animals it has no adverse effects on health”…isn’t it related to Laminitis in horses?”

    I didn’t mean that it has no adverse effects in any animal; I meant that there are animals in which it has no adverse effects.

  5. mousethatroared says:

    Thanks for the interesting overview HH. I can’t see myself invest the time or money in such a hefty book, but maybe there will be a podcast done with the author at somewhere.

    “A plurality of behavioral strategies can exist in a population of animals, and a prominent dichotomy is between the hawks and the doves, between the soldier (physical strength and aggression) and the diplomat (cognitive abilities and social manipulation).”

    This in an interesting idea, but I would like to see if such a duality is a reality. Some of the most physically strong folks I know also have excellent cognitive skills. This may be because the folks I know who tend to intense sports are into rock/mountain climbing, triathlons and the like, which require strategy and planning for success. Maybe I hae a bias selection, but anecdotally, it seems that the athletic and non-athletic folks I know have similar cognitive abilities. Clearly this doesn’t disprove the concept, but it does make me question it.

    Still it is good to see that people are putting new ideas out there with a mind toward testing.

  6. dinseattle says:

    Evolutionary origins of insulin resistance: a behavioral switch hypothesis.

    open access article by Milind G Watve

    http://www.biomedcentral.com/1471-2148/7/61

    (does the book cite any studies at all with a correlation or association between being obese or diabetic and cognitive skills? Or being diabetic and being a better diplomat?)

  7. daedalus2u says:

    The problem with a “thrifty gene” hypothesis for T2D is that metabolic rate is increased in T2D. That is basal metabolic rate is higher. My interpretation is that this is due to more slip in conversion of O2 to ATP. There is more superoxide produced and more O2 consumed to produce the same ATP. This is the opposite of what you would want for “thrift” and the opposite of what is observed in calorie reduction.

  8. Angora Rabbit says:

    I’m with the posters as being skeptical about the book. At least until I can make time to read a 400pp book (sadly unlikely as I’m unwilling to spend $200 on it). I would say that his “Old Paradigm” is more accurately phrased as “The simplified version we give to undergrads.” His OP omits a number of complexities surrounding NIDDM/Type 2. A *majority* of mammals can develop NIDDM and it isn’t fair for Watve to declare that the exception rather than the rule is correct – that’s cherry-picking. We know in humans that the disease is multifactorial with significant genetic, inflammatory, environmental, and other influences. We already know that brain does play an appreciable role through satiety factors, the HPA axis, etc. We also understand that there a number of physiological changes that factor into the physiology in addition to the reduced glucose clearance. I doubt that there is any physician or endocrinologist in the field who believes that “controlling blood glucose” will totally prevent the disease’s pathology. Many of the points in his New Paradigm are “duh” things that we already know and are well studied.

    Short-term insulin resistance might indeed be a useful evolutionary strategy. But is it evolutionarily useful when it goes on, continuously, for decades? That is the human disease we are combating.

    To me, this book sounds rather like one of the conversations I have with students who have their eyes opened when they understand that the disease is far more complex than the simplified version we present to them early in their training.

    I am also suspicious that this link to temperament / behavior / stress. It sounds like one of those “destressing will cure your disease” hypotheses, which is still pretty much sCAM. Points 2 and 3 trouble me.

  9. goodnightirene says:

    Thanks, Angora Rabbit–points 2 and 3 bothered me too, but without reading the book, I don’t feel qualified to critique and I’m probably not qualified to read the book! But as you are a pharmacist (correct?) I feel better about my “bothers”.

  10. daedalus2u says:

    The problem with this hypothesis is that there really isn’t much of a correlation between metabolism and cognitive skills. There are good reasons for this. Having a functional brain is an extremely important factor in staying alive. This is why the brain prioritizes maintaining consciousness over preventing degeneration. I know, this sounds counter-intuitive, but it isn’t. All neurodegenerative diseases are difficult to diagnose early. Why? Because people’s brains remain functional as they degenerate.

    Maintaining functionality is prioritized over preventing degeneration. Alzheimer’s is difficult to diagnose in its early stages. Maintaining consciousness requires that millions upon millions of cells all work together “in sync”, each doing something different such that the ensembles of millions of cells instantiate things like thoughts and thinking and forming memories of those thoughts.

    ATP levels and cellular “housekeeping” is done one cell at a time and is regulated internally to each individual cell. How is it possible for millions upon millions of cells to “go bad” simultaneously in terms of ATP production while remaining “in sync” for the much more subtle and difficult process of instantiating consciousness?

    The brain needs to self-regulate its metabolism under diverse conditions. If there is a temporary shortage of substrates, as when running from a bear, to lose consciousness is certain death. Losing millions of brain cells is no big deal. When there are insufficient substrates (O2 and glucose), the brain enters a state of ischemic preconditioning. This occurs by temporarily shutting down pathways that take longer than the anticipated ischemic event to occur. If the metabolic task can’t be completed before the bear is escaped from, then you don’t need what ever that task was going to do to escape, so you can shut it down and use the ATP the task was going to consume to help in your escape.

    Ischemic preconditioning is known to occur in every tissue compartment. It is pretty clear it can’t be a permanent state or organisms would have evolved to be in that state permanently so as to have more ATP for reproduction. That hasn’t happened, so ischemic preconditioning can’t be a long term state. What would happen if it goes on for too long? What are the long term metabolic tasks that can be put off for later? Clearing of damaged proteins? Repair of damaged cells? Replacement of mitochondria? Transport of cargo in axons?

    What would you see if these were happening? Accumulation of oxidized and agglomerated proteins, accumulation of damaged cells, reduction in mitochondria number and status (increased slip and ROS), reduced movement in axons, characteristic of reduced H2O diffusion on MRI also called white matter hyperintensities.

  11. Angora Rabbit says:

    @Irene – I’m in nutritional sciences; Dear Spouse is the pharmacologist / enzymologist. I’m constantly amazed at what nutritionists have to know, melding biochemistry (my training) and physiology. It’s been fun.

    @Daedelus2u – I think brain is actually pretty low on the list of priorities for energy, in some ways. At resting state it’s a big drain. But running means prioritizing muscle over brain (yesterday’s marathon before the sad events). Brain loves glucose but muscle will suck it up first. Which is in some ways the point of the marathon – sparing glucose for brain while convincing the muscle to burn fat even though O2 is limiting. Maybe this is where the ischemic preconditioning comes in? (Must admit I’m not familiar with this for brain.) In iron deficiency, where it is essential for energy generation and O2 transport, brain is low tissue on the priority list. But I think we both agree for similar reasons why the book is not so wise.

  12. daedalus2u says:

    Angora, brain is actually the highest priority. Every other tissue can take a few seconds of ischemia with no adverse effects. Try that with the brain and you become unconscious. A couple minutes of brain ischemia and you could well be brain dead. Organs can be transplanted after sometimes hours of ischemia.

    Running muscle via glycolysis and the brain on the lactate from that glycolysis allows a little bit higher peak muscle ATP production. During glycolysis the limiting factor is disposal of the reducing equivalents stored in lactate. Rather than use those reducing equivalents in the muscle or liver, use them in the brain which has to be aerobic anyway. The brain can’t do glycolysis (mostly).

    Brain can run on ketone bodies which are made from fat, but you have to be in ketosis for that to happen. The only things that can’t run on ketones or fat are the immune cells, red blood cells, and lactation. Replenishing glycogen after it has been depleted in muscle requires glucose, but that can also come from amino acids (in small quantities).

  13. Badly Shaved Monkey says:

    d2u

    Similarly to Dr Hall’s commentary on the book that is the subject of this blog, I am impressed by your chain of reasoning about glucose, insulin and finally NO, but I am in no way competent to judge it’s validity. Nonetheless, I read it in anticipation of a punchline and didn’t feel I got one. So, could you say where you were headed with your argument a bit more explicitly so a dumb monkey can get the point?

    Thanks.

  14. daedalus2u says:

    The defining characteristic of diabetes, high blood sugar, isn’t the problem. The problem is not enough glucose inside of cells. When there isn’t enough glucose inside of cells, the only thing that physiology can do it put more glucose into the blood stream.

    In T1D, insulin doesn’t work because it lowers blood sugar, insulin works because it causes expression of more GLUT transporters so more glucose gets into cells, those cells stop sending “I am starving” signals and the liver stops dumping glucose into the blood stream. The problem in T2D is that even with hyperglycemia and hyperinsulinemia there are cells that are not getting enough glucose so they keep sending “I am starving” signals and the liver and pancreas keep dumping glucose and insulin in the blood stream.

    You can have both T1D and T2D simultaneously.

    The reason people with T2D get obese is because it is really hard to not eat when your body is getting starvation signals all the time. Your body does need more carbohydrate because some cells don’t have enough glucose inside. That carbohydrate supplies ATP via glycolysis, which produces lactate which needs to be disposed of. There are no excretion pathways for lactate, it needs to be metabolized into something else. The liver can turn it back into glucose, but the liver doesn’t have infinite capacity. Every cell can turn lactate into fat, so that is what happens. Adipose cells turn lactate into fat but as low NO proceeds, you start getting mitochondria depletion even in fat, so other cells start to turn lactate into fat; liver, kidney, even muscle. Ectopic fat is a really bad sign.

  15. milindwatve says:

    I am delighted that my book is being discussed on this platform. Most, if not all, doubts and issues are as anticipated and one can find adequate and elaborate answers in the book itself. I admit that it is a rather fat book and that might keep many readers away, but that is because I could anticipate possible doubts, objections and skepticism and felt the need to be elaborate enough to answer them in anticipation. I am sure reading the book would clear most issues and we can always discuss more about the rest. The role of nitric oxides is very important and is treated that way in the book. Angiogenesis and its dynamics is a part of the mechanisms discussed in the book. The brain/ muscle priorities are contextual and that is also discussed at length.

    Although reading the book can be a good solution to most issues, I will clarify some points here

    1. I do talk about a trade off between physical strength and social manipulation skills, but a trade off does not mean that physically strong individuals cannot be intelligent. The trade-off only means that physically weaker individuals are under a greater pressure to use their social skills in an attempt to compensate for their physical weakness. A strong individual may or may not need them.
    2. The original argument about insulin resistance in other animals is that in a wide variety of taxa ranging from worms to mammals partial impairment of insulin signaling (the parallel of insulin resistance in humans) results in increased longevity. Some of the mammalian longevity genes such as “klotho” appear to increase longevity by inducing insulin resistance. This paradox is recognized, stated factually and discussed at length to find possible logical solutions in the book.
    3 The main content of the book is about genes, molecules and pathways that connect behavioral strategies to endobolic states and why such pathways would have evolved.

    I would welcome any skepticism or criticism specifically about these pathways, the evidence for them and the accompanying interpretations.

    milind

  16. Badly Shaved Monkey says:

    Thanks, d2u

    But what is the practical upshot of your train of reasoning?

  17. Angora Rabbit says:

    @Daaedelus2U – I think we both misunderstood each other. I understood you to be referring to glucose energy, which is what I was referring to but didn’t state it clearly. I am quite familiar with ketones and brain fuel choice etc.

    An alternate look at NIDDM/Type 2 is that the influence is 50/50 genes and environment. The underlying causes appear to be genetic, with environment playing a secondary role of allowing gene phenotype to emerge. For example, 5% of NIDDM have an allelism in glucokinase that slows its activity, meaning that blood glucose is cleared more slowly. As we uncover these allelisms, the common thread is often that, ultimately, there is slightly slower clearance of glucose, which allows to disease to slowly unfold over decades, provided that energy intake exceeds expenditure. The leptin story was brilliant in mice, but apart from a few overt mutants, it hasn’t played out much in humans, even with the raft of orexigenic hormones we now know about.

    What troubles me about your posts here is the absolutism. There isn’t a single cause of, say, NIDDM. These diseases are multifactorial. To say that “the reason people with T2D get obese is…” troubles me because it smacks of “one true cause.” It’s rather like sayng “Death was caused due to a lack of O2.” There are many factors that play in. And this is me saying this, who is very much a drilll-down, reductionist researcher. It’s the multifactorial nature that is why these diseases take decades to emerge.

    And isn’t the limiting factor of glycolysis the ability to bring in O2, so that pyruvate can be sent into TCA? It’s when O2 is limiting that reducing equivalents become relevant for glycolytic flux. The point of athletic training for aerobic events is to pull in adequate O2 so that one gets full oxidation of CHO and CH2 to CO2. But now our posts are starting to conflate metabolic flux in exercise vs. rest, and of course those pathways will be very different.

  18. WilliamLawrenceUtridge says:

    D2U, your chain of reasoning, what I could grasp after a quick read, is fascinating. The discussion between you and Angora Rabbit is also delightful to watch. I think Badly Shaved Monkey missed the punchline though, which comes in at the end with “nitrous oxide” – a topic I think you have mentioned once or twice in the past :)

    I kid, I know you do NO work and obviously know a lot about it. I wish I could understand your points on a more substantive level and engage in an actual debate, bit it’s so far over my head we could use it as a space elevator if we could only get a strong enough chain. Please keep talking, it’s an education to read!

  19. goodnightirene says:

    @D2U

    What is meant by “ectopic fat”? I know what ecotopic means, but don’t get it in this usage. :-(

  20. morris39 says:

    @D2U 16th
    Your ideas are clearly developed and apart from the conclusion ( very interesting) AFAIK fairly mainstream. However there are other views e.g. senescent cells lose their ability to efficiently metabolize glucose and fatty acids due to some mitochondrial impairment. NEFA metabolism is also impaired in obese/diabetic individuals and may contribute to glucose intolerance. You do not bring these factors into the discussion. Can you comment whether this is because you believe these other factors are negligibly small or non-existent.

  21. daedalus2u says:

    Angora, I disagree, I think there is a single cause of T2D. Who will get it, when, and under what environmental conditions is extremely complicated. But if you compel cells to get more ATP from glycolysis than the vasculature has the capacity to supply glucose for, then you will get T2D. You may get other conditions first, but eventually you will get T2D.

    The main factor in that is the background NO level which sets a number of control setpoints. Capillary spacing is an critically important one, so is the threshold for mitochondria biogenesis, the threshold for activation of HIF-alpha. The operating point for O2 consumption of mitochondria is an important control point also, but it is one that is set locally (to each mitochondrion) so it is very hard to measure and is dynamic anyway.

    The idea that disorders are some percentage genetic and some percentage environmental is false. I appreciate that people have looked at a lot of things that way, and have fit data to those types of models, but those models do not reflect actual physiology. All phenotype properties result from both the genome and the environment. It is wrong and does not aid in understanding to try and divide disorders into genetic and environmental components.

    Ectopic fat is accumulation of fat storage droplets in tissues other than adipose tissue.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366269/

    WLU, it is nitric oxide (NO), not nitrous oxide (N2O).

    Morris39, what makes cells go senescent? What makes mitochondria go senescent? Mitochondria have a lifetime of about a month (in rat CNS). There is continuous turnover and replacement of mitochondria throughout the lifespan. Why does that normal ongoing replacement fail? Mitochondria biogenesis is triggered by NO, so presumably if there is insufficient NO there would end up being insufficient mitochondria.

    Repair of cells is not the highest priority of physiology. Staying alive is the highest priority. During ischemia, cells are too busy trying to stay alive to devote resources to keeping themselves repaired. Once the repair systems get too badly damaged, then the cell loses the capacity to repair itself.

    Like all things in physiology, the fraction of resources devoted to repair and to immediate volitional consumption is regulated. If that regulation is screwed up, and too little is devoted to repair, there are no immediate symptoms. There may even be the (false) perception of improved health, of increased vigor because more ATP is available for immediate consumption. That is what stimulants do, they increase the capacity to do volitional work. Where does that ATP come from? Do stimulants somehow improve on 2+ billion years of evolution? I don’t think so. What I think happens is that stimulants “hack into” the control system that regulates how ATP is utilized. Spend less on repair and you will have more to run from a bear, or more to party all night long.

    In my conceptualization, senescence of cells occurs secondary to interference with normal control signaling through disruptions to normal basal NO levels. I am working to commercialize something that will fix this.

  22. cramko says:

    D2U, do you think that the signaling molecules IL-6 and -15, and the sirtuins have significant roles in this as well? I believe that there has been some interesting work along these lines as well.

  23. cramko says:

    D2U,

    do you think that the signaling molecules IL-6 and -15, and the sirtuins have significant roles in this as well? I believe that there has been some interesting work along these lines as well.

  24. Badly Shaved Monkey says:

    WLU

    I think you have mentioned once or twice in the past

    Are you implying d2u is suffering from moNOmania?

    d2u

    I think I’m still dangling without any clear idea of the practical upshot of your line of reasoning. If it is all true, proportionate and relevant to T2D, what should be done about it?

  25. daedalus2u says:

    BSM, in my conceptualization T2D is one of the physiological states brought on by not enough NO/NOx. Until that low NO/NOx status is fixed, physiology is going to continue to be skewed in that direction.

    There are a number of things that can be done to improve NO/NOx status, eating green leafy vegetables for their nitrate content. Aerobic exercise causes higher blood flow and that shear on the endothelium causes the release of NO. Meditation of the type practiced by the Dalai Lama increases NO/NOx via neurogenic NO production in the brain. Other types of thinking do so too, but that specific type of meditation is particularly effective. Stress is a low NO state, so avoiding stress is good. Helping people instead of hurting them helps too. I think this is the physiology behind karma. If you treat others badly your whole life, that puts you in a state of stress and that stress activates fight-or-flight which lowers NO/NOx levels and decreases repair of damage. Over a lifetime that damage increases and accelerates senescence in people who harm over people who do good. I suspect this is why most people who are doing harm generate the delusion that they are doing good. That delusion by the perpetrator mitigates some of the adverse effects of hurting people on the perpetrator. I think that is why the worst harms are often done by people who believe they are doing good.

    There is cross-talk between many of the signaling pathways that use NO/NOx, so raising it via one method can help. There is not complete cross-talk, the different pathways do result in different effects which are very likely idiosyncratic. These pathways are extremely complicated and exhibit hysteresis, and feedback regulation, so they are difficult to “hack into”. NO signaling is too important to be regulated by something as simple as dietary levels of L-arginine (an approach that many are trying to use). There are no long-term placebo-controlled trials of L-arginine that show improvements in NO mediated health problems (that I am aware of). There are short-term trials that show positive effects but the longest trials don’t. I am pretty sure that is due to compensatory regulation because NO signaling is too important to be strongly affected by diet.

    As I mentioned, I am working on commercializing another approach to raising NO/NOx levels, topical application of ammonia oxidizing bacteria. That isn’t ready yet, but at some point it will be.

  26. TonyMach says:

    m(

    I always expected that working on etiology makes an disease easier to understand, not harder. I’m not sure, is this meant as an satire? While we are at it, such “behavioral” reasoning always reeks like the age of idealism to me (with its “primacy of the mind” thinking) – and it seems to me that idealism seek in this case shelter in the evolutionary discipline, arguably the most materialistic of all disciplines. Who falls for such crap?

    If you rather want snark instead of satire, then how about you try this for a change:
    http://high-fat-nutrition.blogspot.com/2012/11/protons-physiological-insulin-resistance.html

    (I’m sure the so inclined reader can figure out the evolutionary angle and how it relates to T2DM all by themselves.)

  27. Badly Shaved Monkey says:

    Thanks, d2u.

    I will admit to reading your contributions here and never being quite sure whether to regard your views as cranky moNOmania or mainstream. Can you see why I might think that? Is the centrality of NO your obsession or a fair representation of physiology?

    What do others think?

    Just to be clear, I really do not have the background to judge the quality of d2u’s arguments, but they certainly are impressively detailed and seemingly internally consistent.

  28. daedalus2u says:

    My primary focus is nitric oxide. However I am not looking for NO to be more important than it actually is. There are some very compelling evolutionary circumstances and contingencies that have made NO uniquely important as a signaling compound for eukaryotes.

    Unfortunately I don’t think there is anyone who is up to speed on the breadth and depth of NO physiology like I am. I haven’t published my stuff, so I don’t blame people for not being up to speed. There are are a couple who do appreciate the central role that NO has in signaling. The idea that NO is so important isn’t even my original idea.

    Other people in the NO field do agree with me where our expertise overlaps. Usually people who disagree with me are not experts in the NO field, they are in some other field trying to understand NO and get caught up in some common mistakes that non-NO experts make. I appreciate that it is difficult for someone to justify the time to get up to speed on NO until they appreciate how important it is and that can’t be appreciated until you are up to speed on it.

    Experimental methods in NO physiology are quite challenging because the levels that are important are extremely difficult to measure (sub ppb) and differences in those levels matter. In some cases the interpretations of data in the literature concerning NO are not correct. There is no good data in the literature that I disagree with or that conflicts with my conceptualization. But NO physiology is so complicated that there are things that seem counter-intuitive.

    Very often non-experts try to dismiss my ideas because of the confident tone I use in describing them (as Angora mentioned above). I don’t know how to respond to that. Lately I have been looking at physiology from the perspective of control (I am an engineer after all), and a number of things just fall out from first principles when you do that. A good example is hormesis. There is a conference on hormesis next week at UMass Amherst.

    http://www.dose-response.org/

    They have an excellent lineup the second day. There are excellent reasons from first principles why hormesis has to be the correct dose response. I will be presenting a poster on why that is.

  29. Badly Shaved Monkey says:

    Thanks, d2u.

    I’m sure you can see the risk of sounding like a ‘One True Cause’ crank.

    One thing that does occur to me in discussions like this, again not pretending to specific expertise in the field of NO, is that physiology and biochemistry are a complex mesh of relationships and, as a matter of self-evident logic, it is possible to pick one path through such a mesh and claim that this path is the causal path with all the rest of the mesh now being viewed as subsidiary side branches. A trivial response would be to say that if you block your identified path and if the system packs up then you have proven that your pathway of interest is critical and central. But the problem is that in an interdependent system blocking any one of a number of processes can disrupt its overall function. And if you have picked on one moiety or process to be your focus, then disrupting the mesh somewhere remote from that process will doubtless have some effect on your locus of interest.

    All of the above holds true even before you have to consider that any data you have to support your hypothesis that a certain pathway is critical is necessarily quantitative and bounded by margins of error. Once you start to chain together a load of steps, the confidence with which you can assert that the first element in the chain is tightly, uniquely and critically linked to the last link dissipates to nearly zero.

    Are the Americans here familiar with James Burkes’ Connections series from the 1970s? His schtick was to pick a path through the history of technology making a series of unexpected connections (hence the title) as if those connections were both necessary and sufficient to connect the beginning of the chain with its end. Even as a youngster, I was sceptical of the validity of the approach, but it was still one of my favourite programmes.

    I end up somewhat of the view that picking any single pathway or mediator as dominantly critical is an essentially flawed approach once the complexity of the system reaches a certain level. I’m just an ignorant clinician and for much of what we do, we have s limited number of rather blunt sticks with which we can whack at any problem and on a daily basis, which of the whole zoo of mediators is altered in detail, our relevant output is whether clinical amelioration can be reliably achieved. As Dr Crislip says, “Me find bug. Me kill bug. Me go home.” Part of this slightly dismal pragmatic approach derives, I’m sure, from the fact that I am a vet and our therapeutic options are significantly less well developed and proven than they are for medics.

    One lesson I am prepared to take from the world of nutty SCAMsters is that a reductionist approach has limitations when the system under investigation is irreducible complex. Even medics must recognise that, while steroids are the answer to many clinical syndromes, we are using very blunt sticks indeed and the black box we are hitting is huge and very vaguely demarcated.

    On the other hand, this does not mean that we should abandon the project of deeper investigation of biology, but it certainly does mean that I’m not the right person to do it. I’m quite happy to sit on the margins and be given more accurate and delicate sticks with which to beat black boxes that have been subdivided by research into smaller individual units.

  30. Badly Shaved Monkey says:

    Typo. Failed to close a mark-up code. Again, with emphasis in the right place…

    “claim that this path is the causal path”

  31. Badly Shaved Monkey says:

    There is a parody fable that illustrates my argument. I’ve read better versions but Google is not finding them for me this morning so this one will have to suffice;

    http://www.personalbest.ca/Newsletter/2006/15052006.htm

    “One of my favourite stories is the argument between the brain, the heart and the butt over who is the most important part of the body. Arrogantly the brain professed to be the body’s most important organ. It created emotion, thoughts and directed the body on the vast majority of its daily functions. The heart argued that it transported the oxygen around the body and without it the body would be paralyzed within minutes. When the butt tried to debate its value to the body, the rest of the organs laughed and made fun of him. “How could the butt be the most important organ”, the others questioned. Disappointed at the lack of respect he was getting, the butt decided to stop working. Day one was uncomfortable. Day two became more painful. By day three the brain became foggy, the heart started beating much harder and the lungs and kidneys started to fail. Finally by day four, the brain, heart, liver, kidney and lungs all recognized the importance of the previously un-respected butt.”

    [The Anglo version I was trying to find uses the word 'bum' instead of 'butt' and to my English ears that would be better]

  32. WilliamLawrenceUtridge says:

    @D2U

    I agree with BSM in that the line, in extremely sophisticated reasoning, between a crank and a genius is a narrow one, and with his claim of moNOmania/”one true cause” eroding the weight of your otherwise very, very interesting points. Further, your statement:

    Unfortunately I don’t think there is anyone who is up to speed on the breadth and depth of NO physiology like I am. I haven’t published my stuff, so I don’t blame people for not being up to speed. There are are a couple who do appreciate the central role that NO has in signaling. The idea that NO is so important isn’t even my original idea.

    also impacted your credibility. However, I am merely a commenter on a skeptical website, not a professional or researcher. Obviously I am both underqualified, and irrelevant in terms of the ability to comment on your ideas and how you express them. If you are genuinely on to something, I hope you publish soon and in volume as the world needs more science! But naturally, you are far better able to, and more credible regarding, your professional field than I am. I have two questions, if you’ll indulge them from an uninformed rank amateur:

    1) How will topical increased NO help systematically? Doesn’t NO break down extremely quickly? How readily can it penetrate the skin to reach the blood vessels and presumably increase systematic NO? Feel free to pop in weblinks instead of describing, though if you’re trying to commercialize then obviously you may not publicize this level of detail!

    2) How would anaerobic exercise fit into your model? It produces energy through glycolytic metabolism rather than the Krebs cycle (please forgive me if my terms are off, exercise physiology was over a decade ago). But it’s more transitory, would it actually build tolerance rather than pathology? Would T2Dtics be better off doing 50m sprints than 30 minute walks?

    Thanks!

  33. daedalus2u says:

    BSM, I appreciate that it is easy to think (actually project) that what ever you are working on is the most important thing. Humans do this because of hyperactive agency detection, and the compulsion to be at the top of a top-down hierarchy. You can’t understand physiology from the top-down, because there is no “top”. It is all bottom-up emergent properties of complex systems that are examples of self-organizing criticality.

    You can use a top-down model for some things, provided you appreciate that it is wrong and don’t try to extend it beyond where it is useful. An example is the model of human behaviors that uses the “mind” as a real object. The mind is not a real object. What we call the mind is an emergent property of the brain. Trying to fit the idea of the mind as a real object into biology (which is really chemistry (which is really physics)) doesn’t work and you get people trying to figure out how the mind (as a real object) can do stuff. It can’t because the model breaks down and becomes not useful.

    Some electronic circuits you can model as discrete components with discrete values of resistance, capacitance, inductance connected together by wires. That works for DC circuits. It works for some low frequency AC circuits. It doesn’t work for antennas. This is the problem many humans have with trying to understand physiology, they want to use a “lumped” parameter top-down model (homeostasis) when there isn’t any “top” to exert top-down control.

    The impression that people get that physiology is modular and top-down is mostly due to human hyperactive agency detection. There are top-down things, but they only work by having very simple top-down signals that invoke extremely complex local control. To control every cell in the liver to do something, you need a control signal to every cell to “tell” that cell what to do, and in sufficient detail.

    The OP is about T2D. That is something you can’t look at using lumped parameters. You have to understand how glucose is actually distributed from the blood stream to cells. Each cell is exposed to different levels of glucose at its surface. How can billions of cells all self-regulate their absorption of sufficient glucose in concert with all the other billions of cells when the degrees of freedom available from the top-down (blood glucose and insulin levels) are very sparse? There have to be local control systems that deal with the billions of degrees of freedom necessary to deliver the right amount of glucose to each cell. The expression of GLUT due to different amounts of insulin is one such mechanism. Insulin is consumed in the lymph, so cells farther from a capillary get less insulin as well as less glucose. The closest cells have to become “insulin resistant” so as to allow insulin to get to cells farther down the lymph stream so as to allow more GLUTs to be expressed so the same glucose can be taken up with a lower external glucose concentration (lower because glucose has been consumed by cells “upstream”).

  34. Mika says:

    Folks! We apparently have the AUTHOR of the book in question reading and willing to respond to your questions. So stop talking past each other and bring the issues to him, so we can all benefit! :-)

  35. morris39 says:

    Dr. Milind Watve @ 17Apr
    Perhaps you would be kind enough to comment, I’m sorry I have not read your book or have access to it. I have been experimenting with diet, rest and exercise for almost 3 years using methods which might be called orthogonal to conventional views but with steady slow and really unusual improvement in my health. I will not go into details because some readers of this blog are very prone to personal attacks with zero evidence of the particular circumstance. I was not obese or diabetic but did seem to have some impairment of glucose and alcohol metabolism; the motivation was a flare-up in chronic periodontal infection . It seems to me that in my particular case the major factors are: gut bacteria control and achievement of a narrow equilibrium state (body weight, energy intake, energy partition). For example my appetite has self-adjusted so that regulation seems automatic, I can greatly reduce or increase food intake over a period of several days without any discomfort. So my questions are: What is a likely natural time scale for metabolism adjustment, cell renewal time? Is a state of “just so” metabolic equilibrium one plausible explanation for the state disease and repair? Thanks

    1. Harriet Hall says:

      @morris39,

      I hope Dr. Watve will respond, but meanwhile I’d like to point out that he does not claim any practical applications of his ideas to patient treatment at this time. That would be WAY too premature.

      @all,
      Logically, Watve’s hypothesis is consistent with the evidence, but will need to be tested before anyone can say it is superior to other explanations. It is unfair to judge his ideas without reading his book, and premature to say that he is “wrong.”

  36. dinseattle says:

    Is Watve’s hypothesis consistent with the evidence? See the link I posted above. While one cannot access his whole book without spending a chunk of change, he does have an article from 2007 summarizing his hypothesis including links to sources. The sources I checked out did not really seem to say what he claimed they said. But I didn’t check them all and what do I know?

    I would love to have more people with more knowledge of the domain read that article and discuss their reactions.

  37. Artour says:

    Russian MDs tested thousands of diabetics and found that all of them suffer from chronic hyperventilation. Overbreathing has also been found in all 5 Western clinical studies that measured ventilation rates in diabetics: 2-2.5 times more than the norm:
    http://www.normalbreathing.com/cause-of-diabetes.php

    Effects? Reduced O2 delivery to cells (tissue hypoxia) due to hypocapnic vasoconstriction causing chronic inflammation, generation of free radicals, elevated blood sugar (as a part of the fight-and-flight response), possible insulin resistance and dozens of other abnormalities.

    Can a Western doctor address this health problem of chronic hyperventilation? What does the medical schools teach?

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