Andrew Kim Blog

Before getting into this post, I have one piece of news to announce. I’ll be writing for Matt Stone’s January newsletter, probably on the topic of physical attractiveness. You can sign up for the newsletter now before the inaugural December issue is sent out.

This topic, which I’ve written a blog post about[*] with regard to the impact of stress on facial symmetry, I think is important given the warped view people apparently have of their bodies, and it is crystal clear to me now that a big part of the problem is, I hate to say it, probably the most popular diet movement now: the paleo/primal movement.

This issue is closer to me than I care to say. The pursuit of beauty in Korean culture has reached a point of sickness, even among guys, to where more people at younger ages are opting for, or at least thinking about, plastic surgery, procedures that are not necessarily free of invasiveness. I don’t understand their ideals as to what constitutes beauty but, like the situation here, they are, in effect, manufacturing the traits that the opposite sex finds attractive to give off the perception of health, rather than doing the opposite: manufacturing health to promote physical attractiveness. And there is quite a bit of evidence in the literature, which I’ve been reading casually again of late, to suggest that the latter approach is, within reason, legitimate. That is to say, physical attractiveness is reflection of a person’s genetic, reproductive, emotional, mental, and physical health, all of which are amenable to the appropriate environmental factors.

Unfortunately, with the improvements in the advancements of surgical procedures and the sophistication with which makeup is applied, manufacturing physical attractiveness is not hard to do. I can’t help but think, if only they would put as much effort into curing a disease . . . I kid. Well, sort of.

For regular readers, it goes without saying that stress is a major theme of this blog. And given the centrality of the stress to all things concerned with health, metabolism, aging, and disease, as well as its fundamental importance to understanding those concepts, I’ve chosen to do this by way of rational deliberation. So you can bet that I will probably incorporate stress, as it relates to physical attractiveness, in the newsletter. But as for the rest of this post, I’ll provide some background information – in particular on stress – on the things I’ll probably discuss in that newsletter article, as a means to satisfy my urge right now to put fingers to keyboard.

I think most of us know, or are at least aware of, the relationship between stresses and how we look, feel, and perform in life. However, you may not know that that intuition is grounded in a relatively big body of scientific evidence.

One hormone, the main focus of attention in the literature in this regard although there are others, is cortisol.[†] The regulation of cortisol is surprisingly complex, and to elucidate the mechanisms by which it contributes to diseases has been a challenge. Although there still exists a gap, which may not be filled anytime soon (owing partly to not even having an idea of how to do so), some have merely closed that gap in light of the side effects inextricably linked to Cushing’s syndrome, a condition where cortisol is secreted excessively. The idea is that because people with the syndrome develop cardiovascular disease, diabetes, fat in morbid places, thinning skin, etc., healthy people (or those who are just below the point of clinical detection for Cushing’s) who are afflicted by the same conditions are overexposed to cortisol, too. A leap of faith unjustified without the requisite data to do so, to say the least.

What is clear is that the regulation of cortisol goes off the rails and out of control as we age and in disease. I won’t go into why this happens here, but the effect is that our exposure to cortisol has a tendency to increase, whereas in youth and in health, upon the exposure to a stressor, cortisol should come in, do its thing, and shortly (this is the operative word) thereafter be cleared from the body. In fact, all the stress hormones should work this way. But in old age and in disease, cortisol is not only secreted in excess upon the exposure to the same stressor, but it also persists in the blood longer; these are the conditions whereby irreversible (another operative word) degenerative changes begin to develop that, in an insidious fashion, weakens our ability to bounce back from subsequent stressors.[‡]

I think it’s probably worth pausing here to clearly define what stress is. Fundamentally, it entails a mismatch; a mismatch between the stressors we are exposed to and our ability to mount an effective response so as to restore the balance[§]that was disturbed by that stressor. That’s it. So it’s clear that a stressor can be anything; in this light, an immune reaction to getting a flu shot or the characteristic changes that occur in adipose tissue from becoming fatter are considered stressors.

Okay, let’s get back on track. . . .

If you’ve seen what young guys in Korea look like, or I should say the look they strive for, it’s funny and sad at the same time. They look like pretty women, straight up. I should say that all the traits that they strive for are the traits that, from a rudimentary perspective, are the ones that are at odds with what the opposite sex finds attractive.[**] Paunch fat,[††] for instance, is a sign of dominance and power in men, a feature that has probably been sexually selected for. In fact, having some extra fat – not being rail thin or having the bodily dimensions of a woman – may not only be inherently healthier, but may also serve as cues for a robust immune system and reproductive health, which is probably why this is feature that women have historically found attractive, more so than the secondary sex characteristics, for instance. Just saying.

(Correspondingly, big boobs, slightly protruding paunches, and curvy thighs and butts are some of the forms and shapes men inherently find attractive; it’s only now that the anorexic look has assumed the role of the ideal body form among women.)

Excessive stress, in the most basic terms, leads to excessive exposure to cortisol (which is probably why, whatever this is worth, low-carbohydrate dieters start to take on the Cushing’s face). Cortisol shares an inverse relationship with testosterone, and this is the pattern – low testosterone and high cortisol – that has been distinctly found to associate with the traits (e.g. even sweat smell) that deters the opposite sex. That’s not to say that high testosterone levels, even in the high normal physiological range, is ideal, either. You could read those studies rather than accept my position here; in the midst of doing that, you’ll see how complex it can get, especially after adding psychological factors, early life experiences, and developmental variables into the mix. Suffice it to say here, higher is not necessarily better, and does not correlate well at all with perceived attractiveness; higher levels also correlate with poorer performances on certain cognitive abilities.

Chronic and excessive stress, in the most broadest sense, not only kills, but it also ruins our health and therefore impacts negatively on our physical attractiveness. The ability to bounce back (you get my meaning now I hope), is therefore an indicator of how much stress we’ve sustained, and how effectively we’ve dealt with that stress. Manufacturing physical attractiveness to incidentally give off the perception of health (e.g. reproductive health) is as backwards as it could get. So is conforming your body shape to that which is deemed merely culturally acceptable, at the expense of your physical, psychological, and emotional wellbeing.

It is important to bear in mind, if you haven’t picked up on it already, that the experiments in which the traits considered attractive or unattractive by the opposite sex were compared with measures, such as salivary hormone concentrations, are correlative in nature; the difficulty lies in converting that correlative data into proof of cause and effect; unfortunately, I don’t think we have the slightest idea of the means to do that.

Be that as it may, an important point is that men and women know, and generally agree upon, what they find attractive in the opposite sex, and that the concept of physical attractiveness is not so much in the eye of the beholder, as much as it is seated in biology, and therefore amenable to environmental influences such as stress. Beauty is also not merely skin deep; it is, I believe, a real indicator of our overall health. Incidentally, it serves to explain why physical attractiveness correlates fairly well with social status, financial status, and other traits such as social competence, intelligence, and affability.

I hate to leave readers hanging, but the reason for writing this post was to generate thought on the topic, as well as anticipation for the newsletter article I mentioned at the outset. In that article, I plan to discuss some of the means to help to regulate the stress hormones, and to prevent the apparently inevitable decline in the tissues’ responsiveness to those hormones.

I also plan to discuss the possible role of a certain neurotransmitter in physical attractiveness. Neurotransmitters, from my own observations, are egregiously misunderstood and oversimplified to the point where their discussion becomes meaningless. Deliberately or not, people have blurred the line between the function and metabolic effects of certain neurotransmitters in the central nervous system and in the body. A case in point is serotonin. And that sloppy belief has become pervasive because, well, that’s just how the Internet works.

Anyway, look forward to that. I hate to be vague but I’ll be busy for a while so I can’t say when I’ll post again here. Regardless, I want to take this occasion to thank all the readers for, well, reading. I also want to thank the people who have sent me messages and emails of support; I’ve had some really interesting exchanges through these communications, especially with the people who are as open-minded as I strive to be. I hope, in my short stint, I have provided content worth your while; a respite from the blogs that require a Ph.D. to demystify (and seem to be written for no other purpose than to stroke the writer’s own ego, without regard for the audience) and the drove of health and nutrition blogs devoted to regurgitate, over and over again, a certain way of eating and living.[‡‡]

[*] An early blog post that was taken down due to overwhelming formatting issues that I didn’t want to deal with for one more second of life.

[†] If you recall, cortisol was the main hormone of interest of Han Selye.

[‡] Selye said that this ability to bounce back was limited by a predetermined amount of “adaptational energy” with which we were genetically endowed. Suffice it to say here, he was probably incorrect in his belief.

[§]“Homeostasis,” technically.

[**] Unless of course the goal is to look like a pretty woman in which case, so be it. Even if I try, I will never fully understand Korean culture.

[††] Fat located on the outer ventral wall of the abdomen, centered on the belly button.

[‡‡] Because I wanted to get a blog post out before the end of the weekend so that I could attempt to be productive on Monday, I wrote this one quite fast today. So it probably suffered in quality, seeing as how I didn’t have a chance to edit it in the way I would’ve liked. Please bear with me on any writing and/or grammatical errors you may find.

Dear reader,

My guest post for Matt Stone’s January newsletter has just gone live. You can get to it from here. One of my main purposes for writing about physical attractiveness was to create awareness, generate interest, and initiate a dialogue on the topic – a topic that I think most people have at least thought about, but rarely in an organized or practical way. By no means is the article meant to be final. It is merely a starting point for as much continuing investigation as you have the urge and time for. Please don’t hesitate to share your comments on the forums attached to the newsletter over there; I look forward to reading them.

Happy New Year!

Andrew

It’s popular to talk about certain foods that stimulate thermogenesis, or heat production, as a means to aid in weight loss – the most fashionable of which is probably coconut oil. While that’s all good and desirable, the heat generated upon eating makes a relatively small contribution when compared to all the heat generated by all the reactions in the body, including the process of keeping the gut in a state of continuous readiness to digest and assimilate the next meal.

All metabolic processes in the body generate heat. In other words, metabolism is unavoidably heat-generating. The minimum amount of heat generation is set by the resting metabolic rate,[*] which is, in turn, set by the thyroid hormone, among other ancillary factors. The heat generated from eating – directly related to the energy costs of digesting, absorbing, and converting the myriad of components of food into their appropriate storage forms – adds to the heat generated by the resting metabolic rate. As far as diet-related heat generation is concerned, of all the macronutrients, protein has the greatest effect. Carbohydrate has a lesser effect than protein, and fat has a negligible effect.

Eating can also activate uncoupling proteins, whose function is to process nutrients for heat rather than energy in the mitochondria. Although the extent to which this adds to heat generation is probably minor, the intensity with which these uncoupling proteins generate heat is governed and fine-tuned by hormones, in particular thyroid hormone and noradrenalin.¹ Uncoupling helps to decrease oxidative stress, while maintaining a high rate of ATP generation – an example of a substrate cycle in which a substance (in this case a proton gradient across the inner mitochondrial membrane) is generated and subsequently dissipated, in a reverse reaction using different enzymes, wasting energy in the process.²

Although fat has a negligible effect in terms of increasing heat generation after eating, it does play an important role in regulating body temperature, as one of the myriad of reactions mentioned above not involved with eating. This reaction, in which fat is used to generate heat, is another example of a substrate cycle. In essence, triacylglycerol, composed of 3 fatty acids and 1 glycerol, is broken down (lipolysis) and the fatty acids subsequently released are taken back up by the releasing fat cell and esterified into triacylglycerol therein.[†] This process, lipolysis and esterification, constitutes one substrate cycle, and the heat generated from the reactions in said cycle plays an even greater role in regulating body temperature than the physical role of fat as an insulator! Like the uncoupling proteins, this substrate cycle is regulated by thyroid hormone and noradrenaline.

At least on the order of days, weeks, or even months, the addition of a particular food into a person’s diet in the absence of other changes will probably not have a significant effect in terms of changing a person’s body fat and weight. A case in point is MCT oil, which has been promoted hard for its ability to aid in weight loss. The results of clinical studies in which MCT oil was put up against a different oil and weight changes were tracked over time have been overwhelmingly unimpressive to say the least. Yet, a value to which it is not legitimately entitled continues to be placed on MCT oil by the likes of Dave Asprey and the atrocity that is the Bulletproof Diet.

However, the effects of changing the composition of the fats in a person’s diet are not as ineffectual as I may have indicated above. Interesting are the experiments in which behavioral changes are observed upon changing the fatty acid composition of the diet of an animal kept in captivity. Lizards, for instance, will become more active at night and prefer to spend more time in colder places so their bodies become colder by increasing the PUFA in their diets; on the other hand, reducing the PUFA in their diets will elicit the opposite behavior. For what it’s worth, perhaps nothing to you, I’ve always had a low tolerance to heat – the slightest increase in temperature would make me break out in a sweat, and make my nose stuffy and ears bright red. But since reducing the fat and increasing the sugar in my diet (effectively reducing the PUFA in my body), my tolerance to heat has improved and I layer up more than I used to as the ambient temperature goes down.

Of course, there is a ceiling on the degree to which the metabolic rate can be increased, being limited by the risk of overheating from running things so quickly, among other things. But the main factor that limits a person’s metabolic rate is the availability of oxygen.

Oxygen decreases the reliance on non-oxidative metabolism, and, merely by the law of mass action, leads to more energy generation and less fat storage. I suppose exercise, by strengthening the heart and respiratory system – and therefore blood circulation and lung ventilation – would help to increase the efficiency of the delivery of oxygen to tissues. However, exercise need not be heavy and exhaustive to be effective, only regular and consistent. Isotonic movements, in which tension is applied and work is accomplished, is probably less stressful than isometric movements, in which no work is performed but much heat is generated.[‡] The great force and resistance involved in isometric movements tends to compress blood vessels to where blood perfusion becomes greatly reduced so as to create a significant degree of tissue hypoxia, resulting in a greater reliance on non-oxidative metabolism and higher levels of lactate. Bulging muscles may look good (I guess?) but they appear to come at a price.

But other stressors can decrease the availability of oxygen to tissues, in part by increasing the use of fat for fuel. More glucose is used non-oxidatively as a result, which, in turn, depletes glycogen and increases lactate and acidity. As it happens, this stress-induced oxygen depletion is usually offset because the increase in acidity and lactate increases the efficiency with which oxygen moves from the blood to tissues by way of the Bohr effect and the increase in 2,3-diphosphoglycerate (2,3-DPG) within red blood cells. The ratio of pyruvate to lactate is one of the best indicators as to the extent of oxidative versus non-oxidative metabolism.

A healthy and robust metabolism implies low levels of the stress hormones. Limiting the stress hormones limits the use of fat for fuel and the production of lactate and ensures the efficient turnover of ATP. As it happens, ATP, bearing a high density of negative charge, binds and keeps noradrenalin, positively charged under physiological conditions, inside storage ‘bubbles’ inside cells, regulating their release.[§] (The fact that both ATP and noradrenalin are involved in pain transmission further serves to explain their co-localization inside cells.) The carbon dioxide and heat generated as by products of metabolism both increase the delivery of oxygen to tissues, like lactate does, and, stated above, more oxygen means more energy generation and less fat storage. The oxidative metabolism of glucose generates the most heat, carbon dioxide, and ATP.

The capacity to use the increased oxygen is limited by the availability of all the B vitamins, including thiamin, riboflavin, niacin, pantothenic acid, and others. A regular and adequate supply of these vitamins improves the reserve and capacity of the Krebs cycle and respiratory chain. The active thyroid hormone, T₃, stimulates all the reactions involved in the oxidative metabolism of glucose, increasing the requirement for all the B vitamins. The ingestion of simple carbohydrate also increases the requirement for the B vitamins, in particular thiamin.³

If the body temperature cannot be kept up naturally, the next best option is to keep warm artificially as to keep all the chemical processes in the body operating as fast as they would at higher temperatures. Trapped air is particularly important to conserve heat in cold ambient temperatures. Therefore insulation, which for us means clothing, is an important factor determining the amount of heat lost from the body. The thickness, in particular, as well as the looseness and color of the clothing determines how effective it is as an insulator.

Questions I get a lot relate to digestion and the simplest thing to do with problems concerned with digestion is to increase the body temperature as high as to what’s tolerable. Not only is digestion, and therefore the extraction of nutrients, slower at lower temperatures, but parasites and bacteria also have a greater chance of breaking through the gut lining to cause serious infections at those temperatures. To make matters worse, the activity of the immune system decreases as the temperature decreases, so the likelihood of mounting an effective immune response to the pathogens that do get into the body decreases, too.[**] Within narrow limits, the temperature at which the body ‘sets’ is determined by the composition of the fats in a person’s diet: the most protective fats are the ones that are the most saturated.

The percentage of PUFA in tissues limits the rate of energy expenditure. One reason for this is that at higher temperatures, the spontaneous oxidation of PUFA – therefore the production toxins – increases as the temperature increases. Since reading about hibernation as it relates to PUFA in HLAF, I’ve been thinking more and more about this idea. Lo and behold, squirrels, professional hibernators, must carefully eat just the right amount and kinds of nuts and seeds in order to store enough PUFA in their tissues for a successful hibernation through the winter, but not so much as to disrupt hibernation from the excessive production of toxic PUFA oxidation products.

Although obesity in humans is associated with a shorter lifespan, in wild animals there is no such association, unless they are domesticated and deliberately fattened by humans. Obviously a multifactorial and complex matter, the saturation index and therefore the fat composition of the diet, is one factor that may explain these associations.⁴

log (maximum lifespan years)

Combined with the observation that a higher (resting) energy expenditure is generally associated with a longer lifespan^5,6 we are beginning to move even further away from the idea that fat is merely an inert sink in to which surplus nutrients are converted and stored until they are needed elsewhere in the body.

The formation of fat from carbohydrate is an extremely inefficient process – only by eating carbohydrate in incredible amounts over long periods of time will a person begin to create and accumulate fat made from carbohydrate.⁷ The conversion of carbohydrate to fat is simply a highly energy-consuming process and the activity of the fat synthesizing enzymes is not nearly as active as they are in other animals, like birds and rodents. So the most efficient way to change the fat composition of the body is by adjusting the fat composition of the diet. Butter, cocoa butter, tallow, and suet are among some of the most saturated and stable fats currently known. Good quality chocolate is unusually high in the commonest saturated fats in mammals: palmitate and stearate. Shifting the diet to include more of these fats and less of more unsaturated fats is sufficient to bring about the positive changes discussed up to now.

Regarding lab tests to assess the state of a person’s metabolism, unless the person is experienced interpreting those tests, tests aren’t as important or informative as signs and symptoms are.

For instance, and because I received this question recently, blood levels of histamine are useless because, as it happens, histamine is concentrated locally. So regardless of normal, or even low, levels of histamine in the blood, a person could still be exposed to high amounts of histamine (and would benefit from an anti-histaminic agent – my personal favorites being meclizine and diphenhydramine.)

Furthermore, having normal blood glucose levels, as deemed by the “establishment,” does not as a matter of course imply that there is a normal use of glucose by cells. So despite normal blood glucose levels, it would be impossible to rule out the existence of a deficit in energy production resulting from the inadequate oxidative metabolism of glucose. By the same token, high blood glucose levels do not necessarily spell gloom and doom; in fact, it could mean quite the opposite. If cells are burning glucose intensely, for instance, certain hormones are released that in turn stimulate the liver to make more glucose in order to keep up with the increased demands for glucose. A case in point is exercise, during which glucose levels increase at the same time muscles are vigorously burning glucose.

In cases such as these, a doctor may have no choice but to declare a clean bill of health when the patient feels anything but. Or, even worse, they may result in treatments that are 180 degrees off the mark. I’ve read too many cases like the one in which a person was declared to have diabetes and was treated with drugs that, in one way or another, decrease blood glucose levels despite the fact that the person’s symptoms did not line up with that diagnosis all along.

I say all this to say that blood tests are not foolproof in that when interpreting them, it should be remembered that biological markers are dynamic in nature, and one test result merely represent a snapshot in time. In many cases, a proper diagnosis isn’t possible in the absence of multiple tests under different conditions, such as when the patient is sick versus well. Given the complexity of diseases and the variability among people, arriving at an accurate diagnosis is an art as much as it is a science, guided by intuition as much as by years of experience and practice. Sometimes, the response to an empirical treatment is used to make a diagnosis.

Of all the signs and symptoms, monitoring the axillary body temperature every morning will yield the biggest bang for your buck. The temperature to aim for is about 98° F. The body temperature, in conjunction with improvements in other non-specific signs and symptoms (e.g. fatigue, apathy, drowsiness, mental depression) and general well-being should be used to guide treatment decisions. Exercise, including isotonic contractions, improves cardiopulmonary fitness, and therefore the delivery of oxygen, and increases musculature and bone density – both of which increase the resting metabolic rate and the capacity for heat regulation. Small meals consisting of sugar and protein throughout the day helps to keep the blood sugar up and the stress hormones down. Since the conversion of carbohydrate to fat is so inefficient, adding small amounts of fat in the diet – in particular good quality chocolate, butter, tallow, and suet – is protective.

REFERENCES

1. Hernández, A. & Obregón, M. J. Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein expression in rat brown adipocytes. Am. J. Physiol. Endocrinol. Metab.278, E769–77 (2000).

2. Brand, M. D. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol.35,811–20 (2000).

3. Lonsdale, D. A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid. Based. Complement. Alternat. Med.3, 49–59 (2006).

4. Pamplona, R. et al. Mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals. J. Lipid Res.39, 1989–94 (1998).

5. Speakman, J. R. et al. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell3, 87–95 (2004).

6. Speakman, J. R., Selman, C., McLaren, J. S. & Harper, E. J. Living fast, dying when? The link between aging and energetics. J. Nutr.132, 1583S–97S (2002).

7. Acheson, K. J. et al. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am. J. Clin. Nutr.48, 240–7 (1988).

[*] The metabolism required to maintain life.

[†] Because glycerol is not taken back up into fat cells as efficiently as glucose is, for every round of this substrate cycle, glucose is taken up from the blood and converted to glycerol in fat cells.

[‡] Imagine straining at stool while on the toilet as an example of an isometric movement.

[§] Noradrenalin bears a positive charge under physiological conditions because the acidity (pKa) of its amine groups is less than the acidity inside cells. So, more noradrenalin’s amine groups are protonated, and therefore positively charged, under physiological conditions, allowing them to form salt linkages with negatively charged ATP molecules.

[**] Fats also alter the immune system directly. For instance, omega-3 fatty acids suppress the immune system, decreasing the resistance to infections and wound healing, whereas saturated fats do not.

ATP and thyroid are closely related in that the thyroid hormone is essential for the rapid turnover of ATP, both inside and outside of cells. ATP, in turn, affects processes as diverse as pain, inflammation, blood clotting, bone formation, cognition, blood pressure, and insulin secretion – among many others.

Considering the intensive research currently underway to develop compounds with specificity for ATP receptors in various tissues, and the wide range of disorders these compounds could, when it is all said and done, treat, it is obvious that ATP, in particular its turnover, has a wide range of drug-like effects that are independent of its role in energy metabolism. All of the conditions that have been linked with hypothyroidism – most comprehensively by Broda Barnes – can, in my estimation, be traced back to the impact of thyroid hormone on ATP.

Well known now is that ATP is involved in repair and regeneration processes following injury or stress to tissues. Platelets, for instance, express certain ATP receptors (the discovery of which drug companies have capitalized on with the blockbuster drug Clopidogrel) that, upon binding ADP, an ATP metabolite, undergo conformational changes that ultimately lead to the formation of a blood clot. ATP also binds and activates the smooth muscle cells of blood vessels, powerfully causing them to constrict so as to limit the loss of blood following an injury. And, equally as important, ATP acts on sensory nerves, whose job is to sense harmful stimuli in the body and to transmit those messages to the brain – without which we would lack the wherewithal to quickly withdraw from harmful situations or to keep away from a damaged body part while it healed. In the presence of thyroid hormone, all of these processes function to full capacity.

ATP is released from neurons and non-neuronal cells in either a controlled way or in an erratic way, for instance, when there is tissue damage and the ATP stored in cells spill out into the extracellular space. In addition to acting on sites outside of the cell in which it is produced, ATP executes basic physiological processes as an intracellular mediator such as insulin secretion. In fact, ATP is present, albeit in tiny amounts,[1] in the cytosol of all cells.

Diabetes is a topic I have written a post on in the past with a focus on the mechanisms that inhibit the complete combustion of glucose by cells. One point of neglect was in regards to the role of ATP. In essence, the oxidative metabolism of glucose and the subsequent generation of ATP is a major pathway for insulin secretion. But ATP also acts in a more general way, being released with acetylcholine or noradrenalin, as a co-transmitter, from nerve endings that extend from the brain to the pancreas. Indeed, specific ATP receptors, of the P2Y class, have been identified on insulin-secreting cells in the pancreas. Ultimately, ATP results in elevated calcium levels in these cells, which is the trigger to release insulin. Interestingly, biotin enhances the synthesis of ATP in the pancreas by increasing the rate of glucose oxidation.¹

Following meals, the rapid rise in insulin and blood glucose levels is normal and desirable – contrary to uninformed opinion. As a general rule, what is abnormal is when a person’s blood glucose levels do not rise by at least 50 percent from baseline fasting levels. Almost all of the oral diabetes drugs that I can think of off-hand, including the most successful ones (such as Onglyza, Januvia, Byetta, and Symlin), work by way of enhancing the secretion of insulin and suppressing the secretion of glucagon. Still and all, diet gurus know what researchers and doctors do not know, because high protein, low carbohydrate diets are posed as the best diet for diabetes owing, in part, to the ability of these diets to keep insulin down and glucagon up. An adequate amount of protein is essential, and should ideally be eaten at every meal. But in order to use that protein as constructively as possible, it should be offset with carbohydrate and minerals, such as from fruit.

And because fruit also contains fructose, which does not stimulate the release of insulin nearly as much as glucose, it helps to potentiate glucose-stimulated insulin secretion, presumably by intensifying the depolarization of insulin-secreting cells more than glucose could alone.² In general, fruit also contains mineral salts of potassium, magnesium, and calcium that are highly absorbable; they also contain little to no starch.

Cardiovascular disease is considered a major (and highly fatal) complication of diabetes. But the thyroid and cardiovascular disease are highly connected, too. Broda Barnes described one case study after another of the striking absence of cardiovascular disease in patients on thyroid replacement therapy.³ Barnes attributed this protective effect mainly to the fact that thyroid hormone prevented the accumulation of the water-loving jellylike material called mucopolysaccharide in the connective tissue of the heart and blood vessels, causing thickening, as well as to reduced circulation.

As it happens, the metabolism of ATP (and of other purines) goes off the rails in hypothyroidism as well. In platelets, for instance, the activity of the enzymes that degrade ATP increases, resulting in an excess of ADP in relation to ATP and therefore errant clot formation.⁴

In general, the complications seen in diabetes are the same complications seen in hypothyroidism, and the fact that the so-called “diabetic complications” sometimes precede the onset of diabetes suggests that those who are diagnosed as diabetic, by a standard glucose tolerance test, may actually be hypothyroid. A person who is hypothyroid has a slower rate of digestion, absorption, and assimilation of nutrients so that when blood samples are drawn during a glucose tolerance test, blood glucose levels will appear elevated not because of diabetes, but because of the sluggish extraction of glucose from the intestines. Hypothyroidism also slows the uptake and oxidative metabolism of glucose by cells.⁵

The rapid degradation of ATP from hypothyroidism not only affects the cardiovascular system, but also the brain. The impairment of cognition in hypothyroidism, in fact, could simply come down to the decline in ATP levels, caused by upregulation of the activity of an ATP degrading enzyme.⁶ Thyroid hormone ‘lights up’ the brain like caffeine does, in that they both lead to an increase in blood glucose levels and shift the balance away from ADP, an inhibitory neurotransmitter, to ATP, an excitatory neurotransmitter.

T3, which is ‘stored’ inside cells (as opposed to T4, which is mainly ‘stored’ in the bloodstream), guards against the depletion of ATP, whose turnover is needed continuously in the brain to promote the growth and development of the axons of certain brain cells.⁷ However, in hypothyroidism, the energy charge decreases, and all cellular processes, in effect, slow down so as to decrease metabolic requirements.⁸ The presynaptic inhibition of neurons in the brain, for instance, accounts for the neuroprotective effects of intravenous injections of adenosine.⁹

The fact that adenosine worsens many of the symptoms of asthma by – causing bronchoconstriction, stimulating the release of histamine from mast cells, and promoting hyper-reactivity of airway neurons – further speaks to its relationship with hypothyroidism, as merely raising blood glucose levels softens, and sometimes momentarily completely eradicates, those symptoms of asthma. It has been said that asthmatics, compared to non-asthmatics, do not release the counterregulatory hormones, especially adrenalin, when the blood glucose levels dip below normal. But, asthmatics have many of the features of hypothyroidism, such as the tendency to concentrate potassium and sodium in the blood. What is more, adenosine, which accumulates in hypothyroidism, stimulates the production of mucopolysaccharide in the airway of asthmatics, as well as inflammation.¹⁰ It would be interesting and informative to compare the presence of asthma in hypothyroid versus euthyroid individuals.

The effects of thyroid hormone replacement have historically been both immediate and delayed, further reinforcing the idea that the benefits of such therapy is executed by ATP. The P2X receptor is an ion-channel linked receptor, whose activation takes milliseconds. On the other hand, the activation of the P2Y receptor initiates an intracellular cascade ending in an increase in intracellular calcium levels and changes in gene expression, which can take from hours to days.

Anything but merely a molecule involved in energy metabolism, ATP also assumes the role of neurotransmitter, hormone, and intracellular mediator. Free ATP molecules are found, in tiny amounts, in every cell in the body, and they are released either constitutively or in response to stress or tissue injury, by way of exocytosis or simultaneously with other neurotransmitters from neurons. Receptors for these ATP molecules, as well as their metabolites, have been identified in virtually every site in the body that has been checked so far, and pharmaceutical companies are chomping at the bit to get their drugs that target various ATP receptors approved for a myriad of indications including pain, inflammation, rheumatoid arthritis, and cystic fibrosis. But simply optimizing thyroid functioning, by signs and symptoms and not lab tests, including the basal body temperature, shifts the ratio of ATP to its metabolites, and therefore the pattern of receptors and targets that are occupied and activated. If hypothyroidism is suspected, foremost, the basal body temperature should be checked and corrected with changes in the diet (mainly avoiding carbohydrate restriction and under-eating) and thyroid replacement therapy, if needed, before moving onto more invasive and riskier interventions.

REFERENCES

1. Sone, H. et al. Biotin enhances ATP synthesis in pancreatic islets of the rat, resulting in reinforcement of glucose-induced insulin secretion. Biochem. Biophys. Res. Commun.314, 824–9 (2004).

2. Kyriazis, G. A., Soundarapandian, M. M. & Tyrberg, B. Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc. Natl. Acad. Sci. U. S. A.109, E524–32 (2012).

3. Barnes, B. Hypothyroidism: The Unsuspected Illness. (Whiteside Limited, 1976).

4. Bruno, A. N. et al.5’-nucleotidase activity is altered by hypo- and hyperthyroidism in platelets from adult rats. Platelets16, 25–30 (2005).

5. Solini, A. et al. Defective P2Y purinergic receptor function: A possible novel mechanism for impaired glucose transport. J. Cell. Physiol.197, 435–44 (2003).

6. Bruno, A. N. et al. Hypo-and hyperthyroidism affect the ATP, ADP and AMP hydrolysis in rat hippocampal and cortical slices. Neurosci. Res.52, 61–8 (2005).

7. Rathbone, M. P. et al. Trophic effects of purines in neurons and glial cells. Prog. Neurobiol.59,663–90 (1999).

8. Brundege, J. M. & Dunwiddie, T. V. Role of adenosine as a modulator of synaptic activity in the central nervous system. Adv. Pharmacol.39, 353–91 (1997).

9. Cunha, R. A. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem. Int.38,107–25 (2001).

10. Wilson, C. N. Adenosine receptors and asthma in humans. Br. J. Pharmacol.155, 475–86 (2008).

[1] Millimolar concentrations

INTRODUCTION

I recently had the opportunity to attend a physician-only-lecture at a hospital about the use of ketogenic diets for the treatment of epilepsy in children. If you at least casually follow the discourse on this dietary approach on the interwebz, especially with regard to the interest of effecting cures, you’d probably think that not only should all children with epilepsy be placed on a ketogenic diet, but that failing to do so amounts to nothing less than egregious malpractice; another failure of the medical profession to employ the best treatments available because of the inherent evils of pharmaceutical companies and of patent medicine.

The truth is, although there are a myriad of proposed mechanisms as far as how ketogenic diets work (review articles have been rapidly accumulating in many different medical publications) no one can really say one way or the other, and to suggest otherwise points to an utter lack of thoroughness in reading of the literature on the topic, a bias in the interpretation of said literature, or both.

I say this in part by way of criticism and disgust, and in part because I know how complex neuropsychobiology and neuropharmacology (and related disciplines) are and have always been owing mainly, in my estimation, to the lack of experimental methods sophisticated enough to draw definitive conclusions; in particular, the inability to convert correlational data derived from such experimentation to proof of cause and effect. What is clear, however, is that there is an energy deficiency in various neurological disorders including epilepsy; that is to say, a deficiency of glucose and oxygen, the primary substrates by which cells of the nervous system generate energy, which is evidenced by a respiratory quotient[*]that stabilizes at 1.0 therein.

Therefore, the most parsimonious explanation for why ketogenic diets work, when they do, is that the ketone bodies so generated are supplying neurons (and glial cells) with energy, which would normally be provided by glucose, thereby preventing these cells from literally succumbing to the demands placed on them, by all the stressors they have to deal with on a moment to moment basis. Why then do children with epilepsy develop energy deficiency problems? Or stated another way, why do they lose the ability to generate energy by way of the oxidative metabolism of glucose, in which carbon dioxide, rather than lactic acid, is produced? This is a question too complex and speculative to have a discussion on for this audience and for the space I’ve allotted myself here. Just know for now that this mismatch, between energy reserves and energy demands, represents the essence of the problem.

I’m fully aware of the fact that my post thus far, five paragraphs in, lacks a thesis of any kind whatsoever. Annoying, I know. I also know readers in particular appreciate a neat list of recommendations based on a solid foundation of evidence that should have been presented in the body of the article.

But rather than do that, because of the speculative nature of the subject matter, I want to finish up this post by doing two things. The first is to describe, in the simplest way possible, the way in which the brain should work, especially with regard to energy and stress. The second is to have a general discussion of a few, in my estimation, means to preserve and optimize this system, based on the preceding theoretical discussion.

By endeavoring to focus on mechanisms (which is the best we could do at this point if we wish to avoid overstating any point) you should see why the focus on particular foods (e.g. the sweet potato) or painting ourselves into a corner by restricting our diets to only those foods that have been deemed “evolutionarily-approved” (whatever that exactly means), is not only utterly silly, but also arbitrary and fatally flawed.

ENERGY DEMANDS VS. ENERGY RESERVES

Energy problems should be expected to manifest in the brain first and most notably because the brain, per unit weight, is the most voracious consumer of energy, namely glucose, of all the organs in the body. (The brain represents merely 2 percent of the body’s total weight yet accounts for 15 percent of the body’s total energy expenditure.) So when a deficiency of energy does occur, the brain and associated structures, which coordinate processes as diverse as memory, learning, mood, and behavior, are impacted quite notably.

One reason as to why the ketogenic diet may ‘work’ is that ketone bodies have a sedative effect in the brain, like the neurotransmitters gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB), thereby protectively reducing the energy demands so as to prevent cells from literally overworking themselves to the point of malfunction and death.

What first got me thinking about the similarities between GABA, GHB, and ketone bodies was an internship I had at one of the major poison control centers in the U.S., where it was drilled into the interns by the medical director that valproic acid (brand name Depakene), a drug used for seizures and structurally similar to both GABA and ketone bodies, would when taken in excess cause ammonia to accumulate to toxic levels in the blood (for which carnitine would be given as an antidote.) Suffice it to say here, the fact that the toxic accumulation of ammonia is a side effect of valproic acid reinforces the idea that the ketone bodies and valproic acid are acting in the ways that GABA normally would in the brain.

In the brain, under normal circumstances GABA derives from glucose by way of the highly prevalent brain amino acid glutamate. In the absence or improper use of glucose, valproic acid, or ketone bodies – those compounds that are structurally similar to GABA – are probably ‘filling in’ for the glucose-derived GABA that, for whatever reason, is missing.[†]The synthesis of GABA is intimately tied to the oxidative metabolism of glucose, which entails the use of enzymes found exclusively in the brain.

In all, valproic acid mimics the effects of GABA, and the ketone bodies are probably acting in a similar yet more basic way, owing to their structural similarity.[‡]The not-so-rigid dichotomy between the excitatory and the inhibitory systems in the brain is thusly shifted to favor the latter system, whereby the flow of electrical signals through various brain pathways defensively becomes depressed. Lowering the energy charge in the cell (i.e. depleting ATP) has a similar effect, activating the enzymes that synthesize GABA from glucose and depleting brain dopamine (evidenced by elevated dopamine turnover rates when GABA is introduced exogenously in relatively large amounts). These enzymes are dependent on vitamin B6, a deficiency of which predisposes to seizures in children and adults.

In healthy and young people, this system should kick in in the face of prolonged or excessive stress, which rapidly depletes energy stores in the brain. Healthy and young people should also be more resilient to ‘running out’ of energy, owing partly to the efficiency by which the glucocorticoid system operates in their bodies since the glucocorticoids, in excess, interfere with the storage of glucose in brain cells.[§] The turnover of GABA is many times higher than that of other neurotransmitters, such as acetylcholine and dopamine, suggesting that the brain has many homeostatic mechanisms in place to maintain GABA concentrations within a certain physiological range under a wide range of external conditions.

SUMMARY/CONCLUSIONS

1. To me, like the use of synthetic glucocorticoid products, ketogenic diets, as of now, is nothing more than a last-ditch effort when all other means fail. Merely a symptomatic solution, there are probably long-term consequences associated with having this system chronically active and in overdrive. I’ve heard mentioned offhand by a Paleo blogger that high fat diets relieve anxiety in rats by way of GABA, apparently without reading the study that was linked to support this claim. Some of the beneficial effects of these diets can be attributed to the surge in glucose brought about by the stress hormones, temporarily relieving the energy stress caused by the deficiency of glucose, so as to prevent the irreversible degradation of brain structural material that would otherwise supply that energy, as well as GABA. At the same time, owing to their purported sedative and inhibitory effects in the brain, the ketone bodies themselves are neuroprotective. However, the ketone bodies incidentally block the oxidative metabolism of glucose.

2. Vitamin B6 is a cofactor (tightly bound) of two enzymes: one involved in the synthesis of glucose-derived glutamate and one that makes GABA from glutamate. A deficiency of vitamin B6 decreases its concentrations in the cells that make GABA, favoring the inactive state of the two vitamin B6-dependent enzymes involved in making GABA. In point of fact, a diet deficient in vitamin B6 in children and adults can lead to seizures that respond dramatically to treatments that include the vitamin.[**]

3. The amino acids taurine and glycine have similar receptor interaction patterns as GABA. As such, taurine and glycine induce 'inhibitory' effects in the regions of the brain where they are active. Animal studies show that chronically low intake of these amino acids, or their precursors, could lead to irreversible degenerative changes in the brain, eyes, and spinal cord.

4. The rationale behind the use of pharmaceutical anti-depressants (i.e. stimulants) stems largely from experiments in which correlations are made between levels of certain neurotransmitters in the brain (or their metabolites in the blood and urine) and the ability of animals to which stressors are imposed, to cope and to avoid developing conditioned helplessness, where the animals simply give up and fail to perform effective avoidance responses to subsequent stressors.

Whether these measured neurotransmitters are, in fact, the cause of depression – a condition that is already poorly defined – is uncertain, as, if you recall, the wherewithal currently available to study these relationships lack the requisite sophistication.

However, as I’ve stated before, animals permitted to develop effective means to cope with stressors have lower levels of anxiety, which, in turn, make then more effective at coping with stressors. GABA, and probably the ketone bodies and valproic acid, helps individuals cope more effectively with various stressors, in part by reducing anxiety, without adding to the energy stress like the anti-depressants, which now bear the black box warning, the most serious of all warnings, alerting clinicians and patients of an increased risk of suicidal thoughts and behaviors in children and young adults. Cortisol levels are also lower in animals with effective coping mechanisms. To put things in more concrete terms, the ability to turn fears and worries into plans and actions soften all of the energy problems described above and help to preserve brain functioning.

5. The rapidity with which learning is acquired I think reflects how efficiently the systems in the brain and the body ‘work’ to maintain energy availability and the delicate balance among dopamine, serotonin, cortisol, noradrenalin and GABA.

The distinction, however, between learning and simple arousal and stimulation should be made and recognized, especially when interpreting experiments designed to study the ins and outs of learning. Suffice it to say here, reducing anxiety and employing effective coping techniques facilitates the acquisition of the biochemical and physical changes in the brain that are thought to signify learning. Learning implies adaptability to changes in the environment, the capacity for which, according to Han Selye and others, determines our susceptibility to disease, aging, and death.

6. Maintaining steady blood glucose levels helps to prevent the drastic changes in glucose availability to the brain, of which merely transient interruptions can cause harm. I’ve found through my own experimentation that small, mixed meals spaced out equally throughout the day are superior to large, intermittent meals.

Dear reader,

From hereon out, I’ll be writing for Matt Stone’s site, 180degreehealth, somewhat regularly as a site author, so some of my future articles will be posted there, not here. I’ll be sure to let you know each time one of my posts go live over there.

Happy Thanksgiving,

Andrew

[*]A respiratory quotient of 1.0 indicates pure glucose use in relation to protein and fat.

[†]Glucose can be converted to GABA, but ketone bodies and fatty acids can’t.

[‡]Because I was asked once already (email), and because its’ probably on the minds of readers now, I’ll mention here so as to dodge answering the same question that as a supplement, GABA is probably useless, as GABA, being highly charged, is unlikely to cross into the brain from the blood, and very little GABA is found outside the central nervous system.

[§]The primary glucocorticoid secreted by the adrenal cortices is hydrocortisone, or cortisol.

[**]Since there are many other vitamin B6-dependent enzymes in the brain, we can’t say for sure that the improvements seen upon the addition of vitamin B6 are due to effects on the GABA system only.

Smart drugs, or “nootropics,” are a topic I’ve stayed cleared of until now because, well, the idea of using them was stupid. Not only is the research on those so-called smart drugs severely deficient and inadequate; but also the evidence on which people make their decision to use them or not derive largely from anecdotes found on Internet forums, which are fishy to me and notoriously unreliable.

There are a few problems as to why the situation on the topic of smart drugs is in disarray. The first is that a distinction between simple arousal and stimulation versus true learning is often sloppily made or passed over. The second is that there is too much emphasis placed on manipulating neurotransmitters, namely choline, serotonin, histamine, dopamine, and norepinephrine. And the third is that there is a tendency to deemphasize (or to gloss over altogether) the availability and metabolism of glucose, as well as the hormones that govern and interact with these processes, such as insulin, thyroid hormone, and cortisol.

Mitochondria, the sites where the oxidative metabolism of glucose occur, are found in abundance in and nearly everywhere in brain cells – from cell bodies to all the way down to the tip of axons. The positive effects of glucose on memory and cognition are now fairly well established. So I think it would be reasonable to suppose that investigations in to substances to improve cognition should probably start there – with metabolic support, the degree of which will probably vary depending on a person’s age, insulin sensitivity, stress levels, among other related factors.

In addition to its role in regulating glucose levels in the body, insulin, which I touched on in my diabetespost last year, is important for the process of forming memories in an area of the brain called the hippocampus, via the same signaling pathways insulin acts through in the body. Insulin also happens to increase the metabolic intensity in the hippocampus, and this is probably the reason why cognition worsens in diabetes. Generally, mentally draining tasks quickly deplete extracellular glucose, and artificially replacing that glucose – either systemically or by way of microinjections directly into the brain – restores the capacity of the brain to form memories, for instance.

Derivatives of thiamine, a critical nutrient involved in the oxidative metabolism of glucose, such as benfotiamine and sulbutiamine, are being used to improve cognition, and pyrithiamine, an anti-metabolite of thiamine (that inhibits the synthesis in the brain of thiamin triphosphate) leads to degenerative changes in the brain.

Compared to other organs, in the brain, with the exception of probably certain fats and amino acids, every substance needed is made from glucose. For instance, consider that when glucose is incubated in flasks containing brain cortical slices, the amino acids aspartate and glutamate appear in mere minutes. So glucose is not only important for generating energy, but also for acting as a starting material to make other substances needed by the brain.

I’ve written some of my thoughts about ketogenic diets a few months ago, and why I think they are effective – which isn’t often. I wouldn’t recommend such a diet to the masses for a myriad of reasons, but even chronic low-carbohydrate diet adherents could probably follow the diet (why I don’t know) without perceivable cognitive effects because a variety of systems kick in to maintain a normal supply of glucose to the brain. But over time, the brain becomes flooded with cortisol, whose higher-than-average levels already correlate with (sub-clinical) cognitive deficits in the elderly, as well as Alzheimer’s disease. It turns out that cortisol interrupts the provision of glucose to the hippocampus and to the rest of the brain so as to impair learning and memories from being laid down effectively. Chronic, elevated levels of cortisol also destroy the hippocampus.

Taming stress is critical in keeping cortisol suppressed, and this entails avoiding missed meals, under-eating, and severe carbohydrate restriction. Han Selye said that activities as unrelated as possible to the activity causing stress at the moment was the most effective means of reducing stress – in particular, exercise; I think light aerobic exercise and simple stretching routines are probably the most effective forms (they have been for me). Extra amounts of the antioxidant vitamins – A, C, and E – are probably protective, too, against the oxidative stress produced by the excessive cortisol exposure; thyroid hormone prevents oxidative stress.

Thyroid hormone ‘lights up’ the brain like caffeine does, and one of the most basic ways it does this is by increasing the supply of glucose. Thyroid hormone, acting by way of the hypothalamus and the sympathetic nervous system and therefore the brain, stimulates the release of glucose by the liver and synergizes with insulin to intensify the uptake and oxidative metabolism of glucose in the brain and in the body. In fact, thyroid hormone directly stimulates the transcription of the glucose transport proteins (GLUT) in the body, and probably the brain, too – just like insulin does. Cortisol, on the other hand, interferes with these transport proteins, antagonizing insulin and thyroid hormone in effect; cortisol also indirectly inhibits the release of thyroid hormone from the thyroid gland. (The low metabolic rate seen in Alzheimer’s disease I think is indicative of hypothyroidism and helps to explain the impaired glucose uptake and oxidation measured in Alzheimer’s brains, including the hippocampus.)

Valproic acid was recently in the news because it was shown to aid in the ability to acquire perfect pitch, or the ability to perfectly discriminate musical notes, an ability generally thought to only be capable of being acquired during critical periods of hearing development. Actually, the ability of valproic acid to improve the plasticity of the brain has been known for several years now; but the doors are now open to use the drug to aid in the development of other skills as effortlessly as is seen in very young children, such as in the acquisition of languages.

Valproic acid is structurally similar to a neurotransmitter called GABA, which is derived from glucose by way of glutamate, and enhances the action of GABA that is already present. Therefore, valproic acid would probably stand to benefit the most those in whom the availability or metabolism of glucose has become impaired or reduced. GABA turns over faster than any other neurotransmitter in the brain, indicating its rapid use and importance therein. It’s no surprise that defects in glucose metabolism leads to seizures, epilepsy, and other degenerative brain disorders, and that valproic acid is used and is effective for those conditions. Ditto for ketone bodies, which are also similar to GABA.

A few people I’ve had the chance to talk to have told me that they’ve had negative experiences using synthetic thyroid hormone products. Finding the right dosage takes time, on the order of months, and the right dosage varies from person to person and within the same person based on other factors. Bear in mind that having too much thyroid hormone can be as equally as bad as not having enough regarding all of the things discussed above. (Broda Barnes said that most of the adults he worked with could get away with a daily dosage of 2 grains of a desiccated thyroid product, which is about 1/2 of a synthetic combination product; only rarely did his patients need more than that.)

REFERENCES

References for this post will be added shorty; I apologize for the inconvenience.

Because people can build up large stores of (essential) nutrients — enough to maintain proper physiological functioning for as long as years — diseases arising from dietary deficiencies should be expected to develop slowly and a long time after a deficient diet was imposed. But for the same reason, it’s extremely difficult to determine the essentiality of a particular nutrient, especially when the requirement for the nutrient is relatively low, as well as the fact that foods contain an array of nutrients in varying proportions.

However, two scientists, husband and wife, working in the Botany Department of the University of Minnesota, crafted a clever and sophisticated (but not full proof) way to test the idea as to whether certain fatty acids were “essential” or not.

Although the idea that the fat-soluble vitamins were essential to good health were proven beyond a doubt by the mid-1920s, when George and Mildred Burr suggested that certain fatty acids – in particular, linoleic acid – were not only merely fuel and vehicles for absorbing the fat-soluble vitamins, but also essential nutrients in themselves, they came up against skepticism from other scientists.

In a series of papers published by the Burrs – in particular the seminal 23-page paper published in 1929 – where the idea as to the essentiality of certain fatty acids was put forth, it was said that these “essential” fatty acids (EFAs) were cofactors for key metabolic processes. And when these EFAs were present in excess, they were burnt to fuel other metabolic processes.

The Burrs’ ideas were supported by their results: mere drops of flax oil or corn oil — both of which are rich in linoleic acid — daily for over 40 days reversed the characteristic signs and symptoms (like flaky feet, tails, and skin) brought on by the strict fat-free diets that were imposed on their rodent subjects. Lard worked, too. On the other hand, coconut oil — which contains only saturated and monounsaturated fatty acids — had no such effect. Because the addition of arachidonic acid, derived from linoleic acid, had a similar effect as linoleic acid, it was fair to suppose, which the Burrs did, that the beneficial effects of linoleic acid was due to its role as a precursor as well.

Since some of the defects resulting from the fat-free diets can be reversed by the addition of omega-3 fatty acids, and since mammals (likely) don’t have the wherewithal to convert omega-3 fatty acids to omega-6 fatty acids (and vice versa), it also wouldn’t be possible to rule out that some general physical and/or chemical property of the long-chain polyunsaturated fact acids are responsible for reversing the conditions brought about by a strict fat-free diet.[*]

Fatty acids are bound to various parts of cells and to various structures outside of cells, and changes in the kinds of fatty acids available changes the physical properties of the tissues to which they’re bound. Fatty acids come in many flavors, yes, but the variety isn’t infinite. But there are so many enzymes that act on many different fatty acids that the combination of the effects increase considerably. These effects typically take months or years to manifest.

As an example, consider for a second the molecule oleamide, which is essentially a molecule of oleic acid (omega-9), except that that -OH on the carboxylic acid group at the end of the molecule is replaced by an -NH2.

Oleamide induces sleep in animals. (Though, it’s unclear whether it’s the parent molecule itself or its cleavage products, ammonia and oleic acid.) However, when the diet is altered to the extent that EFAs displace the saturated and monounsaturated fatty acids in the brain, the same enzymes that make oleamide instead make similar molecules from EFAs. As to the consequences of this change — who knows?

It’s been said that the reversal of the symptoms seen upon the addition of the “EFAs” was due to the slowing of the rodents’ metabolic rates by the EFAs. As to the validity of that idea — I have my doubts. Most importantly, the symptoms didn’t just stop getting worse; they began to reverse quickly, eventually to the point of complete cure.

While keeping the metabolic rate up is good, especially when food is available, it’s not so good when food — particularly carbohydrate — is not available. If you’ve read any of the available literature on fasting, you’d know that there’s is an old observation, which has now become an accepted truth, that the desire for food goes away when a person is ill because food has to be withheld so that the body, through its vast wisdom, can activate its magical healing mechanisms.

The reality is simpler than that. When ill, the desire for food goes away to accelerate lipolysis so as to increase the supply of fatty acids to cells, namely to immune cells. As regular readers of this blog are well aware of, lipids in the blood are far more dangerous than lipids stored away in fat tissue. So this momentary drastic increase in lipolysis and increase in free fatty acids — especially polyunsaturated fatty acids — represents an emergency move that, while not without repercussions, allows us to fight off infections to live another day.[†] Apparently, small amounts of polyunsaturated fats are needed to manufacture immune cells at high rates.

But the Burrs’ rodents didn’t display the constellation of symptoms that would suggest a higher than normal metabolic rate, let alone hyperthyroidism. Nor was there a definitive way that the Burrs tested for it. It’s quite possible, and the Burrs say as much, that the exquisitely small amounts of fat simply improved the digestion and assimilation of the other nutrients eaten with it.

Suffice it to say here, the laboratory created fat-free diet is not a diet that can be recreated in the real world. The Burrs encapsulated the challenges in creating the purely fat-free diet in the following quotation: “In fact, it is impossible to conduct a fat-free experiment if corn-starch is used as a source of energy since it carries 0.6 per cent of fatty substance which is within the granule . . . the diets contained appreciable amounts of fat.”

Extremely extensive measures were taken to create the diets, which consisted of sugar, casein (highly purified to remove anything but casein [most importantly, fat]), B-complex vitamins (from dried yeast extract), and vitamins A and D (extracted from cod liver oil). The percentages of these ingredients were gradually changed to meet the changing nutritive demands as the rodents aged. The most important part of this step was that it allowed for even more of the “impurities”, i.e., fat, to be excluded, by replacing increasingly more of the casein with sugar.

The point is that it’s virtually impossible for a person to eat a diet that’s as deficient in fat, let alone polyunsaturated fat, as the Burrs’ diet. Many conditions have been linked to a polyunsaturated fatty acid or an EFA deficiency (most famously cystic fibrosis) yet these links are tentative or may have nothing to do with the conditions at all, and they may simply be indicative of a larger problem, like a generally poor diet or digestion. In the end, the argument as to whether these EFAs are, in fact, essential, is still moot, but it’s not an argument we need to entangle ourselves in — ever.

Of course, there are gradations in the effects of varying the amount and/or types of fats in the diet. Deliberately increasing the intake of polyunsaturated fats at the expense of saturated fats, for instance, reduces the useful activity of components of the immune system — especially natural killer cells and interleukin-2.[‡] In other words, PUFA, most strongly the omega-3s, decrease our resistance to (potentially lethal) infections.[§] But, this is a topic for a whole new post(s) . . . maybe.

References

References will be posted as soon as possible. (I encourage you to hate me for the delay.)

[*] This concept — the close relationship between the physical properties of a molecule with its structure and the ability to predict the physical properties of a molecule based on its structure — should be no surprise to the readers of this blog. And it should not be forgotten!

[†] However, as longs the fatty acids are taken up, stored, or burnt as fast as they’re released, the repercussions are minimized greatly.

[‡] To be more clear and precise, IL-2, a cytokine released from helper T cells, increases levels of natural killer cells and T cells.

[§] They also impair wound healing

In college, I made it a routine to take as many credits as possible every semester. On top of working and volunteering, I was consistently burdened with a schedule fit for two students because, well, I’m Asian and that’s what Asians are supposed to do. I was never complacent and I never allowed myself to live in the moment to stop to enjoy my achievements and successes. I was crazy obsessed with productivity and always looking towards the next rung in the academic/professional ladder to climb — often at the expense of a ‘normal’ social life.

It’s not a surprise that, even though I made it a priority to take care of my physical health, by the second semester of my junior year, my health collapsed — unbeknownst to anyone else. I still managed to achieve all of my goals, pushing through the pain the entire way, and at the same time managing to keep all of my options open for life after college.

Yet, I knew I had done irreversible damage to myself. I think I was too ashamed and embarrassed to share what I was going through with anyone else. This wasn’t supposed to happen to me — after all, I was the person who had it all figured out. Personality and behavioral changes were the most distressing symptoms I experienced, and continued to experience in graduate school. Bouts of anxiety began to strike, alongside indigestion, insomnia, and crippling tension headaches. Worst of all, I was nearly emotionless. I was well informed on physiology and pathophysiology back then and I’d even hazard to say that I offered sound advice to friends who came to me with nondescript health issues. But the only person I couldn’t help was myself, and this thought would make me even worse.

Skipping meals, forgetting to eat, sleeping on average one fewer day per week, and constantly striving for perfectionism in all aspects of my life finally caught up with me. But no matter what I tried, I just couldn’t snap out of it. Maybe it was my deeply ingrained socialization to work excruciatingly hard and to excessively please/impress others with status and accomplishments, and to deem their definition of success more important than my own definition. Or maybe it was the Korean in me which was why I was so stubborn as to continue on my path, despite the fact that it was paved with pain and suffering.

I had the pick of the litter after college as to what graduate school/career path I wanted to pursue — one good that came out of my obsessiveness. I chose the easiest one because, well, all the things that mattered to me then, and meant nothing to me.[*] I wanted to get/feel better, and have as much time as possible on the side to, for once, read everything I wanted and to read and to pursue everything I wanted to pursue, instead of doing what other people — most of whom I don’t give a shit about — expected of me.

Making these tough decisions, alone, improved the symptoms I was experiencing — not by much but noticeably. I was able to finish up my graduate work, on less than 50 percent brainpower and energy, while the entire time, keeping all of my health issues a secret, except to my parents. To be honest, it was painful, and I still feel regret as to how much more enjoyable the experience would’ve been for me if I’d just opted to take time off before continuing on. But I was at least afforded time to figure out what had happened to me: I was stuck in a hypoglycemic trap.

It’s important to know that every minute, the brain, on average, executes three cycles of a series of reactions that convert glucose to energy and has a respiratory quotient of 1.0, indicating an oxidation of glucose and not fatty or amino acids. So the brain is dependent on a steady and constant supply of glucose, and it’s no surprise that an interruption or change in this supply can lead to behavioral and personality changes, which was what I was experiencing.

All the anxiety and tension I had, yet for a long time was unaware of, and the fact that my body was constantly poised to “fight or flee” was predisposing my blood sugar to drop below “normal.” The indigestion, insomnia, and anxiety were all symptoms of an overactive sympathoadrenal system, whose job is to raise blood glucose levels by extracting glucose from the liver, among other mechanisms, by way of cortisol and adrenalin. As a result of this “alarm” state, my blood glucose levels would increase, after which insulin, secreted by the pancreas, would bring the levels back down to “normal.” But in the process, my blood glucose levels would drop below“normal”; that is, what is required to function normally (not what is deemed normal by the “establishment”). This is the trap. (What’s worse, even after the alarm state would shut down, the relative hypoglycemia and its accompanying symptoms would persist.)

I’m excited to see that Matt Stone, who has a voice in the community, is writing about this topic — a topic that is either haphazardly and lazily brushed off as not existing or, even worse, unknown altogether. I have yet to read his bookon the topic, but I think one point of neglect is the idea of normal versus functional.

As to hypoglycemia testing, reliable conclusions cannot be made on the basis of two isolated fasting (or non-fasting) oral glucose tolerance tests. Variables such as the method of testing, the time of testing, and concomitant symptoms are contexts against which blood glucose readings should be assessed. How silly would it be to deem a person to be “healthy” because his blood glucose levels fall within the “normal” range despite the fact that he was having an “attack” at the same time? And are we justified in brushing off a blood glucose level reading because it falls a mere two or three points below “normal”? I don’t think so. (Yet, it is a common occurrence.) A single blood glucose level reading is virtually worthless; instead, we should focus on dynamics.

I’ve tested my blood glucose levels when very symptomatic and when not symptomatic, in addition to all the times in between. I’ve recorded that when I was very symptomatic, about an hour after eating a meal, my blood glucose levels wouldn’t rise by more than 50 percent from baseline levels. I speculatively attributed this to either a sluggish extraction of nutrients from my intestines (which could indicate hypothyroidism [a la Broda Barnes]) or to an over secretion of insulin.[†]

On the other hand, when not symptomatic, my blood glucose levels would sky rocket about an hour after meals. As to the significance of these observations, I have some ideas; however, none of them are concrete enough to discuss here and now, except to say that if you were to plot my glucose levels over time following a meal, the curve would appear flat, which indicates, in accordance with my symptoms, that my blood sugar levels weren’t rising high enough to meet the demands of my brain and nervous system. Yet, they weren’t dipping low enough to deem me “hypoglycemic” per the current cutoffs.[‡]

I think the fact that diabetes and hypoglycemia can be diagnosed in the same patient depending on when and the kind of test performed speaks to the gross inadequacies of the current system of differential diagnosis and confusion about how to interpret glucose tolerance tests. Glucose tolerance tests can be informative, as long as they are performed properly — that is, for at least 6 hours in order to record the tail end of the curve. However, and I’ve said this before, symptoms and responses to a particular treatment is one of the surest ways to make a diagnosis.

I think the pattern of occurrence of a patient with asthma, ulcers, hypoglycemia and diabetes could help to clarify the existence of hypoglycemia in a person. In a person with all of these conditions, when an asthma attack strikes, he would be labeled as hypoglycemic if his blood glucose were tested at the time. On the other hand, he would be labeled as diabetic if his blood glucose levels were checked when his ulcers were acting up. In other words, diabetes seems to protect against asthma[§]yet worsen ulcers, whereas hypoglycemia, which indicates low levels of the stress hormones, is associated with worsening asthmatic symptoms. Obviously not conclusive, this pattern would be worth checking for and considering as part of a differential diagnosis. Thyroid conditions, allergies, salt, and potassium (among some other things) could be included as well, which affect and are affected by blood glucose levels.

It took a while, but as I sit here now, I’m reminded of the journey to get back to the person I was in my younger years. My mindset and priorities are inverted from what they were, and, I’ve let go of the idea of letting the opinions of other people dictate the decisions I make in my life. Call it an enhanced self-esteem or shamelessness, but it took me a long ass time to get to this point (maybe its the stubborn Korean in me), and upon letting these ingrained ideas go, while consistently reminding myself to eat regularly, I’ve finally reached a point of normality (not exactly sure what that means) and I’m okay with allowing myself to be satisfied and complacent, and to celebrate my past accomplishments — finally.[**]

This post is off the beaten path from my usual fare. It wasn’t meant to provide medical advice. It was meant to remind myself to remember to live in the moment; to enjoy my achievements when they happen;[††] to maintain hope; to have compassion and understanding for others (who may be going through what I did); to take the time to think deeply about the motives for what I’m striving for; and instead of working to accumulate and hoard inherently worthless degrees, awards, certificates, and even recognition to some extent (all of which I’m not implying are unimportant), to work to accumulate and hoard love, goodwill, pleasure, and gratitude – all the things I neglected in my younger years that ultimately led to me pouring out my personal thoughts to write this post tonight. I’m still a work in progress, and I’m certainly in no position to dole out advice. But just as Hans Selye said, “the inventor of the best race car is not necessarily its best driver.”

[*] I realized this really quickly, thinking of myself as a rat in a wheel, running as hard as I could for the sake of it.

[†] Because cortisol interferes with the conversion of T₄ to T₃, and because T₄has a permissive effect on adrenalin, we can conceive of another trap in which the effect of adrenalin on tissues becomes intensified. Adrenalin stimulates the HPA axis, causing more cortisol to move into the blood, further reinforcing the inhibition on the conversion of T₄ to T₃.

[‡] My brain responded, for lack of a better description, with a sit down strike.

[§] Certain asthma medications raise blood glucose levels.

[**] Around the time my dog died, which was around the time I first realized that I had completely overcome my health challenges, was the first time I ‘felt’ real emotion in years. I cried, hard. And it felt really good.

[††] And when you’re down or frustrated, think about those accomplishments, which no one can take away from you.

Of all the stimuli that we’re constantly adapting to, whether well or not so well, food is without question the most significant. Think about it: There’s nothing that we’re exposed to as frequently, as intimately, as long as, or as much as in shear bulk as food. What’s more, food, namely natural food, is highly complex chemically. As such, food, like any other potential stressor, can elicit reactions that are “maladaptive” and chronic exposure to a food to which a person is sensitive can cause the same conditions that are caused by chronic stress — rheumatoid arthritis, thyroid imbalances, ulcers, headaches, obesity, hypoglycemia.

It’s no surprise that food sensitivities have been linked to and blamed for causing virtually every symptom in the books. It’s also no surprise that a diagnosis is so difficult to make, and why there is so much controversy amid its existence. I think the controversy surrounding the existence of food sensitivities was made famous by the work of the pediatric allergist B.F. Feingold.

Feingold was sure that hyperactivity in children was caused by sensitivities to contaminants and additives in foods. His diet for hyperactive children was free of all artificial colors, flavors, preservatives, propellants, nutritional supplements, etc., and though his idea was met with aggressive skepticism, there were/are sound reasons to argue for his theory, the most important of which was that many children benefited from the diet.

But food sensitivities can also exist to things that aren’t deliberately added to foods. Antibiotics, arsenic, and steroid hormones are things added to the feed of livestock that end up in meat, milk, and eggs. In addition, plant foods, even the highly hybridized ones, contain chemicals, such as salicylates that can be highly allergenic and irritating. Other contaminants, such as lead, an industrial waste product, are taken up by grains, vegetables, and shellfish with a relatively high affinity, and evidence for this increased lead exposure can be found in our bones, which contain more lead than ever before.

Feingold and his theory aside, it’s important to understand that there are deliberately added and naturally occurring contaminants in food, which act as toxins, allergens, irritants, and/or carcinogens, that are regularly ingested, absorbed, and produce a wide range of physiological effects that may or may not be perceptible (at least in the short-term). Sensitivity to these ingested contaminants is based largely on the effectiveness of our defenses against them.

There are primary three lines of defense against the contaminants with which we’re constantly confronted.

First, the GI tract, liver, and kidneys provide wide-ranging and general protection against these contaminants — provided they’re healthy and functional. A person with lung problems, for instance, would be more susceptible to inhaled things, such as nitrogen and sulfur oxides. A person with liver problems would be more susceptible to fat-soluble things because the liver converts fatty compounds into water-soluble ones, which can be removed by way of the kidneys from the blood. And a person with kidney problems would be more susceptible to water-soluble things.

Second, contaminants that reach the blood and tissues in the body can acutely activate the HPA axis to prompt the secretion of cortisol, which represents another line of defense. Susceptible people are people who do not mobilize their adrenal (or thyroid) reserves to these contaminants; they are therefore relatively more sensitive to their environments. Although the mechanisms are incompletely understood, cortisol and thyroid hormone protect against and mitigate sensitivities to contaminants by limiting the release of histamine and by raising blood sugar levels — a radical idea first put forth in the 1960s.

And third, a person’s nutrition status is an important line of defense that, compared to the other two variables, is within our control to improve and strengthen. An adequate intake of calcium, magnesium, and zinc, for instance, by the principle of displacement/chelation, protects again lead, cadmium, and fluoride toxicity. The kinds of fats and proteins in a person’s diet are a major factor, too.

A general distinction, however, should be made between sensitivities and intolerances so as to not mistake one for the other. Think about milk for a minute.

Milk is often avoided by most adults due to the distressing symptoms it causes: bloating, burping, cramping, farting, diarrhea, constipation. These are symptoms of an intolerance to lactose because of a lactase deficiency. Intolerances to foods, or more precisely to the components of foods, abound. And identifying them isn’t always as easy as identifying lactose intolerances.

Allergies, compared to intolerances, derive from antibodies produced against specific food proteins. True allergic reactions are immediate and explosive versus intolerances, which are way more variable in their presentation. One way to determine if an allergy is at play is to try milk from animals other than cows. For instance, the ability to drink goat milk but not cow milk without symptoms strongly indicates an allergy, not an intolerance, as milk from all mammals contains lactose.[*][†]

Allergies are harder to get around then intolerances, and if your unlucky to have an allergy, the surest fix is avoidance of the food(s) to which you are allergic. On the other hand, intolerances can be overcome so long as the cause is identified — often easier said than done. It’s been reported in forums that intolerances to milk can be gradually overcome. The idea is that the regular consumption of milk will gradually stimulate the production of lactase. This idea, though reasonable, is not supported by experimental data as far as I know.[‡]

Although allergies are more potentially lethal than intolerances, the latter is more widespread and easier to miss — which make intolerances more insidious. There are three main reasons why clinical diagnoses for food intolerances are so elusive.

First, clinical symptoms arise from complex reactions to broken down products of food — most of which are unknown and/or inadequately studied.[§] Second, the symptoms of food intolerances are extremely varied in quality, intensity, and duration, just as the manifestations of chronic stress are, and they can show up in any body system. In addition to that, a particular food can produce different sets of symptoms in different people. And third, the timing of symptoms can be highly unpredictable; that is, the interval between the exposure to a food and the occurrence of symptoms can vary among people and within the same person.

Regardless of whether an intolerance or allergy is at play, both are perceived of as stressors. Stress, in turn, increases our susceptibility to allergies and intolerances. As such, when exposure to foods and diets to which we are allergic or sensitive is prolonged or excessive, evil things are likely to ensue.

Chronic stress leads to the excessive secretion of ACTH, cortisol, GH, adrenalin, and glucagon — all of which eventually results in the following biochemical derangements (skip over this list if you’re uninterested in the grueling biochemical details):

1) Excessive accumulation of fat in places not meant to store much fat

2) Influx of water into cells and cellular swelling

3) Oxidation of fat and decrease in ATP generation

4) Oxidative stress

5) ‘Disorganization’ of the mitochondrial respiratory chain

6) Deposition of calcium in soft tissue

Cortisol is a major factor, as it potently causes the preferential oxidation of fat, which, for reasons I won’t get into here, promotes deficiencies in oxygen. An oxygen deficiency stimulates specialized cells called fibroblasts, which secrete and lay down collagen (i.e., scar tissue), so as to increase the distance through which oxygen has to diffuse to reach cells. In a vicious cycle, the oxygen deficiency intensifies, stimulating more collagen-secreting cells, which, in turn, lay down more collagen, and so forth.

In the heart, for instance, a decrease in oxygen availability from excessive cortisol exposure can impair the heart muscle’s ability to pump blood while at the same time increasing the heart rate by stimulating beta-adrenergic receptors. So although the cardiac output may be unaffected at first, over time, the reduced stroke volume results in less blood pumped per heartbeat, intensifying the oxygen deficiency further.[**] Suffice it to say, cortisol is an important factor in cardiovascular disease.

Glucose, fructose, and insulin can help to prevent some of the consequences of excess cortisol exposure, especially in the heart. Simply increasing blood glucose levels helps to reduce a person’s reactivity to allergies and intolerances and improves allergies and intolerances already established. However, the reliance on cortisol or other adaptive hormones to do so, over time, has serious consequences, like the ones listed above. Anything that inhibits phosphodiesterases or increases the metabolic rate reduces a person’s sensitivity by putting a brake on histamine release. Choline, which synergizes with histamine in causing the ‘effusive’ symptoms of allergic reactions, can be blocked by anti-histamines, which is partly why some anti-histamines are also classified as anti-cholinergics. Vitamin A protects against stress-induced tissue damage, including in the thymus and spleen.

We could deliberately expose ourselves to cortisol excessively, by replacing carbohydrate in our diet with fat, or by eating less frequently or not enough. Chronic dieters get what I call the “face” with thickening of their mid sections and thinning of their extremities from excessive protein break down. Call it a mild, sub-clinical form of Cushing’s combined with hypothyroidism. Depression and irritability are not uncommon either. But these ugly effects are really just the tip of the iceberg.

Hans Selye said that every stressful event left a “scar.” Conceptually, I interpret this in the following way: When there’s a mismatch between a stressor and the ability of our bodies to mount an adaptive response to restore balance caused by that stressor — in which case balance would only be partially restored — our bodies become that much more vulnerable to future stressors. This imbalance carries over to the exposure to every subsequent stressor so as to put cumulatively more strain on our adaptive mechanisms until eventually the adaptive mechanisms collapse and disease results.[††]

A diet that raises cortisol is a diet that by definition is stressful. The surest way to raise cortisol through diet is to adopt a “ketogenic diet.” There’s probably no faster way to “scar” the shit out of yourself than that. I do urge people to tap into their senses and sensibilities for a second and kick dirt on the idea of becoming the “ultimate fat burning man” or “bulletproof” or “fat-adapted” or whatever. These are made up ideas put forth by marketers masquerading as experts. Diet-oriented marketers are sleazy and will say anything, seriously (stepping off soapbox now).

There are many causes and contributors to food allergies and intolerances. It’s incredibly complex, yes, but it’s well known that stress predisposes to and aggravates both of them. Environmental contaminants are rampant, more than ever, yet adjusting certain nutritional factors and raising blood sugar levels can protect against and reduce a person’s sensitivities to them, although the reasons why are not completely understood. Discerning whether a food allergy or intolerance is at play becomes more difficult when considering allergies of the chronic, low-grade variety. However, the symptoms of either one respond to the same interventions, evidenced by the fact alleviating one condition has positive effects on the other. The adaptive hormones and mechanisms represent an important line of defense against the contaminants to which we’re commonly exposed. Despite this, it’s important to understand that over reliance on these hormones and mechanisms have long-range effects that not only sensitize us to future exposures to contaminants, but they also sensitize us to other stressors — injury, illness, fatigue, noise, psychological strain, temperature changes. . . .

[*] Lactase (the enzyme that degrades lactose into glucose and galactose) is produced and secreted by mucosal cells of the jejunum. When there isn’t enough lactase, lactose either move into the blood undigested, after which they are excreted in urine (minor pathway), or they pass into the colon, where they are fermented by bacteria to various acids and gases, particularly carbon dioxide (major pathway).

[†] There are two other simple tests that involve ingesting some lactose and either (1) waiting for symptoms or (2) measuring blood glucose levels shortly after.

[‡] I am, however, interested in anecdotes of people who have overcome lactose intolerances this way.

[§] This is why skin testing is useless.

[**] A similar situation occurs at high altitude.

[††] This is also how Selye conceived of the aging process, and there’s good evidence to support his model.

Wow, it’s been four and a half months since my last blog post so I’m guessing best case, my readership has fallen by half; worst case, I’ll be writing this post to myself. But it’s not my fault, and if it’s any consolation it hasn’t been enjoyable at all. I’ve been under the gun the entire time and basically subsisting on some of the best local brownies and cookies, which is fun in the beginning but eventually gets gross. The crankiness and recurring headaches I’ve been having are probably signs that I’m reverting back to my old ways and should probably step back to take a breath. But this blogging hiatus and mini burn out has opened the doors for me to again contemplate stress and fundamental ways to prevent and counteract it, starting all the way back from Hans Selye.

Not to get too off track but I'm continuously amazed by Selye's knack for bringing together disparate pieces of data to produce unified ideas, principles, and theories. Of course an important by-product of this gift was that it laid down the basics for what eventually became understood as the generalized stress response — the idea that the hypothalmic-pituitary-adrenal cortex pathway would become activated regardless of the quality or nature of a stressor.

Cortisol exposure is a major effect of activating this pathway. Because cortisol promotes fat metabolism while inhibiting glucose metabolism, more molecules of oxygen are consumed and fewer molecules of carbon dioxide are produced to permeate into the mitochondria, causing the mitochondrial respiratory system to operate less efficiently or improperly since oxygen is needed to maintain the cell in its living state and carbon dioxide (along with iron, NAD+, CoQ10, etc.) functions as a cardinal adsorbent would in mitochondria. Continued respiration is dependent on maintaining a “delicately poised” state of the respiratory proteins, which is largely dependent on these cardinal adsorbents, as the concentrations of potassium, calcium, sodium, and magnesium ions are relatively low and fixed. In essence the cardinal adsorbents allow potassium and magnesium — whose adsorption is required to generate ATP — to preferentially adsorb to important respiratory proteins at the expense of calcium and sodium.

On an even more basic level, an increase in acidity primes the enzyme that synthesizes ATP in mitochondria, and a change in electron density underlies the change in acidity (pKa) of ionizable functional groups. By adjusting the electron density of the respiratory proteins, cardinal adsorbents allow for the selection adsorption of one ion, potassium and magnesium, over others, and this process regulates the activity of the enzyme that generates ATP.

With fatty acid oxidation, reduction, excess calcium, ATP loss, magnesium loss, low oxygen, and cell swelling tend to predominate, whereas glucose oxidation, ATP(and/or magnesium), respiration, and oxygen tend to oppose these processes. Gerald Pollack says that in order to live we need structured water. But in order have it, we need ATP because to maintain the living state, cardinal sites need to be occupied by ATP. The mere presence of ATP changes the size and shape of mitochondria. ATP increases the efficiency by which ATP is generated and loss of respiratory control goes hand in hand with the loss of ATP.1

By increasing free fatty acids and promoting the oxidation of fat, cortisol promotes a reduced state in which ATP is released, NADH predominates over NAD+, calcium and sodium replace potassium and magnesium, and the use of glucose decreases. In effect and most fundamentally, excess cortisol, like other electron-donating cardinal adsorbents, perturbs the balance of the mitochondrial respiratory chain. And because an overly reduced cell state represents a “dead state,” and because an impairment of respiration is a non-specific process, and considering “cells form tissues, tissues form organs, and organs form whole organisms,” I can at least say this will lead to body wide problems — though I’m not able to say exactly what those problems will be. (Though I would expect organs most dependent on ATP — the heart and nervous system — would be most vulnerable.)

Characterized by a gradual loss of biochemical organization in cell cytoplasm, degenerative cellular processes are usually associated with disturbances in energy metabolism. Cell swelling is typical of these degenerative changes, with an increase in sodium inside cells; if severe enough, the mitochondria may swell, too. Inflammation compounds all these problems, which is why agents that block or limit histamine, prostaglandins, bradykinin, serotonin, neutrophils, monocytes, etc., are so important, especially as we age. The addition of ATP instantly reverses these degenerative effects. Adequate nutrition and a normal blood supply are essential as well. On the other hand, excessive fat oxidation reduces oxygen and predisposes to these degenerative changes, including the fatty infiltration of cells.

“Uncouplers” are usually seen as good and desirable for wight loss but they do so by disrupting the delicate balance in the respiratory proteins alluded to above. The classical uncoupler 2,4-dinitrophenol, an acidic aromatic compound, for instance, as an electron donating cardinal adsorbent disturbs the electronic balance of the respiratory proteins as to impair the delicate oscillatory nature of the respiratory proteins through which ATP is generated. In effect uncouplers favors the state in which the ATP generating enzyme becomes active, opposing the effect of ATP. And in the absence of potassium the continued exposure to uncouplers blocks respiration, leaving the cell in a dead, swollen state. Extra potassium is vital whenever uncouplers are involved. The swelling caused by uncouplers such as thyroid hormone, for instance, are almost immediately reversed by potassium (and ATP). Insulin, on the other hand, parallels the effects of ATP.

Low carbohydrate diet advocates often compare the effects of fasting to carbohydrate restriction; although superficial comparisons can be made, they are fundamentally different in their effects — especially with regard to the interest of the delicate balance of the mitochondrial respiratory proteins. Though both are fundamentally stressful, the effects of fasting are more measured and tends to reduce the body’s exposure to things that could further disrupt or interfere with continued respiration. The fasting literature is interesting, mainly because of the painstaking detail with which the cases of complete fasts were described (by authors such as Upton Sinclair) and because the conclusions that can be drawn from the cases are subject to less interpretation than those of carbohydrate-restricted diets. But most interestingly, considering the fact that the diseases largely characterized by underlying metabolic disturbances (e.g., cancer) were completely reversed by complete fasts, something carbohydrate-restricted diets cannot lay claim to yet, the net effect of fasting on respiration is probably slightly positive.

I intended to make this post about stress but I guess I failed because it quickly veered into the complicated hell that is cell physiology and low-carbohydrate diets, of which discussing has become a bane of my existence. But have I really veered off that much? I think a solid groundwork has been laid from which to discuss ways to stress proof ourselves from anything.2 I plan to continue to update as to how I’m doing and I’m thinking about including some of the things I’m doing to recover from my latest burnout and to prevent future burnouts. I think that would make for interesting discussion … if anyone is still reading this blog. Good night.

1 This can be quantified by way of calculating the respiratory control index

2 Straight up stole this term from Danny Roddy

In my first “fact check” of Dr. Ray Peat, I had discussed the mechanisms by which insulin exerts its effects from the conventional textbook point-of-view. I’ve gotten mostly good feedback on that post, and some idiotic ones, from the people who obviously didn’t take the time to read it, or if they did failed to understand it.

Briefly, the conventional view is that insulin, upon being secreted by the β-cells of the pancreatic islets, acts on and activates the insulin receptors, initiating the insulin-signaling cascade. This activation of the insulin receptor then provides a docking site for the insulin receptor substrate (IRS) proteins, which thereafter activate kinases in the vicinity that contain a specific SH2 domain, namely the kinase that phosphorylates the 3-position of the membrane lipid phosphatidylinositol 4,5-bisphosphate (PI 3,4 P₂) to phosphatidylinositol 3,4,5-trisphosphate (PI 3,4,5 P₃).

Figure 1 Insulin signaling pathways in the cell.

GLUT = glucose transporter (lower right)

This lipid product, PI 3,4,5 P₃ thereafter activates the kinase, PDK1, and PDK1 phosphorylates and activates Akt, another kinase that moves throughout the cell’s cytoplasm, executing most of insulin’s actions, the most important of which for this post is the translocation of the glucose transporters from the cytoplasm to the plasma membrane.

This complex insulin-signaling cascade, which I’ve simplified a great deal, is obviously dependent on an intact plasma membrane that’s impermeable (or semi-permeable) to glucose, as well as glucose transporter proteins that are ready to be called into action at a moment’s notice. (Others like Roden et al. have even gone as far as to suggest that the passage of glucose through the plasma membrane is, inherently, the rate limiting step in the use of glucose [Roden, 2004].) There are a few issues with this scheme.

For one, in the absence of insulin, glucose freely passes through the plasma membrane and into the cell’s cytoplasm, such that at equilibrium, the glucose concentration inside the cell is 20 to 30 percent of the glucose concentration in the blood (Randle & Smith, 1958a, 1958b). Two, the evidence that there’s a defect of sorts in the glucose transporters in diabetes is conspicuously sparse. And three, glycogen tends to accumulate in insulin resistant tissues, indicating a block on glucose use downstream of the glucose phosphorylation step upon arrival into the cell by way of the previously mentioned glucose transporters (Sakamoto & Holman, 2008).

So the impairment of glucose use is taking place inside the cell, rather than at its border, in which the glycolytic enzymes operate. Dr. Gilbert Ling believes, and has shown in a series of experiments in the 1950s and 1960s, that the rate at which glucose moves into the cell’s watery interior is governed by the availability of glucose “adsorption sites” on certain proteins and enzymes. The plasma membrane has little to nothing to do with this process.

Insulin, in Dr. Ling’s sense, functions a an cardinal adsorbent, which is basically any substance (e.g., hormones and drugs) that interacts strongly with proteins at very low doses (i.e., potent), changing the protein’s electronic state; this electronic perturbation, so to speak, in turn is transmitted like dominoes to the rest of the protein and other proteins. The proteins unfold a bit as a result, exposing their glucose adsorption sites, which preferentially bind glucose over other sugars, in a stereoselective manner.

In the resting living state where, like in prepared Jello-O, water is structured in close association with cellular proteins, as well as ions and other molecules (e.g., potassium and ATP), and so glucose has a reduced solvency in the water inside the cell than in the water outside the cell.

Figure 2 Ling's association-induction hypothesis. The figure on the right represents the resting living state and the one on the left, the active living state. The squiggly lines are single protein molecules, X⁺ is potassium, and Z could be insulin in this case.

So in the resting living state, and in the absence of insulin, in which the glucose adsorption sites become unexposed, glucose is found at higher concentrations in the blood than in the cell’s cytoplasm and adsorbed to intracellular proteins and enzymes. This accounts for the unequal distribution of glucose across the plasma membrane (at least 4.5-fold higher concentrations outside the cell than inside the cell). No pumps or transporters are required.

Given the conventional model, how does one account for this unequal distribution of glucose across the plasma membrane in the absence of insulin? We could evoke the idea of a glucose pump of sorts. Though this pump would have to operate bidirectionally; that is, at high rates when the glucose concentration in the blood is low; and at low rates when the glucose concentration in the blood is high, permitting glucose to move into the cell in droves. Energy would be continuously used to maintain these pumps, and membrane proteins would provide the channels through which glucose could pass, via facilitated diffusion, into the cell. (There are too many issues with this scheme to consider it further at this point.)

When energy is used (for reasons that will be discussed in another post) the cell, which operates cooperatively as a unit, destabilizes a bit, and this allows glucose, as well as calcium, to move into the cell in droves. Under the control of insulin, glucose adsorption sites on proteins and enzymes become exposed, and glucose is burned to replenish the ATP. At the same time, carbon dioxide is produced, which functions to stabilize the resting living state and, via the Bohr effect, increases the efficiency with which oxygen is unloaded from the red blood cells, curtailing the production of lactate (and protons). In this highly energized, resting living state, potassium is preferentially adsorbed to the ionized carboxylate groups on intracellular proteins. (This satisfactorily explains why the administration of glucose and insulin can uncomfortably lower blood potassium levels.)

Insulin, glucose, and oxygen are at the core of our resistance to stress, as Danny Roddyhas pointed out, and now we have a firmer basis for understanding why this is.

Take for example what would happen, in terms of Dr. Ling’s association-induction hypothesis, in ischemia (low oxygen availability) of the heart, which represents an extreme case that offers up a glimpse of the provision of support by oxygen, glucose, insulin, and carbon dioxide.

Glycogen is a readily mobilizable fuel source in the heart that’s increasingly called upon as the blood supply of oxygen lessens. Almost instantly, glycogen provides free glucose molecules, which is oxidized to generate ATP, and, once more, in an all-or-none manner, this electronically shifts proteins in a way that maintains the highly energized, resting living state in the face of stress. (Glycogen is replenished by fructose more efficiently than any other single nutrient.)

Over time, or if glucose and oxygen are not available, or available in inadequate amounts, the cell destabilizes, and as a result calcium, which is normally excluded due to its reduced solvency in structured cellular water, is permitted to move into the cell in droves (i.e., calcium overloading). Cellular water is structured, to some extent—somewhere between the states of liquid water and solid ice—by the presence of ATP.¹

Calcium overloading, via excessive excitation or from ATP depletion, over time, irreversibly transitions the cell into the so-called “dead state,” which is a concept—that is, being dead or alive—the conventional model (i.e., membrane-pump theory) has failed to adequately explain. (As I’ve said before ATP is synonymous with life.)

Oxygen is depleted as the cell becomes increasingly reliant on the use of fatty acids to generate ATP, accelerating the build up of lactate. At the same time, the flux of glucose through the pyruvate dehydrogenase enzyme (PDH) complex, which carries out a key step in the metabolism of carbohydrates, essentially linking glycolysis to the citric acid cycle,² slows, and ultimately comes to a stop, further contributing to lactate buildup.

Figure 3 PDH complex (blue) regulation via reversible phosphorylation (inactive, right) and dephosphorylation (active, left) by kinases (PDK 1,2,3, or 4) and phosphatases (PDP 1 or 2). Recall that fructose is one of the activators of the PDH complex.

The buildup of toxic metabolites and the loss in cell structure leads to an impaired functioning of tissues and their death quickly ensues. The provision of glucose, oxygen, and insulin, however, can short-circuit and reverse this vicious cycle.

The oral hypoglycemic drugs, like glipizide, are associated with an increased risk of cardiovascular death. This warning was first made based on a long-term prospective study which was set up to evaluate the efficacy of four different (non-insulin) classes of oral diabetes drugs in the 1970s that included over 800 diabetics. The persistent warped view of diabetes—that is, it is a disease of excessive blood sugar—has made it possible to continue the practice of treating diabetics for the sole purpose of "controlling blood glucose levels."

I’ve for the purpose of keeping this discussion as reader friendly and short as possible, simplified concepts as much as I could and left out the details, calculations, experiments that have led to some of the assumptions made herein. I’ve also in this discussion left out the role of hormones, which adds another layer of complexity to the entire picture.

Thinking about physiology in terms of Dr. Ling’s conception of everything is hard to do (at least for me) and I’ve seen others try, but whether they realize it or not, they’ve oscillated back and forth between Dr. Ling’s model and the conventional model.

Nonetheless the argument of "context" is not applicable to my first "fact check" where I challenged Dr. Peat's position regarding the role insulin assumes in the blood glucose regulation. Much of the work cited in defense of Dr. Peat is not only difficult to track down, but they can also by difficult to grasp and can be, at times, obscure to my conventionally-educated scientific mind. Yet, my position regarding Dr. Peat's quote on the role of insulin in the post I've been alluding to hasn't been successfully refuted, even given Dr. Ling's conception of cell physiology, but I'm still interested in having a thoughtful discussion about it in the comments section.

References

Randle, P. J., & Smith, G. H. (1958a). Regulation of glucose uptake by muscle. 1. The effects of insulin, anaerobiosis and cell poisons on the uptake of glucose and release of potassium by isolated rat diaphragm. The Biochemical journal, 70(3), 490–500. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1196696&tool=pmcentrez&rendertype=abstract

Randle, P. J., & Smith, G. H. (1958b). Regulation of glucose uptake by muscle. 2. The effects of insulin, anaerobiosis and cell poisons on the penetration of isolated rat diaphragm by sugars. The Biochemical journal, 70(3), 501–8. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1196697&tool=pmcentrez&rendertype=abstract

Roden, M. (2004). How free fatty acids inhibit glucose utilization in human skeletal muscle. News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society, 19, 92–6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15143200

Sakamoto, K., & Holman, G. D. (2008). Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. American journal of physiology. Endocrinology and metabolism, 295(1), E29–37. doi:10.1152/ajpendo.90331.2008

1 others in the field have confirmed this quality of cellular water.

2 PDH complex carries out the metabolism of pyruvate to acetyl CoA, a central point in all of metabolism that intertwines the oxidation of protein, fat, and carbohydrate.

Since the discovery of the so-called “glucose-fatty acid cycle” in 1963, there has been more and more evidence accumulating linking free fatty acids with diabetes (Randle, Garland, Hales, & Newsholme, 1963). Briefly, the glucose-fatty acid cycle describes a competition, whereby the use of glucose becomes impaired by the presence of fatty acids and, to a lesser extent, vice versa (Cook, King, & Veech, 1978).

Others had hinted at this fatty acid-induced blocking effect of sorts before. Among them, was a guy named Apollinaire Bouchardat, a French pharmacist, who gave his diabetic patients sweet fruit and bread made from gluten, and had good results. Others had applied Bouchardat’s dietary prescription and achieved equally good success. More recently, an English physician, William Budd, following on the heels of these pioneers, gave his diabetic patients around 8 ounces of sugar daily, with only the intent of slowing the cachexia that was characteristic of long-standing poorly controlled diabetes. Not only did most of his patients stop wasting away, but they also began to stop losing sugar in their urine when given this “saccharine treatment” (Hughes, 1862).

Another prominent clinician-researcher, Harold Himsworth, who was also first to show that insulin sensitivity in the tissues is reduced in diabetics, decades later, suggested, based on his clinical experiences and a review of the population data that high intakes of dietary fat (which raises free fatty acid levels) caused diabetes, and that diets rich in carbohydrates and low in fat were protective of it (Himsworth, 1934a, 1934b, 1936).

Kahn et al. thereafter, via multivariate analyses, in effect, reconfirmed the data that had been amassed by Himsworth, by showing that men who ate more sugar were less likely to develop diabetes later on than those who ate less of it—believe it or not (Kahn et al., 1971). By the 1980s, sugar had been pretty much exonerated from the diseases that were, speculatively, being assigned to it.

The experiences of these researchers are at odds with the conception firmly held by most contemporary clinicians and lay people, that diabetes is a disorder of having too much glucose or insulin in the blood. If this were the case, restricting carbohydrates or taking a drug that lowers blood glucose or insulin levels to normal, should be expected to change the course of diabetes 180 degrees.

The results of three relatively recent clinical trials, though far from perfect, softened the confidence in this approach. Briefly in the trials, older diabetics were assigned to receive either the standard of care or a more intensive regimen, in which blood glucose levels, by various means, were to be lowered to normal, or near-normal, levels for the purpose of reducing deaths from strokes and heart attacks. Taken together, more deaths were incurred from all causes in the subjects whose blood glucose levels were reduced to normality the most (Gerstein et al., 2008; Patel et al., 2008; Duckworth et al., 2009).

(The so-called “insulin-sensitizer” rosiglitazone immediately comes to mind, which now bears a black box warning about this increased cardiovascular risk.)

This begs the question, if carbohydrates and sugar are not the cause of diabetes, and if elevated levels of glucose and insulin aren’t either, ideas that have been bandied about among bloggers and very popular health- and diet-websites, what exactly is? Bearing in mind the incipient defect in diabetes—that is, insulin resistance—the glucose-fatty acid cycle that was previously described, and assimilating the clinical experiences of Bouchardat and others, we will first and foremost, turn to the enzyme complex pyruvate dehydrogenase (PDH) in exploring this question.

The PDH complex is a crucial enzyme that links the metabolism of glucose via glycolysis in the cytoplasm and via the Krebs cycle in the mitochondrion. I’ve discussed elsewhere that the major inhibition of glucose is taking place here, rather than at the shuttling of glucose into the cell through the plasma membrane, for instance (Randle & Smith, 1958a, 1958b).

Fatty acids, both directly and indirectly, inactivate the PDH complex, preventing the metabolism of glucose to carbon dioxide, whereas carbohydrates have the opposite effect. Diabetics generally have elevated levels of free fatty acids in the blood, and this accounts for many processes that go off the rails in them, including (1) an impaired ability to switch from one fuel source (e.g., fat) to another (e.g., glucose) and (2) a 2- to 4-fold increased risk of cardiovascular disease compared to non-diabetics.

The inhibition of the PDH complex prevents the metabolism of pyruvate to acetyl CoA, the point at which the metabolism of carbohydrate, fat, and protein converge (figure 1).

Figure 1 Overview of metabolism

This in turn, backlogs the glycolytic enzymes upstream of the PDH complex. As as a result, free glucose molecules accumulate in the cell, and following their concentration gradient, move back out into the bloodstream (Sonksen, 2001).

PDH is not only inhibited by fatty acids, but also by the products of their oxidation (Bowker-Kinley, Davis, Wu, Harris, & Popov, 1998). Conversely, glucose oxidation supplies pyruvate, which directly stimulates PDH activity, and activates (and increases the expression of) acetyl CoA carboxylase, an enzyme that puts a brake on fatty acid oxidation (Bouzakri et al., 2008) by way of generating malonyl CoA (figure 2). This latter process is referred to as a carboxylation reaction and as such, carbon dioxide, which is generated in greater amounts by glucose oxidation than fatty acid oxidation, pushes the reaction forward.

Figure 2 Malonyl CoA , generated from glucose oxidation, puts a "brake" on fatty acid oxidation.

PDH, which is highly regulated, is neither altered nor transcribed less abundantly. Instead, PDH is more likely being kept in an inactive state by various factors, namely the free fatty acids, ketone bodies, and lactate—the levels of which are elevated in diabetes, in accordance with the original experimental observations that led to the discovery o the glucose-fatty acid cycle (McCromack, Edgell, & Denton, 1982).

Though both fatty acids and glucose generate acetyl CoA, the similarities stop there.

For one, glucose oxidation reduces the oxygen costs of energy (ATP) generation, and ATP regulates, through mechanisms that are more speculative, the passage of glucose into cells. The oxidation of fatty acids consumes more oxygen than the oxidation of glucose does, and so leads to a lower oxygen tension therein.

The reduction in the oxygen tension in turn, stimulates the proliferation of fibroblasts that secrete collagen, and this newly laid collagen reduces the oxygen tension further by extending the distance by which oxygen has to diffuse to reach cells. The fibroblasts thereafter lay down more collagen and so on, in a typical positive feedback fashion, and this could eventually lead to greater degrees of atherosclerosis, as cholesterol, compared to other lipids, requires the greatest amount of oxygen for its oxidation.

Drugs that shift the preferential fuel use from fatty acids to glucose (some of which are in the pipeline) have been shown to be highly protective for diabetics and as a side effect, cardiovascular disease. This is because ATP is generated with a greater oxygen economy. Metabolic stress, which is elicited by the rapid depletion of ATP, can override the glucose-fatty acid cycle, in which case glucose would be converted to lactate rather than carbon dioxide (Bergeron et al., 1999; Young, Radda, & Leighton, 1996).

On the other hand, the currently used oral “hypoglycemic” drugs carry the unwanted side-effect of death from strokes and heart attacks (uncovered first in the 1970s by the University Research Diabetes Group)—events for which the task of lowering blood glucose levels was undertaken in the first place. (The evidence that these drugs [not insulin] protect against cardiovascular disease is also sparse.)

Two, the excessive delivery of fatty acids to tissues, as a protective reflex of sorts, increases the expression of uncoupling proteins therein, leading to a decreased generation of ATP (and the subsequent impaired functioning of tissues). In the pancreas, for instance, the increased expression of the uncoupling proteins, by depleting ATP, keeps the voltage-gated calcium channels closed, the opening of which is required for the secretion of insulin (figure 3) (Zhang et al., 2001).

Figure 3 The uncoupling proteins (UCP) are the means by which the electrons derived from glucose are dissipated as heat, rather than employed to generated ATP. ATP is needed to stimulate insulin secretion from the beta cells of the pancreas (Zhang et al, 2001).

Three, glucose oxidation, more than fatty acid oxidation, leads to a greater production of gas, carbon dioxide. The unloading of oxygen from red blood cells to tissues is blunted as a result (per the Bohr effect), further reducing the oxygen levels (figure 4). (This is reflected in the respiratory quotient.) Diabetics, as a rule, expire less carbon dioxide than non-diabetics do (Simonson, Tappy, Jequier, Felber, & DeFronzo, 1988).

Figure 4

Top: The deoxygenated state of hemoglobin is maintained by the cell's acidity (H+) namely through the production of carbon dioxide (CO2), which carboxylates the amine (NH2) groups on the hemoglobin proteins (not shown), enhancing their acidity, and so their ability to form salt linages with other positively-charged parts of the hemoglobin molecule. Hemoglobin's oxygen molecules are released to tissues as a result.

Bottom: The salt linkages (red squiggly lines) stabilize the deoxygenated state of hemoglobin (T structure). The loss of salt linkages allows hemoglobin to bind oxygen molecules with a greater affinity (R structure).

Four, a consequence inherent in a high rate of fatty acid oxidation is the buildup of fatty acid metabolites in the cell (such as ceramides and diacylglycerols), which ultimately impair the so-called “insulin receptor” via pathways that converge on the activation of protein kinase C (Erion & Shulman, 2010).

Five, a lower respiratory quotient goes along with a lower cellular energy charge, and this alone could explain many processes that go off the rails in diabetes. For instance, when the energy charge in the cell decreases, sodium moves into the cell (reducing sodium levels in the blood) and the cell’s ability to retain potassium diminishes. This could account for why diabetics have higher-than-average levels of aldosterone, the secretion of which, from the adrenal cortices, is triggered by falling sodium, or rising potassium, concentrations (figure 5) (Hollenberg et al., 2004; Kraus, Jäger, Meier, Fasshauer, & Klein, 2005; Maalouf, Cameron, Moe, & Sakhaee, 2010).

Figure 5 Regulation of aldosterone (Aldo) secretion by potassium (K+) and sodium (Na+) levels in the blood.

Aldosterone is linked to many adverse consequences, including inflammation, vascular problems, loss in insulin sensitivity, and the replacement of healthy tissue with scar tissue. Lo and behold, drugs that antagonize the aldosterone (mineralocorticoid) receptors have been shown to slow the progression of diabetic complications (Bender, McGraw, Jaffe, & Sowers, 2013). The effects of aldosterone are at odds with those of insulin, in that insulin has a pro-metabolic effect, whereas aldosterone has an anti-metabolic effect.

Six, fatty acid oxidation increases the tendency for lactate and protons to accumulate, both of which are elevated in parallel with free fatty acids, and in obesity and diabetes (Chen, Varasteh, & Reaven, 1993; Reaven, Hollenbeck, Jeng, Wu, & Chen, 1988). Lactate, like free fatty acids, interferes with insulin signaling, reinforcing the insulin resistant state (Choi et al., 2002; Depré, Veitch, & Hue, 1993).

And seven, it’s conceivable that the excessive oxidation of fatty acids, especially against the backdrop of oxidative stress, could impair the functioning of tissues further through the generation of advanced glycation end (AGE) products from acetone (namely through its conversion to methylglyoxal) produced as a result of high rates of fatty acid oxidation in the liver. (Credit goes to Dr. Chris Masterjohn for providing clarification on this for me.) Hyperglycemia, it turns out, could assume a secondary, or permissive, role in this process.

So in summary, it’s my contention that the excessive mobilization and oxidation of fatty acids—a signature of sorts of the diabetic metabolism— impairs insulin actions, primarily by way of inhibiting the PDH complex (Koves et al., 2005). Simply put, when free fatty acid levels are elevated, the metabolism of glucose to carbon dioxide becomes impaired, and glucose is rerouted to lactate instead. This has important implications for the cardiovascular disease—of which, to recap, diabetics have an increased risk of.

So, in my roundabout way, how does this translate to recommendations that you could start applying now if you are diabetic or trending towards it? This isn’t my area of expertise and, really, others elsewhere have done a good job in this regard.

Nonetheless, tentatively, I would recommend, in no particular order, to (1) supplement with vitamin B1 (cofactor of the PDH complex) and (2) magnesium (helps retain ATP in the cell), (3) eat sugar as in fruit in preference to starches as in grains and tubers, (3) reduce excess body fat if you have it, and replace it with muscle, which serve as sinks for free fatty acids, (4) reduce the fat in the diet and replace them with carbohydrates and protein, keeping calories more or less the same. (I’ve found, and most dieters knows, that the loss of muscle occurs long before the fat stores become depleted, which is why carbohydrates are superior to fat during periods of weight loss, as carbohydrates are strongly anabolic), (5) opt for small meals over large ones in order to maintain steadier blood glucose levels over the course of a day, and (6) de-stress as much as possible by, for instance, getting into the habit of creating and writing down plans for how you will get an A on an upcoming exam, cope with a major life change, complete a paper, win an argument, etc. This can be more powerful than executing the plan itself . . . it has been for me at least.

REFERENCES

1. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–9 (1963).

2. Cook, G. A., King, M. T. & Veech, R. L. Ketogenesis and malonyl coenzyme A content of isolated rat hepatocytes. The Journal of biological chemistry 253, 2529–31 (1978).

3. Hughes, J. Quarterly summary of the improvements and discovereis in the medical sciences. The American Journal of the Medical Sciences 44, 232–235 (1862).

4. Himsworth, H. P. Dietetic factors influencing the glucose tolerance and the activity of insulin. The Journal of physiology 81, 29–48 (1934).

5. Himsworth, H. P. Management of diabetes mellitus. British medical journal 2, 137–41 (1936).

6. Himsworth, H. P. High carbohydrate diets and insulin efficiency. British medical journal 2, 57–60 (1934).

7. Kahn, H. A. et al. Factors related to diabetes incidence: a multivariate analysis of two years observation on 10,000 men. The Israel Ischemic Heart Disease Study. Journal of chronic diseases 23, 617–29 (1971).

8. Gerstein, H. C. et al. Effects of intensive glucose lowering in type 2 diabetes. The New England journal of medicine 358, 2545–59 (2008).

9. Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. The New England journal of medicine 358, 2560–72 (2008).

10. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. The New England journal of medicine 360, 129–39 (2009).

11. Randle, P. J. & Smith, G. H. Regulation of glucose uptake by muscle. 1. The effects of insulin, anaerobiosis and cell poisons on the uptake of glucose and release of potassium by isolated rat diaphragm. The Biochemical journal 70, 490–500 (1958).

12. Randle, P. J. & Smith, G. H. Regulation of glucose uptake by muscle. 2. The effects of insulin, anaerobiosis and cell poisons on the penetration of isolated rat diaphragm by sugars. The Biochemical journal 70, 501–8 (1958).

13. Sonksen, P. H. Insulin, growth hormone and sport. The Journal of endocrinology 170, 13–25 (2001).

14. Bowker-Kinley, M. M., Davis, W. I., Wu, P., Harris, R. A. & Popov, K. M. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. The Biochemical journal 329 ( Pt 1, 191–6 (1998).

15. Bouzakri, K. et al. Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes 57, 1508–16 (2008).

16. McCormack, J. G., Edgell, N. J. & Denton, R. M. Studies on the interactions of Ca2+ and pyruvate in the regulation of rat heart pyruvate dehydrogenase activity. Effects of starvation and diabetes. The Biochemical journal 202, 419–27 (1982).

17. Bergeron, R. et al. Effect of AMPK activation on muscle glucose metabolism in conscious rats. The American journal of physiology 276, E938–44 (1999).

18. Young, M. E., Radda, G. K. & Leighton, B. Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR--an activator of AMP-activated protein kinase. FEBS letters 382, 43–7 (1996).

19. Chan, C. B. et al. Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 50, 1302–10 (2001).

20. Zhang, C. Y. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105, 745–55 (2001).

21. Simonson, D. C., Tappy, L., Jequier, E., Felber, J. P. & DeFronzo, R. A. Normalization of carbohydrate-induced thermogenesis by fructose in insulin-resistant states. The American journal of physiology 254, E201–7 (1988).

22. Erion, D. M. & Shulman, G. I. Diacylglycerol-mediated insulin resistance. Nature medicine 16, 400–2 (2010).

23. Hollenberg, N. K. et al. Plasma aldosterone concentration in the patient with diabetes mellitus. Kidney international 65, 1435–9 (2004).

24. Kraus, D., Jäger, J., Meier, B., Fasshauer, M. & Klein, J. Aldosterone inhibits uncoupling protein-1, induces insulin resistance, and stimulates proinflammatory adipokines in adipocytes. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme 37, 455–9 (2005).

25. Maalouf, N. M., Cameron, M. A., Moe, O. W. & Sakhaee, K. Metabolic basis for low urine pH in type 2 diabetes. Clinical journal of the American Society of Nephrology : CJASN 5, 1277–81 (2010).

26. Bender, S. B., McGraw, A. P., Jaffe, I. Z. & Sowers, J. R. Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease? Diabetes 62, 313–9 (2013).

27. Chen, Y. D., Varasteh, B. B. & Reaven, G. M. Plasma lactate concentration in obesity and type 2 diabetes. Diabète & métabolisme 19, 348–54 (1993).

28. Reaven, G. M., Hollenbeck, C., Jeng, C. Y., Wu, M. S. & Chen, Y. D. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 37, 1020–4 (1988).

29. Depré, C., Veitch, K. & Hue, L. Role of fructose 2,6-bisphosphate in the control of glycolysis. Stimulation of glycogen synthesis by lactate in the isolated working rat heart. Acta cardiologica 48, 147–64 (1993).

30. Choi, C. S. et al. Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling. American journal of physiology. Endocrinology and metabolism 283, E233–40 (2002).

31. Koves, T. R. et al. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. The Journal of biological chemistry 280, 33588–98 (2005).

It’s refreshing to see people beginning to think clearly and rationally and move away from gimmicky diets that have little basis in fact, reality, or objectivity, and to ones that are firmly seated in all aspects of human physiology and science.

After all, this is why most of us choose to eat a certain way, that is to be as healthy as we can be, both physically and mentally . . . not to, say, replicate how our caveman ancestors supposedly ate and lived.

It’s due to this line of reasoning that carbohydrates, and especially sugar and fructose, have fallen by the wayside of late, driven by an irrational fear, bordering on obsessiveness, that’s evolved to where sugar is now conceived of as a toxic poison and blamed for causing diabetes, cancer, obesity, gout, etc. (Thank you Dr. Lustig.)

It’s important to point out that sugar is used by virtually every cell in the body to generate energy, or ATP. The brain is especially reliant on glucose for optimal functioning: The brain represents only 2 percent of the body’s total weight yet accounts for 15 percent of the body’s total energy expenditure. ¹ Indeed, the brain is a voracious sugar guzzler, and sugar, not ketone bodies, is its preferred fuel source, despite popular discourse to the contrary. Insulin and sugar make us smarter ² so it stands to reason that ketosis has the opposite effect.

The oxidation of sugar, compared to the oxidation of fatty acids, generates ATP with a greater efficiency and oxygen economy. The excessive oxidation of fatty acids explains many of the processes that go off the rails in conditions like diabetes, in which diabetics are forced to burn fatty acids in proportion to their degree of insulin resistance.

ATP is synonymous with life, and the efficiency and intensity with which we produce it is at the core of our resistance to stress and illnesses.

Figure 1 Structural representation of the ATP molecule, which consists of, from the left, an adenine ring, a ribose sugar, and three phosphate groups. The so-called high-energy bond is the bond between the two terminal phosphate groups. ³

I think most people are aware of the molecule, ATP, as it relates to providing energy in the form of high-energy phosphate bonds for nearly every energy-requiring process in the body.

However, it’s becoming clear to more and more people that the energy gained from splitting the terminal high-energy phosphate bond is less than that gained from ATP simply sitting on its receptor sites on proteins inside cells. What is more, ATP, under resting conditions, needn’t be continuously broken down and rebuilt to maintain an unequal distribution of ions and solutes across the plasma membrane, and thus the volume and shape of cells and other subcellular structures. ATP, in its native state, is also now recognized as a neurotransmitter, growth factor, membrane depolarizer, pain perception mediator, nerve cell protector, cancer fighter, and intracellular signaling molecule (discussed later).

Consider what would happen in the absence, or even reduced concentrations, of ATP, at the most basic level. The intracellular proteins, in the absence of ATP, would reassume their default, tangled form from their linear, extended form when ATP is bound. Cells would, as a result, no longer be able to exclude the passage of solutes, ions, and water, and in turn the cells would lose the ability to regulate their size, shape, and structure, resulting in their swelling, injury, or death—all initiated by the loss, or reduced generation, of ATP.

Figure 2 Depicted above is an intracellular (or mitochondrial) protein molecule in its default, tangled state (i.e., without ATP) maintained by intramolecular salt linkages and hydrogen bonds. In this case, cells lose the ability to regulate water and thus, their size, shape, and structure, ultimately resulting in swelling, injury, or death.⁴

It’s now firmly established (though the idea was resisted for decades) that the ATP molecule itself functions as a neurotransmitter in the central, peripheral, and enteric nervous systems. In the brain and spinal cord, for instance, ATP regulates the communication among neurons and between neurons and support cells called glia. In the intestines, ATP, which is released by nerve cells that permeate the digestive tract, stimulates rhythmic contractions therein and prompts the secretion of the digestive juices and enzymes.⁵

Inside the cell, acting as a signaling transducer, ATP closes the potassium channels, and this has important effects that range from controlling the smooth muscle contractions of blood vessels to the secretion of insulin by the pancreas; ⁶ in the bones, activation of the ATP receptors stimulates the bone-building cells and inhibits the bone-destroying cells; and in the skin, the ATP receptors regulate the normal turnover of skin cells, so as to maintain the normal regeneration and healing of skin.

One factor that stimulates ATP generation at high rates is the pro-metabolic hormone, insulin. Insulin is needed to metabolize glucose oxidatively, without which glucose would be converted, anaerobically, to lactate. Lactate, like free fatty acids, interferes with the oxidative metabolism of glucose.

Figure 3 Fates of pyruvate. The generation of acetyl CoA, via PDH, generates carbon dioxide and leads to respiration; the generation of lactate, via LDH, is fermentation. Pyruvate is reduced to lactate when the PDH complex is inhibited as in when fats are burnt excessively.

Insulin was, to the famous cancer researcher and Nobel laureate, Otto Warburg, a factor that checked the growth of tumors, and in the absence of insulin, glucose would promote it.⁷ It is now clear that insulin exerts this anti-carcinogenic effect by activating the enzyme complex, pyruvate dehydrogenase (PDH), which represents the bridge between glycolysis and the Krebs cycle. Cancer cells are defined, according to Warburg, by their large reliance on fermentation, via glycolysis, because respiration is injured or impaired, resulting in an energy deficiency.

If we were to accept the theory of Warburg and others, that a high efficiency of energy generation determines structure, and that structure in turn, namely of the protein complexes of the respiratory chain, determines how we produce energy—via respiration or fermentation—then, glucose, oxygen, and insulin are the fundamental factors that make up the provision of support against cancer formation.

Warburg also noted that the availability of blood sugar (in the presence of insulin) had no effect on the growth or survival of tumors, and so restricting sugar in hopes of staving off cancer is as fruitless an endeavor as restricting cholesterol to prevent cardiovascular disease, or restricting calcium to slow the progression of pathological calcification processes in the arteries, and so on.

ATP interacts and binds directly to the inner mitochondrial membrane, maintaining the protein complexes therein in a fully extended, water-polarizing state, as alluded to above. (As an aside, caloric restriction, or maintaining a high metabolism keeps, helps to maintain the mitochondrial respiratory chain in a “delicately poised state,” that is between the fully oxidized and fully reduced state.)

Figure 4 The carboxyl group (COO^-) selectively binds to potassium (K⁺) when the protein is extended by the presence of ATP.⁴ It’s been shown that the loss of respiratory control parallels the loss of potassium, after which respiration comes to an abrupt halt.⁴ ATP and magnesium are needed to maintain K⁺ in its adsorbed state on proteins, so magnesium and ATP are co-cardinal adsorbents, if you will, and work together to maintain the respiratory chain.

When the mitochondria are highly reduced, such as when an increased energy supply is unmatched by a proportional increase in energy demands or when fatty acids are burnt excessively or when oxygen availability declines, the proteins in the respiratory chain can no longer maintain their fully extended conformation, and as a result potassium and ATP are squeezed out of the mitochondria and are lost, and reactive oxygen species (ROS) are generated in high amounts. With this loss of ATP, the respiratory chain, in turn swells and destabilizes, and in conjunction with the increase in ROS, energy generation becomes impaired, reducing ATP availability further.

Ultimately, the structure of the respiratory chains would be incrementally lost, and the cells would, like yeast, begin to rely more and more on fermentation—the enzymes for which are found freely in the cytoplasm—for energy. Herein we see that there is a strong association between respiration with structure and a lack of association between fermentation with structure.

In addition to ATP, ubiquinone (a.k.a. CoQ₁₀), NAD⁺, and iron (found in the cytochromes and iron-sulfur proteins) function as cardinal adsorbents in the mitochondrial respiratory chain. Essentially, these cardinal adsorbents, upon gaining or losing electrons, via long-range electronic effects, allow the shift in the preferential adsorption of one ion over another by the ATP generating enzyme, ATPase, as the ATPase enzyme is linked, electronically, to the entire respiratory chain.

Figure 5 ATPase shown structurally and cooperatively linked to the respiratory chain along the inner mitochondrial membrane.

With the exception of magnesium and NAD⁺ (made from vitamin B₃ [niacin]), diets are usually adequate in terms of supplying the nutrients that function as cardinal adsorbents in the mitochondria. Bear in mind that cholesterol lowering drugs known as statins inhibit the synthesis of ubiquinone. So if you’re taking a statin, like tens of millions currently are, consider supplementing with ubiquinone (at around 100 to 200 mg daily) to replace what is being depleted.⁸(This is probably why statins have been linked to an increased incidence of cancer and cancer deaths in some studies.)

The structure of ubiquinone resembles that of vitamins K and E, so it’s conceivable that in the absence of ubiquinone, vitamins K and E could stand in its place. (Credit goes to Heath Kurra for making me aware of this.)

One of the potential diabetes drugs I’ve come across in my research is the halogenated carboxylic acid, dichloroacetate (DCA), which, as a side effect, suppresses the growth of tumors. DCA works by activating the previously mentioned PDH complex, thereby enabling the oxidative metabolism of glucose. Currently, DCA is used to lower lactate levels in children with congenital lactate acidosis (with great success) ⁹ but it turns out that DCA could open up a new way of treating cancers, that is metabolically per Warburg’s hypothesis.¹⁰ Furthermore, metformin, probably the most widely used and successful diabetes drug of all time, is currently under investigation for use in the prevention of breast cancer.¹¹

(I suspect that DCA could function as a cardinal adsorbent in the cell, just like ATP and magnesium do.)

Upon the continual replacement of respiration by fermentation, as the cells divide, the once highly differentiated cells in the body fail to develop and the looser the connection between structure and energy generation becomes. This is, according to Warburg, what cancer really is: A last ditch effort by cells to generate energy, by any means possible, in order to compensate for the energy lost by way of respiration because if energy generation were to fall below a certain minimum that is needed by the cell unconditionally, the cell would die.

Sugar is beginning to be seen in a different light of late for reasons that I don’t fully understand by those who in the recent past, firmly held that sugar was a toxic poison. But sugar was already exonerated in the 1980s by major health organizations from the degenerative diseases that were being, speculatively, assigned to it.

In reality, sugar, in the form of fruit promotes respiration and, in part through insulin, is protective against diabetes and cancer. Fruit supplies other nutrients that support respiration, including magnesium, potassium, vitamin B₁, and vitamin c, which also promotes the absorption of iron in the intestines. Carbohydrates, in general, suppress the liberation of fatty acids and amino acids, and inhibit the production of ketone bodies and glucose in the liver, all of which prevent the oxidative metabolism of glucose, via the PDH complex, and interfere with the "delicately poised state" of the mitochondrial respiratory chain. Fructose, present in fruit but not starches, stimulates the synthesis of cholesterol more than any other single nutrient, and this means that ubiquinone would almost assuredly be produced in the amounts needed by cells.

Sugar (e.g., candy, soda, pure cane sugar, etc.) can be eaten in small or modest amounts, but the lion’s share of one’s sugar should, ideally, come from fresh, ripe, organic fruit and fruit juices for the nutrients listed above. Losing excess body fat, if you have it, also tends to promote respiration, partly by lowering free fatty acids.

Diets that are high in fat are not necessarily incompatible with a high rate of energy generation by way of the oxidative metabolism of glucose. (Though I do think high fat dieters, in most cases, are living on the edge of subsistence in this regard.) Caloric restriction, paradoxically, does not result in a decreased rate of respiration or metabolism when measured per lean mass.^12,13

To conclude, the generation of ATP supports respiration, and the rapid use of ATP without a proportional increase in ATP generation results in an increased reliance on fermentation, which can only support a primitive type of life; that is, one that supports growth without development.

Insulin, glucose, and oxygen are at the core of our resistance to stress and illnesses. There are issues inherent in the excessive oxidation of fatty acids in preference to glucose, the reasons for which are beyond the scope of this post. (Though Danny Roddy explains it here.) However, suffice to say, glucose oxidation, more than fatty acid oxidation, supports a highly energized cellular state, per Dr. Gilbert Ling’s vision of cell physiology, and this in turn establishes a firmer connection between energy generation and structure, allowing cells—and by extension people—to exist at the highest possible state of functioning, refinement, complexity.

References

1. Guyton A, Hall J. Textbook of Medical Physiology. 11th ed. Saunders; 2006:1104.

2. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326–34. doi:10.1016/j.psyneuen.2004.04.003.

3. Szent-Györgyi A. Bioenergetics. New York: Academic Press Inc. 1957.

4. Ling GN, Ochsenfeld MM. A historically significant study that at once disproves the membrane (pump) theory and confirms that nano-protoplasm is the ultimate physical basis of life--yet so simple and low-cost that it could easily be repeated in many high school biology classrooms. Physiological chemistry and physics and medical NMR. 2008;40:89–113. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20070042.

5. Burnstock G. Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. BioEssays : news and reviews in molecular, cellular and developmental biology. 2012;34(3):218–25. doi:10.1002/bies.201100130.

6. Burnstock G, Krügel U, Abbracchio MP, Illes P. Purinergic signalling: from normal behaviour to pathological brain function. Progress in neurobiology. 2011;95(2):229–74. doi:10.1016/j.pneurobio.2011.08.006.

7. Warburg O, Wind F, Negelein E. the Metabolism of Tumors in the Body. The Journal of general physiology. 1927;8(6):519–30. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2140820&tool=pmcentrez&rendertype=abstract.

8. Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Molecular aspects of medicine. 1994;15 Suppl:s187–93. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7752830. Accessed March 13, 2013.

9. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate. Archives of disease in childhood. 1997;77(6):535–41. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1717417&tool=pmcentrez&rendertype=abstract. Accessed March 3, 2013.

10. Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Frontiers in oncology. 2013;3:38. doi:10.3389/fonc.2013.00038.

11. Taubes G. Cancer Prevention With a Diabetes Pill ? 2012;335(January):2012.

12. McCarter RJ, Palmer J. Energy metabolism and aging: a lifelong study of Fischer 344 rats. The American journal of physiology. 1992;263(3 Pt 1):E448–52. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1415524. Accessed October 16, 2012.

13. McCarter RJ, Herlihy JT, McGee JR. Metabolic rate and aging: effects of food restriction and thyroid hormone on minimal oxygen consumption in rats. Aging (Milan, Italy). 1989;1(1):71–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2488303. Accessed October 16, 2012.

I recently read on the interwebz that fish oil lowers triglyceride levels in the blood by depositing them in the arteries. I have known about this triglyceride lowering effect, and whether I should be taking fish oil as a supplement as is recommended by major health organizations, alternative health practitioners, and my mom.

As a whole, I think the clinical trial evidence for fish oil for the prevention and treatment of cardiovascular disease, especially of late, have been disappointing, to say the least, and this goes for the other conditions for which fish oil has been, for years now, said to benefit. Fish oil does in reality lower triglycerides but what is the trade-off?

Studies like this one by Angerer et al., for instance, in which subjects who were randomized to receive fish oil—1.65 grams of omega-3 fatty acids per day— or a placebo demonstrated, after two years, a greater degree of atherosclerosis in the carotid arteries of the subjects who had received fish oil compared to those who had received a placebo.¹

The presence of highly reactive methylene groups renders PUFA highly susceptible to peroxidation processes, and the more double bonds a PUFA molecule has, the greater the chance becomes. As an example, DHA and EPA are more susceptible than arachidonic acid (AA), which are both more susceptible than linoleic acid (LA) and alpha linolenic acid (ALA) to lipid peroxidation processes.

PUFA can peroxidize and decompose in the blood and in cell membranes (in which they're found in phospholipids), though they're probably protected more in the membranes than in the blood.² A certain amount of PUFA in membranes seems to be needed for physical and signaling purposes.

The accumulation of AGE and PUFA decomposition products, namely those derived from LA and AA, are potent risk factors for cardiovascular disease. Although I don’t think omega-3 fatty acids are necessarily deleterious in any and all amounts, I do think that with respect to the previously mentioned cardiovascular risk factors, we should regard omega-3 fatty acids no differently as we do omega-6 fatty acids, as all PUFA, because of the presence of said reactive methylene groups, can undergo peroxidation processes. (Funnily, omega-3 fatty acids are the worst in this regard.)

The LDL particle contains a large “lipid core” composed primarily of cholesterol esters. A cholesterol ester is composed of a cholesterol molecule that is attached to a fatty acid molecule, the identity of which is determined, primarily, by the types of fats and oils we eat. In humans, the predominate fatty acid present in cholesterol esters is LA³; herein is where the action lies.

Each component of the cholesterol ester can undergo oxidation reactions: Cholesterol tends to form epoxides, whereas LA is further oxidized to hydroxyoctadecadienoic acid (HODE). HODE itself is a potent promoter of inflammation, activator of PPAR-γ, and stimulator of IL-1β release from white blood cells.

HODE bearing LDL particles can be taken up, via LDL receptors, into cells, thereby initiating degenerative processes therein. Oxidative processes such as these accumulate in vascular tissue with aging. This is clear. If LA, whose only source is our diets, is the principle source of oxidative products in LDL particles, then the recommendation to replace saturated fats — which can’t be oxidized like PUFA can — for LA containing oils may have been worse than it has been recently described.⁴

Although cholesterol can oxidize and decompose to toxic byproducts, oxidized LA is much more abundant than oxidized cholesterol is in LDL particles, so the focus on cholesterol by major health organizations is probably misplaced. Simply put, oxidized LDL is toxic, and the PUFA, not the cholesterol, found therein is what is predominantly oxidized. LA and its oxidation products predominate in atherosclerotic plaques as determined by analyses of samples of these plaques with HPLC followed by gas chromatography techniques.⁶ (Palmitate, surprisingly, is found in nearly equally high amounts.)

The LA peroxidation products can also glycate the lysine residues found in the LDL particle itself, namely apolipoprotein E, a protein whose function is to bind to the LDL receptor. In the absence of functional apolipoprotein E, LDL particles are instead taken up by white blood cells (macrophages), which take up modified LDL particles, seemingly without limit, after which they are ultimately deposited as plaques in the arteries.⁵

Across taxa, the membrane peroxidizability index correlates with maximum lifespan years.⁷ This has been proposed as the main mechanism by which caloric restriction extends lifespan⁸, and is probably due to the slight decrease in thyroid hormone and insulin levels in the blood of those who embark on eating less food, as insulin and thyroid hormone modulate the activity of the desaturase enzymes. In mice, this is associated with mitochondrial synthesis and an increased production of ATP.⁹

Although I try to keep PUFA in my diet as low as possible, I will, every so often, eat a fat slab of oily fish, a handful of cashews, and even junk food that contains seed oils. I don’t think it’s necessary to avoid these foods because of the presence of small amounts of PUFA in them as there are other factors in our diets that counteract their potentially harmful effects. Also, the composition of fats we eat is not the sole determinant of our susceptibility to lipid peroxidation processes. And on top of that, we have the ability to remove these toxic lipid peroxidation products after they form. So stressing about consuming a small amount of PUFA would be kind of, sort of, neurotic.

It should be borne in mind that the studies in which omega-3 fatty acids have been shown to be either ineffective or harmful employ omega-3 fatty acid supplements. . . . I think there is a good possibility that omega-3 fatty acid containing foods would have a different effect, and I don't think there is enough cause to rigorously avoid them.

REFERENCES

1. Angerer, P., Kothny, W., Störk, S. & Von Schacky, C. Effect of dietary supplementation with omega-3 fatty acids on progression of atherosclerosis in carotid arteries. Cardiovascular research 54, 183–90 (2002).

2. Spiteller, P., Kern, W., Reiner, J. & Spiteller, G. Aldehydic lipid peroxidation products derived from linoleic acid. Biochimica et biophysica acta 1531, 188–208 (2001).

3. Berg, J. M., Tymoczko, J. L. & Stryer, L. Biochemistry. 1026 (W. H. Freeman: 2006).

4. Ramsden, C. E. et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ (Clinical research ed.) 346, e8707 (2013).

5. Steinbrecher, U. P. Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. The Journal of biological chemistry 262, 3603–8 (1987).

6. Waddington, E., Sienuarine, K., Puddey, I. & Croft, K. Identification and quantitation of unique fatty acid oxidation products in human atherosclerotic plaque using high-performance liquid chromatography. Analytical biochemistry 292, 234–44 (2001).

7. Pamplona, R. et al. Mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals. Journal of lipid research 39, 1989–94 (1998).

8. Hulbert, a J. Metabolism and longevity: is there a role for membrane fatty acids? Integrative and comparative biology 50, 808–17 (2010).

9. Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science (New York, N.Y.) 310, 314–7 (2005).

Please bear with me for this one, as I want to address a comment that was left on my blog regarding fish, namely how it exerts its beneficial effects. Apparently, the folks over at PHD believe fish oil is beneficial by way of hormesis, which is the idea that the exposure to small doses of a toxin fortifies our resistance to it upon subsequent exposures.

In the case of fish oil, the previously mentioned decomposition products, derived mainly from DHA and EPA hydroperoxides, are the toxins that elicit hormetic responses. Toxic in themselves, these lipid hydroperoxides are the starting material for a host of highly toxic decomposition products, including 4-hydroxyhexenal (4-HHE), which is the one that is usually evoked to discuss the potentially beneficial hormetic effect of fish oil.

4-HHE corresponds to 4-hydroxynonenal (4-HNE), which is generated from linoleic acid (LA) and arachidonic acid (AA). Compared to 4-HNE, there have been fewer studies conducted with respect to the toxicity of 4-HHE. However, I think it would be reasonable to assume, given their structural similarities, that 4-HNE and 4-HEE would produce similar effects in the body. (2-hydroxyheptanal, also derived from LA, has similar effects to 4-HNE.) Regardless, 4-HNE can be, and is probably, produced from EPA and DHA as well.¹

4-HNE is highly reactive and highly toxic, plain and simple. It’s also physiologically relevant because LA and AA are the major PUFA found in mammalian tissue, especially in phospholipids and lipoproteins. Aldehydes like these, and their oxidation products, like oxime and pyrazoline, have been found to accumulate in old age,² atherosclerosis, and inflammatory conditions like rheumatoid arthritis.³

It’s interesting to me that 4-HEE, which belongs to the same class of molecules as 4-HNE, is now being postulated to be primarily responsible for the cardioprotective effects of fish oil. (In my opinion, which may mean nothing to you, this explanation has arisen in response to realization that much of the fish oil sold and found in the body is already rancid.) 4-HNE, as I alluded to in my last blog post, is found in LDL particles and it is by this route that 4-HNE becomes deposited in atherosclerotic plaques.⁴

These aldehydes are also potent glycators of amine groups found in certain lipids and amino acid residues of proteins. Glycation, or more precisely the formation of a Schiff base, is the first step in the generation of advanced glycation end products (AGE), and they are formed from both glucose and PUFA, despite what internet diet experts would have you to believe. Diabetics, who suffer from higher rates of AGE generation than nondiabetics do, have been found to have high levels of these precursor lipid peroxidation products.⁵

EPA and DHA, immediately upon their ingestion, become incorporated into tissue lipids, including cardiolipin. Cardiolipin is a special phospholipid found only in the inner mitochondrial membrane, and it is closely tied to the efficiency with which we produce energy, or ATP: the higher the cardiolipin saturation index, the lower the proton conductance, and the more ATP we produce. What is more, a higher saturation index renders mitochondria highly resistant to damage by free radicals and reactive oxygen species (ROS), including those produced by fish oil, and is associated with lower levels of ROS in vivo. (Hormesis is not needed.)

Caloric restriction increases the saturation index of membranes, namely by downregulating the expression and decreasing the activity of the desaturase enzymes, resulting in a higher ratio of LA to AA and ALA to DHA and EPA. This is the main mechanism by which caloric restriction exerts its beneficial effects. Taking fish oil in hopes of inducing a questionably beneficial hormetic effect, by raising the concentration of EPA and DHA in membranes, would produce the exact opposite effect.

As to hormesis, I don’t think we need to add to our, already high, free radical burden. In fact, in mammals, low levels of cellular ROS are associated with the highest maximum lifespan years, for a given metabolic rate. Further, these reactive PUFA oxidation products are detected in even young, healthy tissue, albeit in smaller amounts than in those that are old or diseased.

I could enumerate the systematic reviews, published just this year, showing, one after another, the lack of beneficial effects of fish oil supplementation for the various conditions that fish oil, for years, has been promoted to help. But, you could do that on your own, and I’m pressed for time as it is. (I have no business writing this post.) Thankfully, save for this egregious example, people haven’t been recommending to take large doses of this stuff.

In closing, the people who recommend to take fish oil and to eat lots of fish to increase our long-chain omega-3 intakes are the same people who promote ancestral diets. Yet, a substantial amount of people throughout human history have had to rely on land-foods, not fish, so their omega-3s would have been coming ALA, not EPA and DHA. Nonetheless, as I stated in my previous post, small amounts of whole oily fish is probably benign, as whole fish, for instance, contains potent lipid peroxide scavengers called furan fatty acids.⁶

References

1. Beckman, J. K., Howard, M. J. & Greene, H. L. Identification of hydroxyalkenals formed from omega-3 fatty acids. Biochemical and biophysical research communications169, 75–80 (1990).

2. Sawada, M. & Carlson, J. C. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mechanisms of ageing and development41, 125–37 (1987).

3. Muus, P., Bonta, I. L. & Den Oudsten, S. A. Plasma levels of malondialdehyde, a product of cyclo-oxygenase-dependent and independent lipid peroxidation in rheumatoid arthritis: a correlation with disease activity. Prostaglandins and medicine2, 63–5 (1979).

4. Berliner, J. A. et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation91, 2488–96 (1995).

5. Sato, Y. et al. Lipid peroxide level in plasma of diabetic patients. Biochemical medicine21, 104–7 (1979).

6. Spiteller, G. Furan fatty acids: occurrence, synthesis, and reactions. Are furan fatty acids responsible for the cardioprotective effects of a fish diet? Lipids40, 755–71 (2005).

The red meat-carnitine study¹ has made the rounds on the interwebz and many a blogger has had an opportunity to thoroughly deconstruct it, and, as usual, the data presented in the study did not, in any way, warrant the sensationalism and conclusion—that the consumption of red meat could lead to heart disease on the basis of its carnitine content—drawn by the press and media. (Though, the distinction that having “healthy” gut flora as opposed to normal or unhealthy would inhibit the conversion of carnitine to TMAO is lost on me.)

It was an easy one to swat down, but what was interesting to me was the fervor and vitriolic, yet laser sharp, scrutiny (and of course, all wrapped up with the obligatory pleas for critical thinking), with which this particular study was jumped on by the Paleo diet community in the defense of their sacred cow: red meat.

The inverse relationship between the quality assessment of a study and confirmation bias is ever present in science, and not necessarily wrong, but members of diet movements tend to take it to a level that ends up making me feel uncomfortable and nauseous. It's simply human nature to scrutinize studies that tend to disagree with our preconceived beliefs more intensely than those that tend to agree with them, but this bias rears its ugly head so often and so blatantly in the Paleosphere so as to be reprehensible.

Don't get me wrong, the reporting of the aforementioned red meat study was abominable, and the critiques of it that I have had a chance to read have been clear, unequivocal, and spot on (especially this one).

The point that I'm trying to call attention to is that when we push, or try to push, our philosophy to its ultimate conclusion, we end up moving beyond the realm of science and into the land of religion, and so far as my observation and experience go, this is precisely what diet movements end up becoming. We should strive to be as critical of the studies that agree with our beliefs as we are of the ones that don’t.

Skepticism is admirable, especially when applied to studies that get blown out of proportion, like this one. But so too is the ability to think clearly, and we should be equally cautious as to not allow our skepticism carry us away to where we begin to willfully, recklessly, or unreasonably discredit evidence that contradicts our established beliefs. However, when there are intellectual or financial interests, or issues of credibility at stake, guarding against this from happening becomes more and more difficult to do. I'm an optimistic person, but the times are full of ominous signs and warnings with the introduction of things like this, and the rise of neurotic Internet diet "authorities."

Anyway, without further ado, per Charles Grashow's request, here is what I ate today. I think I’m done eating.

correction: there were mistakes on the first food list that are now fixed (I also drank another can of soda and ate a marshmallow)

REFERENCES

1. Koeth, R. A. et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature medicine (2013).doi:10.1038/nm.3145

INTRODUCTION

I’ve been paying much more attention to the human intestinal microbial landscape because of the red meat-carnitine study, and more recently, this one. There is a growing body of compelling evidence linking the types of bacteria that colonize our intestines, and therefore the types of toxins we are exposed to, and our risk of diseases that include obesity.

I’ve written about this before, namely with respect to the gram-negative bacterial toxin, lipopolysaccharide (LPS), as it relates to physical attractiveness, as well as the apparent beneficial metabolic effects of sterilizing the intestines of all microbial life.

I don’t want to dwell on this matter, but I do want to try to delve further into the intricacies of the topic and the evidence in which many of the suppositions are based, and towards the end, shed light on some pathways that open up possibilities for intervention.

ENDOTOXIN: A BACTERIAL TOXIN

Certain intestinal bacteria (gram-negative) have an outer cell wall component called LPS. Unlike other bacterial toxins, LPS is not secreted, but is instead released by bacteria upon their destruction or death.

LPS is predominantly taken into the body from the intestines, via newly made chylomicrons, subsequently reaching the bloodstream, whereupon coming into contact with pathogen-recognizing receptor complexes on the surface of immune cells, activate inflammatory pathways. (Obese people have higher circulating levels of LPS than lean people do.)

Intestinal bacteria produce LPS continuously throughout the course of a day, and there is a diurnal variation in blood LPS levels, with peaks following meals, especially high-fat meals. Chronically feeding rodents high-fat diets leads to changes in their intestinal flora, increasing the proportion of gram-negative bacteria to gram-positive bacteria, and this is accompanied by a modest rise in blood LPS levels and low-grade inflammation.

When present in very high amounts (as seen in septic shock, perforated ulcers, or peritonitis), LPS creates widespread blood clotting, stimulates the secretion of proinflammatory cytokines by macrophages, and activates the complement system to generate chemoattractants and adhesion molecules. In short, LPS initiates an immune response, and large doses of LPS can result in life-threatening illnesses.

Many of the effects elicited by LPS are executed through its interaction with a receptor complex found, for all intents and purposes, on the surface of immune cells, namely monocytes and macrophages. Upon this interaction, the monocytes and macrophages begin to upregulate their expression of NF-κB, which, in turn, activates a host of related genes that promote inflammation and aging, notably skin aging.¹

NF-κB, for instance, induces the gene expression of COX-2, and, via TNF-α, the inducible nitric oxide synthase (iNOS), which generates a reactive gas called nitric oxide (NO). In the pancreas, NO suppresses insulin secretion; in the muscles, NO reduces insulin sensitivity; and in the fat cells, NO, by way of phosphorylation, activates HSL. As a result, free fatty acids (FFAs) are released into the bloodstream in droves.²

TNF-α and FFAs act on the same receptor complex that LPS does, so we can immediately conceive of a vicious cycle, whereby the inflammatory state initiated by LPS becomes amplified. Blocking the receptors for LPS, deleting the gene for the LPS receptor,³or eradicating intestinal bacteria all together with antibiotics, protect against diet-induced anything,⁴ as we saw again with red meat and eggs, and, most interestingly (to me at least), allow for animals to eat more food without getting fatter.⁵

FREE FATTY ACIDS AND ADIPOSE TISSUE

A vicious cycle is initiated upon the exposure to LPS that leads to a persistent elevation in blood FFAs. (This is a topic for a future post, so I will keep this discussion as brief as possible.) This probably occurs through the development of inflammation in the adipose tissue, with the activation of adipose tissue-resident macrophages and thereafter, the recruitment of additional macrophages via the enhanced expression of the chemoattractant protein called MCP-1. Inflammation, through mechanisms that are less clear, begets FFA mobilization, and elevated levels of FFAs, in turn, beget inflammation in the adipose tissue, and so on.

Inflammation and oxidative stress are initiated in the adipose tissue by LPS, as well as by FFAs, and we at least know that these factors are not acting in isolation, but rather in a feed-forward mechanism of sorts.

Different fatty acids also have been shown to have differential effects in the body upon mobilization.⁶ Saturated fats, as a rule, are the greatest promoters of inflammation, which should be expected as they bear the closest resemblance to the LPS molecule itself. (The lipid portion of LPS is composed of medium-chain saturated fatty acids, like those found in abundance in coconut oil.)

An analogous process occurs in the adipose tissue in obesity, in which large fat cells become inflamed via the infiltration of adipose tissue by macrophages, and as a result of adipocytes themselves producing inflammatory proteins that in turn, also leads to the development of insulin resistance in the body. Like in the case of LPS, this is probably executed through NO, as deletion of iNOS prevented the impairment of insulin signaling by a high-fat diet.⁷

EICOSANOID PATHWAYS, ASPIRIN, AND OTHER NSAID

Arachidonic acid (AA), upon liberation by phospholipases, is metabolized by cyclooxygenases (COX).

Without a doubt, the COX pathway is crucial for generating an immune response to LPS, but because linoleic acid (LA) is present in such higher amounts compared to AA, and because LA is not a substrate for the COX, the products of the lipoxygenases (LOX), which can act on both LA and AA, are probably of greater physiological relevance, at least in mammals. No one, I think, would dispute the statement that the LOX pathway, namely the 5-LOX pathway, is highly involved in the LPS-induced metabolic derangements.⁸

Aspirin is an interesting drug, and I’ve been thinking about it more of late, and this recent blog postspurred the writing of the one you’re now reading. Aspirin irreversibly inhibits COX-1 and modifies (via acetylation) COX-2. (Is there a COX-3?⁹)

COX-1 is said to be “constitutively active,” meaning it is active, to varying extents depending on the tissue, all the time, and is involved in general “housekeeping” functions, like maintaining he stomach’s mucus lining. COX-1 also generates thromboxane A₂, a prostanoid that promotes platelet activation and aggregation, thereby regulating blood clotting.

COX-2, on the other hand, is normally undetectable in most cells, being induced in response to inflammatory stimuli. Bear in mind that both COX-1 and COX-2 carry out the same basic reaction. The main difference lies in their tissue distribution.

Selective COX-2 inhibitors have not fared so well in clinical trials, as they’ve been associated with an increased risk of heart attacks and strokes, largely attributed to their ability to inhibit the vascular production of PGI₂ that synergizes with 13-HODE—derived from LA—to inhibit the aggregation of platelets and to relax the blood vessels.

However, opinions are divided as to whether this applies to low-doses of aspirin as well. Ordinarily speaking, such deductions would not be unreasonable, if only we were uninformed of aspirin’s 15-LOX stimulating effect.¹⁰

15-LOX not only acts on AA, but it also acts on LA, generating 15-HETE and 13-HODE, respectively. 15-HETE inhibits the production of superoxide radicals, suppresses white blood cell (PMNL) migration across cytokine-activated endothelia, relaxes vascular smooth muscle cells,^11,12and can be further metabolized to the anti-inflammatory lipoxins (and the inflammatory leukotriene B4, which the presence of mead acid[ETA] inhibits the generation of). 15-LOX appears to preferentially oxidize LA to 13-HODE over AA to 15-HETE, irrespective of the levels of AA and LA present in tissues.

There are a couple of observations that point to the possible therapeutic potential of low-dose aspirin therapy.

1. In colorectal cancers, the expression of 15-LOX is downregulated.

2. In advanced stages of atherosclerosis, the expression of 15-LOX is upregulated.

The upregulation of 15-LOX is critical for the induction of apoptosis by NSAIDs. This would, I suppose, play a major role in aspirin’s purported chemoprotective effects, as would the slow conversion of 13-HODE to 13-KODE (ketooctadecadienoic acid), which has been shown to have tumor-suppressant properties. (To be clear, I’m merely speculating here.)

Recall from my lipid peroxidation series (parts 1, 2, and 3) that there is a dramatic accumulation of HODEs that accompanies atherosclerosis. However, I’m open to the possibility that this increase could represent a protective response that serves to limit the progression of atherosclerosis.

But at the same time, I’m not ruling out the possibility that these LA, and to a much lesser extent AA, derived 15-LOX products are merely correcting the damages initiated by other lipid peroxidation processes, especially those that go on nonenzymatically. Another LA derived HODE, for instance, synergizes with 2,4-decadienal (a PUFA oxidation product derived from both LA and AA) to stimulate the release of IL-1β by macrophages. IL-1β, in turn, promotes white blood cell adhesion to the endothelia, inflammation, and vascular smooth muscle cell proliferation (all bad).

Aspirin is useful in that it inhibits COX, stimulates 15-LOX, and inactivates NF-κB, providing multilayers of protection with minimal risk of side effects, and because of this I think it could serve to curtail the damages caused by both obesity and LPS when used in low doses.

CONCLUSION

The processes outlined above I think illustrate clearly the interplay, and overlap, among the immune system, metabolism, and our nutritional status. Now that I have a chance to read other blogs, I see this motif about “gut bacteria” recurring, and how all our problems would be solved if we would just put more focus there. And according to the general consensus, the liberal use of probiotics is precisely what everyone ought to be doing. (Of course, fermented foods are superior because they are more “natural.”)

I do think the animal studies are interesting, and fun to read, but I have my doubts as to how effective “probiotics” really are, and whether simply adopting a normal diet and losing excess body fat, if you have it, would not correct the metabolic derangements that are affecting people like an epidemic.

In the meantime, low doses of aspirin, eating smaller and balanced meals, spread out equally throughout the day, and if you suspect dysbiosis, getting tested for it and treated properly by a medical doctor I think affords adequate protection against the things discussed herein. A stimulant laxative I think could help to reduce the intestinal bacterial load, and therefore the exposure to bacterial toxins like LPS.

REFERENCES

1. Adler, A. S. et al. Motif module map reveals enforcement of aging by continual NF- B activity. 3244–3257 (2007).doi:10.1101/gad.1588507.analytic

2. Staiger, H. et al.Palmitate-induced interleukin-6 expression in human coronary artery endothelial cells. Diabetes53, 3209–16 (2004).

3. Davis, J. E., Gabler, N. K., Walker-Daniels, J. & Spurlock, M. E. Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring, Md.)16, 1248–55 (2008).

4. Suganami, T. et al. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochemical and biophysical research communications354, 45–9 (2007).

5. Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the United States of America104, 979–84 (2007).

6. Schaeffler, A. et al. Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology126, 233–45 (2009).

7. Perreault, M. & Marette, A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nature medicine7, 1138–43 (2001).

8. Ito, S. et al. Leukotriene B4/leukotriene B4 receptor pathway is involved in hepatic microcirculatory dysfunction elicited by endotoxin. Shock (Augusta, Ga.)30, 87–91 (2008).

9. Davies, N. M., Good, R. L., Roupe, K. A. & Yáñez, J. A. Cyclooxygenase-3: axiom, dogma, anomaly, enigma or splice error?--Not as easy as 1, 2, 3. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Société canadienne des sciences pharmaceutiques7, 217–26 (2004).

10. Vanderhoek, J. Y., Ekborg, S. L. & Bailey, J. M. Nonsteroidal anti-inflammatory drugs stimulate 15-lipoxygenase/leukotriene pathway in human polymorphonuclear leukocytes. The Journal of allergy and clinical immunology74, 412–7 (1984).

11. Uotila, P. et al. Relaxing effects of 15-lipoxygenase products of arachidonic acid on rat aorta. The Journal of pharmacology and experimental therapeutics242, 945–9 (1987).

12. Thomas, G. & Ramwell, P. Induction of vascular relaxation by hydroperoxides. Biochemical and biophysical research communications139, 102–8 (1986).

Introduction:

I’m probably treading on thin ice here, but I’ve been thinking about why milk would cause acne in some people. I have not the means of forming a solid judgment but initially, I was thinking offhand that the high calcium content in milk could be a factor. Excess calcium impairs the absorption of zinc and a zinc deficiency depletes vitamin E and thus vitamin A. Zinc and vitamin A are particularly protective against the development of acne.¹

I think this highlights how complex nutrient interactions can get as well as the importance of examining all possibilities and assumptions when we attempt to draw associations between two things. It’s tempting to assume that one thing causes another simply because they regularly occur simultaneously, or one regularly occurs before the other in time. Leaping to a cause and effect conclusion is easier and faster, no doubt, than to take due cares to investigate the relationship so as to rule out all possible alternative explanations.

Many, unfortunately, do not shoulder such care—unintentionally or not. But I leave this train of thought.

Bacteria are often said to be the cause of acne but I’ve always had my doubts about this model. Antibiotics—applied topically or taken orally—do in fact improve and prevent acne, sometimes quite dramatically, but I think the explanation as to how this happens lies outside the idea that antibiotics merely kill bacteria, P. acnes, present on the skin. Lo and behold, bacteria are not unconditionally required for acne.²

Lipid peroxidation is undoubtedly at play in the development of acne lesions. And understanding the interplay among vitamin A, vitamin E, and fatty acids I think will permit us to move away from an intolerable deal of guesswork and to a more rational approach to this seemingly implacable foe that affects people of all ages.

Vitamin A

A deficiency of vitamin A, or retinol, is not thought to be a problem among adults as much as an excess of vitamin A is. (Of course with the exception of alcoholics, since beta-carotene is metabolized to retinol by the same dehydrogenase enzyme that detoxifies alcohol to acetaldehyde. So the presence of alcohol slows the conversion of beta-carotene to retinoic acid, permitting beta-carotene to accumulate in the body.)

However, a thyroid deficiency, as well as a deficiency of retinol and vitamin B12, impairs the secretion of bile, which is needed to absorb dietary retinol.³ In other words, a retinol deficiency can reinforce itself, that is, unless the pattern can be short-circuited with a good diet.

I have to pause for a moment to say that supplementation with vitamin A should be undertaken with discretion. Reviewing the toxicological data, vitamin A interacts with many supplements and drugs, sometimes to a significant degree, and the range of doses that produce intoxication is apparently very wide: One person may be able to take hundreds of thousands of units for weeks without indications of toxicity, while another person may experience acute intoxication from just one small dose of vitamin A. There are obviously many factors at play that determine a person’s tolerance to vitamin A.

Retinol is oxidized in the skin to its more active metabolite, retinoic acid. The skin not only oxidizes retinol to retinoic acid, but it also stores retinol in the cell’s fatty regions. Under the right conditions, retinol is liberated from its storage site, and converted to retinoic acid, which can then bind to nuclear “retinoic acid receptors” to exert the full force of vitamin A’s effects. It is thus fair to suppose that vitamin A’s toxicity—which mainly results from too much retinoic acid—is buffered against by the coordinated release and oxidation of retinol.

(Could those who are more sensitive to vitamin A merely be fast metabolizers?)

Retinol

Retinoic acid

Certain human skin cells have little capacity to esterify (i.e., store) retinol, so they must depend on the continuous uptake of retinol from the circulation. The liver has a tremendous capacity to store vitamin A: At utmost, we can say that the liver can normally store enough vitamin A to hold a person over for 5 to 10 months without any intake of vitamin A.⁴

(Nonetheless, it’s been known, at least since the 1920s, that although an animal that is vitamin A deficient may appear normal and healthy, yet have an impaired ability to reproduce and a tendency to breakdown in health in the prime of life compared to an animal that is not vitamin A deficient.)

Retinol—applied to the skin or taken orally—can help to fight back the excess sebum production and proliferation of skin cells initiated by lipid peroxidation processes. Retinoids are synthetic forms of vitamin A that are supposedly employed in lieu of retinol because retinol would become toxic in the doses needed to treat acne. Considering the egregious side effects associated with the use of retinoids, and despite the wide range of toxic doses associated with the use of retinol, I would still more often than not opt for retinol first.

Skin lipids

Free fatty acids and squalene are major lipids that make up sebum. Squalene is highly unsaturated in structure and highly susceptible to peroxidation and photodegradation. The byproducts, squalene peroxides, promote acne, roughening of skin, and wrinkling.^5,6 The free fatty acids, when polyunsaturated, degenerate to promote the peroxidation of nearby lipids, including squalene, whereas saturated fats do not.

Squalene

Oils applied to the skin are readily metabolized, and investigations in which oils are applied to skin cells have provided insights into the role of different lipids in the pathophysiology of skin-related disorders—including acne. Applying unsaturated fatty acids to the skin, for instance, almost instantly causes skin cells to take up calcium.⁷ This influx of calcium leads to abnormal keratinization in follicles and, subsequently, the plugging of pores, encouraging acne development.

Intracellular calcium also liberates PUFA, activates lipoxygenases (LOX), which convert PUFA to lipid hydroperoxides that are then rapidly reduced to lipid hydroxides, and, by activating perixosome-proliferater activated receptors (PPAR) in the skin, increase the expression of cyclooxygenases (COX), which convert PUFA to prostaglandins. These PUFA oxidation products further reinforce the conditions that favor acne development. COX inhibitors, applied topically, are routinely used to treat acne, and a LOX inhibitor, zileuton, has been shown to be effective in treating acne as well—topically and orally.⁸

Because of their bulky conformation, unsaturated fatty acids also reduce the skin’s barrier integrity, which leads to abnormal keratinization and clogging of pores, too.⁹ Saturated and trans fats are weak PPAR activators, not substrates for LOX or COX, and very long chain saturated fatty acids (with cholesterol) enhance the skin’s barrier function. Medium chain saturated fats, such as lauric acid, can worsen acne in some people by activating toll like receptors (TLR) in the skin. Sebum from pre-pubertal children contain more omega-9 fatty acids and less omega-6 fatty acids compared to sebum from adolescents when acne begins to appear.

Vitamin E

A vitamin E deficiency, or an excess of polyunsaturated fat, depletes vitamin A. This is because while vitamin E, an antioxidant, spares vitamin A from being degraded, it also prevents the oxidation of polyunsaturated fats. So when polyunsaturated fats are present in tissues in large amounts, less vitamin E is available to protect vitamin A from degradation. Generally, our requirement for vitamin E increases as our consumption of polyunsaturated fat increases.¹⁰

It has been calculated that at least 0.6 milligrams of vitamin E are needed for every gram of polyunsaturated fat ingested. But the protection provided by vitamin E diminishes as increasing amounts of polyunsaturated fats are ingested.¹¹

Although toxicity to large amounts of vitamin E has not been definitively shown before now, large amounts of vitamin E can be protective in some contexts. For instance, in areas of heavy air pollution, in which levels of ozone and other atmospheric oxidants are high, large amounts of vitamin E can help to protect the lungs from tissue damage.¹² Further, large amounts of vitamin E help to promote repair of tissue following burn injuries.¹³

Such protection is apparently direct and indirect. That is, vitamin E not only mops up free oxygen, but by sparing vitamin A, known as the “anti-infection vitamin,” vitamin E prevents damage to the epithelial cells (i.e., skin) of the body. Vitamin A, in turn, enhances the efficacy of vitamin E in giving resistance to diseases. And good thyroid function increases our requirement for both vitamin A and vitamin E.

Vitamin E is also known as the “anti-sterility” vitamin, and I think this is in part due to its ability to spare vitamin A, which protect skin surfaces, including the skin that lines the gonads.

Vitamin E, over the years, has had lavish claims made on its behalf as to preventing and curing various conditions; after reviewing the bare facts, however, not much more can be said about it at this point.

Conclusion

The development of acne is beginning to be seen as having an inflammatory origin, in which lipid peroxidation processes take center stage. I’ve discussed this elsewhere in a different context, but the eicosanoid metabolites derived from lipoxygenase enzymes—namely 15-HETE and LTB₄—as well as their parent compound, arachidonic acid, are ligands for PPAR activation in the skin’s sebaceous glands.¹⁴ PPAR activation, in turn, increases the expression of COX, which generates prostaglandin E₂ in in the skin to cause abnormal skin cell proliferation and lipogenesis therein, as well as inflammation.

Danny Roddy has written an interesting blog post about the role of prostaglandin E₂ in hair loss. We can now, tentatively, add acne to the list of conditions impacted negatively by COX and prostaglandin E₂.

Recall that the presence mead acid, generated when the diet is deficient in the essential fatty acids, inhibits the generation of LTB₄, and salicylates (and generally NSAIDs) inhibit the generation of prostaglandin E₂. Vitamin E is carried to and from the skin’s surface by way of sebum, so topically applied vitamin E could help to put a brake on the lipid peroxidation processes that lead to the development of full-blown acne. Selenium works with vitamin E to suppress random oxidation processes in the skin. Schisandra fruit (dried or fresh), tea, and cannabis (leaf) contain natural LOX inhibitors and are generally safe to use.¹⁵

References

1. Brandt, S. The clinical effects of zinc as a topical or oral agent on the clinical response and pathophysiologic mechanisms of acne: a systematic review of the literature. Journal of drugs in dermatology : JDD 12, 542–5 (2013).

2. Zouboulis, C. C. et al. What is the pathogenesis of acne? Experimental dermatology 14, 143–52 (2005).

3. Mandal, S. K. & Dastidar, A. G. Hypothyroidism as a possible aetiology of vitamin A deficiency. Journal of the Indian Medical Association 83, 339–40 (1985).

4. Guyton, A. & Hall, J. Textbook of Medical Physiology. 1104 (Saunders: 2006).

5. Chiba, K., Yoshizawa, K., Makino, I., Kawakami, K. & Onoue, M. Comedogenicity of squalene monohydroperoxide in the skin after topical application. The Journal of toxicological sciences 25, 77–83 (2000).

6. Chiba, K., Sone, T., Kawakami, K. & Onoue, M. Skin roughness and wrinkle formation induced by repeated application of squalene-monohydroperoxide to the hairless mouse. Experimental dermatology 8, 471–9 (1999).

7. Katsuta, Y., Iida, T., Inomata, S. & Denda, M. Unsaturated fatty acids induce calcium influx into keratinocytes and cause abnormal differentiation of epidermis. The Journal of investigative dermatology 124, 1008–13 (2005).

8. Zouboulis, C. C. et al. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Archives of dermatology 139, 668–70 (2003).

9. Yamamoto, A., Takenouchi, K. & Ito, M. Impaired water barrier function in acne vulgaris. Archives of dermatological research 287, 214–8 (1995).

10. Meydani, M. Vitamin E requirement in relation to dietary fish oil and oxidative stress in elderly. EXS 62, 411–8 (1992).

11. Valk, E. E. & Hornstra, G. Relationship between vitamin E requirement and polyunsaturated fatty acid intake in man: a review. International journal for vitamin and nutrition research. Internationale Zeitschrift für Vitamin- und Ernährungsforschung. Journal international de vitaminologie et de nutrition 70, 31–42 (2000).

12. Elsayed, N. M., Mustafa, M. G. & Mead, J. F. Increased vitamin E content in the lung after ozone exposure: a possible mobilization in response to oxidative stress. Archives of biochemistry and biophysics 282, 263–9 (1990).

13. Kuroiwa, K. et al. Metabolic and immune effect of vitamin E supplementation after burn. JPEN. Journal of parenteral and enteral nutrition 15, 22–6

14. Thuillier, P. et al. Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors. The Biochemical journal 366, 901–10 (2002).

15. Schneider, I. & Bucar, F. Lipoxygenase inhibitors from natural plant sources. Part 1: Medicinal plants with inhibitory activity on arachidonate 5-lipoxygenase and 5-lipoxygenase[sol ]cyclooxygenase. Phytotherapy research : PTR 19, 81–102 (2005).

Part I, II

Out of curiosity, using cronometer, I decided to see how much PUFA I was eating on a daily basis for a week. It was tedious but, on average, I had consumed about 5 grams of PUFA a day, and substantially greater amounts of monounsaturated and saturated fats. An essential fatty acid (EFA) deficiency is out of the question at this level, at least per the clinicial signs and symptoms, but I naturally began to wonder what my tissues would look like if I had been consuming much less PUFA, essentially depleting myself of linoleic acid (LA) and arachidonic acid (AA).

It turns out that the synthesis and presence of eicosatrienoic acid (ETA), or mead acid, would increase, in proportion to the exclusion of the EFAs from the diet, and the appearance of ETA can occur in a matter of days. You’ll seldom find information on ETA in textbooks and in searches on databases that index scientific articles, like PubMed, other than the fact that it serves as a marker for an EFA deficiency. The mere presence of ETA is also usually taken as evidence that an EFA deficiency has caused, or contributed, to the condition that tends to coexist with it.

But an EFA deficiency per se is not always at play, as there could be an inability to synthesize and desaturate fatty acids properly, in which case the addition of PUFA would probably provide benefit. (PUFA have indispensable signaling and structural functions, namely in the phospholipids that are found in cell membranes.) Or, it could merely indicate an overall poor diet.

Despite what's typically said to the contrary, saturated fatty acids are critical components of phospholipids, not merely of triglycerides, as well, and the importance of this is seen no more dramatically than in the lungs.

Normally, phospholipids bear one PUFA molecule and one saturated fatty acid (SFA) molecule, but the lungs are unique in that they incorporate two molecules of palmitic acid. The reason for this is simple: Phospholipids with straight-chain fatty acids pack neatly into small spaces when the lungs deflate and readily spread out when the lungs inflate, acting as “anti-glue” of sorts (or technically, as surfactants). So the replacement of a PUFA molecule for a SFA molecule permits the lungs to inflate properly with only modest increases in air pressure, thereby decreasing the amount of muscular work needed to breathe. The loss or replacement of a SFA molecule for a PUFA molecule would be catastrophic, especially in neonates whose lungs don’t develop fully until just before birth.

In enzymatic processes, PUFA that can bend into a tight hairpin shape, so as to facilitate the formation of a ring structure, can be oxidized to a host of messenger molecules collectively called eicosanoids. So, cis oriented PUFA can participate in these reactions, whereas trans oriented PUFA can’t, which explains why trans fatty acids are more resistant to enzymatic (and nonenzymatic) peroxidation processes, and thus not likely to lead to inflammation (and oxidative stress) like other PUFA.¹ (The alarmism and the pleading, in sepulchral tones, to avoid trans fatty acids at all costs, at least thus far, is unfounded and gross. Ew.)
Besides arachidonic acid (AA), other 20-carbon PUFA, including eicosapentaenoic acid (EPA), an omega-3 fatty acid, and ETA, an omega-9 fatty acid, can form their own series of eicosanoids.

The range of processes that these eicosanoids are involved in are too numerous to list here, but I want to call attention to the idea that the eicosanoids (prostaglandins, thromboxanes, and leukotrienes) have effects in the body that are contingent on the starting PUFA from which they're derived, and this is governed, for all intents and purposes, by the relative amounts of AA, EPA, and ETA present in our tissues.
The addition of ETA, for instance, increased the percentage of ETA in the tissues and organs of rats in proportion to the percentage of linoleic acid (LA) in their diets, and the presence of ETA inhibited the production of leukotriene-B₄, which is highly inflammatory and implicated in many diseases.² (Credit goes to Dr.Ray Peat, via an email exchange, for making me aware of this.) Similarly, the addition of EPA, a major fatty acid in fish oil, decreases the generation of leukotriene-B_4,but probably by way of a slightly different mechanism.³

Nonetheless, the enzymes that generate the leukotrienes are the same enzymes that generate free radicals and a host of PUFA peroxidation products that oxidize LDL particles and are involved early on in atherosclerosis.^4,5 ETA is chemically more stable than EPA, so could serve the purpose of curtailing the production of the inflammatory leukotriene-B₄, among the other eicosanoids, in a safer way. (Though, whether this approach is as rationale in practice as it is in theory has yet to be properly tested and decided on.)

The liberation of PUFA is accompanied by the depletion of ATP, through its conversion to cAMP, and low levels of ATP accelerate lipid peroxidation processes. Further, cardiolipin, which interacts with the proteins of the inner mitochondrial respiratory chain (especially those of complexes I, III, and IV),⁶ become more unsaturated with aging, and this is one way by which the cardiolipin content in cells can decrease, resulting in a decreased efficiency of ATP generation. (In one animal study, the presence of docosahexaenoic acid [DHA] in cardiolipin was significantly associated with oxygen wasting, whereas the presence of palmitoleic acid was inversely associated with oxygen wasting.⁷) So, the higher the cardiolipin saturation index, already relatively resistant to peroxidation, the more ATP would be produced, and this in turn would provide further protection against peroxidation processes.⁸

As an aside, thyroid hormone induces cardiolipin biosynthesis, but at the same time reduces the saturation index therein, favoring AA to LA, rendering cardiolipin more susceptible to lipid peroxidation processes. Totally in line with this, in hyperthyroidism there is appreciable amounts of oxygen wasting.

In summary, in the absence or deficiency of one type of PUFA, another can stand in its place as storage triglycerides, structural elements in phospholipids, and substrates for enzymatic processes. The omega-9 series, of which ETA is a member, are anti-inflammatory like the corresponding members of the omega-3 series are, but are more resistant to lipid peroxidation processes, the products of which are linked to the development of cardiovascular disease. As a rule, the lower the exposure to the EFAs, the greater the rate of ETA production (far exceeding the constitutive rates of ETA production in mammals), and the greater percentage of ETA will be present in tissues, which may be beneficial for inflammation and oxidative stress. And finally, caloric restriction has been shown to decrease the activity of the desaturase enzymes, by slightly lowering thyroid and insulin levels, and this in turn helps to preserve, and to restore, the cardiolipin associated with youth.

REFERENCES

1. Smit, L. A., Katan, M. B., Wanders, A. J., Basu, S. & Brouwer, I. A. A high intake of trans fatty acids has little effect on markers of inflammation and oxidative stress in humans. The Journal of nutrition141, 1673–8 (2011).

2. Cleland, L. G. et al. Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic acid. The Journal of nutrition126, 1534–40 (1996).

3. James, M. J., Gibson, R. A., Neumann, M. A. & Cleland, L. G. Effect of dietary supplementation with n-9 eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid synthesis. The Journal of experimental medicine178, 2261–5 (1993).

4. Kühn, H., Heydeck, D., Hugou, I. & Gniwotta, C. In vivo action of 15-lipoxygenase in early stages of human atherogenesis. The Journal of clinical investigation99, 888–93 (1997).

5. Takahashi, Y., Zhu, H. & Yoshimoto, T. Essential roles of lipoxygenases in LDL oxidation and development of atherosclerosis. Antioxidants & redox signaling7, 425–31

6. Chicco, A. J. & Sparagna, G. C. Role of cardiolipin alterations in mitochondrial dysfunction and disease. American journal of physiology. Cell physiology292, C33–44 (2007).

7. Dumas, J.-F. et al. Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis. Journal of hepatology54, 320–7 (2011).

8. Paradies, G. et al. Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free radical biology & medicine27, 42–50 (1999).

I apologize for the long break but I hope to be back for a while. I’ve been getting many emails and messages since my hiatus, and, I promise, I will try my best to get to all of them. I really appreciate the kind words I’ve been receiving, and, if I may say so without presumption, see it as a good augury of success that I’m providing decent content. Okay, onward.

Regarding some of these messages, a theme all too familiar is gaining weight on restrictive diets, or not being able to eat “anything” without getting fatter. I’m working on a guest post for Matt Stone’s siteabout this topic, and ways in which to overcome it, especially those who have been lifelong dieters or under-eaters. One person emailed me recently saying that she could not eat more than about 700 calories per day without gaining weight. This has been a matter of absorbing interest of mine of late, and I have some ideas I wish to delve into, but herein, I will briefly discuss the one macronutrient that, I think, almost everyone agrees is the least fattening of all the macronutrients: protein.

The person who I think made the soundest points and most compelling argument for getting adequate amounts of high quality protein was the nutritionist, Adelle Davis. According to Davis, low protein intakes were a major cause of fatigue, bad posture, thinning hair, brittle nails, water retention and swelling, low resistance to infections, weak digestion, and poor circulation. In a word, inadequate protein intake accelerated aging. (For what it is worth, I've found that eating about 15 to 20 grams of protein at each meal also elevates my mood for hours afterwards.)

The thyroid researcher and clinician, Broda Barnes, however, noted that high protein, low calorie diets, often employed to treat diabetics at the time, had an inhibitory effect on the thyroid and metabolic rate, and that he could eat about 1,000 extra calories, without gaining any weight, by eating less protein and disproportionately more (mainly animal) fat, while keeping his carbohydrate intake low.

Why a high protein intake would have an inhibitory effect on the thyroid, I'm not completely sure yet. Most obviously, on such a diet, much energy is expended in converting protein to glucose, and, over time, the counterregulatory hormones are maintained at higher levels. Cortisol is one such hormone that inhibits the conversion of T₄ to T₃. Adrenalin, whose effect on tissues is permitted by T₄, is another such hormone that inhibits insulin secretion and stimulates the hypothalamic-pituitary-adrenal axis, further reinforcing the inhibition on the conversion of T₄ to T₃.

High protein diets without sufficient amounts of fat or carbohydrate appear to aggravate hypothyroidism, and so, long-term, are probably ineffective for weight loss, and unnecessarily restrictive. Protein is often said to be the most satiating nutrient, but I think this is because of its effect on the thyroid and metabolism, as much as it is the fact that it is meeting the body’s need for it. The resulting hormonal changes would also tend to favor the storage of fat in the abdominal area, further inhibiting the thyroid,¹ and the resulting metabolic changes would tend to favor the elimination of thyroid hormone from the body.²

Ray Peat has taken the matter further, suggesting that it is specifically the cysteine, methionine, and tryptophan amino acid residues in proteins that are anti-thyroid and anti-metabolic, and on this basis, recommends to minimize the consumption of muscle meat in favor of gelatin, which is unusually deficient in cysteine and methionine and lacks tryptophan (and histidine) altogether.

As to how effective gelatin is in building and maintaining bodily protein, especially when used as a major source of protein in the diet by adults, I have my doubts, but as a supplementary source of protein, it could provide the optimal balance of amino acids to support regeneration and repair without impacting the thyroid negatively.

Small amounts of gelatin added to the diet, for instance, promotes positive nitrogen balance, by virtue of its great protein sparing ability, such that we could probably get away with eating less protein; herein lies gelatin's greatest benefit. Gelatin also has been shown to enhance the digestion of other, less digestible proteins — most notoriously plant proteins.³

I have not experimented with large amounts of gelatin (I do make extra-firm Jell-O and eat marshmallows occasionally), and I probably will not until I see more evidence, including anecdotal evidence, for including it as a part of my regular diet. Generally, most fruits are missing tryptophan and methionine; most vegetables are missing tryptophan; and legumes (including peanuts) are missing methionine.

Stress, really, of any kind, when prolonged, increases our requirement for protein, as our bodies do not store protein as it does carbohydrate and fat. Once nitrogen balance becomes negative, bodily tissues are increasingly drawn upon, and we begin to waste away and lose function. However, animal studies have shown that very high protein intakes, about 25 percent of total calories, lead to greater body fatness than lower protein intakes, or about 5 percent of total calories — in line with the points made above. Further, textbooks generally say that merely 35 to 45 grams of protein are needed to prevent negative nitrogen balance — provided energy requirements are met by carbohydrate (or fat).⁴

It is but fair to say that context is important, and protein requirements will vary per your own circumstances; we should strive, for all intents and purposes, to thrive eating the least amount of protein, and this means keeping stress, of any kind, as low as possible.

(Consider uncontrolled diabetes, a condition in which carbohydrate becomes less available as a source of energy; tissue wasting from negative nitrogen balance follows as a result. In this sense, carbohydrate spares protein.)

Balanced proteins, gotten from eating whole, complex animals and animal products, such as sardines, anchovies, eggs, milk products, whole chicken, shellfish, etc., I think, are the best protein sources. You will have to fine-tune the amount, but I have found that 15 to 20 grams of protein per meal, with plenty of carbohydrate is ideal for me. I prefer sugar to starch because too much of the latter I think eventually turns the intestines into a yeast pot.

I have been told that people recommend to restrict both carbohydrate and fat, and to increase the intake of protein as the ideal way to lose weight. (This is actually the commercialized, perverted version of the Paleo diet.) It is difficult to avoid saying that this represents one of the worst, and unnecessarily difficult, methods to lose weight and promote health — hormones and metabolism be damned.

REFERENCES

1. Muscogiuri, G. et al. High-normal tsh values in obesity: Is it insulin resistance or adipose tissue’s guilt? Obesity (Silver Spring, Md.)21, 101–6 (2013).

2. Bregengård, C. et al. The influence of free fatty acids on the free fraction of thyroid hormones in serum as estimated by ultrafiltration. Acta endocrinologica116, 102–7 (1987).

3. Gotthoffer, N. R. Gelatin in nutrition and medicine. 162 (Great Lakes Gelatin Company: 2012).

4. Guyton, A. & Hall, J. Textbook of Medical Physiology. 1104 (Saunders: 2006).

Stress, Distorted Self-Images, and the Sickness of the Pursuit of Physical Attractiveness (plus updates)

My Guest Post for 180 Degree Health Newsletter

Straight Talk on Fats, Metabolism, and Body Temperature

The Unsung Hero of Thyroid Replacement Therapy: ATP

Preserving Brain Function: Principles, Pitfalls, and Practical Conclusions

'Smart Drugs' Are Stupid

Essential Fatty Acids: Should We Be Concerned About Them?

My Health Challenges: A Glance Back at the Past 10 Years

Food Intolerances, Allergies, and Stress: An Overview

I'm Back! Updates, Mini Burnout, and Low Carb Diets Are Still Egregious

Insulin revisited, cell physiology, membrane pumps, and internet commenters

Diabetes, Dangerous Fat, and Protective Sugar

Why cells go bad: a new appreciation and understanding of ATP opens up an untapped avenue for fighting diabetes, cancer, aging, etc.

PUFA, lipid peroxidation processes, and the implications for atherosclerosis and diet

PUFA, lipid peroxidation processes, and the implications for atherosclerosis and diet Part II

What I learned from the red meat-carnitine study (plus what I ate today)

The interplay among the human intestinal microbial landscape, obesity, metabolism, and nutritional status: an overview

Lipid peroxidation, acne, and the complexity of nutrient interactions

PUFA, Lipid Peroxidation Processes, and the Implications for Atherosclerosis and Diet Part III

Protein, the Thyroid Gland, Metabolism, and Conceptions About Weight Loss Diets