Energy and Structure: What can RQ tell us?

I wanted to do a short post quickly before I start packing my apartment to move early this week. Here I just want to look at RQ as a measurement and what it can tell us. I will write more about RMR and how it relates to RQ including different physiological states that influence RQ such as birth, what happens to RQ at the start of breast feeding, how thyroid hormones effect RQ, etc. once I get into my new apartment.

There can be a problem when reading papers as to what it exactly means to have a “high metabolism”. The phrase is loosely defined. But some people, including Dr. Peat, define the strength of the metabolism based on the RQ (respiratory quotient). The RQ is essentially the ratio of carbon dioxide eliminated to oxygen consumed.

Roughly:

RQ = C02 eliminated / O2 consumed

A RQ closer to 1 typically means more carbohydrate is being burned and a value closer to 0.7 typically means fat is being burned.

For some reason there is the idea that a high RQ closer to 1 is the same thing as a “high metabolism”. I don’t really know how RQ became associated with the rate of the metabolism. RQ tells you essentially what fuel you are burning, nothing about the rate of your metabolism.

“On a normal diet, his weight was 152 pounds, and his metabolic rate was from 9% to 12% below normal, but after six months on the diet it had increased to 2% below normal. After three months on the sugar and milk diet, his weight leveled off at 138 pounds. After being on the diet, when he ate 2000 calories of sugar and milk within two hours, his respiratory quotient would exceed 1.0, but on his normal diet his maximum respiratory quotient following those foods was less than 1.0.

The effect of diabetes is to keep the respiratory quotient low, since a respiratory quotient of one corresponds to the oxidation of pure carbohydrate, and extreme diabetics oxidize fat in preference to carbohydrate, and may have a quotient just a little above 0.7.” ~Dr. Peat

“His respiratory quotient increased (producing more carbon dioxide), as well as his rate of resting metabolism.” ~Dr. Peat

“Maintaining a high rate of oxidative metabolism, without calorie restriction, retards the accumulation of PUFA, and a high metabolic rate is associated with longevity. An adequate amount of sugar maintains both a high rate of metabolism, and a high respiratory quotient, i.e., high production of carbon dioxide.” ~Dr. Peat

“At high altitude, or when taking a carbonic anhydrase inhibitor, there is more carbon dioxide in the blood, and the serum phosphate is lower; sucrose and fructose increase the respiratory quotient and carbon dioxide production, and this is probably a factor in lowering the serum phosphate.” ~Dr. Peat

Needless to say, the only point with which I agree with from above is that carbohydrate increases RQ and fructose is effective at the task. The literature supports that.

It seems that as we age RQ increases and if you believe that a higher RQ is a measure of the rate of metabolism this can lead to some paradoxical conclusions. If that is what you think, you don’t have to do anything, your RQ will increase without any dietary intervention.

In obesity and diabetes it is observed that RQs tend to be higher (more towards 1). Aging, disease, and other metabolic derangements at the end of the day all basically stem from hypoxia (Douglas & Haddad, 2008).

“Similarly, individuals with a high 24-hour respiratory quotient (RQ) are more likely to gain weight than those with a low RQ.” (Ravussin, 1995)

“Over a 7-year period, mean unadjusted and adjusted 24-hour RQ increased (p < 0.01). Cross-sectional data analysis showed that both the unadjusted (r = 0.19, p < 0.03) and adjusted (r = 0.19, p < 0.03) 24-hour RQ correlated with increasing age while adjusted BMR (r = -0.21, p < 0.02) correlated inversely with age.” (Rising, Tataranni, Snitker, & Ravussin, 1996)

“Subjects with higher 24-h RQ (90th percentile) independent of 24-h energy expenditure were at 2.5 times higher risk of gaining greater than or equal to 5 kg body weight than those with lower 24-h RQ (10th percentile).” (Zurlo et al., 1990)

“In contrast obese patients who succeeded to retain the weight loss achieved initially by the VLCD at 2-yr follow-up (weight losers) or those who did not exhibit weight fluctuations (weight noncyclers) were characterized by a significantly lower RQ.” (Hainer, Kunesova, & Parizkova, 1999)

“High nonsleeping RQ (NSRQ) predicted 2-year change in FM independently of energy balance, circulating insulin, and insulin sensitivity. This observation suggests that low postprandial fat oxidation may uniquely predispose obesity-prone individuals to accrual of adipose tissue.” (Ellis, Hyatt, Hunter, & Gower, 2010)

cho thyroidThe real world is a fascinating place.

Now a high RQ is not always associated with weight gain, this is why RQ really should not be associated with the rate of metabolism. If you are into calorie counting, you can have a high RQ on a high carbohydrate diet without gaining weight. But DNL is going to be very active. You’ll be burning fat just as quickly as you make it. Your triglycerides will probably increase, but they might not if you are taking thyroid. which is going to enhance fatty acid oxidation.

Aside: Thyroid hormone itself stimulates DNL. DNL is reduced in hypothyroidism and treatment with T3 increases DNL.

T3 also decreases the RQ (Barbe et al., 2001).

Of course long term you are going to run into a lot of side effects as DNL will eventually not be able to supply the demand T3 places on fatty acid oxidation. This is speculative, but I think a reasonable partial explanation for why a lot of people on a low-fat-high-carbohydrate-diet taking thyroid probably feel better when they eat more saturated fat.

References

Barbe, P., Larrouy, D., Boulanger, C., Chevillotte, E., Viguerie, N., Thalamas, C., … Langin, D. (2001). Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 15(1), 13–15. doi:10.1096/fj.00-0502fje

Douglas, R. M., & Haddad, G. G. (2008). Can O2 dysregulation induce premature aging? Physiology (Bethesda, Md.), 23, 333–49. doi:10.1152/physiol.00023.2008

Ellis, A. C., Hyatt, T. C., Hunter, G. R., & Gower, B. a. (2010). Respiratory quotient predicts fat mass gain in premenopausal women. Obesity (Silver Spring, Md.), 18(12), 2255–9. doi:10.1038/oby.2010.96

Hainer, V., Kunesova, M., & Parizkova, J. (1999). Respiratory quotient in obesity: its association with an ability to retain weight loss and with parental obesity. Sbornik …, 101(1), 99–104. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10953639

Ravussin, E. (1995). Metabolic differences and the development of obesity. Metabolism: Clinical and Experimental, 44(9 Suppl 3), 12–4. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7674909

Rising, R., Tataranni, P. A., Snitker, S., & Ravussin, E. (1996). Decreased ratio of fat to carbohydrate oxidation with increasing age in Pima Indians. Journal of the American College of Nutrition, 15(3), 309–12. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8935448

Zurlo, F., Lillioja, S., Esposito-Del Puente, A., Nyomba, B. L., Raz, I., Saad, M. F., … Ravussin, E. (1990). Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. The American Journal of Physiology, 259(5 Pt 1), E650–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2240203

The entrenched individual

“When something out of the ordinary happens, it is ridiculous to say that it is a mystery or a portent of something to come. Eclipses of the sun and moon, comets, clouds that flutter like flags, snow in the fifth month, lightning in the twelfth month, and so on, are all things that occur every fifty or one hundred years. They occur according to the evolution of Yin and Yang. The fact that the sun rises in the east and sets in the west would be a mystery, too, if it were not an everyday occurrence. It is not dissimilar. Furthermore, the fact that something bad always happens in the world when strange phenomena occur is due to people seeing something like fluttering clouds and thinking that something is going to happen. The mystery is created in their minds, and by waiting for the disaster, it is from their very minds that it occurs. The occurrence of mysteries is always by word of mouth.” ~Yamamoto Tsunetomo

It’s interesting how words, phrases, ideas, and behavior go through multiple stages of metamorphosis within the context of a culture, subculture, and individual level.

Metamorphosis in insects ends with a self-sufficient organism able to consume energy and reproduce. After reproduction, the insect soon dies leaving it’s offspring to fulfill both an environmental and reproductive purpose. But metamorphosis is a linear process; there is a beginning and an end. What emerges from the cocoon is something refined for a specific purpose. Words, phrases, ideas, and behavior tend to have a linear development, but follow circular patterns of refinement until their meaning becomes either precise or meaningless.

Nutrition is difficult to define. For some it is lists of safe foods. For others it’s all about having energy to do what one wants to do in life for as long as possible. And there are a majority of people who don’t concern themselves with defining it.

It is the commercialization of nutrition and my interest in psychology that eventually interested me (besides my own self-experimentation and observations) in the psychological impact of nutrition, pre- and post-, on behavior.

I have found, in observation, that an idea a culture is attempting to define follows a process with patterns that can be developed into behavioral frameworks, which predicts the refinement process. It is the process of refining the definition of an idea that isolates or unites different groups of people. This process is similar to Max Weber’s idea of “rationalization” in the context of religion.

One cannot be down on people who are led to and fro by different dietary paradigms. This process is a consequence of rationalization driven by the unconscious. Likewise, one cannot be down on an entire culture defined by its government officials or religion. Its nature is what has allowed us to survive without the interconnection that now defines our world. Developed personality and individuality in the Jungian sense is a unique occurrence.

In the modern world there is less need for reliance on others. But there is still a need for passing on of knowledge, tradition, and wisdom, suitable for survival, social interactions, and going about daily activities. Science and the Internet are impacting cultural instinct, traditions, and wisdom through exposure. I view this exposure neutrally. Complete confidence on what others deem as fact is often a mistake just as being overly self-reliant and reinventing the wheel again is inefficient. There is a cautious balance to be struck, especially in a time when there is a shift in consciousness and the process of cultural diffusion is active.

An intelligent, thinking, and reasoning being must strike a balance between the two. It is this balancing act that allows cultural evolution to occur and new paradigms to develop which will be tested by successive generations. What works stays, what doesn’t work leaves; better ways of doing things slowly filter out older ways of doing things. New ways of thinking philosophize old traditions and religions. For example: Thomas Aquinas, applying Greek philosophy to biblical texts, or Martin Luther, nailing his grievances to the Catholic cathedral door.

These events happen when there is a shift in unconsciousness. And what follows is a revolution in cultural knowledge to try and rationalize why we did things the way we did in the past and why it is justified to change things for the future. Radicals entrenched in their beliefs usually, but not always, die in these shifts of thinking; literally or by sacrificing the personality. Being a martyr for a particular paradigm has never been a personally natural inclination. When the individual is cornered and experience is conflicted with lacquered beliefs, the individual is faced with options of entrenching themselves behind belief or taking steps to evolve in another direction. It is the collateral damage of opposing extreme views in groups of people that often drive cultural evolution. At some point we must put aside belief and continue moving forward. A fight to the death is not a viable option except for the delusional.

“We should not let ourselves be burnt for our opinions: we are not that sure of them. But perhaps for this: that we may have and change our opinions.” ~Nietzsche

What is difficult for the entrenched individual is not the new shift, but the shift that points to years or a life wasted and genuine interests forsaken. There is a saying: “You can’t teach an old dog new tricks.” Few people are so downright stubborn. But these defining qualities are common enough that most of us are familiar with these individuals.

Entrenching is not the new idea but rather the aversion to self-confessing an error approaching things in a new way.  The conflict does not arise out of the new idea but arises out of the individual. These individuals place too much power in words and ideas. These people are the real dangers in society—not the originators of new ideas. It takes much more than an individual to do anything with a dangerous idea, just as it takes much more than an individual to do something with a useful idea. Ideas have to be stated and different people must implement them before they can become a useful or dangerous reality.

Despite modern man’s large brain, the rational portion seems atrophied in most. This allows erroneous thought to pervade in popular culture and society, causing harm. Capitalistic,  mechanistic, and authoritarian thinking makes this easy to do.

Some ideas tend to have cyclical natures occurring and reoccurring throughout history, often shifted or changed slightly but still keeping their original essence or philosophy. Observations have personally demonstrated that ideas are cyclical simply because what is current is not satisfying and causes gas and bloating. When enough people smell the stink they become uneasy and start to look for new solutions.

People try old ideas, not simply for the sake of the new, but for the promise of something better (or curing chronic boredom).

Old ideas come and go and are cyclical for many reasons. One reason assumes there is validity to the idea, yet for whatever reason remains underdeveloped in that period of time. There have been plenty of ideas left undeveloped because of a requirement for a different field of science. Later, some of these ideas ended up being game changers in the modern era.

Another reason is simply that the idea was not valid. When people do try old, invalid ideas in their life, you will often find that these people are constantly trying to justify the validity of their dug up treasure. Foolishness is the virtue of the wise.

There is nothing vain about exploring history through a modern perspective and trying old approaches when modern and fringe approaches fail. Trying is one thing. Trying is not miserably “riding it out”. Loosely illustrated, trying means taking an interest in the cello and with every passing lesson there is improvement in both technical aspects and style; persistently trying means taking up the cello and despite best efforts never being able to complete the first lesson, despite trying for several weeks, months, or years. For those, the cello, despite intense interest, will always remain just an interest.

When something does not work for you, be bold, ask questions and seek answers.

“Possessing opinions is like possessing fish, assuming one has a fish pond.  One has to go fishing and needs some luck—then one has one’s own fish, one’s own opinions.  I am speaking of live opinions, of live fish.  Others are satisfied if they own a cabinet of fossils—and in their heads, convictions.” ~Nietzsche

Some thoughts on aspirin

Filip left a comment asking about aspirin, this was another one of those comments turned into post type deals.

So speaking of aspirin. There are some dots to connect here, and definitely some different trains of thought that you can ride, but have a look at the following articles and follow the paper trail.

First this:

Paterson, J. R., Baxter, G., Dreyer, J. S., Halket, J. M., Flynn, R., & Lawrence, J. R. (2008). Salicylic acid sans aspirin in animals and man: persistence in fasting and biosynthesis from benzoic acid. Journal of Agricultural and Food Chemistry, 56(24), 11648–52. doi:10.1021/jf800974z

“To examine the possibility of a gastrointestinal bacterial source for SA, two small groups of germ-free mice were assayed for SA. The pooled serum from six mice treated with neomycin, 100 mg/kg/day, for 4 days before sacrifice had a slightly higher concentration of SA in serum (0.309 μmol/L) than the pooled serum sample from six untreated animals (0.268 μmol/L). Another germ-free animal model studied was the Sprague−Dawley rat delivered by caesarean section, reared in a sterile environment, and fed sterilized food. A group of eight such germ-free animals had a pooled serum SA level of 0.166 μmol/L, approximately 2.5 times greater than the pooled serum salicylic acid level of 0.069 μmol/L from a group of control animals. The net effect of minimizing or eliminating a contribution from colonic bacteria in these animal models was therefore enhancement of serum SA levels in the host animal.”

“Results of SA levels in a large variety of animals showed that those species regarded as primarily carnivorous had levels comparable to those measured in herbivores. Some bacteria, notably mycobacterial, yersinia, and pseudomonas species, synthesize SA to enhance iron chelation, so there was a possibility that gut, particularly colonic, bacteria might be the source of SA not readily explicable by lack of dietary exposure. However, preliminary study of two germ-free animal models reported here showed the net effect of minimizing or eliminating a contribution from colonic bacteria was, in fact, an increase in serum SA levels.”

Then there is this interesting little snippet:

A review of the literature by Heiby cites an interesting experiment on rat that perhaps shed some light on the risk of stomach bleeding. Aspirin was far more toxic to rats fed a high carbohydrate diet than it was to rats fed a high protein diet. A deficiency of magnesium increased this toxicity, especially in pregnant animals. Gastric ulceration in non-pregnant rats was very severe on the high carbohydrate diet (14, p. 255). On the basis of these animal studies, it is interesting to speculate that the apparent increase over the last half-century in the risk of stomach bleeding due to aspirin use may be the result of the large increase in dietary carbohydrate during the same period.

I originally came across that here. But as it is written there, there are differences in the in-text citations and I was not able to track down a paper to verify that observation.

George has some thoughts on aspirin as well.

And Peter mentions this (there is also a bit on coconut oil in the following paragraph if you follow the link, for the few that asked about that):

Anyone reading Chris or Emma’s blogs will realise that aspirin, and possibly other related salycilates from plants, cause the pancreas the secrete extra insulin. Avoid. Gluten and wheat germ agglutinin (both from wheat, barley and rye) are (or contain) insulin mimetics, avoid. Casein stimulates insulin secretion, avoid. Pharmaceutical NSAID probably do the same as salycilates, avoid if possible.

O.k. Now for some of my thoughts.

As for daily use, I don’t know. In general, I like things that uncouple the mitochondria. However, to speculate, there is a difference between an energy substrate that uncouples mitochondria and a compound that uncouples mitochondria. I think that the latter can deplete ATP to an extent that is undesirable (which would be dose dependent)., but I can also think of some situations where that type of uncoupling would confer some desired effects. In my endotoxin and fructose post I talked about depleted ATP impacting tight-junction (occluding junctions or zonulae occludentes) integrity. Which makes this interesting. Whereas some saturated fat (e.g. palmitic acid) which also uncouples the mitochondria maintains tight-junction integrity.

Speculating some more, a lot of people get nosebleeds from aspirin use. When you get a nose bleed, you notice it, blood dripping out of your nose, that to me is like a rupture. You don’t notice one or two blood cells on your upper lip, you notice a good amount of blood coming out. That is a tremendous failure in the integrity of the tight-junctions in capillaries. Now imagine consuming some fructose (which is depleting ATP too and probably weakening tight-junctions). It is hardening your arteries and when they are nice and calcified, lets say you take some aspirin and one of your calcified capillaries “fractures”, but see now your blood is thin and blood comes spouting out. Sounds quite like an aneurysm.

Because fructose isn’t going to calcify your vascular system overnight, I’m sure little microscopic breaks happen here and there in the tight-junctions which get clotted. Imagine a wooden handrail that thousands of people have run their hands across, some parts keep their shine, other parts chip off and loose their luster. It’s a handrail with character. Or have you ever filled a balloon up and over time you notice certain parts of it are thin and thick as the air diffuses out? Between the clotting and inflammation, I’d say damaged parts of the vascular system might swell much like the thick and thin sections of a balloon under uneven pressure caused by variations in thinness and thickness of vascular/capillary walls. Have you ever untied a worn out balloon that has been sitting in the sun and tried to blow it back up again? It’s never quite the same, and I would imagine the brittleness from the deteriorated rubber would be an interesting way to think about the pathophysiology of a nose bleed or aneurysm. It just fractures at a weak point and pops if you blow it up big enough e.g. a sudden increase in heart rate.

O.k. now this brings me back to aspirin. Sometimes when I’m writing with an old fashioned pencil the tip breaks off in a way where you can kind of fit it back into the pencil and continue writing with it. That of course is not very versatile because you almost always have to write with less pressure and kind of turn the angle of the pencil where the lead broke to keep the bit of lead in. If you have some clots just waiting to break off it would make sense to lower the viscosity of your blood so as not to disturb them. I would say aspirin would be pretty useful for that.

Anyway, I think aspirin might be useful to solve some acute symptoms. And hey, maybe a low-dose aspirin is legit. But don’t forget about the first paper. Like I said, there are a few different trains of thought to ride. Preventing an “aspirin deficiency” would be a better bet. At least that is what I think.

Fructose and Endotoxin

“What was it Oscar Wilde said? ‘The well-bred contradict other people, the wise contradict themselves.’ If you have insight into a body of knowledge, you are going to discover science that contradicts your view. You either modify your model, which if it is sound will survive and benefit from such adjustments, or you put on well-bred airs.

This is the distinction between science, where you are interested in learning new things, and wise enough to contradict yourself as a result, and dogma, accepting which will force you to contradict others (or indeed censor them) unless they agree with you.” ~George Henderson

There was a time when I had a fairly liberal view on the issue of sugar. Sugar resurged when people seemed to be having all kinds of problems with low carbohydrate diets. And to a great many people sugar seemed to resolve some issues. I cannot debate that. I also cannot vouch for the pros or cons of long-term use of liberal amounts of sugar in other people. Some people claim it has helped them to their surprise, others have claimed it has destroyed their health. It is a paradox.

However, I can vouch for myself and a few other people that sugar without a doubt  had an absolute negative impact on my/their health in the long-term. Sugar can be useful in some instances e.g. emergency medicine. No doubt that in a calorically malnourished individual sugar can have seemingly positive effects. Despite that, I think there are better and safer ways, lest you want to risk re-feeding syndrome.

But here I want to discuss something briefly that I’ve observed. A quick browse around Ray Peat centered forums and you find that a lot of people have digestive issues. They eat sugar, and if they only eat sugar they seem to do o.k. for a while until they start to introduce new food. Foods that I would consider quite normal. I’m sure there are people who claim that sugar improved their digestion. Fair enough.

I’ve always found the issue of endotoxin intriguing especially when it comes to “leaky gut”. The entire issue of endotoxin is an interesting one. In the end we probably die from sepsis and hypoxia, if something else doesn’t get you first. Yet endotoxin seems to play an important role in immune health. It’s the kind of thing where you want to be in control of it. You don’t want none and you don’t want too much for too long. And of course somewhere in one on my posts I’m quite sure I linked to a study discussing the possibility of a hormonal role for endotoxin.

Endotoxin is not really something that I worry about. Saturated fat is quite good at keeping the tight junctions healthy and functioning. There are a few people around the web who have discussed this. So I’m not going to rehash.

Anyway, there are people whose digestive problems get worse when they eat sugar. There are host of reasons and angles really to look at this. But I want to focus on the effect of fructose. Fructose is quite effective at depleting ATP (Mayes, 1993). That is not a good thing considering that when ATP is depleted, the cells will enter a stressed state. No ATP=comprised cell function. This would have a ripple effect throughout an organism long-term causing all kinds of systematic symptoms which essentially stems from inefficient or inhibited respiration.

I would imagine that depleted ATP would compromise tight junction function. Something which would probably lead to endotoxin “leaking” everywhere. So here you have a situation where when tight junction function is compromised, you literally have LPS poisoning tissue. On the other side of the coin you also have the effect where fructose seems to “tighten” capillaries (Chakir, 1998; Yuan et al., 2007). Some people have viewed this as a good thing. I view it negatively. I want my capillaries to maintain their elasticity and permeability. I want my tissues to always be able to have efficient gas exchange and waste removal. One can easily see how tightened capillaries can cause hypoxia in peripheral tissues. Which of course is something we see in diabetics, not to mention hypertension. As well, I would imagine this could increase systematically serum levels of endotoxin.

You want to maintain the elasticity of the vascular system. You want it to be able to “breathe” properly. One of the sites of endotoxin detoxification is in the lungs. If your capillaries are hardened, detoxification of endotoxin is compromised. Once again, a feature of diabetes induced by fructose is endotoxemia (Kavanagh et al., 2013).

Another feature of fructose feeding is also hyperinsulinemia/insulin resistence (of the wrong sort) (Chakir, 1998). Fructose probably hardens the arteries. If you eat sugar (which is fructose and glucose), fructose will eventually have the effect of hardening the arteries, thus blocking insulin from transporting the glucose bit to where it belongs.

I would say for me personally it is impossible to maintain a liberal disposition with fructose, I can definitely see some cases where small amounts of it could have a potential hormetic effect. But in the long term I think liberal use of fructose is unwise.

Aside: It is interesting to note that some lactic acid bacteria strains protect from endotoxin (Nanji, Khettry, & Sadrzadeh, 1994).

References

Chakir, M. (1998). Reduction of Capillary Permeability in the Fructose-Induced Hypertensive Rat. American Journal of Hypertension, 11(5), 563–569. doi:10.1016/S0895-7061(97)00411-1

Impaired insulin transcapillary transport and the subsequent decrease in insulin delivery to target organs have been suggested to play a role in insulin resistance. These defects were studied in fructose-fed rats, an animal model with insulin resistance. For this study, male Sprague-Dawley rats were fed with either a 60% fructose enriched (F) or a standard chow diet (N) for a total of 2, 4, or 8 weeks. Capillary permeability to albumin was assessed at the end of each dietary period by quantifying the extravasation of albumin-bound Evans blue (EB) dye in different organs. Unanesthetized animals were injected with Evans blue dye (20 mg/kg) in the caudal vein 10 min before being killed and EB dye was extracted by formamide from selected organs collected after exsanguination. As expected, rats had an increase in blood pressure upon feeding with fructose at 4 and 8 weeks (F, 149 +/- 3 mm Hg; N, 139 +/- 3 mm Hg; P < .05). Using this technique, we showed a 56% and a 51% reduction in capillary permeability in skeletal muscles at 4 and 8 weeks of fructose feeding, respectively (4 weeks: N, 44.5 +/- 5.0 microg/g of dry tissue; F, 19.8 +/- 4.2 microg/g of dry tissue; P < .01 and 8 weeks: N, 23.3 +/- 3.7 microg/g of dry tissue; F, 11.3 +/- 4.0 microg/g of dry tissue; P < .05). Similar changes were observed at 4 weeks in the thoracic aorta (N, 82.8 +/- 8.8 microg/g of dry tissue; F, 53.0 +/- 5.1 microg/g of dry tissue; P < .02) and skin (N, 36.0 +/- 5.3 microg of dry tissue; F, 15.0 +/- 2.3 microg/g of dry tissue; P < .02) and at 8 weeks in the liver (N, 107.5 +/- 4.3 microg/g of dry tissue; F, 80.9 +/- 3.2 microg/g of dry tissue; P < .01). In conclusion, fructose feeding is accompanied by a significant and selective reduction of Evans blue leakage primarily in skeletal muscle and liver, and transiently in the skin and aorta, consistent with a role for decreased tissue insulin delivery in insulin resistance.

Kavanagh, K., Wylie, A. T., Tucker, K. L., Hamp, T. J., Gharaibeh, R. Z., Fodor, A. A., & Cullen, J. M. C. (2013). Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. The American journal of clinical nutrition, 98(2), 349–57. doi:10.3945/ajcn.112.057331

BACKGROUND: Controversy exists regarding the causative role of dietary fructose in obesity and fatty liver diseases. Clinical trials have indicated that negative health consequences may occur only when fructose is consumed within excess calories. Animal studies have suggested that fructose impairs intestinal integrity and leads to hepatic steatosis (HS). OBJECTIVES: We assessed nonhuman primates after chronic ad libitum and short-term calorically controlled consumption of a high-fructose (HFr), low-fat diet (24% of calories). Microbial translocation (MT), microbiome, and metabolic health indexes were evaluated. DESIGN: Seventeen monkeys fed 0.3–7 y of an HFr ad libitum diet were compared with 10 monkeys fed a low-fructose, low-fat diet (control). Ten middle-aged, weight-stable, fructose-naive monkeys were stratified into HFr and control groups fed for 6 wk at caloric amounts required to maintain weight stability. Metabolic endpoints, feces, liver, small and large intestinal biopsies, and portal blood samples were collected. RESULTS: Monkeys allowed ad libitum HFr developed HS in contrast to the control diet, and the extent of ectopic fat was related to the duration of feeding. Diabetes incidence also increased. Monkeys that consumed calorically controlled HFr showed significant increases in biomarkers of liver damage, endotoxemia, and MT indexes and a trend for greater hepatitis that was related to MT; however, HS did not develop. CONCLUSIONS: Even in the absence of weight gain, fructose rapidly causes liver damage that we suggest is secondary to endotoxemia and MT. HS relates to the duration of fructose consumption and total calories consumed. These data support fructose inducing both MT and ectopic fat deposition in primates.

Mayes, P. A. (1993). Intermediary metabolism of fructose. The American journal of clinical nutrition, 58(5 Suppl), 754S–765S. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8213607

Most of the metabolic effects of fructose are due to its rapid utilization by the liver and it by-passing the phosphofructokinase regulatory step in glycolysis, leading to far reaching consequences to carbohydrate and lipid metabolism. These consequences include immediate hepatic increases in pyruvate and lactate production, activation of pyruvate dehydrogenase, and a shift in balance from oxidation to esterification of nonesterified fatty acids, resulting in increased secretion of very-low-density-lipoprotein (VLDL). These effects are augmented by long-term absorption of fructose, which causes enzyme adaptations that increase lipogenesis and VLDL secretion, leading to triglyceridemia, decreased glucose tolerance, and hyperinsulinemia. Acute loading of the liver with fructose causes sequestration of inorganic phosphate in fructose-1-phosphate and diminished ATP synthesis. Consequently, the inhibition by ATP of the enzymes of adenine nucleotide degradation is removed and uric acid formation accelerates with consequent hyperuricemia. These effects are of particular significance to potentially hypertriglyceridemic or hyperuricemic individuals.

Nanji, A. A., Khettry, U., & Sadrzadeh, S. M. H. (1994). Lactobacillus Feeding Reduces Endotoxemia and Severity of Experimental Alcoholic Liver (Disease). Experimental Biology and Medicine, 205(3), 243–247. doi:10.3181/00379727-205-43703

We have previously shown a relationship between plasma endotoxin levels and severity of alcoholic liver injury in the intragastric feeding rat model. We attempted to reduce both circulating endotoxin and liver injury in this model by administering a lactobacillus strain (species GG) which survives for prolonged periods in the gastrointestinal tract. Male Wistar rats were fed ethanol and liquid diet containing corn oil (CO+E). Another group of animals (CO+E+L) received the diet containing ethanol plus a daily bolus of lactobacilli GG concentrate (10(10) CFU). All animals were sacrificed after one month. All animals had plasma endotoxin measurements and evaluation of severity of pathologic changes in the liver. The weight gain and blood alcohol levels were similar in both groups. The mean +/- SE of the pathology score was significantly higher (3.4 +/- 0.85) in the CO+E group compared to the CO+E+L group (0.5 +/- 0.3, P < 0.01). The virtual absence of pathologic changes in the latter group was accompanied by significantly lower endotoxin levels (8.4 +/- 2.9 pg/ml in CO+E+L group vs 48.3 +/- 7.8 pg/ml in CO+E group, P < 0.01). Feeding of strains of lactobacilli that survive in the gastrointestinal tract reduces endotoxemia and alcohol-induced liver injury in the rat. Lactobacillus species GG provides a potential nontoxic form of therapy for both endotoxemia and alcoholic liver disease.

Yuan, S. Y., Breslin, J. W., Perrin, R., Gaudreault, N., Guo, M., Kargozaran, H., & Wu, M. H. (2007). Microvascular permeability in diabetes and insulin resistance. Microcirculation (New York, N.Y. : 1994), 14(4-5), 363–73. doi:10.1080/10739680701283091

Microvascular barrier injury has been implicated in the initiation and progress of end organ complications of diabetic mellitus. Plasma leakage and fluid retention are seen in various tissues of diabetic patients or animals at the early stages of the disease before structural microangiopathy can be detected. Clinical and experimental evidence suggests that hyperglycemia, often accompanied with insulin deficiency or insulin resistance, causes impaired autoregulation and increased permeability in microvessels. Multiple molecular pathways have been identified as contributors to the altered fluid homeostasis, including increased polyol flux that promotes oxidative stress, advanced glycation that leads to carbonyl stress, and excessive glucose metabolism that results in protein kinase C activation. These abnormal metabolic activities are associated with the production of pro-inflammatory cytokines and growth factors, which can stimulate an array of signaling reactions and structural changes at the endothelial barrier and ultimately cause microvascular leakage. Interventions that manipulate these metabolic and inflammatory pathways have demonstrated efficacy in delaying the progress of diabetic microvascular complications; however, their direct effects and mechanisms of action on the microcirculation remain elusive. A deeper understanding of the molecular basis of diabetes-induced endothelial barrier dysfunction will provide a framework for the development of new therapeutic targets to treat this chronic and debilitating disease process.

Calcium to phosphorus ratio

“Of the eighteen elements of which the human body is composed, all of which are presumably essential, several are needed in very small quantities. A few are required in liberal quantities. The normal adult needs to receive from the foods eaten one-half to one gram of calcium or lime per day. Few people receive more than one-half of the minerals present in the food. The requirements of phosphorus are approximately twice this amount. Of iron we need from one-seventh to one-third of a gram per day. Smaller amounts than these are required of several other elements. In order to utilize these minerals, and to build and maintain the functions of various organs, definite quantities of various organic catalysts which act as activating substances are needed. These include the known and unknown vitamins.”

Interesting that Price observed calcium to phosphorus ratio of 1:2 in healthy traditional tribes. Undoubtedly it would be hard to flip this ratio unless you were a dairy herding tribe.

References

Price, W. A. (2008). Nutrition and physical degeneration. La Mesa, CA: Price-Pottenger Nutrition Foundation.

 

What to eat?

7-SAV137-perfectroast-400x330One of things that many find difficult with Dr. Peat is that you can read pages and pages of his ideas and at the end of it you basically are left guessing what it is that you are going to eat. Never mind the inaccuracies. People like Danny Roddy and forums like Peatarian, Ray Peat forum and Co. have attempted to make recommendations through their interpretations. There are some interesting graphics and the sort all around the web, based on those ideas.

I’m all for theory and all that jazz and cool diagrams and inverted pyramids, but really, like I have written before in various places, most people are interested in nutrition because they are sick, not because they want to become nutritionists. They just want to get better and get on with their lives. In that sense I believe in something practical.

My unimpressive advice is to source your diet from cattle. This means eating things like steaks, roasted bones (the marrow), liver, oxtails, suet, tallow, (insert whatever part of the cow you fancy here). Those things are good to eat cooked however you like. This also means that all dairy such as cheese (fresh or aged), yogurt of any type e.g. Kefir, FAGE, (insert any type of plain full fat yogurt here), sour cream, whole milk, cream, half and half, butter, etc. Although I’m using the cow here, as a specific example, really, any ruminant animal and their milk and milk products are good to eat e.g. sheep, bison, goat, etc.

Eat till you are full and drink as much milk as you like. Suet is useful for a lot of things, a lot of people like to use coconut oil, but suet is cheaper in most cases and I think it is better to use along with butter. I don’t recommend coconut oil.

There is no doubt that you can carve out a fine existence living off of those things.

Things to minimize: starch and sugar. Non-starchy vegetables are a fine and welcome addition to any stew as well as whatever spices and seasonings you like. For example, carrots, celery, leek, garlic, onion, (those are just random vegetables, no, there is no reason for me mentioning them, and no they do not hold magical power), all of these things you will find in hearty stews, as well as seasonings for your meat which adds wonderful flavor. Boiled greens are also good to eat, they can be boiled in water with a pinch of salt, cooked until they have a pleasant taste, drained, and then covered with a bit of cream or butter.

The major source of CHO will be coming from dairy. There is no magic number of carbohydrates I recommend I just recommend that you drink a fair amount of milk something like 1.5-2+ quarts per day. Lactose in milk is sufficient to supply the amount of glucose you need. Galactose is also unique in that it enhances OXPHOS and reverses the inhibitive effect on respiration caused by glucose and fructose (Aguer et al., 2011; Chico, Olavarría, & de Castro, 1978; Diaz-Ruiz, Rigoulet, & Devin, 2011; Dott, Mistry, Wright, Cain, & Herbert, 2014; Marroquin, Hynes, Dykens, Jamieson, & Will, 2007; Sussman, Erecińska, & Wilson, 1980).

Eat till you feel satisfied, eat when you are hungry, and don’t count anything, don’t worry about phosphate (Hettleman, Sabina, Drezner, Holmes, & Swain, 1983), don’t worry about trying to get a certain number of this or that. Focus on getting creative with the infinite amount of dishes you can prepare with these rich ingredients.

Coffee, chocolate, beer, wine, and tea, are always welcome, and I think nicotine is useful.

Salt your food to taste (MENEELY, TUCKER, & DARBY, 1952; MENEELY, TUCKER, DARBY, & AUERBACH, 1953).

References

Aguer, C., Gambarotta, D., Mailloux, R. J., Moffat, C., Dent, R., McPherson, R., & Harper, M.-E. (2011). Galactose enhances oxidative metabolism and reveals mitochondrial dysfunction in human primary muscle cells. PloS one, 6(12), e28536. doi:10.1371/journal.pone.0028536

BACKGROUND: Human primary myotubes are highly glycolytic when cultured in high glucose medium rendering it difficult to study mitochondrial dysfunction. Galactose is known to enhance mitochondrial metabolism and could be an excellent model to study mitochondrial dysfunction in human primary myotubes. The aim of the present study was to 1) characterize the effect of differentiating healthy human myoblasts in galactose on oxidative metabolism and 2) determine whether galactose can pinpoint a mitochondrial malfunction in post-diabetic myotubes. METHODOLOGY/PRINCIPAL FINDINGS: Oxygen consumption rate (OCR), lactate levels, mitochondrial content, citrate synthase and cytochrome C oxidase activities, and AMPK phosphorylation were determined in healthy myotubes differentiated in different sources/concentrations of carbohydrates: 25 mM glucose (high glucose (HG)), 5 mM glucose (low glucose (LG)) or 10 mM galactose (GAL). Effect of carbohydrates on OCR was also determined in myotubes derived from post-diabetic patients and matched obese non-diabetic subjects. OCR was significantly increased whereas anaerobic glycolysis was significantly decreased in GAL myotubes compared to LG or HG myotubes. This increased OCR in GAL myotubes occurred in conjunction with increased cytochrome C oxidase activity and expression, as well as increased AMPK phosphorylation. OCR of post-diabetic myotubes was not different than that of obese non-diabetic myotubes when differentiated in LG or HG. However, whereas GAL increased OCR in obese non-diabetic myotubes, it did not affect OCR in post-diabetic myotubes, leading to a significant difference in OCR between groups. The lack of an increase in OCR in post-diabetic myotubes differentiated in GAL was in relation with unaltered cytochrome C oxidase activity levels or AMPK phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results indicate that differentiating human primary myoblasts in GAL enhances aerobic metabolism. Because this cell culture model elicited an abnormal response in cells from post-diabetic patients, it may be useful in further studies of the molecular mechanisms of mitochondrial dysfunction.

Chico, E., Olavarría, J. S., & de Castro, I. N. (1978). Crabtree effect induced by fructose in isolated hepatocytes from fed rats. Biochemical and biophysical research communications, 83(4), 1422–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/29632

Diaz-Ruiz, R., Rigoulet, M., & Devin, A. (2011). The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression. Biochimica et biophysica acta, 1807(6), 568–76. doi:10.1016/j.bbabio.2010.08.010

During the last decades a considerable amount of research has been focused on cancer. Recently, tumor cell metabolism has been considered as a possible target for cancer therapy. It is widely accepted that tumors display enhanced glycolytic activity and impaired oxidative phosphorylation (Warburg effect). Therefore, it seems reasonable that disruption of glycolysis might be a promising candidate for specific anti-cancer therapy. Nevertheless, the concept of aerobic glycolysis as the paradigm of tumor cell metabolism has been challenged, as some tumor cells exhibit high rates of oxidative phosphorylation. Mitochondrial physiology in cancer cells is linked to the Warburg effect. Besides, its central role in apoptosis makes this organelle a promising “dual hit target” to selectively eliminate tumor cells. From a metabolic point of view, the fermenting yeast Saccharomyces cerevisiae and tumor cells share several features. In this paper we will review these common metabolic properties as well as the possible origins of the Crabtree and Warburg effects.

Dott, W., Mistry, P., Wright, J., Cain, K., & Herbert, K. E. (2014). Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity. Redox biology, 2, 224–33. doi:10.1016/j.redox.2013.12.028

Mitochondrial toxicity is increasingly being implicated as a contributing factor to many xenobiotic-induced organ toxicities, including skeletal muscle toxicity. This has necessitated the need for predictive in vitro models that are able to sensitively detect mitochondrial toxicity of chemical entities early in the research and development process. One such cell model involves substituting galactose for glucose in the culture media. Since cells cultured in galactose are unable to generate sufficient ATP from glycolysis they are forced to rely on mitochondrial oxidative phosphorylation for ATP generation and consequently are more sensitive to mitochondrial perturbation than cells grown in glucose. The aim of this study was to characterise cellular growth, bioenergetics and mitochondrial toxicity of the L6 rat skeletal muscle cell line cultured in either high glucose or galactose media. L6 myoblasts proliferated more slowly when cultured in galactose media, although they maintained similar levels of ATP. Galactose cultured L6 cells were significantly more sensitive to classical mitochondrial toxicants than glucose-cultured cells, confirming the cells had adapted to galactose media. Analysis of bioenergetic function with the XF Seahorse extracellular flux analyser demonstrated that oxygen consumption rate (OCR) was significantly increased whereas extracellular acidification rate (ECAR), a measure of glycolysis, was decreased in cells grown in galactose. Mitochondria operated closer to state 3 respiration and had a lower mitochondrial membrane potential and basal mitochondrial O2 (•-) level compared to cells in the glucose model. An antimycin A (AA) dose response revealed that there was no difference in the sensitivity of OCR to AA inhibition between glucose and galactose cells. Importantly, cells in glucose were able to up-regulate glycolysis, while galactose cells were not. These results confirm that L6 cells are able to adapt to growth in a galactose media model and are consequently more susceptible to mitochondrial toxicants.

Hettleman, B. D., Sabina, R. L., Drezner, M. K., Holmes, E. W., & Swain, J. L. (1983). Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice. The Journal of clinical investigation, 72(2), 582–9. doi:10.1172/JCI111006

The basis for skeletal muscle dysfunction in phosphate-deficient patients and animals is not known, but it is hypothesized that intracellular phosphate deficiency leads to a defect in ATP synthesis. To test this hypothesis, changes in muscle function and nucleotide metabolism were studied in an animal model of hypophosphatemia. Mice were made hypophosphatemic through restriction of dietary phosphate intake. Gastrocnemius function was assessed in situ by recording isometric tension developed after stimulation of the nerve innervating this muscle. Changes in purine nucleotide, nucleoside, and base content of the muscle were quantitated at several time points during stimulation and recovery. Serum concentration and skeletal muscle content of phosphorous are reduced by 55 and 45%, respectively, in the dietary restricted animals. The gastrocnemius muscle of the phosphate-deficient mice fatigues more rapidly compared with control mice. ATP and creatine phosphate content fall to a comparable extent during fatigue in the muscle from both groups of animals; AMP, inosine, and hypoxanthine (indices of ATP catabolism) appear in higher concentration in the muscle of phosphate-deficient animals. Since total ATP use in contracting muscle is closely linked to total developed tension, we conclude that the comparable drop in ATP content in association with a more rapid loss of tension is best explained by a slower rate of ATP synthesis in the muscle of phosphate-deficient animals. During the period of recovery after muscle stimulation, ATP use for contraction is minimal, since the muscle is at rest. In the recovery period, ATP content returns to resting levels more slowly in the phosphate-deficient than in the control animals. In association with the slower rate of ATP repletion, the precursors inosine monophosphate and AMP remain elevated for a longer period of time in the muscle of phosphate-deficient animals. The slower rate of ATP repletion correlates with delayed return of normal muscle contractility in the phosphate-deficient mice. These studies suggest that the slower rate of repletion of the ATP pool may be the consequence of a slower rate of ATP synthesis and this is in part responsible for the delayed recovery of normal muscle contractility.

Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D., & Will, Y. (2007). Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicological sciences : an official journal of the Society of Toxicology, 97(2), 539–47. doi:10.1093/toxsci/kfm052

Many highly proliferative cells generate almost all ATP via glycolysis despite abundant O(2) and a normal complement of fully functional mitochondria, a circumstance known as the Crabtree effect. Such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, such as the inhibitors rotenone, antimycin, oligomycin, and compounds like carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), that uncouple the respiratory electron transfer system from phosphorylation. These cells are also resistant to the toxicity of many drugs whose deleterious side effect profiles are either caused, or exacerbated, by impairment of mitochondrial function. Drug-induced mitochondrial toxicity is shown by members of important drug classes, including the thiazolidinediones, statins, fibrates, antivirals, antibiotics, and anticancer agents. To increase detection of drug-induced mitochondrial effects in a preclinical cell-based assay, HepG2 cells were forced to rely on mitochondrial oxidative phosphorylation rather than glycolysis by substituting galactose for glucose in the growth media. Oxygen consumption doubles in galactose-grown HepG2 cells and their susceptibility to canonical mitochondrial toxicants correspondingly increases. Similarly, toxicity of several drugs with known mitochondrial liabilities is more readily apparent in aerobically poised HepG2 cells compared to glucose-grown cells. Some drugs were equally toxic to both glucose- and galactose-grown cells, suggesting that mitochondrial impairment is likely secondary to other cytotoxic mechanisms.

MENEELY, G. R., TUCKER, R. G., & DARBY, W. J. (1952). Chronic sodium chloride toxicity in the albino rat. I. Growth on a purified diet containing various levels of sodium chloride. The Journal of nutrition, 48(4), 489–98. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/13000527

MENEELY, G. R., TUCKER, R. G., DARBY, W. J., & AUERBACH, S. H. (1953). Chronic sodium chloride toxicity in the albino rat. II. Occurrence of hypertension and of a syndrome of edema and renal failure. The Journal of experimental medicine, 98(1), 71–80. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2136278&tool=pmcentrez&rendertype=abstract

Sustained arterial hypertension developed in male, albino rats chronically fed diets rich in sodium chloride with demineralized drinking water available ad libitum. After 12 months of the experimental regimen a positive, linear correlation (r = 0.91) was found between the systolic blood pressure and the concentration of sodium chloride in the diet. A syndrome of edema and renal failure was observed in 18 per cent of the group fed at the level of 7.0 to 9.8 per cent of sodium chloride. Significant histologic changes occurred in the kidneys and certain other organs in rats consuming rations containing these levels of NaCl. The relative volume of the radiosodium space was increased in the rat by high dietary sodium chloride.

Sussman, I., Erecińska, M., & Wilson, D. F. (1980). Regulation of cellular energy metabolism: the Crabtree effect. Biochimica et biophysica acta, 591(2), 209–23. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7397121

The Crabtree effect (inhibition of respiration by glycolysis) is observed in cells with approximately equal glycolytic and respiratory capacities for ATP synthesis. Addition of glucose to aerobic suspensions of glucose-starved cells (Sarcoma 180 ascites tumor cells) causes a burst of respiration and lactate production due to ATP utilization for glucose phosphorylation by hexokinase and phosphofructokinase. This burst of activity is followed by inhibition of both respiration and glycolysis, the former to below the value before glucose addition (Crabtree effect). Both the respiratory rate and the glycolytic flux appear to be regulated by the cytosolic [ATP]/[ADP][Pi] albeit by completely different mechanisms. Respiration is regulated by the free energy of hydrolysis of ATP, such that the rate increases as the [ATP]/[ADP][Pi] decreases and decreases as the [ATP]/[adp][Pi] increases. The regulatory enzymes of glycolysis are activated by ADP (AMP) and Pi and inhibited by ATP. Thus both respiration and glycolysis increase or decrease as the [ATP]/[ADP][Pi] decreases or increases. The parallel regulation of both ATP-producing pathways by this common metabolite ratio is consistent with the cytoplasmic [ATP]/[ADP][Pi] being an important determinant of homeostatic regulation of cellular energy metabolism.

Low phosphorus: What to do, what to do?

Another shorter one.

As we can see, low phosphorus makes people miserable (De Lorenzo, Hargreaves, & Kakkar, 1998; Land et al., 1993; Laroche, 2001).

There are some mentions of oral supplements and such but I think it is best just to eat meat. And continue eating your dairy.

References

De Lorenzo, F., Hargreaves, J., & Kakkar, V. V. (1998). Phosphate diabetes in patients with chronic fatigue syndrome. Postgraduate medical journal, 74(870), 229–32. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2360873&tool=pmcentrez&rendertype=abstract

Phosphate depletion is associated with neuromuscular dysfunction due to changes in mitochondrial respiration that result in a defect of intracellular oxidative metabolism. Phosphate diabetes causes phosphate depletion due to abnormal renal re-absorption of phosphate be the proximal renal tubule. Most of the symptoms presented by patients with phosphate diabetes such as myalgia, fatigue and mild depression, are also common in patients with chronic fatigue syndrome, but this differential diagnosis has not been considered. We investigated the possible association between chronic fatigue syndrome and phosphate diabetes in 87 patients who fulfilled the criteria for chronic fatigue syndrome. Control subjects were 37 volunteers, who explicitly denied fatigue and chronic illness on a screening questionnaire. Re-absorption of phosphate by the proximal renal tubule, phosphate clearance and renal threshold phosphate concentration were the main outcome measures in both groups. Of the 87 patients with chronic fatigue syndrome, nine also fulfilled the diagnostic criteria for phosphate diabetes. In conclusion, we report a previously undefined relationship between chronic fatigue syndrome and phosphate diabetes. Phosphate diabetes should be considered in differential diagnosis with chronic fatigue syndrome; further studies are needed to investigate the incidence of phosphate diabetes in patients with chronic fatigue syndrome and the possible beneficial effect of vitamin D and oral phosphate supplements.

Land, J. M., Kemp, G. J., Taylor, D. J., Standing, S. J., Radda, G. K., & Rajagopalan, B. (1993). Oral phosphate supplements reverse skeletal muscle abnormalities in a case of chronic fatigue with idiopathic renal hypophosphatemia. Neuromuscular disorders : NMD, 3(3), 223–5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8400863

A 57-yr-old man presented with a long history of undiagnosed fatigue but no evidence of bone disease. He was noted to have hypophosphatemia due to an idiopathic phosphaturia. Marked abnormalities of exercising skeletal muscle detected by phosphorus magnetic resonance spectroscopy and by plasma metabolite measurements were consistent with mitochondrial dysfunction. Oral phosphate supplements restored plasma phosphate concentration and muscle biochemistry to normal and produced considerable improvement in symptoms and exercise tolerance, although the phosphate concentration in muscle was only marginally low and increased little by treatment. We conclude that hypophosphatemia should be excluded in unexplained fatigue.

Laroche, M. (2001). Phosphate, the renal tubule, and the musculoskeletal system. Joint, bone, spine : revue du rhumatisme, 68(3), 211–5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11394620

A component of ATP, phosphate is at the hub of the energy-related mechanisms operative in muscle cells. Together with calcium, phosphate is involved in bone tissue mineralization: thus, a chronic alteration in the metabolism of phosphate can induce bone and joint disorders. Diagnosis of chronic hypophosphatemia. Serum phosphate, calcium, and creatinine should be assayed simultaneously. Serum calcium is increased in hypophosphatemia caused by hyperparathyroidism and decreased in osteomalacia. Urinary phosphate excretion should be measured in patients with a normal serum calcium level and a serum phosphate level lower than 0.80 mmol/L. A decrease in urinary phosphate excretion to less than 10 mmol/24 h strongly suggests a gastrointestinal disorder, such as malabsorption, antacid use, or chronic alcohol abuse. In patients with a urinary phosphate excretion greater than 20 mmol/24 h, the maximal rate of tubular reabsorption of phosphate (TmPO4) and the ratio of TmPO4 over glomerular filtration rate (GFR) should be determined to look for phosphate diabetes. Manifestations and causes of phosphate diabetes in adults. Moderately severe phosphate diabetes in adults manifests as chronic fatigue, depression, spinal pain, and polyarthralgia, with osteoporosis ascribable to increased bone resorption. Although many cases are idiopathic, investigations should be done to look for X-linked vitamin D-resistant rickets missed during childhood, a mesenchymatous tumor, or Fanconi’s syndrome with renal wasting of phosphate, glucose, and amino acids. Management of phosphate diabetes. Phosphate supplementation and, in patients with normal urinary calcium excretion, calcitriol produce some improvement in the symptoms and increase the bone mineral density. Whether dipyramidole is clinically effective remains unclear.

Energy and Structure: Phosphorus

Short post.

Ah, phosphorus. Sounds like the name of a Greek mythology character. Before I discuss glucose and carbon dioxide in response to some comments on the last post, I wanted to discuss a bit about phosphorus.

Meat is good, especially ruminant meat, all the bits you love and all the bits that induce a gag reflex, especially when you can get a hold of the grass fed sorts.

Phosphorus is important.

ATP is good. Adenosine triphosphate.

A lot of readers who read this blog are concerned about calcium and phosphorus. There is this thought pattern that less phosphate is better, which leads to phosphate is harmful, which eventually leads to a less is more type of mentality i.e. restriction.

Your ability to produce ATP is pretty important. You don’t just consume glucose and then phosphate appears from nowhere. It has to come from somewhere. Bad things happen when you eat a lot of carbohydrate and there is a lack of phosphorous in the diet, as carbohydrate places a demand on hexokinase, which requires phosphate to bind glucose to phosphate (glucose-6-phosphate) during glycolysis.

What happens when you are fed a phosphorus deficient diet? (Hettleman, Sabina, Drezner, Holmes, & Swain, 1983; Kilic, Demirkol, Ucsel, Citak, & Karabocuoglu, 2012)

Since the amount of phosphorous in your food is going to have an impact on ATP production, and ATP is the energy currency of cells, you can expect that a deficiency is going to systematically effect the entire organism. Indeed that is what we see in hypophosphatemia: weakness, bone pain, increased susceptibility to infection, numbness and tingling of the extremities, appetite suppression, cold extremities, difficulty swallowing, and a host of other “hypo” like symptoms.

Aside: Fructose is particularly effective at wasting phosphorus as well as inhibiting the absorption of calcium (Bergstra, Lemmens, & Beynen, 1993; Burch et al., 1980; Douard et al., 2010, 2013; Kizhner & Werman, 2002).

References

Bergstra, A. E., Lemmens, A. G., & Beynen, A. C. (1993). Dietary fructose vs. glucose stimulates nephrocalcinogenesis in female rats. The Journal of nutrition, 123(7), 1320–7. Retrieved from http://europepmc.org/abstract/MED/8320569

The effect of dietary fructose vs. glucose on kidney calcification (nephrocalcinosis) was studied in female rats. Fructose or glucose was incorporated into purified diets formulated either according to the nutrient requirements of rats or made nephrocalcinogenic by the addition of phosphorus (19.4 instead of 12.9 mmol/100 g diet) or by restriction of magnesium (0.8 instead of 1.6 mmol/100 g diet). Irrespective of the background composition of the diet, fructose consistently produced higher kidney calcium concentrations than did glucose. Fructose also raised kidney weight, expressed either as wet weight relative to body weight or as absolute dry weight; this greater kidney weight was not explained by the extra calcium. Fructose generally induced greater urinary concentrations of phosphorus and magnesium and lowered urinary pH compared with glucose. The greater urinary phosphorus concentrations in rats fed fructose may be responsible for the nephrocalcinogenic activity of this monosaccharide. Fructose stimulated the absorption of phosphorus and magnesium, which explains the higher concentrations of these minerals in the urine.

Burch, H. B., Choi, S., Dence, C. N., Alvey, T. R., Cole, B. R., & Lowry, O. H. (1980). Metabolic effects of large fructose loads in different parts of the rat nephron. The Journal of biological chemistry, 255(17), 8239–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6773936

Rats were given large parenteral loads of fructose and the different segments of single nephrons then analyzed for fructose metabolites, fructose metabolizing enzymes, and nucleotide high energy phosphates. Fructokinase and fructose-1-P aldolase activities, and all the major metabolite and nucleotide effects, were confined to the proximal tubule. The proximal straight segment had the highest fructokinase and suffered the greatest changes. In this segment, fructose-1-P rose to 60 mmol/kg (dry weight basis) and glycerol-3-P and glucose-6-P reached 8 and 12 mmol/kg, respectively. ATP fell 80% and GTP (judging from the changes in GTP plus GDP) fell by the same percentage, but UTP was less affected. Total adenylate decreased 50%. In the proximal convoluted tubule, where fructokinase was lower and fructose-1-P aldolase higher than in the straight segment, fructose-1-P rose ony one-fourth as much and glucose-6-P was almost unchanged. In contrast, glycerol-3-P rose more, reaching 16 mmol/kg. Other substances measured along the nephron were glycerol-3-P dehydrogenase, fructose-1,6-bisphosphate aldolase, fructose, glucose, fructose bisphosphate, triose phosphate, and 6-P-gluconate. Control ATP levels were found to be highest in the distal tubule.

Douard, V., Asgerally, A., Sabbagh, Y., Sugiura, S., Shapses, S. A., Casirola, D., & Ferraris, R. P. (2010). Dietary fructose inhibits intestinal calcium absorption and induces vitamin D insufficiency in CKD. Journal of the American Society of Nephrology : JASN, 21(2), 261–71. doi:10.1681/ASN.2009080795

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.

Douard, V., Sabbagh, Y., Lee, J., Patel, C., Kemp, F. W., Bogden, J. D., … Ferraris, R. P. (2013). Excessive fructose intake causes 1,25-(OH)(2)D(3)-dependent inhibition of intestinal and renal calcium transport in growing rats. American journal of physiology. Endocrinology and metabolism, 304(12), E1303–13. doi:10.1152/ajpendo.00582.2012

We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca(2+) transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca(2+) absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca(2+) transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca(2+) transport rate as well as in expression of intestinal and renal Ca(2+) transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca(2+) transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca(2+) transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca(2+) and vitamin D deficiency.

Hettleman, B. D., Sabina, R. L., Drezner, M. K., Holmes, E. W., & Swain, J. L. (1983). Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice. The Journal of clinical investigation, 72(2), 582–9. doi:10.1172/JCI111006

The basis for skeletal muscle dysfunction in phosphate-deficient patients and animals is not known, but it is hypothesized that intracellular phosphate deficiency leads to a defect in ATP synthesis. To test this hypothesis, changes in muscle function and nucleotide metabolism were studied in an animal model of hypophosphatemia. Mice were made hypophosphatemic through restriction of dietary phosphate intake. Gastrocnemius function was assessed in situ by recording isometric tension developed after stimulation of the nerve innervating this muscle. Changes in purine nucleotide, nucleoside, and base content of the muscle were quantitated at several time points during stimulation and recovery. Serum concentration and skeletal muscle content of phosphorous are reduced by 55 and 45%, respectively, in the dietary restricted animals. The gastrocnemius muscle of the phosphate-deficient mice fatigues more rapidly compared with control mice. ATP and creatine phosphate content fall to a comparable extent during fatigue in the muscle from both groups of animals; AMP, inosine, and hypoxanthine (indices of ATP catabolism) appear in higher concentration in the muscle of phosphate-deficient animals. Since total ATP use in contracting muscle is closely linked to total developed tension, we conclude that the comparable drop in ATP content in association with a more rapid loss of tension is best explained by a slower rate of ATP synthesis in the muscle of phosphate-deficient animals. During the period of recovery after muscle stimulation, ATP use for contraction is minimal, since the muscle is at rest. In the recovery period, ATP content returns to resting levels more slowly in the phosphate-deficient than in the control animals. In association with the slower rate of ATP repletion, the precursors inosine monophosphate and AMP remain elevated for a longer period of time in the muscle of phosphate-deficient animals. The slower rate of ATP repletion correlates with delayed return of normal muscle contractility in the phosphate-deficient mice. These studies suggest that the slower rate of repletion of the ATP pool may be the consequence of a slower rate of ATP synthesis and this is in part responsible for the delayed recovery of normal muscle contractility.

Kilic, O., Demirkol, D., Ucsel, R., Citak, A., & Karabocuoglu, M. (2012). Hypophosphatemia and its clinical implications in critically ill children: a retrospective study. Journal of critical care, 27(5), 474–9. doi:10.1016/j.jcrc.2012.03.005

PURPOSE: The aims of this study were to determine the prevalence of hypophosphatemia and to discuss the clinical implications of hypophosphatemia in critically ill children. MATERIALS AND METHODS: A retrospective review of the medical records of children admitted to the pediatric intensive care unit from December 2006 to December 2007 was conducted. RESULTS: In 60.2% (n = 71) of the patients, any serum phosphorous level at admission and at the third day or seventh day after admission to pediatric intensive care unit was in hypophosphatemic range. Sepsis was present in 22.9% (n = 27) of the children studied and was associated with hypophosphatemia (P = .02). Hypophosphatemia was also associated with use of furosemide (P = .04), use of steroid (P = .04), use of β(2) agonist (P = .026), and use of an H(2) blocker (P = .004). There was a significant association between hypophosphatemia and the rate to attain target caloric requirements by enteral route (P = .007). The median time to attain target caloric requirements by enteral route was 2.9 ± 1.9 (0.2-10) days in the normophosphatemic group and 4.4 ± 2.8 (0.3-12) days in the hypophosphatemic group. In the multiple regression model, solely the rate to attain the target caloric requirements by enteral route demonstrated independent association with hypophosphatemia (P = .006; β = .27; 95% confidence interval, 0.02-0.09). Significant association was found between hypophosphatemia and the duration of mechanical ventilation and between hypophosphatemia and pediatric intensive care unit length of stay (P = .02 and P = .001, respectively). CONCLUSIONS: Critically ill pediatric patients are prone to hypophosphatemia, especially if they cannot be fed early by enteral route. Hypophosphatemia is associated with an increased duration of mechanical ventilation and increased length of stay in the pediatric intensive care unit, suggesting that active repletion might improve these parameters.

Kizhner, T., & Werman, M. J. (2002). Long-term fructose intake: biochemical consequences and altered renal histology in the male rat. Metabolism: clinical and experimental, 51(12), 1538–47. doi:10.1053/meta.2002.36306

The use of fructose as a pure sugar has considerably increased in the last 3 decades, especially as a sweetener in carbonated beverages. Our previous studies showed that long-term fructose intake adversely affected several age-related metabolic parameters. The purpose of the present study was to compare the consequences of long-term fructose intake with those of glucose or sucrose on renal morphology and on several biochemical parameters used to estimate renal function. Male rats were fed a commercial diet for 16 months, and had free access either to water (control) or to 250 g/L solutions of fructose, glucose, or sucrose. Fructose-drinking rats exhibited higher liver weights compare to the other dietary groups. Control rats excreted significantly less urinary output than all sugar groups, which did not differ from each other. No differences were observed in fasting plasma fructose, glucose, and creatinine levels, or in urinary glucose levels. Fructose consumption resulted in elevated urinary fructose levels, higher creatinine clearance, and marked proteinuria. The tested sugars had influence on the molecular weight distribution of urinary proteins in the ranges of 10 to 16, 25 to 35, and 75 to 85 kd. Histological examination revealed that fructose consumption led to the formation of foci of cortical tubular necrosis with chronic inflammatory infiltrate, accumulation of tubular hyaline casts, thickening of the Bowman’s capsule, mesangial thickening due to collagen deposits, and the occurrence of hemosiderin in tubular cells. These data suggest that fructose has a negative impact on kidney function and morphology. Further research is required to elucidate the precise mechanisms by which long-term fructose consumption hampers renal metabolism.