“I think of myself as one of those stairs with only three steps, which are in libraries and that allow you to take books from the shelves that are higher up.”. Luciano De Crescenzo
“I think a three-step stairs is enough for anything important, I like to keep things as close to ground level as possible.” Raymond Peat, PhD
People with a low metabolic rate and hypothyroidism produce much less carbon dioxide than healthy people, and they lose it more easily. Carbon dioxide protects and stabilizes cells in a very general way, because of its effects on cell water, ATP, and GABA.
To understand the basic concepts of fatigue, it’s important to have a basic understanding of cell water and energy metabolism, e.g. the competition between environmental oxygen and carbon dioxide (the Haldane-Bohr effect), as well as the one between lactic acid and carbon dioxide. The presence of fatigue implies dysregulations in the cellular water and mineral balance, which is disrupted during inflammation, swelling, and excess water uptake (fatigued cells take up water).
“Breathing pure oxygen lowers the oxygen content of tissues; breathing rarefied air, or air with carbon dioxide, oxygenates and energizes the tissues; if this seems upside down, it’s because medical physiology has been taught upside down. And respiratory physiology holds the key to the special functions of all the organs, and to many of their basic pathological changes.” Raymond Peat, PhD
Although it does seem upside down, too much oxygen in the atmosphere prevents the tissues of the stressed organism from getting adequate oxygen. The competition between oxygen and CO2 is described by the Haldane-Bohr effect, destabilizing each other’s binding to hemoglobin.
At high elevation, mild hypoxia takes place, because the air contains relatively less oxygen. With less competition from oxygen, more CO2 can be retained in the tissues. This is extremely important for people in bad health, who produce little CO2 and have high lactate, because they can start accumulating more CO2 in their tissues, and more CO2 will suppress lactate.CO2 and lactate have opposing effects.
Lactic acid is basically produced and accumulated in the tissue as a result of inefficient metabolism and glycolysis. When oxidative metabolism isn’t efficient, less CO2 is produced and retained, and in hypothyroid people lactic acid can be produced even at rest.
“The presence of lactic acid, which indicates stress or defective respiration, interferes with energy metabolism in ways that tend to be self-promoting. Harry Rubin’s experiments demonstrated that cells become cancerous before genetic changes appear. The mere presence of lactic acid can make cells more susceptible to the transformation into cancer cells. (Mothersill, et al., 1983.) The implications of this for the increased susceptibility to cancer during stress, and for the increased resistance to cancer at high altitude, are obvious.” Raymond Peat, PhD (“Altitude and Mortality”)
T3, the active thyroid hormone, increases glucose oxidation and CO2 production. There is evidence that staying at high altitude directly increases T3 concentrations. 
I think it would be accurate to state that hypothyroid people start having a sort of “oxygen debt”, and that too much oxygen in the atmosphere that’s found at sea level prevents recuperation and the appropriate oxygenation of the tissues. However, the transition to the mild hypoxia should be gradual, because during about the first couple weeks, the oxygen debt is temporarily increased, because of the adaptation that is taking place in the blood, changing its composition.
In early 2017 and a fair amount of time before, I was seriously hyperventilating most of the time, my oxygen debt was high, I was producing high amounts of lactic acid even with very low levels of activity (or at rest), and I would produce and retain very little CO2. When I got to Mexico City (altitude about 7500 feet), I came down with symptoms of sudden altitude sickness for the few hours I was staying there. Ascending too rapidly can be lethal for people in precarious conditions, causing strong and rapid development of edema in the lungs and brain. Many people who report bad effects from altitude have just ascended too much in too short a time. As soon as I got to about 6000 feet, the bad symptoms went away.
“According to Meerson, ascending more than 200 feet per day produces measurable stress. People seldom notice the effects of ascending a few thousand feet in a day, but it has been found that a large proportion of people have bleeding into the retina when they ascend to 10,000 feet without adequate adaptation. Presumably, similar symptomless bleeding occurs in other organs, but the retina can be easily inspected.” Raymond Peat, PhD (“Altitude and Mortality”)
“…a sudden rise can be fatal for someone in very bad condition; it’s important to stay a few days at a moderate altitude, with an average daily increase of about 100 meters.” Raymond Peat, PhD
Moderate altitude conventionally is considered to be anything below 1500m. I think in the case of human metabolic adaptation to it, “moderate altitude” can be anything below 2000m. The best way to approach altitude adaptation is to be less active during the first days, and to spend at least a week or two between 1500m and 2000m, before going higher, if that’s the plan. The level of activity should be gradually adjusted according to how one feels. People from sea level who go to Mexico City not only are ascending too much in too little time, but generally approach the adaptation wrongly, by not being active according to how they feel, and breathing very polluted air, or using airplanes.
Although the benefits in the altitude studies seem to be completely gradual from 0 to up to 3600m, I think below 1500m, they start being metabolically irrelevant, or better said -not noticeable, and from 1500m and beyond they start to make a difference.
There are a number of ways with which high altitude is good for the health and longevity.
CO2, intracellular pH, and mineral balance
“People who live at very high altitudes live significantly longer; they have a lower incidence of cancer (Weinberg, et al., 1987) and heart disease (Mortimer, et al., 1977), and other degenerative conditions, than people who live near sea level. As I have written earlier, I think the lower energy transfer from cosmic radiation is likely to be a factor in their longevity, but several kinds of evidence indicate that it is the lower oxygen pressure itself that makes the biggest contribution to their longevity.” Raymond Peat, PhD (“Altitude and Mortality”)
The lower oxygen pressure at high altitude slightly lowers cells’ pH, with a tendency toward acidity, and allows greater retention of CO2. One of the features of hypothyroidism and estrogen excess is a direct effect of estrogen on the body fluids, diluting the blood. Estrogen and serotonin increase antidiuretic hormone (vasopressin), so hypothyroid people have “diluted” (hypo-osmotic) body fluids. Although an undirect effect may come from increased thyroid hormone after the adaptation, there seems this direct effect of altitude on intracellular pH, making it more acidic, that is fairly equivalent to thyroid’s effect. In this context, we have to think of carbon dioxide as an antioxidant, preventing disruptions of cells’ water balance. Salt has an activating effect on cellular water, probably because it increases osmolarity itself. 
The mild hypoxia that happens at high altitude causes a slight tendency toward intracellular acidosis, and I think it’s the more acidic pH that leads to cells’ increased endurance and resistance to stress. Adaptation to high altitude, and living at it, makes energy harder to deplete. At high altitude, it’s harder to get fatigued than at sea level, but the concept of “fatigue” shouldn’t be reduced to “feeling tired”–understanding what fatigue means cellularly is fundamental to understand inflammation and aging. Swelling and water uptake by cells is what happens when the mineral balance is disrupted, but a higher carbon dioxide concentration, and a more acidic pH, makes it harder to happen. As a result, sodium and magnesium are less easily lost (the same way they’re better retained when thyroid function is good), and calcium less easily enters the cells, causing excitation. Reducing calcium in the diet does not prevent calcium ions to enter the cells and cause excitation, but it rather favors this process.  Vitamin K, regulating calcium metabolism, has the equivalent effect in a number of stabilizing ways. It not only activates calcium dioxide production, but also ensurses it gets into the bones, as well as the calcium, preventing excitation and hauling it outside of the cell. 
During the night, the stress hormones (cortisol, adrenaline) rise, predisposing cells to inappropriate excitation more than during the day. Many things can be done to minimize nighttime inflammation, but living at high altitude mitigates some of this stress, because of carbon dioxide antiexcitatory and antioxidant properties.
In the relaxed cell calcium stays as a extracellular ion, but when excitation takes place, calcium ions enter the cells. During excitation, the cells increase their energy demand, and when it isn’t met, cellular death happens. In young people, or in healthy people, excitation episodes leave some residual damage that’s easily repaired (and the mineral balance restablished with some food and rest), but during stress, and with large amounts of accumulated polyunsaturated fats and iron with aging, any episode of the sort is harder to repair, weakening the whole system and the ability of the defensive mechanisms to come to the aid of the destabilized organism.
“But, when the tissues contain large amounts of polyunsaturated fats, every episode of fatigue and prolonged excitation leaves a residue of oxidative damage, and the adaptive mechanisms become progressively less effective. When the most powerful adaptive mechanisms, such as the timely synthesis of progesterone, pregnenolone, DHEA, T3, and the inhibitory transmitters, GABA and glycine, fail, then some of the primitive defense mechanisms will become chronically activated, and even sleep may fail to restore normal cellular water and metabolism. Hyperventilation often becomes a problem, making capillary leakiness worse.” Raymond Peat, PhD (“Fatigue, aging, and recuperation”)
Since calcium and magnesium are less retained and more easily lost during hypothyroidism, it would be therapeutical and appropriate to supply them more frequently. Living at high altitude or supplementing thyroid hormone (T3) increases their retention and prevents their loss. Adequate calcium and supplements of vitamin D (to keep it at about 50-55 ng/ml ) and K, to respectively increase its absorbtion and improve its metabolism, is necessary to normalize CO2 production, as well as to lower lactate and cellular excitation. Inadequate calcium in the diet, with a diet that’s dominated by phosphates, can alone be the cause of chronic fatigue. Since glycine has many antiinflammatory, antiexcitatory effects on cells, and proteins are better absorbed than isolated aminoacids, getting a fair portion of the protein intake from gelatin is one of the best way to relieve many syndromes that involve central inflammation, especially brain syndromes.
Cosmic Rays, LET, Radiations
There is a lot of misinformation about ionizing radiations and altitude, and most of it was caused by the (successful) attempt to justify exposures to them in various ways, starting from Wi-Fi and airplanes, to more serious things, such as mammograms, CAT scans, and nuclear power.
Ultraviolet radiations’ are toxic, and their strength increases with altitude, so it’s good to be cautious with sun exposure in high places. Quito, Ecuador, has been classified as the city with the strongest UV rays in the world. 
However, the damage done by cosmic rays is mitigated at high altitude compared to sea level. The energy level of the radiation is what determines whether it’s absorbed by tissues (and in what amount) or passing through without interacting much with them. The amount of it that’s absorbed by the tissues (or any material) is defined as the Linear Energy Transfer (LET). Many rays have the ability to penetrate the tissues without interacting with them, or to just deposit their energy within their surface, of a few millimeters or a few cells. 
“An alpha particle deposits all of its energy in the space of a few cells as it comes to rest, a primary cosmic ray passes through without such massive interaction. Low voltage x-rays, used in mammograms, lose more of their energy in the tissue and cause more damage than high energy x-rays or gamma rays. Low voltage x-rays cause more skin damage when making an image, because they don’t penetrate as well. Ultraviolet rays (even lower voltage than the “softest” x-rays) deposit all their energy in the first 2 or 3 millimeters.
John Gofman, Ernest Sternglass, Rosalie Bertell, Chris Busby, and the website ratical.org have written honestly about ionizing radiation.” Raymond Peat, PhD
Tertiary cosmic rays are much more toxic than primary or secondary ones, because of their lower energy (causing them to have a higher LET), and at high elevation they are less intense because they’re a result of collision of primary rays with air atoms. At high altitude, the atmosphere is thinner, so those collisions happen less. Interestingly, I learned that if one stays between big structures (for example, skyscrapers), the damage of cosmic rays tends to intensify, because they’re slowed down by them, lowering their energy even more.
“All the talk about cosmic ray exposure in airplane travel was developed to make people accept nuclear power, medical x-rays, and bombs. In 1959 Linus Pauling commented on the figures showing lower cancer mortality in Denver than in the sea level cities, and said there had to be something wrong with the figures, because of the cosmic rays. Insurance companies had figures at least from the beginning of the 20th century showing clear differences in cancer rates, lower at higher altitude. A cancer geographer agreed with Pauling, and decided to use melanoma (as a supposedly radiation-caused cancer) incidence within the state of Texas to show the altitude effect, and even with the moderate differences in altitude within the state, the evidence clearly showed that Pauling’s idea of cosmic ray effects was wrong—the incidence was higher at lower altitudes.” Raymond Peat, PhD
“The lower energy particles will even stop in your tissue rather than passing through. And I don’t think anyone really understands why the faster ones interact less but it’s put to use in linear accelerators, for example, they can adjust the voltage of protons or other particles and shoot them into your body at a given energy designing it so that they all slow down and stop near a tumor and where they’re slowing down and stopping, they’re causing the most damage when they go through quickly like a, a cosmic ray at high altitude. They just leave a slight trail of ionization rather than a very intense cloud of secondary reactions. A typical physics professor’s explanation for that is that if you imagine the substance as a, a meteor swarm and a spaceship traveling through that. If the spaceship goes very slowly, it surely get hit by a swarming meteor. But if it zooms right through it, it has a chance of getting passed without interactions.” Raymond Peat, PhD
As a general rule, it’s reasonable to supply the minerals (calcium, sodium, magnesium, potassium) appropriately, as well as using other foods that are rich in nutrients and easy to digest. Milk, cheese, fruit, and coffee, or water from some boiled leafy greens, while salting food to taste, would provide a good balance of those minerals in a safe way, while using eggs, liver and seafood regularly to assure a good intake of vitamins and trace minerals (mainly selenium, copper, iodine, and zinc). Too much phosphates from meats and fish has the ability to deplete cellular energy, so, if eaten, they should be part of a balanced diet with adequate calcium and using gelatin, rich in glycine, at the same time as a meat meal, would be a great help. Powdered eggshells are a good source of calcium carbonate, and can be taken with meals.
Spending time at high elevation would provide changes in the blood that I estimate will fade quite a bit only after about two years, so it can be done periodically. Since our society has been designed to eliminate meaningful choices for most people, and the chance of being explorative, adapting our lifestyle according to new knowledge we acquire, has been denied by the current sociocultural environment, other techniques improving CO2 retention and respiration, reducing lactate and hyperventilation, can be used.
Acetazolamide is a medication that is being used succesfully for mountain sickness, but even if taken at sea level, it improves CO2 retention and causes the same slight acidosis that happens at high elevation –estrogen, hypothyroidism, cause respiratory alkalosis, the opposite of it. Cyproheptadine, a “first generation” antihistamine, not only blocks histamine and serotonin, but has calcium-blocking actions and its broad range of protective effects tends to correct the breathing and reduce cellular excitation.  Calcium, sodium, vitamins D, K, activate carbon dioxide production, so supplementing them can be helpful. A little sodium bicarbonate in water can temporarily increase CO2 concentrations, as well as carbonated drinks–Coca Cola, for example. Simple sugars, instead of starches should be preferred when at least a sweet fruit is available; starches disrupt mineral balance, cause blood sugar dysregulations and feed intestinal bacteria, so especially in people with a predisposition of overgrow bacteria, they should be avoided. Fructose, in fruit and in sucrose (50% of it) has the ability to increase CO2 production and oxygen consumption when compared to starch or pure glucose.  Fructose and niacinamide also have the ability to lower intracellular phosphate, to reduce the amount that’s absorbed by the intestine and to favor its elimination (or inhibit reabsorbption) by the kidneys. 
“A diet that provides enough calcium to limit activity of the parathyroid glands, and that is low in phosphate and polyunsaturated fats, with sugar rather than starch as the main carbohydrate, possibly supplemented by niacinamide and aspirin, should help to avoid some of the degenerative processes associated with high phosphate: fatigue, heart failure, movement discoordination, hypogonadism, infertility, vascular calcification, emphysema, cancer, osteoporosis, and atrophy of skin, skeletal muscle, intestine, thymus, and spleen (Ohnishi and Razzaque, 2010; Shiraki-Iida, et al., 2000; Kuro-o, et al., 1997; Osuka and Razzaque, 2012). The foods naturally highest in phosphate, relative to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added phosphate. Foods with a higher, safer ratio of calcium to phosphate are leaves, such as kale, turnip greens, and beet greens, and many fruits, milk, and cheese. Coffee, besides being a good source of magnesium, is probably helpful for lowering phosphate, by its antagonism to adenosine (Coulson, et al., 1991).” Raymond Peat, PhD
“Stress, shock, inflammation, aging, and organ failure are, in important ways, respiratory problems.” Raymond Peat, PhD
Valle de Bravo, Mexico (altitude about 6,000 feet)
 1. Eur J Appl Physiol Occup Physiol. 1998;77(1-2):37-43.
Pre-adaptation, adaptation and de-adaptation to high altitude in humans: hormonal and biochemical changes at sea level.
Savourey G, Garcia N, Caravel JP, Gharib C, Pouzeratte N, Martin S, Bittel J.
High altitude residence is known to modify body biochemistry and hormone status. However, the effects of such a sojourn on these status observed at sea level both immediately and later after return are not as well established as are the effects of an intermittent acclimation. The aim of this study was therefore to investigate these changes. To achieve our objectives, nine subjects received intermittent acclimation at low pressure in a barometric chamber (8 h daily for 5 days, day 1 at 4500 m, day 5 at 8500 m) before an expedition to the Himalayas. Hormonal and biochemical changes were studied using samples of venous blood taken at sea level before and after acclimation, after return from the expedition and 1 and 2 months after descent. Concentrations of thyroid hormones, adrenaline, noradrenaline (NA), hormones of hydromineral metabolism (aldosterone, renin, arginine vasopressin, atrial natriuretic peptide) as well as prolactin, cortisol, insulin and endothelin 1 were measured. Biochemical measurements made were plasma osmolality, and concentrations of glucose, total cholesterol, total proteins, pre-albumin, transferrin, complement 3C, apolipoproteins A1 and B and serum iron. Acclimation induced no alteration in hormone (except for NA with increases of about 1.5, fold P < 0.05) and biochemistry data. After the expedition, hormone responses were characterized by a higher total triidothyronine concentration (+18%, P < 0.05) while other hormones did not vary. A linear relationship was found between thyroid-stimulating-hormone and body mass changes after the expedition (r = 0.67, P < 0.05). The observed increased concentrations of plasma proteins and total cholesterol (P < 0.05) could be related to the restoration of lean body mass. At 1 and 2 months after return, no changes in hormones were observed but a significant decrease in transferrin concentration was noticed. The higher serum iron concentration reported after 1 month (P < 0.05) could have been the result of a physiological haemolysis. It was concluded that both acclimation and the expedition in the Himalayas affected hormone status and body biochemistry status even though the observed changes were slight and rapidly reversed.
 Endocrinology. 1976 Jan;98(1):84-90.
Effects of hyperosmolarity on the cyclic AMP concentration and lipolysis of the
adipocyte stimulated by adrenocorticotropic hormone.
Wada M, Akanuma Y, Kimura N, Nagata N.
The effects of ACTH on 3′,5′-cyclic AMP (cAMP) levels and lipolysis were
examined on isolated adipocytes incubated in either isosmolar or hyperosmolar
media. The ability of ACTH to induce intracellular cAMP accumulation was greatly
enhanced by incubating cells in hyperosmolar sucrose (100 to 400 mM) solutions.
Hyperosmolar solutions prepared by the addition of either NaCL, glucose or
mannitol enhanced the ACTH effect on cAMP to the same extent as did the
hyperosmolar sucrose solution, but hyperosmolar urea solutions did not have such
an effect. The effect of hyperosmolarity was shown only in cells stimulated by
lipolytic hormones, and the effects were still evident in the presence of high
concentrations of theophylline, indicating the effect of hyperosmolarity is to
facilitate hormone action on the receptor-coupler system of the adipocyte
membrane. The action of glucagon on cAMP was augmented much less than the
actions of ACTH and isoproterenol. Basal as well as ACTH or exogenous cAMP
stimulated lipolysis was lower in hyperosmolar sucrose solutions. Some mechanism
by which hyperosmolarity interferes with the metabolic sequence beyond the
accumulation of cAMP was suggested.
26: Arch Int Physiol Biochim. 1975 Aug;83(3):435-41.
Effect of PCO2 on epinephrine-induced lipolysis in isolated fat cells.
Vega FV, de Cingolani GE.
The effect of different pHs obtained by changing the PCO2 and the effect of PCO2
at constant pH on the lipolysis induced by epinephrine in isolated fat cells
have been investigated. An inhibition of activated lipolysis was found in
acidosis while in alkalosis no significant change was detected. When the
experiments were performed at different PCO2s but at constant pH, the results
showed an inhibition of lipolysis by high PCO2 whereas low PCO2 did not affect
it. It is concluded that either acidosis or high PCO2 lead to an inhibition of
the lipolysis induced by epinephrine in isolated fat cells. As regards alkalosis
and low PCO2 it seems likely that the intracellular pH is not affected to the
same extent as in alkalosis by high [HCO(-3)] or under the conditions of the
present experiments the [H+] needed to alterate lipolysis was not reached.
Eur J Clin Nutr. 2003 Dec;57 Suppl 2:S69-74.
Effects of changes in hydration on protein, glucose and lipid metabolism in man:
impact on health.
Keller U, Szinnai G, Bilz S, Berneis K.
Division of Endocrinology, Diabetology and Clinical Nutrition, Basel,
Alterations of cell volume induced by changes of extracellular osmolality have
been reported to regulate intracellular metabolic pathways. Hypo-osmotic cell
swelling counteracts proteolysis and glycogen breakdown in the liver, whereas
hyperosmotic cell shrinkage promotes protein breakdown, glycolysis and
glycogenolysis. To investigate the effect of acute changes of extracellular
osmolality on whole-body protein, glucose and lipid metabolism in vivo, we
studied 10 male subjects during three conditions: (i) hyperosmolality was
induced by fluid restriction and intravenous infusion of hypertonic NaCl (2-5%,
wt/vol) during 17 h; (ii) hypo-osmolality was produced by intravenous
administration of desmopressin, liberal water drinking and infusion of hypotonic
saline (0.4%); and (iii) the iso-osmolality study comprised oral water intake ad
libitum. Plasma osmolality increased from 285+/-1 to 296+/-1 mosm/kg (P<0.001
during hyperosmolality, and decreased from 286+/-1 to 265+/-1 mosm/kg during
hypo-osmolality (P<0.001). Total body leucine flux ([1-(13)C]leucine infusion
technique), reflecting whole-body protein breakdown, as well as whole-body
leucine oxidation rate (irreversible loss of amino acids) decreased
significantly during hypo-osmolality. The glucose metabolic clearance rate
during hyperinsulinaemic-euglycemic clamping increased significantly less during
hypo-osmolality than iso-osmolality, indicating diminished peripheral insulin
sensitivity. Glycerol turnover (2-[(13)C]glycerol infusion technique),
reflecting whole-body lipolysis, increased significantly during hypo-osmolar
conditions. The results demonstrate that the metabolic adaptation to acute
hypo-osmolality resembles that of acute fasting, that is, it results in protein
sparing associated with increased lipolysis, ketogenesis and lipid oxidation and
impaired insulin sensitivity of glucose metabolism.
Effects of vitamin K on calcium and bone metabolism.
 Radiat Prot Dosimetry. 2008;128(2):234-8.
 Med Phys. 2007 Jan;34(1):183-92.
 J Radiol Prot. 2009 Mar;29(1):5-21.
 Review of relative biological effectiveness dependence on linear energy transfer for low-LET radiations
Fructose and dietary thermogenesis.
OBJECTIVE: We tested the hypothesis that luminal fructose regulates NaPi-2b.
We perfused into the intestine fructose, glucose, and nonmetabolizable or poorly transported glucose analogs as well as phlorizin.
NaPi-2b mRNA concentrations and Pi uptake rates in fructose-perfused intestines were approximately 30% of those in glucose and its analogs. NaPi-2b inhibition by fructose is specific because the mRNA abundance and activity of the fructose transporter GLUT5 (glucose transporter 5) increased with fructose perfusion, whereas those of other transporters were independent of the perfusate. Plasma Pi after 4 h of perfusion was independent of the perfusate, probably because normal kidneys can maintain normophosphatemia. Inhibiting glucose-6-phosphatase, another fructose-responsive gene, with tungstate or vanadate nonspecifically inhibited NaPi-2b mRNA expression and Pi uptake in both glucose- or fructose-perfused intestines. The AMP kinase (AMPK)-activator AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) enhanced and the fatty acid synthase-AMPK inhibitor C75 (3-carboxy-4-octyl-2-methylenebutyrolactone trans-4-carboxy-5-octyl-3-methylenebutyrolactone) prevented fructose inhibition of NaPi-2b but had no effect on expression of other transporters. NaPi-2b expression decreased markedly with age and was inhibited by fructose in all age groups.
Energy levels in enterocytes may play a role in NaPi-2b inhibition by luminal fructose. Consumption of fructose that supplies approximately 10% of caloric intake by Americans clearly affects absorption of Pi and may promote Pi homeostasis in patients with impaired renal function.
Studies with rats have found that an interaction between fructose and magnesium affects macromineral metabolism; high dietary fructose significantly increased kidney calcification in both male and female rats, particularly when dietary magnesium was low. This study tests the hypothesis that an interaction between dietary fructose and magnesium adversely affects macromineral homeostasis in men.
Eleven men aged 22 to 40 years were fed a mixed, Western diet for four 42-day dietary periods in which dietary magnesium was either approximately 170 or 370 mg/day and dietary fructose was either 4% or 20% of energy. A decaffeinated beverage containing high fructose corn syrup replaced cornstarch, bread and rice in the low fructose diet to give the high fructose diet.
High dietary fructose significantly (p<0.01) increased magnesium balance during both low and high dietary magnesium intakes. Ultrafilterable and ionized serum magnesium also apparently were related to magnesium and fructose intakes; they were higher when fructose was fed and when Mg intakes were high. High fructose depressed calcium balance: the effect tended to be more marked when dietary Mg was low. High dietary fructose also significantly (p<0.005) decreased phosphorous balance. Urinary phosphorous losses were significantly (p<0.001) higher when high dietary fructose was fed. High dietary fructose also increased the concentration of serum alkaline phosphatase (p<0.005).
These findings indicate that dietary fructose adversely affects macromineral homeostasis in humans and suggest further studies to see if a high fructose diet coupled with low dietary magnesium and marginal calcium leads to bone loss.
Niacinamide inhibits intestinal sodium/phosphorus transporters and reduces serum phosphorus in open-label studies. A prospective, randomized, double-blind, placebo-controlled crossover trial was performed for assessment of the safety and efficacy of niacinamide.
Hemodialysis patients with phosphorus levels > or =5.0 mg/dl were randomly assigned to 8 wk of niacinamide or placebo, titrated from 500 to 1500 mg/d. After a 2-wk washout period, patients switched to 8 wk of the alternative therapy. Vitamin D analogs and calcimimetics were held constant; phosphorus binders were not changed unless safety criteria were met.
Thirty-three patients successfully completed the trial. Serum phosphorus fell significantly from 6.26 to 5.47 mg/dl with niacinamide but not with placebo (5.85 to 5.98 mg/dl). A concurrent fall in calcium-phosphorus product was seen with niacinamide, whereas serum calcium, intact parathyroid hormone, uric acid, platelet, triglyceride, LDL, and total cholesterol levels remained stable in both arms. Serum HDL levels rose with niacinamide (50 to 61 mg/dl but not with placebo. Adverse effects were similar between both groups. Among patients who were > or =80% compliant, results were similar, although the decrease in serum phosphorus with niacinamide was more pronounced (6.45 to 5.28 mg/dl) and the increase in HDL approached significance (49 to 58 mg/dl).
In hemodialysis patients, niacinamide effectively reduces serum phosphorus when co-administered with binders and results in a potentially advantageous increase in HDL cholesterol. Further study in larger randomized trials and other chronic kidney disease populations is indicated.