Unifying biology (4) Ketones, fructose, and hypoxia

I have a pathological proclivity leaning towards disenchantment with extremes. Yet, at the same time I cannot help myself, I spend a great deal of my research time exploring extremes in biology. I largely see extremes as sources of inspiration. I do give myself a chance to allow that inspiration to provoke new questions. Sometimes off the wall questions, I’m sure my peers over the years would agree. Sometimes I have posed off the wall questions to my peers just to see what kind of person I am dealing with. Is this a person who is seeking truth or is this a person seeking compliance?

But I mainly direct these off the wall questions to myself, bias is a problem in any scientific discipline, and one of the ways you can limit the bias is by trying to dethrone yourself. I have dethroned myself many times over the years and any internally consistent person truly seeking some element of truth should be comfortable with consuming the proverbial foot or two. I have eaten many pairs of feet.

The truth is I don’t see extremes as outliers, and I don’t see outliers as extremes. I see outliers and extremes as unifiers. I have mentioned in the past that individual ideology can leak into your scientific perspective. This is true for me. My ideology of placing emphasis on the individual as unique and valuable leaks into everything I do. That is a hard pill for some to swallow, even if I fundamentally disagree with you, I still think you are unique and valuable. At the end of the day you are a human. We have that in common. That is all I need. In fact, the people I value the most are the people who challenge my thoughts and ideas. This is where learning occurs.

One of the questions I asked myself years ago is: Why does our physiology produce ketones when we restrict carbohydrate? Now, before you rattle off in your brain all the circumstances under which we produce ketones, read the question: Why do we produce ketones?

One of the central tenants of my hypothesis as I stated in my previous blog post is that we produce ketones when we are hypoxic, whether it be at the cellular level, the tissue level, the organ level, system level or organism level. In other words, when your cells can not utilize oxygen OR there is a lack of oxygen your physiology will produce ketones.

What do I mean by “your cells can not utilize oxygen”? For example, you can be under normal oxygen levels but for a variety of reasons your cells fail to utilize oxygen. Maybe your mitochondria are broken. Similarly, oxygen levels can be lower but maybe you have unbroken mitochondria and you can use oxygen more efficiently. The later would make you more resistant to stress and the former would make you more sensitive to stress.

There are a variety of circumstances under which ketones are produced, ketones are produced in elevated amounts after birth, ketones are produced after exercise, ketones are produced during sleep, ketones are produced during nutritional ketosis, ketones are produced at altitude, ketones are produced during metabolic ketoacidosis, and under many more circumstances.

If you are sharp, you’ll notice that ketones are produced physiologically such as after birth, after exercise, during sleep, and at altitude. You’ll also notice that ketones are sometimes produced in association with different disease pathologies, diabetic ketoacidosis being the most familiar example. Then there are the compounds that can induce hypoxia by interfering with oxygen utilization and ketones are produced. For example, hydrogen cyanide and alcohol.

The one thing all those things have in common whether physiological or pathological or induced is that all those states are states in which oxygen use is limited in some way.

When hypoxia is present so are ketones. In fact, the ketogenic pathways are very ancient even water bears (Tardigrade) make ketones. Interesting.

What other things can elevate ketones? Well we know for sure that by restricting carbohydrate that we can self-induce ketone production and if the production of ketones indicates hypoxia perhaps that might not be an ideal state to be in?

What about fructose? Can fructose increase ketone production? That was one of the off the wall questions I dared to ask myself.

For the purpose of this blog post which serves as an introduction to this concept I will be posting clips from papers, over the next few articles I will provide the citations, for now I want to just cover the basics and tell you a story.

Let’s start with this:

Fructose it seems can induce ketogenesis and if we accept that ketones are an indication of hypoxia and we consider the implications of chronic hypoxia and that it precipitates all disease, all the sudden we have a very plausible explanation for the association of fructose with different disease states.

In the above paper they are validating this:

This group did their homework, they said this is interesting, does this occur under physiological levels? Right? Because we want to know, does this have practical relevance.

Then during the same era, we have this:

One of the interesting things about this paper is the mention that the glycogen content of the liver increased. It is well known that fructose not only increases gluconeogenesis but that fructose in fact inhibits glycogenolysis. What is not well known in some circles is that the elevated gluconeogenesis is a response to the fructose, but at the same time while there is an increase in glycogen formation there is inhibited breakdown of glycogen. Now we have a very good partial mechanism to explain why, while fructose has no need for insulin, why there are transient increases in fasting blood glucose and fasting insulin. This is part of the reason why diabetics often have distended livers. Because glycogenolysis is inhibited glycogen continues to be deposited in the liver, it is an under reported complication of diabetes and can be confused with nonalcoholic fatty liver disease unless a biopsy is done, and a PAS stain ordered.

There are more. But for now, it seems like fructose can induce ketogenesis. The reason for this is because fructose is inducing internal metabollic hypoxia. But that is only if you accept the idea that ketones are generated under conditions of lowered oxygen or inefficient oxygen use. So, is that true?


This was an observation made in the 1930’s. I know some of you like old papers. It was the first observation of its kind. And it was verified by another group in the same era.

Translation as oxygen tension increases BHB is converted back to acetoacetic acid when oxygen decreases acetoacetic acid is converted to BHB.

In the beginning of this short post I mentioned that I have a pathological proclivity leaning towards disenchantment with extremes. In that context, those extremes I am referring to are the polarized cults on both sides of the fence who refuse to consider the arguments each side makes AND the evidence both sides bring to the table. Everybody seems to hate each other these days but what if I told you that there were arguments on both sides that were partially correct and arguments on both sides that are absolutely wrong and that there is a hill in the middle that explains both sides more adequately than each extreme can account for with their own dogma?

So how does this apply practically? Is it a simple matter of avoiding things that cause hypoxia and thus ketogenesis? Do we avoid fructose like it is the Black Plague? Is it really that black and white? Not at all, it’s more elegant than that as we shall see. Much more elegant. No spoilers.

Unifying biology (3) Ketogenesis and hypoxia

One of the questions I’ve been trying to develop an intellectually satisfying answer to for the past decade is: Why did Kwasniewski and Lutz seem to advise against ketosis, was it empirical or esoteric?

I find the hypoxic in utero environment of the fetus and subsequent metabolic transition of the neonate to a normoxic environment and eventual metabolic transformation fascinating. After gestation interesting things are occurring metabolically, increases in lactate, increases in ketogenesis and gluconeogenesis. The scant number of tracer studies looking at infant metabolism seem to indicate that exogenous lactose from breast milk and endogenous glucose as a result of gluconeogenesis is being shunted towards biosynthetic pathways and glucose is metabolically spared. In breast fed infants, glucose concentrations increase cyclically maintaining normoglycaemia. In contrast, infants administered oral solutions of glucose develop cyclical hypoglycemia.

I suspect there are morphological and functional differences between infant and adult mitochondria. There are reasons for this suspicion. Infants administered glucose less than 1 month after gestation present with glucose intolerance and glucose tolerance subsequently increases over the following months of development; additionally, the metabolic substrate profile points in that direction.

Infants have generous amounts of adipose tissue and as the infant transitions to a toddler and child, adipose tissue declines. I would suggest this is a result of maturing mitochondrial morphology and function; and that elevated lactate and ketones reflects fatty acid oxidation (FAO) capacity. This physiological metabolic transition is a result of adapting to an externally normoxic environment. Interestingly, for every 1000 meter increase in elevation there is a reduction in neonate mass and an increase in the incidence of fetal death.

One of the central tenets of my hypothesis is that ketone formation indicates hypoxia be it a histophysiological adaptation to external environmental conditions and physiological stimuli or; a pathophysiological disorder resulting from chronic exposure to compounds and energy substrates that interfere with or block normal histophysiological adaptations. In other words, anything that chronically interferes or blocks normal homeostatic processes produces a maladapted and eventually, unadaptive state, leading to entropy i.e. degeneration and death.  

There is a beautiful cyclical metabolic signature from conception to death reflecting our ability to deal with oxygen and lack thereof; the energy substrates that build and prepare us for an oxygenated environment are eventually the same energy substrates that kill us. We develop in a hypoxic in utero environment and adapt to an oxygen rich environment. After birth and in the presence of oxygen our physiology matures and develops reflecting the external environmental conditions. As our mitochondria learn how to breathe, we slowly loose the ketogenic capacity present during early stages of life and transition to a reliance on fatty acids and develop the capacity to rely on glucose, fructose, and ketones when intermittent hypoxia is present. When intermittent hypoxia is present our mitochondria temporarily uncouple and become physiologically insulin sensitive and glucose is used to facilitate adaptation via biosynthetic pathways.  

As we age our ketogenic capacity continues to decline along with a diminishing fatty acid oxidation capacity. In the context of this decline, not only do we lose the ability to produce adequate ketones to continually adapt to intermittent hypoxia, our mitochondria degenerate losing the ability to metabolize fatty acids and our physiology becomes more and more reliant on glucose as a metabolic substrate and as a result we lose the ability to maintain physiological insulin resistance. Slowly the adaptive state of intermittent physiological insulin sensitivity becomes pathophysiological and we lose the physiological insulin resistance of our youth.

As I have reflected on in the past, glucose is a primitive energy substrate, a glucose driven metabolism, contrasted with glucose used as a biosynthetic substrate in the context of a fatty acid driven metabolism, will drive primitive histophysiology and the subsequent degeneration of the orchestra. Every day the orchestra slowly goes out of tune and eventually the musicians slowly start disappearing, eventually the conductor has no musicians and he will turn to the audience, take a bow, and you will take your last breath.

In the end you will suffocate to death.

Why did Kwasniewski and Lutz seem to advise against ketosis?

  1. Whether they knew better or not, chronic ketosis indicates hypoxia.
  2. The conservative amount of glucose needed to stay out of deep chronic ketosis facilitates physiological insulin resistance and supports adaptive physiological insulin sensitivity during intermittent hypoxia.
  3. Ketosis reflects fatty acid oxidation capacity.  

Unifying biology (2) Aside on iron (Fe)

This is an aside but worth talking about.

Typically, we talk about heme and nonheme iron when we are going to discuss iron in biology. And one of the reasons I don’t worry about my hemochromatosis too much even though heme iron is more “bioavailable” and I like red meat is because the heme iron, the kind found in meat, is bound to a hemeprotein. That I eat red meat is contrarian.

In the case of hemoglobin this hemeprotein functions somewhat like a “conditional loop”, when pH is low and carbon dioxide is high (as in hypoxia i.e. generally a lack of oxygen to cells, tissues, organs, and the organism) hemoglobin will “release” oxygen to surrounding tissues.

When the situation is reversed higher pH and low carbon dioxide hemoglobin will “up take” oxygen. It is a controlled situation and hypoxia inducible factors seem to mediate part of this controlled situation.

My suspicion is that under normal atmospheric conditions being metabolically hypoxic (intake of significant amounts of fructose at sea level under normoxia) can be problematic and partially explains why sea level diabetics often have relief of symptoms at altitude. [This is a dynamic interaction with many environmental conditions to include energy substrates, the picture being painted will become clear as this series progresses.]

Fructose can chelate with inorganic iron. Ingested nonheme iron needs to be reduced to be absorbed and used appropriately which our intestinal cells can do. Prior to that conversion iron can react with compounds such as ascorbic acid or fructose.

In parallel, fructose tends to cause hemoglobin to release its bound iron and reduce oxygen affinity of hemoglobin and this is probably why we see iron implicated in many different phenotypical states (disease states), while the total picture is more complex than a single variable, iron is an important nexus to facilitate understanding. This unbound iron can do damage in the right contexts.

In diabetic-like phenotypes, fructose in erythrocytes (red blood cells) is about 3-4 times higher than it is in non-diabetic phenotypes. When hemoglobin is incubated with fructose, fructated hemoglobin forms (similar to glycated hemoglobin but with fructose instead of glucose). When ferrozine is added to a solution containing ferrous iron, the ferrozine binds with ferrous iron and produces a magenta colored solution. This is something you would do if you want to confirm that fructated hemoglobin is releasing its iron. Indeed, when ferrozine is added to a medium containing fructated hemoglobin it turns magenta reflecting the level of fructosylation/fructation, proportionally.

We know that fructose fructates hemoglobin, and we know it disrupts the heme protein causing an increase in free iron and this partly explains the interference with oxygen affinity. One other interesting thing to point out regarding iron containing protein complexes is that cytochrome p450 is an iron containing protein. Cytochrome p450 is involved with steroid hormone synthesis, xenobiotic and polyunsaturated fatty acid metabolism. 

All cells are constantly turning over heme which is facilitated by heme oxygenase (HO) to produce carbon monoxide, ferrous iron (Fe2+) and biliverdin/bilirubin. Bilirubin binds to albumin and is transported to the liver where it binds with glucuronate and is excreted (glucuronidation). This is normal physiology.

In fructose induced nonalcoholic fatty liver states there is an increase in deposited iron that is attenuated by heme oxygenase. Heme oxygenase requires oxygen, protons (H+), and NADPH and increases superoxide dismutase activity. Acutely, our physiology can handle this when we are at our baseline phenotype. Chronically this reaction cannot sustain, and this is for several reasons, most importantly, failure of oxygen delivery inhibits palmitic acid driven mitochondrial oxidative phosphorylation and increases the reliance on glycolytic energy metabolism. One of the other over looked aspects of a reliance on glycolytic energy pathways is that the mitochondria participate in the generation of steroid hormones and normal cellular function, you need palmitic driven OXPHOS for this occur. The question is, which comes first disrupted oxygen delivery or inhibited OXPHOS by fructose? Or are they in parallel?      

At sea level and in the context of sufficient sources of heme iron and saturated fatty acids hemoglobin is saturated with oxygen and oxygen transport occurs normally and is partially under the control of hypoxia inducible factors (HIF).  

However, in the context of excessive fructose in conjunction with nonheme iron as well as fructose interfering with in situ hemoglobin causing iron release and affecting oxygen affinity (and interfering with cellular respiration as a result), fructose and liberated iron from hemoglobin will potentially react with the excess iron and oxygen released from these reactions as well as the oxygen delivered from organism level respiration (breathing) further interfering with oxygen delivery.

In essence—excess fructose in a higher oxygen environment not only disrupts in situ function of hemoglobin but also reacts with unbound nonheme iron and interferes with HO producing a hypoxic phenotype. Until fructose concentrations fall this is a vicious cycle that affects the protein, lipid, and carbohydrate structures of intact cells. Again, acutely we are equipped for such insults. Chronically this leads to accelerated degeneration.     

Unifying biology (1) Definitions and concepts

For the past year or so, I’ve been attempting to develop a hypothesis that unifies a lot of concepts in biology. My primary interest is understanding respiration at the cellular level and at the organism level; understanding the interplay between the two; and how that interplay, manifests as observable physiology, pathology, and psychology.

Just uttering the word unify in scientific circles if you are keen enough to notice, draws a target on your back, and rightfully so. There is no shortage of hair brained drain circling ideas out there. Criticism is welcome.

Though I work in the field of pathology, more specifically histology, I generally prefer the somewhat out of fashion term histophysiology to describe the things that interest me. Here is why:

Histophysiology: a branch of physiology concerned with the function and activities of tissues; structural and functional tissue organization.

Pathology: the study of the essential nature of diseases and especially of the structural and functional changes produced by them; something abnormal; the structural and functional deviations from the normal that constitute disease or characterize a particular disease.

Physiology: a branch of biology that deals with the functions and activities of life or of living matter (such as organs, tissues, or cells) and of the physical and chemical phenomena involved.

Pathophysiology: the physiology of abnormal states.

Histology: a branch of anatomy that deals with the minute structure of animal and plant tissues as discernible with the microscope; tissue structure or organization.

Its more useful from my perspective to understand how cells work rather than deviation from normal, as normal is subjective. I am more comfortable with classifying various diseases and pathologies as dynamic phenotypes.

This is important to me for several reasons. First, classifying various pathologies as phenotypes allows us to understand, at least in thinking, that a disease is an adaptation (bear in mind that adaptation does not necessarily mean the adaptation is subjectively beneficial). The abnormal (phenotype), if you will, is the dynamic response of the cell to dynamic conditions.

The problem with the word disease, with the way we perceive disease, is that it implies that the cell is responding irrationally and independent of the environment when in fact the cell is responding very rationally and quite dependently on the environment.

From a philosophical perspective it is a misunderstanding to say when environmental conditions produce abnormal phenotypes that the environment is somehow defected. In one sense this is true, but only in the sense of how we perceive what normal is. Cells respond to the environment and adapt to the conditions of the environment, rationally. Cells don’t respond independently of their environment for our sake.

While that may sound like semantics it is necessary.

There is a dynamic relationship that the cell has with its environment to include energy substrates. Certain types of cells prefer different kinds of energy substrates. And on a bigger scale, groups of cells that compose larger structures like tissue, control their local environment to ensure they receive proper energy substrates.

When the internal environment of a tissue type no longer has access to a preferred energy substrate the cell/tissue can intermittently physiologically adapt to another energy substrate. However, a chronic shift to an unpreferred energy substrate will eventually cause a shift in the cellular phenotype and through proliferation, eventually affect tissue structure and function. That may or may not be subjectively beneficial.

While cells certainly respond to the conditions of their environment, a group of cells can also generate an internal environment to support their group level goals by using other energy substrates via in situ structure to generate a gradient barrier. The generated gradient barrier that protects the group level preferred environment and access to the tissues preferred energy substrates is called an organ.

Via structure, energy substrates can then be routed to various locations and the preferred mixtures of energy substrates can be taken up by different cells and tissue types that have different requirements to maintain their preferred internal environment to support their overall structure and functionality. It is important to understand that this preferred functionality is interdependent on other tissues/organs behaving in their preferred manner and maintaining their preferred internal environment. The saying: One man’s trash is another man’s treasure applies. When all cells/tissues/organs are interdependently in concert we call this an organism.

When conditions change and a tissue can no longer access its preferred energy substrate, an intermittent physiological switch to another energy substrate occurs, if the access to the preferred energy substrate is chronically bottlenecked, the internal environment of a group of cells fundamentally changes. When this occurs this affects the energy substrate supply to other groups of tissues because the concert is over. A systemic phenotypical shift begins.

If the phenotypical shift is chronic, there is then deviation from the baseline phenotype, this deviation fundamentally alters tissue structure and function and the concert is now playing another piece which you may or may not enjoy.

As humans we strive to keep the original concert going. The piece we enjoy. The piece we call I ormyself. We all sense when something is out of tune. Sometimes its just one violinist others its the whole section and at our worst the whole orchestra is out of tune or no longer playing our favorite piece.

The question is how do we ensure the internal environment stays in concert playing I for as long as possible so you can adapt and respond appropriately to the external environment consciously and unconsciously.

Hyperthyroidism (1) is chronic systemic hypoxia

A member of my Discord server asked a very good question that I haven’t really addressed, here is part of the answer.

I think the speculation that there is a sweet spot is correct as at either extreme of temperature ATP production becomes unstable.

I do remember seeing posts of people claiming they were hypothyroid right around the time Paul Jaminet introduced the Perfect Health Diet. I also remember some of the more extreme people saying the chilliness people where experiencing was a sign that they were doing things right. LOL.

I’m not sure who originated the idea that ketosis was causal in thyroid dysfunction/low T3 except that, very consistently, lower T3 is associated ketosis type diets and starvation and further I’m not quite sure where the idea even comes from as far as being “harmful” as the effect ON SERUM is expected. Not very many of them provided evidence for this, so I’m not sure if it was based on signs and symptoms or symptoms alone. But the effect is physiological not pathological; at least initially.

Regardless, across species there is an inverse correlation between T3 and longevity and like with temperature there probably is a sweet spot for T3 as well but serum measurements are highly variable. What is important is local tissue levels which we don’t have commercial tests for; but we can do this in the lab with PCR, which I have done when I was researching the effects that viruses have on cellular thyroid hormone metabolism.

I’ve mentioned in the past that when cells are provided with the correct energy substrates that hormones are background. There is normal circadian oscillation for catabolic and anabolic processes but in a situation where appropriate energy substrates are used hormones remain in the background.

Lifecycle oscillations of thyroid hormone are also orchestrated by physiological processes such as in utero and during birth, stress, cold, the death of a family member or a bad breakup. In healthy adults, there also is an postive association between T3 and waist size that nobody seems to want to address. Indeed, T3 administration above physiological amounts causes diabetes to develop.

As well, during illness thyroid hormone levels decrease, adjuvant therapy with thyroid hormone during these situations tends to exacerbate the illness pointing in the direction that fluctuation in thyroid hormones is an adaptive process.

Thyroid hormones are catabolic, sometimes they appear anabolic but this is only because during catabolism, anabolic parameters also increase.

Increased T3 is a symptom of hypoxia both at the cellular, tissue, and organism level and the level of hypoxia in vivo is largely an effect of 2 things 1) the predominant metabolic substrates being provided to your cells and 2) the external availability of oxygen.

When does thyroid hormone increase? Under carbohydrate load and under anaerobic/hypoxic conditions. Given that thyroid hormone is catabolic this makes sense, as the increased local thyroid hormone concentration is secondary symptom of anaerobic/carbohydrate metabolism.

But why?

Excess carbohydrates in a normoxic environment is maladaptive, as I’ve pointed out in the past in my energy and structure blog posts, carbohydrates are a primitive fuel source this is why high-level organisms utilize fatty acids for their basal metabolism unless the situation is such that they are in a hypoxic environment. Even in naked mole rats although serum levels of thyroid hormones are low, ultrastructurally (cellular and tissue level) there is increased secretion of the hormones.

One of the functions of thyroid hormones is to orchestrate “form”, what this means is that through very carefully controlled fluctuations in cellular respiration you can change the phenotype of a cell, you can also kill cells with thyroid hormones which is part of their function as well in organisms that go through metamorphosis. For example, in tadpoles as the frog develops thyroid hormones increase to supraphysiological levels at the posterior-proximal junction of the tadpole tail, ROS and autophagy increases and the tail essentially cauterizes off.

Thyroid hormones are a necessary to “keep form”, thyroid hormones activate during carbohydrate/hypoxic situations in order to keep the cells utilizing carbohydrates from degenerating into more primitive cell types, for example, cancer. When this mechanism fails, for any number of reasons, whether it be fueling the basal metabolism with primitive energy substrates, external hypoxia, internal hypoxia from antimetabolic compounds, at the end of the day thyroid hormones help to maintain “form”, structure, and function. In a very real sense not only is thyroid hormone catabolic, it is protective and can be better classified as a stress hormone. It is an organizer.

One of the things that happens during Paleo style diets with all the PUFA, nuts, antinutrients, excess protein, etc., is that all of these things have an inhibiting effect on respiration. While serum levels of thyroid hormones fall, it is only because ultrastructural levels of thyroid hormone increase, that is, more is being used than can be produced, hence the nuclear blast of unsavory symptoms.

So your last point:

“This was the main reason I always steered clear of ketogenic diets. What do you make of that? Could it be simply the cumulative inhibitory effect of PUFA, since these people were probably not discriminating againsts those fat sources? Could it be the compounding of these diets + exercise that causes this? Excessive protein elevating cortisol and that in turn suppressing thyroid function?”

You hit the nail on the head exactly. Lower serum = higher ultrastructural levels = emergency = maintaining form because of the hypoxia induced from Paleo style diets is more important than thermoregulation. Your physiology is redirecting ATP and H+ pools to maintain form to survive verses cozy metabolically generated warmth.

Saturated fat does not do this. I steer clear of ketosis. Ketones are a symptom of hypoxia. We are indeed omnivores, glucose is essential for optimal health, people who say well, we have gluconeogenesis and ketones aren’t thinking about things in the broader context. It’s like, we have those pathways as evidence that yes, some glucose is required and probably optimal, we do not have the high output gluconeogenic pathways that true carnivores have. And when are those pathways active? Hmmm.

I hope that that answers at least part of your question. Ask any follow up questions and I’ll be sure to address them. This is a good topic.

Aside: One of the interesting things to look at is that RPF folks can sometimes initially loose weight, that is a function of elevated thyroid hormones trying to rescue the metabolism, but if they continue and ignore all shitty symptoms all of the sudden they blow the fuck up whether it is weight gain or worsening problems such as panic attacks, helplessness, social avoidance, etc. These of course are all symptoms of hypoxia … unless they start taking thyroid hormone. I prefer the advice “… let us avoid the problem to begin with …” the situation with the folks on the RPF is first physiological then pathological. Yikes.