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.

2 Comments Unifying biology (4) Ketones, fructose, and hypoxia

  1. David

    It’s interesting that you talk a little bit about alcohol consumption. Anecdotally I’ve noticed that drinking some gin at night seems to have some gut sterilizing effect, indicated by a pink tongue in the morning (with less white residue).

    In one of the KMUD interview, Ray said that he thinks the highly distilled and clear alcohols are safest. For me, a gin and tonic really makes me feel good.

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