Thursday, January 25, 2018

Ketones and Ketosis: Physiological and pathological forms

Ketones are compounds that have a specific chemical structure. The figure below (from: Wikipedia) shows the chemical structure of various types of ketones. As you can see, all ketones share a carbonyl group; that is the “O=” part of their chemical structure. A carbonyl group is an oxygen atom double-bonded to a carbon atom.

Technically speaking, many substances can be classified as ketones. Not all of these are involved in the same metabolic processes in humans. For example, fructose is technically a ketone, but it is not one of the three main ketones produced by humans from dietary macronutrients (discussed below), and is not metabolized in the same way as are those three main ketones.

Humans, as well as most other vertebrates, produce three main ketones (also known as ketone bodies) from dietary macronutrients. These are acetone, acetoacetate and beta-hydroxybutyrate. Low carbohydrate diets tend to promote glycogen depletion, which in turn leads to increased production of these ketones. Glycogen is stored in the liver and muscles. Liver glycogen is used by the body to maintain blood glucose levels within a narrow range in the fasted state. Examples of diets that tend to promote glycogen depletion are the Atkins Diet and Kwaśniewski’s Optimal Diet.

A search for articles on ketosis in scientific databases usually returns a large number of articles dealing with ketosis in cows. Why? The reason is that ketosis reduces milk production, by both reducing the amount of fat and glucose available for milk synthesis. In fact, ketosis is referred to as a “disease” in cows.

In humans, most articles on ketosis refer to pathological ketosis (a.k.a. ketoacidosis), especially in the context of uncontrolled diabetes. One notable exception is an article by Williamson (2005), from which the table below was taken. The table shows ketone concentrations in the blood under various circumstances, in mmol/l.

As you can see, relatively high concentrations of ketones occur in newborn babies (neonate), in adults post-exercise, and in adults fed a high fat diet. Generally speaking, a high fat diet is a low carbohydrate diet, and a high carbohydrate diet is a low fat diet. (One occasionally sees diets that are high in both carbohydrates and fat; which seem excellent at increasing body fat and thus reducing life span. This diet is apparently popular among sumo wrestlers, where genetics and vigorous exercise usually counter the negative diet effects.)

Situations in which ketosis occurs in newborn babies (neonate), in adults post-exercise, and in adults fed a high fat diet are all examples of physiological, or benign, ketosis. Ketones are also found in low concentrations in adults fed a standard American diet.

Ketones are found in very high concentrations in adults with untreated diabetes. This is an example of pathological ketosis, even though ketones are produced as part of a protective compensatory mechanism to spare glucose for the brain and red blood cells (which need glucose to function properly). Pathological ketosis leads to serum ketone levels that can be as much as 80 times (or more) those found in physiological ketosis.

Serum ketone concentrations increase proportionally to decreases in stored glycogen and, when glycogen is low or absent, correlate strongly (and inversely) with blood glucose levels. In some individuals glycogen is practically absent due to a genetic condition that leads to hepatic glycogen synthase deficiency. This is a deficiency of the enzyme that promotes glycogen synthesis by the liver. The figure below (also from Williamson, 2005) shows the variations in glucose and ketone levels in a child with glycogen synthase deficiency.

What happened with this child? Williamson answers this question: “It is of interest that this particular child suffered no ill effects from the daily exposure to high concentrations of ketone bodies, underlining their role as normal substrates for the brain when available.”

Unlike glucose and lipoprotein-bound fats (in VLDL, for example), unused ketones cannot be converted back to substances that can be stored by the body. Thus excess ketones are eliminated in the urine; leading to their detection by various tests, e.g., Ketostix tests. This elimination of unused ketones in the urine is one of the reasons why low carbohydrate diets are believed to lead to enhanced body fat loss.

In summary, ketones are present in the blood most of the time, in most people, whether they are on a ketogenic diet or not. If they do not show up in the urine, it does not mean that they are not present in the blood; although it usually means that their concentration in the blood is not that high. Like glucose, ketones are soluble in water, and thus circulate in the blood without the need for carriers (e.g., albumin, which is needed for the transport of free fatty acids; and VLDL, needed for the transport of triglycerides). Like glucose, they are used as sources of energy by the brain and by muscle tissues.

It has been speculated that ketosis leads to accelerated aging, through the formation of advanced glycation endproducts (AGEs), a speculation that seems to be largely unfounded (see this post). It is difficult to believe that a metabolic process that is universally found in babies and adults post-exercise would have been favored by evolution if it led to accelerated aging.


Williamson, D.H. (2005). Ketosis. Encyclopedia of Human Nutrition, 91-98.


Jamie Scott said...

Great post Ned. The table showing the order of magnitude of ketone body concentrations between those eating a high fat diet & those with uncontrolled diabetes is especially valuable.

Byron said...

A great summary.
I like this one

if people starts arguing contra keto.

Ned Kock said...

Thanks Jamie. All the credit goes to Williamson for that excellent article.

Thanks Byron. That article by Pérez-Guisado is indeed very well written and well referenced.

rick said...

Do you worry if carbohydrates are limited, more protein will be required (eaten) for gluconeogenesis? UC Berkeley Nutrition course:
"Buildup of ammonia is toxic to cells" What about kidneys (and in older people?)?

I've heard of some woman having "ammonia" smelling sweat on Robb Wolf's podcast:

Ned Kock said...

Hi rick.

Well, we know that the satiety level of protein-rich foods is high. Translation: your body wants you to eat a certain amount of protein, and discourages you from eating more than that. So stuffing yourself with protein, which may be facilitated by taking in protein supplements, does not sound like a very good thing to me.

The body uses carbs and protein to replenish glycogen stores. Endurance and (particularly) resistance exercise and HIIT (e.g., sprints) deplete glycogen stores. Stress also depletes glycogen stores. Fasting does that too, mostly liver, like stress.

If your glycogen stores are depleted, it seems that eating natural carb-rich foods is a good thing:

Stuffing oneself with more protein than one can stand doesn’t sound advisable. Having said that, ammonia seems to be quickly converted to urea (a much less toxic substance) in normal people. The story may be different for those folks who have kidney problems.

Walter said...

Found this via Free the Animal.

Have a question - someone once told me ketones were a problem, because they are free radicals. I've never seen any reference to this. I have seen a statement that fructose is a free radical.

Here I see that fructose is technically a ketone.

Any thoughts?

Ned Kock said...

Hi Walter.

Fructose has the chemical structure of a ketone but it is not one of the three ketone bodies that are produced and used by our bodies.

From college chemistry, if my memory doesn't fail me, free radicals are chemicals with unbalanced electrons. So they are very reactive, always trying to turn into something (possibly messing things up in the process).

Having said that, free radicals are very important. They are used in a very large number of metabolic processes.

So ketones are definitely not free radicals. Ketones are substances that our body produces and that are used as fuel by many tissues, including muscle. Our brain primarily uses glucose and ketones as fuel, and practically nothing else.

Walter said...

Thank you for your reply.

I understand that free radicals provide benefits (such as your immune system uses them to destroy invading pathogens). I also am not concerned about being in ketosis - I see it as a highly desirable state (most days I consume zero carbs) but I'm always looking to expand my understanding of physiology (the type I diabetic/ketoacidosis thing being an important qualifier to ketosis being a highly desirable state). I didn't deliberately drive myself into ketosis until I was certain that ketoacidosis was only a threat to a type I diabetic.

I also understand that fructose is not a ketone created by our bodies.

If I understand you correctly, the claim that fructose is a free radical then is also incorrect?

I've learned a lot from your posts and appreciate your posts on ketones and and ketosis as well as the other posts. I'm currently working my way from your first post to your most current (I'm at May 26).

Once I'm current I'll be checking in regularly along with the other "usual suspects" (names I'm sure you'd recognize) whose blogs I follow.

Thanks again for your response, your blog, and please clarify if fructose is a free radical.

Walter said...

Just to give some context, the claim that fructose was a free radical was made in the context of the antioxidants in fruit are there to protect the fruit from fructose, which is a free radical.

The antioxidants are there for the fruits benefit, not yours. I think you can see where that claim was heading.

Ned Kock said...

Hi Walter, thanks.

You are correct, fructose is not a free radical. In fact, fructose in fruits may be good for you, especially if you are low in glycogen:

Avishek said...

Walter what have your experiences been with ketosis and being Type I?

And Ned, I suspected I had higher levels of ketones or something post exercise, as I feel extremely focused, which I believe is due to the role of acylcarnitines transporting them to the brain.

That brings up a question, what is the evolutionary purpose of this increase in mental focus/clarity? I find it disturbing to eat in this state as my mind wants to focus and do something. About 30-45 min later it does subside and I am able to eat, but usually it remains and I eat anyway b/c I am hunry

Ned Kock said...

Hi Avishek.

I feel focused and energetic too. And I don't eat anything right after exercise. Usually 1 h after is when I start eating.

buy viagra said...
This comment has been removed by a blog administrator.
Paleolithic diet plan said...
This comment has been removed by a blog administrator.
Ned Kock said...

Spam comments above deleted.

Ned Kock said...

This post is a revised version of a previous post. The original comments are preserved here. More comments welcome, but no spam please!

sharperhawk said...

What do you think of Chris Masterjohn's analysis of the implications of the Arctic CPT-1a variant? In short, in places where diet should favor frequent and deep ketosis, evolution has shut it down because the dangers of ketoacidosis outweigh the benefits of nonpathological ketosis.

Ned Kock said...

Hi sharperhawk. When a mutation is very rare in the general population, but very common among related populations, a possible explanation is the “founder effect”. This could be the main explanation here. A small group of individuals with the same mutation goes on to populate the same area or areas, e.g., Canada, Greenland and Northeast Siberia. The mutation in question may not have any selective advantage. In fact, it may have a selective cost, but remain in the population because: (a) it was in the original “founders”; and (b) its cost is not so high as to have it wiped out from the new populations. Of course, Chris may be right; see also: