Ketosis in a Nutshell – Part 2, Crazy Little Things

Oh, just an alternate fuel system  – no biggie …..

Got Ketones?

When you break down fats for energy production and you do this while there is a low glucose supply, you wind up with a little bit left at the end, which is then metabolized to acetoacetate. Acetoacetate can be metabolized to acetone or beta-hydroxybutyrate. All three of these molecules then circulate in the blood stream.  They are referred to as ketones, although technically beta-hydroxybutyrate does not fit the definition for ketones. Functionally, beta-hydroxybutyrate acts like a ketone in that it can readily be metabolized back to acetoacetate, thus acting as sort of a transit or storage form of ketones.

English: Synthesis of ketone bodies from acety...

English: Synthesis of ketone bodies from acetyl-CoA Deutsch: Synthese von sog. Ketonkörpern aus Acetyl-CoA (Photo credit: Wikipedia)

In chemistry, there are many, many molecules that are of the type classed as ketones.  When we refer to “ketones” in your body, we are specifically meaning the three molecules I have named above.  The term “ketone bodies” has been used as a catch-all phrase for these specific three molecules (one of which is a ketone supplier, rather than a ketone itself).

When it comes to the ketones present in the blood stream, these have been made by the liver predominantly, although the kidneys are a minor source.  We are learning more about ketone metabolism. For example, recent research suggests that cells in the brain that metabolically support the neurons can make ketones and can scale up the production of ketones when needed.  This would be for local use – we don’t think of these as leaving the brain to supply ketones in the blood stream.

How Ketones Function in Your Body  (terminology list at bottom of Part 1)

  • They can be burned as a fuel.  There are three fuel types the body can use – glucose, fatty acids and ketones.  The neurons in the brain can only burn glucose and ketones. The brain uses a lot of energy every day. During fasting or starvation, the body would have to break down a lot of protein to supply the brain with enough glucose for all its energy needs.  In prolonged fasting or starvation, the muscles would be consumed at a quick rate.  Persistence of muscle strength and survival are much longer because ketones can replace a lot of the glucose the brain needs. Ketones can not supply all your needs for glucose. Glucose must be at least at low normal levels in the blood at all times and is produced by the liver as needed (unless metabolic or liver function is very impaired by illness, drugs or genetic metabolic illness).
  • This allows the dietary glucose supply to be low  – in fact, there is no need for glucose from the diet. (Sugars and starches are the source for glucose in the diet. Starch is pure glucose.) This has profound implications for the management of all forms of diabetes and pre-diabetes and impaired insulin function. It also has profound implications in sweet addiction and food addiction.  The body requires much less insulin than when glucose is being absorbed from food as a major part of the diet.
  • Ketones aren’t glucose – they don’t need the glucose transport system, and so are not hindered by insulin resistance. For example, this has implications in Alzheimer’s Disease as research is exploring the theory that part of what is going on in Alzheimer’s Disease is “Type 3 diabetes” – that is, insulin resistance of the brain and abnormal insulin metabolism in the brain.
  • Ketones are burned for energy differently than glucose.  Also, they produce less stress in the mitochondria and cells.  This means there is potential for ketones to be useful to cells that are damaged or stressed or with abnormal metabolism.
  • Burning ketones for energy requires less oxygen to produce a given amount of energy than when burning glucose.  This means ketones have the potential for benefit in situations of low oxygen supply – such as injured tissue or stroke.
  • Ketones are being studied for potential direct effects besides as a fuel – such as increasing adenosine production and thereby suppressing abnormal excitability in the brain.

The topic is much more involved than this list suggests. See links below to very detailed review articles.

The Whole is More Than the Sum of its Parts

In sustained dietary ketosis:

  • there are elevated levels of ketones circulating in the blood (and some research suggests extra ketones being made in the brain)
  • there are the effects noted above on fuel supply and handling
  • the ketone fuel supply is steady and ample
  • the blood glucose level is steady and normal or low normal, with low requirements for insulin

Therefore, when evaluating any apparent benefits observed with dietary ketosis, it is difficult to tease out which of the possible mechanisms (or which combinations of possible mechanisms) are at play. (Again, if you are interested, check out the links below.)

Note that if ketones are elevated because ketones are directly given (this is being developed for medical application) or because of a high intake of medium chain triglycerides, there is not necessarily a low carbohydrate intake from food, and so the effects on blood glucose levels and insulin requirements would not be the same.

Sustained Ketosis Brings A Reduction in Appetite

Something about being in sustained dietary ketosis results in a reduction in appetite, which develops over the first days or, in some cases, weeks. This is not an abolition of appetite (although this can uncommonly occur at the beginning – thought possibly due to a too rapid shift into the starvation/ketosis adaptation). The appetite is not killed, just lessened.

This is a general human reaction to sustained dietary ketosis.  You don’t have to have any trouble handling carbohydrates to have this response.  It doesn’t matter whether you are slim, overweight or obese.  It happens in the young and the old.  It doesn’t matter if you have insulin resistance or not.  Of course, there is variability between people in this, as in all things.  Keep in mind – some people do not seem to be metabolically suited to do well with ketosis and some people should avoid ketosis for various medical reasons.  There are people with rare genetic metabolic problems who should definitely avoid being in ketosis (and this condition may not be obvious, even into young adulthood).

We have little insight into this phenomenon, but it has long been noted. We don’t know what it is about dietary ketosis that causes this. It is likely a combination of more than one of the mechanisms above.  I am not aware of any research attempt to really study this phenomenon.  This seems a little surprising to me given the massive research effort to find usable medications that will lessen appetite.  Of course, such a medication would be a financial block-buster, so there is money available for that research.  Does the degree of appetite reduction relate only to the blood ketone level?  Does it relate more to the degree of stability of the blood sugar?  Do variations in liver glucose output matter – for example, liver insulin resistance or glucose output precipitated by a stress hormone spike?  Can we learn to manage this phenomenon to best take advantage of it?  It would be nice if we had the knowledge to be able to enter this state of reduced appetite with the least costs in terms of effort, dietary limitations, risks, etc.

The reduction in appetite does bring its own risks:

  • it is easy to mistake feeling adequately fed with being adequately nourished
  • it is easy to become lazy about food and meal preparation – eating from a narrow range of foods and not taking the time to prepare vegetables, salads, etc.
  • relying on ketosis for appetite control and using this as a way to avoid learning about and dealing with other factors affecting your appetite/satiety balance, such as stress and sleep.  Good health is always best served by a broad approach to wellness – over-relying on any one health strategy can lead to neglect of other aspects of your health.
  • acting as a source of confusion when people slip in and out of a ketotic state

A Tipping Point in The Balance of Actual and Potential Benefits Versus Actual and Perceived Practical Usability?

The implications of an alternate fuel system are enormous. The major block hindering progress towards more people deriving more benefit from this potential is the actual and perceived difficulties in people learning and following the diet and finding the ketogenic diet worthwhile over time.

The benefits side of the balance going up …

The very successful use of ketogenic diets in epilepsy, as well as the insistence of  patients and patient’s parents that they value this option despite the difficulties involved, has helped spur a growing amount of research into the therapeutic use of ketones and ketosis.  Findings from other fields, such as the theories of so-called “Type 3 diabetes” as a possible factor in Alzheimer’s disease, have also increased the realization of the actual and potential benefits of ketogenic diets.

There is an increased drive to re-consider the benefits of nutritional ketosis given:

  • the now very large numbers of people
  • who have medical problems for which there are presently limited or poor treatment options ( e.g. obesity, blood sugar control, Alzheimer’s, etc.)
  • who might find benefit from nutritional ketosis
  • or who at least might benefit in the near future from further research into the subject area.

How about the practical usability side of the balance?

To be continued ….. Part 3

*** Also, please see addendum published today at the bottom of Part 1

Ketosis in a Nutshell – Part 1, What’s Up? (

Related articles

– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

Some recent publications:  (links fixed)

(1) very interesting recent paper, full text available, plus active links to almost all of the 192 papers in the list of references (“KD” = ketogenic diet):

“Rekindled interest in metabolic and dietary therapies for brain disorders complements new insight into their mechanisms and broader implications. Here we describe the emerging relationship between a KD and adenosine as a way to reset brain metabolism and neuronal activity and disrupt a cycle of dysfunction. We also provide an overview of the effects of a KD on cognition and recent data on the effects of a KD on pain, and explore the relative time course quantified among hallmark metabolic changes, altered neuron function and altered animal behavior assessed after diet administration. We predict continued applications of metabolic therapies in treating dysfunction including and beyond the nervous system.”

The nervous system and metabolic dysregulation: emerging evidence converges on ketogenic diet therapy.

Ruskin DN, Masino SA.  Front Neurosci. 2012;6:33. Epub 2012 Mar 26.

PMID: 22470316  Free PMC Article

(2) extensive review article, full text available, extremely detailed on scientific investigation of metabolic effects of ketones and ketosis

The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies.

Maalouf M, Rho JM, Mattson MP.  Brain Res Rev. 2009 Mar;59(2):293-315.  Review.

PMID: 18845187   Free PMC Article

(3) review article, this links to abstract, but full text does not seem to be open access

“The large categories of disease for which ketones may have therapeutic effects are:(1)diseases of substrate insufficiency or insulin resistance,(2)diseases resulting from free radical damage,(3)disease resulting from hypoxia.”

The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism.

Veech RL.

Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):309-19. Review.

PMID: 14769489

(4) interesting discussion, which challenges some current widely-held concepts in biochemistry.  It would be interesting to see a rebuttal by a biochem prof. Full text available.

Metabolic effects of the very-low-carbohydrate diets: misunderstood “villains” of human metabolism.

Manninen AH.   J Int Soc Sports Nutr. 2004 Dec 31;1(2):7-11.

PMID: 18500949   Free PMC Article

(5) A recent line of research suggests a cautionary attitude towards ketosis as evidence suggests some (or many, or most ??) tumors can be fueled by ketones produced by fibroblasts closely associated to the tumor cells. This is just the most recent of a number of papers regarding this line of research.  Of note, they are not researching the effect of ketones in the blood stream – this research is specifically and only about ketones produced in fibroblasts right by the malignant cells (part of the tumor mass itself).  Also, this work does not negate the line of research suggesting some cancers may be unable to metabolize ketones and may show reduced growth when ketones are high and glucose is low normal (especially malignant gliomas) – see below.

Ketone body utilization drives tumor growth and metastasis.

Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F, Lisanti MP.

Cell Cycle. 2012 Sep 19;11(21). [Epub ahead of print]  PMID: 22992619

(6) ketogenic diet being investigated for potential benefit in brain cancer (Note: there must always be glucose in the blood.  No glucose in the blood equals rapid death.  It is not possible to starve tumors by cutting off the glucose supply in the blood. The blood glucose can be brought down to low-normal, minimally fluctuating levels.)

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

Seyfried TN, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P.

Epilepsy Res. 2012 Jul;100(3):310-26.  PMID: 21885251

10 thoughts on “Ketosis in a Nutshell – Part 2, Crazy Little Things

  1. I am so in love with this post! It so succinctly yet thoroughly explains what ketones are and how they work. One if my long suspected problems that you address is the fact that some people with a mitochondrial disorder do much better with ketones being the source if energy vs ketones. I know I do! Thanks again for a fantastic very informative post!

    • Hi Linda, Thanks for visiting and your kind comments. Yes, I am so looking forward to knowledge about ketones expanding over the near future. Research will catch up with demand for insight eventually, but in the meantime we’ll have to learn from each other’s experiences as best we can. I’ll keep working on this series of posts.

    • Hi Jeffry, thanks for visitng and for kind words. As far as providing people with useful info goes – baby steps compared with your contributions on your website, Facebook and lectures/video. I’m looking forward to your new web site design and blog you have announced.

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