Ketosis versus ketoacidosis, metabolic flexibility or pancreatic disability?

What is the difference between ketosis and ketoacidosis?

Ketosis is the natural production of ketone bodies in the fasted state by the liver and kidney from fatty acids. Ketoacidosis (a.k.a. acetonenia, acetonuria, ketoaciduria, ketonuria) is the result of dysregulated pancreatic β-cell (beta-cell) insulin production.ketosis vs ketoacidosis (Ketoacidosis (acetonenia, acetonuria, ketoaciduria, ketonemia, ketonuria)

Ketosis versus ketoacidosis, metabolic flexibility or pancreatic disability?

Where’s a good definition of ketosis? || Should “ketosis” fall under “ketoacidosis” in a medical dictionary? || Should MeSH modify the current search tree for ketosis? || Is a low-carb diet dangerous? || Ketosis – is it a disease or natural metabolism? |Mesh definitions |10 weeks – Keto over MetS| Ketone Bodies – aren’t those acids instead of proteins? || Ketosis – following the MeSH tree. Is it a disease? || Ketosis – what are the MeSH preferred terms for it? ||Precision or accuracy, does it matter in nutrition? | Ketosis and bio-individuality | How do you differentiate between ketosis and ketoacidosis?

Where is there a ‘good’ definition of ketosis?

I looked up “ketosis” as I was reviewing medical definitions using the US National Library’s MeSH Descriptor Data 2020MeSH uses ketosis as a synonym for the metabolic disease ketoacidosis. MeSH synonyms are Acetonemia, Acetonuria, Ketoacidemia, Ketoacidosis Ketoaciduria, Ketonemia, Ketonuria, and Metabolic Ketoacidosis. Differentiating between a healthy state of metabolic ketosis and a life-threatening illness, ketoacidosis, is important. Ketosis is often used both personally and therapeutically for personalizing nutrition. Would it be appropriate to ask the NIH help desk for a correction or amendment to separate the normal body function from the disease? Here is the thinking:

Should “ketosis” fall under “ketoacidosis” in a medical dictionary?

Perhaps not. Isn’t ketosis a natural body response to the fasted state? Isn’t ketoacidosis an illness? “Ketone bodies” are defined in MeSH in a manner more closely aligned with a natural body function. However, they give ketosis as a synonym for ketoacidosis.

Should MeSH modify the current search tree for ketosis?

Perhaps yes. Currently, a search for ketosis returns medical cases, whereas a search for ketone signals returns articles referring to a “normal” ketogenic metabolism.

  • For example, Ketone bodies as signaling metabolites.[efn_note]Newman, J. C., & Verdin, E. (2014). Ketone bodies as signaling metabolites. Trends in Endocrinology & Metabolism, 25(1), 42-52. https://doi.org/10.1016/j.tem.2013.09.002[/efn_note]
  • Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. [efn_note]Puchalska, P., & Crawford, P. A. (2017). Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metabolism, 25(2), 262-284. https://doi.org/10.1016/j.cmet.2016.12.022[/efn_note]
  • Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation.[efn_note]Evans, M., Cogan, K. E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. The Journal of physiology, 595(9), 2857-2871. https://doi.org/10.1113/JP273185[/efn_note]

Is a low-carb diet dangerous?

Am I missing something? If your doctor believes that ketosis and ketoacidosis are the same, then he might consider a low-carbohydrate diet to be dangerous. There are many anecdotes of diabetics reversing their hypo- & hyperglycemia without ketoacidosis while reducing their need for medication. [efn_note]Halburg[/efn_note],[efn_note]Hallberg, S. J., Gershuni, V. M., Hazbun, T. L., & Athinarayanan, S. J. (2019). Reversing Type 2 Diabetes: A Narrative Review of the Evidence. Nutrients, 11(4), 766. https://doi.org/10.3390/nu11040766[/efn_note] A very low-calorie ketogenic diet (VLCKD) conducted over 4 months showed that ketosis can be an important therapy in obesity and diabetes management. [efn_note]Gomez-Arbelaez, D., Crujeiras, A. B., Castro, A. I., Goday, A., Mas-Lorenzo, A., Bellon, A., Tejera, C., Bellido, D., Galban, C., Sajoux, I., Lopez-Jaramillo, P., & Casanueva, F. F. (2017). Acid-base safety during the course of a very low-calorie-ketogenic diet. Endocrine, 58(1), 81-90. https://doi.org/10.1007/s12020-017-1405-3[/efn_note]

Ketosis – is it a disease or natural metabolism?

We knew in 1917 ketones are protein sparing?

“The protein-sparing power of fat is known to persist in diabetes. Therefore the absolute and relative increase in fat combustion now appears a sufficient explanation of the slight increment of ketonuria following any single fat meal, and the summation of such effects presumably accounts for the results of longer feeding, so that there is at present no evidence of a metabolic distinction between food fat and body fat. The relief of diabetic acidosis by fasting is doubtless due not only to diminished combustion of fat but also to a beneficial effect of undernutrition upon the assimilation of all classes of food. (Allen 1917)[Added emphasis.][efn_note]Allen, F. M. (1917). The role of fat in diabetes. In G. M. Piersol & J. H. Musser (Eds.), The American Journal of the Medical Sciences (Vol. CLIII, pp. 313-371). Lea & Febiger. https://metmult.news/46427[/efn_note]

MeSH equates ketosis and ketoacidosis

MeSH (Medical Subject Headings) is the U.S. National Library of Medicine’s controlled vocabulary thesaurus used for indexing articles for PubMed. I use it to ensure that my writing is in consonance with current medical terminology. However, when it comes to the natural state of ketosis, e.g. where the liver and kidneys generate ketone bodies from fatty acids, there’s a conflict in MeSH.

  • MeSH Heading Ketosis
  • Tree Number(s) C18.452.076.176.652
  • Unique ID D007662RDF
  • Unique Identifier http://id.nlm.nih.gov/mesh/D007662
  • Annotation high levels of ketone bodies; do not confuse with KETOSES (monosaccharides); ketogenesis is probably KETONE BODIES/‌biosyn
  • Scope Note A condition characterized by an abnormally elevated concentration of KETONE BODIES in the blood (acetonemia) or urine (acetonuria). It is a sign of DIABETES COMPLICATION, starvation, alcoholism or a mitochondrial metabolic disturbance (e.g., MAPLE SYRUP URINE DISEASE).
  • Entry Term(s) Acetonemia Acetonuria Ketoacidemia Ketoacidosis Ketoaciduria Ketonemia Ketonuria Metabolic Ketoacidosis Metabolic Ketosis
  • See Also Ketone Bodies
  • Public MeSH Note 91; was see under ACIDOSIS 1975-90
  • Online Note search ACIDOSIS 1966-74
  • History Note 91(75); was see under ACIDOSIS 1975-90
  • Date Established 1991/01/01
  • Date of Entry 1999/01/01
  • Revision Date 2013/07/08

10-weeks of ketosis dramatically improved MetS

Is metabolic syndrome (MetS) reversible? A recent study over several months shows it’s possible.[efn_note]Gibas, M. K., & Gibas, K. J. (2017). Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies. Diabetes & metabolic syndrome, 11 Suppl 1, S385-s390. https://doi.org/10.1016/j.dsx.2017.03.022[/efn_note]

The results demonstrated that the change over time from week 0 to week 10 was significant (p=0.001) in the ketogenic group for weight, body fat percentage, BMI, HgA1c and ketones.  All variables for the ketogenic group out-performed those of the exercise and non-exercise groups, with five of the seven demonstrating statistical significance.

(Gibas 2017)[Added emphasis.]

Ketone Bodies – aren’t those acids instead of proteins?

As you can see it’s good to go to the references. You always learn something. Had you heard of maple syrup urine disease (MSUD) before this? Isn’t MSUD a rare genetic disease in which amino acids aren’t properly processed rather than fatty-acid metabolism? Low-carb enthusiasts would probably agree with the following definition of ketosis. However, it is under ketone bodies in MeSH.

Ketosis – following the MeSH tree. Is it a disease?

Is ketosis a nutritional state or metabolic disease? Is it as a healthy sign of metabolic flexibility? Should it be moved out of the category of Metabolic Diseases?

Nutritional and Metabolic Diseases [C18]

However, a recent study points out the important therapeutic properties of ketone bodies.[efn_note]Han, Y. M., Ramprasath, T., & Zou, M. H. (2020). β-hydroxybutyrate and its metabolic effects on age-associated pathology. Exp Mol Med, 52(4), 548-555. http://doi.org/dsp6[/efn_note]

In addition to acting as an alternative energy source, β-HB (β-hydroxybutyrate) is also a potent metabolite that regulates cellular signals by targeting diverse biomolecules. β-HB is a tiny molecule that can easily pass through cell membranes and circulate throughout the body in the blood vessels, even reaching the brain through the blood-brain barrier (BBB). This feature provides an advantage to β-HB over other existing drugs for the treatment of neurological diseases.

(Han 2020) [Added emphasis.]

Ketosis – what are MeSH preferred terms for it?

Low-carb enthusiasts would agree with MeSh. Ketosis is preferred.

Precision or accuracy, does it matter in nutrition?

In shooting firearms, precision is hitting the same spot over and over, accuracy is hitting the target. If nutrition is not both precise and accurate, can it have the intended results? If we lack language to describe the processes involved in shifting into the fasted state as healthy, won’t that affect medical recommendations? Ketosis is measurable with handheld devices and its salubrious effects are enjoyed by thousands. Is it time to stop classifying it as a metabolic illness?

Both pure and applied science have gradually pushed further and further the requirements for accuracy and precision. However, applied science, particularly in the mass production of interchangeable parts, is even more exacting than pure science in certain matters of accuracy and precision.

Shewhart, W.A.; Deming, W. E. (1939). Statistical Method from the Viewpoint of Quality Control. The Graduate School, The Department of Agriculture. p. 120 [Added emphasis.]

Ketosis and bio-individuality

Bio-individuality may result in different reactions to dietary interventions.

Since individual differences make it difficult to control the optimal circulating β-HB levels by calorie restriction or a ketogenic diet, it is necessary to develop adjustable treatment options, such as KE (ketone ester) administration. As abrupt changes in circulating β-HB may disrupt energy homeostasis, the chiral enantiomer s-β-HB may offer a potential option for therapeutics, as this molecule cannot be used as an alternative energy metabolite.

(Han 2020) [Added emphasis.]

Human biodynamics cannot be mass-produced or easily replicated. Bio-individuality requires adaptation of general practices for each person’s body. Therefore, for personalized nutrition, accuracy and precision matter even more than in factory products. We have the tools to measure ketone bodies and their beneficial effects. Doctors use therapeutic ketogenic diets to alleviate mental and metabolic conditions. Let’s take the term ketosis out of the dog house and bring it into the living room.

How do you differentiate between ketosis and ketoacidosis?

Might clearing up these differences in how medical definitions are classified, facilitate constructive conversations among medical professionals? Might this added clarity benefit patients? Please let us know in the comments.

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Mani Malagón

Captain Mani Malagón (Manuel A Malagón-Fajar), USN (retired), MIT '74 (B.S. Math), US Naval Postgraduate School '86 (M.S.E.E.), US Army War College '99, served in US nuclear attack submarines & commanded USS Olympia (SSN 717). He was assigned to Submarine Force Pacific, 7th Fleet & Mine Warfare staffs, and as Defense Attaché to Chile. He has used a therapeutic ketogenic diet as a principal adjunct to ameliorate his brother’s schizophrenia.

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