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Diverse effects of ketogenic and ketogenic diets

first,Ketone bodies that are naturally present in the bodywhat kind of work does it have?

In recent years, researchers have reported various effects.

In papers and patents on the Ketogenic diet

Emerging physiology of ketone bodies As

The main ones are:



(2) Suppression of    oxidative stress

(6) Suppression of    inflammatory response

(7)    improving kidney function        

​ and so on.

**However, most of these papers are data obtained from mice,​other animals andI don't know yet if it applies to humans.**

Clarified in patents and papers on the ketogenic diet

The main physiological functions of ketone bodies are as follows.


(1) Decrease in blood sugar level
(2)     Suppression of oxidative stress
(3)     anticancer effect
(4)     Protective effect on nerve cells (inhibition of epileptic seizures, etc.)
(5)     Reduction of blood fatty acids
(6)     suppression of inflammatory response

(7)     improvement of kidney function

"Blood sugar level spike suppression effect"

Diabetes is chronically high blood glucose levels caused by excessive glucose in the blood. If left untreated, arteriosclerosis progresses and blood vessels become more susceptible to damage. My blood sugar fluctuates all the time and I was diagnosed with diabetes.It is not uncommon for postprandial blood glucose levels to be 140 mg/dL or higher, even in people who do not. This rise in blood sugar level for about 1 to 2 hours after eating before falling into a state of constant high blood sugar level is called "blood sugar level spike". Controlling "blood sugar level spikes," in which blood sugar levels rise sharply in a short period of time after meals, is the basis of dietary habits to prevent diabetes. Ketone bodies areIt is known to strongly suppress blood sugar level spikes. That is, ketone bodies are known to activate their receptor HCAR2 and promote the uptake of glucose into tissues (eg, skeletal muscles of the arms and legs).



“Acquisition of resistance to oxidative stress (active oxygen)”


Cell survival depends on mitochondrial energy metabolism, but at the same time, it is thought that it is endangered by reactive oxygen species generated from this. Almost all cells have enzymes that remove active oxygen by themselves. Their expression is regulated at the gene level. One such regulation that occurs at the gene level is histone acetylation. When histones are acetylated, enzymes that scavenge active oxygen are produced more and more, and resistance to oxidative stress can be acquired. The presence of ketone bodies at this time promotes acetylation and can further enhance resistance to active oxygen.

A group from the University of Tokyo School of Medicine clarified the mechanism (published in 2013 / US scientific journal Science), and found that ketone bodies bind to histone deacetylase and inhibit it (release the inhibition of histone acetylation). rice field.


"Protection of nerve cells"

Direct administration of ketone bodies to cultured rat hippocampal cells reduced cell death caused by addition of amyloid-β, and similarly, in cultured midbrain cells, it prevented cell destruction by free radicals produced by Parkinson's disease (PK) causative agents. understood. Ketone bodies have the effect of activating gene expression by inhibiting histone deacetylase, a nuclear protein that binds to DNA and regulates gene expression. Ketone bodies act as regulators of gene expression and induce a group of enzymes that remove active oxygen. Ketone bodies thus protect nerve cells. The ketogenic diet may be one of the mechanisms by which neurodegenerative diseases associated with oxidative stress such as Parkinson's disease and Alzheimer's disease are effective.

“Neural cell membrane stabilization effect”

Ketone bodies have the effect of stabilizing the membrane potential of nerve cells and suppressing abnormal excitation. Ketone bodies activate ATP-dependent potassium channels, lower membrane potential, and suppress neuronal abnormal excitation. This is the molecular mechanism by which the ketogenic diet suppresses epileptic seizures. However, the membrane potential stabilizing effect of ketone bodies on nerve cells requires an increase in concentration to at least the mM order, and a thorough ketogenic diet is required. It has been known for more than 100 years that the ketogenic diet is highly effective against intractable epilepsy, but the reason why it is not widely used in clinical practice is that this thorough ketogenic diet is necessary. There is a cause. However, since ketone bodies have the function of maintaining a wide variety of brain functions normally, a ketogenic diet that can increase ketone bodies to the mM order is effective in preventing or treating various neurodegenerative diseases. It is believed that there is.

"Cancer suppression effect"

Ketone bodies suppress the growth of cancer cells and have the effect of regressing cancer. Cancer cells use only glycolysis to proliferate (Warburg effect). In other words, even if mitochondria exist in cancer cells, they are hardly utilized, and most of the energy substrates they need use glycolysis. mitochondCancer cells are known to undergo apoptosis or stop growing under conditions where ketone bodies and other organic acids, which can act directly on the rear, predominate. In addition to acting as an energy substrate for ketone bodies, it has been suggested that ketone bodies may inhibit cancer cell growth through activation of the HCAR2 receptor, inhibiting the growth of many types of cancer cells. reported to do.

"Adjuvant action"

Of particular interest in the cancer-suppressing action of ketone bodies are gliomas. Gliomas are characterized by the following two characteristics. One is that radiotherapy is possible due to its low invasiveness. The other is that most anticancer drugs cannot pass through the blood-brain barrier, so they have little effect on gliomas. On the other hand, ketone bodies are highly transmissible to the brain, and 20-30% of ketone bodies are translocated to the brain. In this sense, the combination of radiotherapy and ketone bodies is a combination with high clinical expectations. Against this background, cancer adjuvant action has attracted attention as a prominent action of the ketogenic diet. We found that irradiation of mouse gliomas significantly improved mouse survival, but radiation plus a ketogenic diet improved mouse survival even more. The effect of ketone bodies on inhibiting the growth of cancer cells is not limited to gliomas, but is observed in many cancer cells, so this report is noteworthy in terms of the effective use of ketone bodies as food in the medical science field. It can be said that the ketogenic diet is effective as a means for significantly enhancing the therapeutic effects of 1) chemotherapy, 2) radiation therapy and 3) surgical therapy, which are the most basic therapies for cancer. Focusing on this adjuvant action, clinical trials for cancer treatment are being conducted in various countries.

​​ " Neutral fat lowering effect"

When a healthy person follows a ketogenic diet, the concentration of ketone bodies in the blood increases. It activates mitochondrial metabolism throughout the body (especially in skeletal muscle).

Therefore, in skeletal muscle, the function shifts in the direction of producing energy (by decomposing fat). The amount of triglycerides taken up from the blood by skeletal muscles is increased, and blood glycerol (triglycerides) is significantly reduced. metabolism like thisThe shift in is an energy shift to permanently eliminate obesity.Conceivable.



"Anti-inflammatory action"

Ketone bodies suppress chronic inflammation. That is, ketone bodiesIt suppresses the function of the protein NLRP3, which is a component of the protein complex necessary to continuously promote sexual inflammation, and suppresses chronic inflammation. In addition, ketone bodies have the ability to activate HCAR2, a receptor for some organic acids, suppress various inflammatory reactions, and consequently suppress cancer. From these basic studies, it can be easily inferred that ketone bodies have inhibitory effects on pathological conditions involving inflammatory reactions such as ulcerative colitis, colon cancer, rheumatism, arteriosclerosis, and obesity.


“Renal function improving effect”


A group at Shiga University of Medical Science has revealed that ketone bodies activate autophagy and suppress diabetic nephropathy.

(Published in July 2020 / American scientific journal   Cell Metabolism) ​

In experiments with mice, administration of a ketone body precursor (1,3-butanediol: 1,3-BD) ameliorated the increase in serum cystatin C and tissue damage, which indicate increased renal dysfunction in a diabetes model. Feeding a substance (butanediol  *1) that converts to ketone bodies in the liver decreases the protein cystatin C in the blood, which indicates a decline in renal function.

Therefore, it can be expected to improve the symptoms of diabetic nephropathy in humans as well.


*For citation sources, please refer to the references below.

*1 / 
Explain butanediol.
1,3-butanediol (a ketone body precursor) is oxidized in the liver to produce 3-hydroxybutyrate (a ketone body), which enters the systemic circulation.


Physiological functions of ketone esters

"Lipolysis by ketone ester diet"

DavidVeech et al. tested mice on synthetic keto 60% of their regular diet carbohydrates.(2012) observed the effects of feeding mice on a ketone ester diet replaced with amine esters. The effect of the ketone ester diet on mice is remarkable, blood ketone body concentration increases 5-3 times compared to the ketone diet, and the mitochondria of brown adipose tissue develop and show a clear internal structure after 1 month of breeding. become. In other words, it was shown that ketone esters increase the concentration of ketone bodies, induce the decomposition of visceral fat, and markedly suppress obesity. Increased uncoupling proteins that promote mitochondrial thermogenesis and accelerated breakdown of intracellular lipids. Uncoupling proteins also increase in subcutaneous adipose tissue, contributing to fat loss.

“Anti-dementia effect of ketone ester diet”

David Veech and colleagues found that feeding mice with Alzheimer's disease a ketone ester diet improved cognitive function. Amyloid-β and phosphorylated tau protein, which are said to be involved in neuronal degeneration, are reduced. Although it is an animal experiment, since ketone bodies improve cognitive behavioral lesions in Alzheimer's disease A, ketone bodies are expected to have similar effects in Alzheimer's disease in humans.

“Improving endurance with a ketone ester diet”

A study of ketone esters by Kieren Clark et al.
It can be said that it is the biggest breakthrough in several years. Drinking Ketone Ester Beverages
Therefore, it was reported that the athlete's endurance and record were significantly improved.
Historically, carb-loading has been used before endurance training for athletes.
Although it was normal to ingest carbohydrates, this actually lowered the record,
Only the ketone ester intake group showed significant improvement in recording. Moreover, this effect is immediate
Effective and detectable tens of minutes after ingestion. In addition, intake of ketone esters
Therefore, it was also found that the decomposition of visceral fat is rapidly promoted. until then ketones
There have been many reports that the functions of the body have an immediate effect on the brain, but this report
Thus, it was shown for the first time that athletes' endurance also improved rapidly.


​ References

[Prior art documents]
[Patent document]
[Patent document 1] JP 2018-166481
[Patent document 2] JP 2018-000073
[Patent Document 3] JP 2017-071644
[Patent Document 4] JP 2018-138549
[Patent Document 5] Special table 2015-514104
[Patent Document 6] W2005/021013
[Patent Document 7] WO2019035486A1
[Patent Document 8] JP 2010-168595
[Patent Document 9] JP 2012-72148
[Patent Document 10] W2008/120778


[Non-Patent Literature]

Nakatani T, Yasuda K, Ozawa K, Tobe T. Changes in blood glucose levels in relation to blood ketone body ratio following hypertonic glucose infusion in 70% hepatectomized rabbits. Eur Surg Res. 1984;16(5):303-311. doi : 10.1159/000128423

[Non-Patent Literature]

Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

2013;339(6116):211-214. doi:10.1126/science.1227166

[Non-Patent Literature]

Tomita I, Kume S, Sugahara S, et al. SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition [published online ahead of print, 2020 Jul 19]. Cell Metab. 2020;S1550-4131(20 )30358-2. doi:10.1016/j.cmet.2020.06.020

[Non-Patent Literature]

Fery F, Bourdoux P, Christophe J, Balasse EO. Hormonal and metabolic changes induced by an isocaloric isoproteinic ketogenic diet in healthy subjects. Diabete Metab. 1982;8(4):299-305.

[Non-Patent Document 1] Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review. Noakes TD, Windt J. Br J Sports Med. 2017 Jan;51(2):133-139.
[Non-Patent Document 2] Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. Gershuni VM, Yan SL, Medici V. Curr Nutr Rep. 2018 Sep;7(3):97-106.
[Non-Patent Document 3] Analysis of energy restriction and physical activity on brain function: the role of ketone body and brain-derived neurotrophic factor. Park CH, Kwak YS. J Exerc Rehabil. 2017 Aug 29;13(4):378- 380.
[Non-Patent Document 4] How Can a Ketogenic Diet Improve Motor Function? Veyrat-Durebex C, Reynier P, Procaccio V, Hergesheimer R, Corcia P, Andres CR, Blasco H. Front Mol Neurosci. 2018 Jan 26;11:15.
[Non-Patent Document 5] Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease). Włodarek D. Nutrients. 2019 Jan 15;11(1).
[Non-Patent Document 6] The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease. Broom GM, Shaw IC, Rucklidge JJ. Nutrition.
[Non-Patent Document 7] Ketogenic dietary therapies for epilepsy and beyond.
deCampo DM, Kossoff EH. Curr Opin Clin Nutr Metab Care. 2019 Apr 24.
[Non-Patent Document 8] 2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control. Rho JM, Shao LR, Stafstrom CE. Front Cell Neurosci. 2019 Apr 30;13:172.
[Non-Patent Document 9] Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Nutr Metab (Lond). 2009 Aug 10;6:31. 
[Non-Patent Document 10] Medical foods for Alzheimer's disease. Shah RC. Drugs Aging. 2011 Jun 1;28(6):421-8.
[Non-Patent Document 11] Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health. Cavaleri F, Bashar E. J Nutr Metab. 2018 Apr 1.
[Non-Patent Document 12] β-Hydroxybutyrate: A Signaling Metabolite. Newman JC, Verdin E. Annu Rev Nutr. 2017 Aug 21;37:51-76.
[Non-Patent Document 13] Biomarkers, ketone bodies, and the prevention of Alzheimer's disease. VanItallie TB. Metabolism. 2015 Mar;64(3 Suppl 1):S51-7.
[Non-Patent Document 14] Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E. Science. 2013 Jan 11;339(6116):211-4.
[Non-Patent Document 15] Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Science. 2015 Mar 20;347(6228):1362-7.
[Non-Patent Document 16] Ketone Bodies as Anti-Seizure Agents. Simeone TA, Simeone KA, Rho JM. Neurochem Res. 2017 Jul;42(7):2011-2018
[Non-Patent Document 17] Tumor Metabolism, the Ketogenic Diet and βHydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy. Woolf EC, Syed N, Scheck AC. Front Mol Neurosci. 2016 Nov 16;9:122.
[Non-Patent Document 18] The influence of ketogenic therapy on the 5 R's of radiobiology. Klement RJ. Int J Radiat Biol. 2019 Apr;95(4):394-407.
[Non-Patent Document 19] The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC. PLoS One. 2012;7 (5): e36197.
[Non-Patent Document 20] Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to AdjuvantBrain Tumor Therapy. Woolf EC, Syed N, Scheck AC. Front Mol Neurosci. 2016 Nov 16;9:122.
[Non-Patent Document 21] The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. Nat Med. 2015 Mar;21(3):263-9.
[Non-Patent Document 22] The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, Pokorná B, Vollbrandt T, Stölting I, Nadrowitz R 2014 May 21;5:3944.
[Non-Patent Document 23] Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat. Veech RL. Ann NY Acad Sci. 2013 Oct;1302:42-48.
[Non-Patent Document 24] A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL. Neurobiol Aging. 2013 Jun;34(6):1530-9. 
[Non-Patent Document 25] Nutritional Ketosis Alters Fuel Preference and Adverse Endurance Performance in Athletes. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT , Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Cell Metab. 2016 Aug 9;24(2):256-68. 
[Non-Patent Document 26] Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. Srivastava S, Kashiwaya Y, King MT, Baxa U, Tam J, Niu G, Chen X, Clarke K, Veech RL. FASEB J. 2012 Jun;26(6):2351-62.
[Non-Patent Document 27] Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Sports Med. 2017 Mar;47(3):383-391.  
[Non-Patent Document 28] Ketone body metabolism and cardiovascular disease. Cotter DG, Schugar RC, Crawford PA. Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1060-76.
[Non-Patent Document 29] Ketoacids? Good medicine? Cahill GF Jr, Veech RL.
Trans Am Clin Climatol Assoc. 2003;114:149-6.
[Non-Patent Document 30] Ketone bodies, potential therapeutic uses. Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. IUBMB Life. 2001 Apr;51(4):241-7.
[Non-Patent Document 31] On the Metabolism of Exogenous Ketones in Humans. Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. Front Physiol. 2017 Oct 30;8:848.
[Non-Patent Document 32] A Ketone Ester Drink Lowers Human Ghrelin and Appetite. Stubbs BJ, Cox PJ, Evans RD, Cyranka M, Clarke K, de Wet H. Obesity (Silver Spring). 2018 Feb;26(2):269 -273


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