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To shed light on new methods of achieving ketosis
Useful article to read in preparation: Keto-adaptation
When we talk about ketones, we refer to beta-hydroxybutyrates (βOHB) and acetoacetate (AcAc) of the primary metabolites of fatty acids. More information on the basics of ketones here.
Exogenous ketones (also known as ketone supplements) and well formulated ketogenic diets have at least one thing in common. Both lead to an increase in circulating beta-hydroxybutyrate (BOHB) concentrations, but are ultimately associated with very different ketosis patterns, as well as different metabolic and physiological outcomes. In short, they should not have equivalent effects simply because they reach similar blood levels of BOHB. Having said that, there are many reasons why we should continue to study the different potential forms and applications of ketone supplements.
In the last few million years, the only way humans could use ketones as fuel was to limit carbohydrates to a value low enough to make the liver produce them. It is difficult for many people to do so in a world that still believes that dietary carbohydrates are good and that lipids are bad. An emerging alternative is to consume ketones as a dietary supplement. Research into their functioning in the body and the benefits they can confer is still in its infancy, but a number of these products are already available for sale. In this section, we will see how exogenous ketones affect ketone levels in the blood and how they can affect health and disease compared to ketones produced in the body.
The two main ketones manufactured by the liver are beta-hydroxybutyrate (BOHB) and acetoacetate (AcAc). Here is a brief summary of the basic information about these ketones:
- It is estimated that a keto-adapted adult can produce 150 grams of ketones or more per day after adapting to a total fast (Fery, 1985), and perhaps 50 to 100 grams per day with a well formulated ketogenic diet. .
- Some AcAc break down naturally to form acetone, which comes out through the lungs and kidneys, giving a chemical smell to the breath when the ketones are rich.
- Much of the AcAc produced in the liver is captured by the muscle and converted to BOHB.
- As part of the keto adaptation process, the way the muscles and kidneys treat BOHB and AcAc changes during the first weeks and months, and thus the ratio of AcAc / BOHB in the blood changes dramatically during the first few weeks and months. first or first two weeks.
- While the ultimate fate of most ketones in the blood must be burned as fuel, BOHB and AcAc appear to play different roles in the regulation of genes and cellular functions.
- BOHB seems to play a more important regulating role than AcAc, but AcAc could play a special role in signaling muscle regeneration (Zou 2016).
Sources and formulations of exogenous ketones
The two compounds commonly referred to as "ketone bodies" (BOHB and AcAc) are produced and used for multiple purposes, from algae to mammals, but rarely at concentrations useful for human extraction. For this reason, chemical synthesis is the source of most exogenous ketones. In addition, most current research and use of ketone-based supplements focuses on BOHB. Indeed, AcAc is chemically unstable – it breaks down slowly to form acetone by releasing a molecule of CO2.
In a ketone-adapted individual with fast ketone metabolism, with up to 100 grams or more oxidized (ie, "burned to produce energy"), the small amount lost in the breath and urine as acetone is minor. But as this failure occurs spontaneously without the help of enzymes, it also occurs in a drink or stored food (even in an airtight container), which makes problematic the shelf life of products containing l & # 39; AcAc. Thus, all current ketone supplements consist of BOHB in a form rather than a natural mixture of BOHB and AcAc produced by the liver.
Another important difference between endogenous and exogenous BOHBs is that most synthetic BOHBs used in food supplements are a mixture of both "D" and "L" isomers, whereas endogenously produced BOHB consists solely of the D isomer. Metabolically, the two isomers are very different and current published information indicates that most of the energy and signaling benefits of BOHB come from the D-form. This is potentially problematic because L isomers are not metabolized by the same chemical pathways as D forms (Lincoln 1987, Stubbs 2017), and it remains to be determined whether humans can convert form L to form D.
Thus, although the L isomers do not appear to be toxic, they are not likely to confer the same benefits as the D forms. In addition, the current dosages of ketones in the blood being specific to the D isomer, it is not likely to confer the same benefits as the D forms. It is therefore difficult to follow the blood levels and the clearance of any isomer L taken in a supplement.
New research on Poly-BOHB, an ancient source of energy
Another source of the D-BOHB isomer is an ancient source of energy for microorganisms. Poly-BOHB is a long chain of linked D-BOHB molecules. It functions in many unicellular organisms as a concentrated glycogen-like energy source in mammals, but whereas glycogen degradation releases individual glucose molecules, hydrolysis of poly-BOHB releases simple molecules of D-cells. BOHB.
It is interesting to note that poly-BOHB has recently played an important role in mammalian mitochondrial membranes, calcium channels in cell membranes and in exotic functions such as protein folding (Dedkova 2014). It exists in a variety of chain lengths, ranging from short to very long. It is not clear if humans can digest and use the poly-BOHB consumed in the diet, but in animals, poly-BOHB seems to have protective functions for probiotics and the intestine. This is a subject in full evolution that we will follow closely.
Ketone salts and esters
Except for this new poly-BOHB form, there are two general formulations for BOHB food supplements – salts derived from the keto acid or an ester formed between the keto acid and an alcohol.
The salts typically use sodium, potassium, calcium or magnesium as the cation. Since these cations vary in molecular weight and valence (1+ or 2+), the amount of minerals delivered per gram of BOHB varies from 10% for the 27% magnesium salt to potassium. Given that the recommended daily intakes of these different minerals range from a few hundred milligrams to 5 grams, while the goal of daily ketone intake to mimic blood levels of nutritional ketosis should be the same. In the order of 50 grams, it would be desirable to achieve this goal with ketone salts. seriously jeopardize the tolerance of minerals to human nutrition.
If administered as a single salt, 50 grams per day of BOHB would require daily intakes of 5.8 g Mg ++, 9.6 g Ca ++, 11.0 g Na + or 18.8 g K +. Even though it is carefully divided into a mixture of these different salts, it would be problematic to consume more than 30 grams of BOHB a day. Again, most ketone salt formulations currently marketed are prepared with a mixture of D and L isomers of BOHB, so that the actual delivered dose of the D isomer, more desirable, is considerably lower. The other concern regarding salt formulations is that, as weak acid salts, they have an alkalinizing metabolic effect that could have a modest but cumulative effect on blood pH and renal function.
Keto esters are more suitable for administering higher doses of BOHB, but repeated dosing can push the boundaries of taste and gastrointestinal tolerance. Rather extensive research has been conducted on a 3-hydroxybutyl 3-hydroxybutyrate compound that is converted by hydrolysis and hepatic metabolism to yield 2 molecules of ketones, probably for the most part D-BOHB (Clarke 2012 and 2014). In a study involving lean athletes, a dose of about 50 grams increased BOHB levels in the blood to 3 mM after 10 min and reached 6 mM 20 min. Submaximal exercises resulted in an increase in the elimination of ketones by 2 to 3 hours and contributed significantly to the total energy consumption of the body during exercise (Cox 2016). This product has been shown to significantly reduce appetite after a single dose (Stubbs 2018), but its effect on body weight in humans over a longer period has not been studied or its effect on control. of blood sugar in 2 diabetes. However, a single dose preceding a glucose tolerance test in healthy humans reduced the area under glucose in the blood by 11% and the ungenerated fatty acid area by 44% (Myette-Cote 2018).
Comparison of ketone (chemical ketosis) supplements with nutritional ketosis
The increase in the number of ketones in response to a well-formulated ketogenic diet is the restriction of dietary carbohydrates, which results in many favorable adaptations. Although both induce a form of ketosis, the lack of carbohydrate restriction in the context of the use of ketone supplements induces a different metabolic profile.
The blood levels of BOHB that can be achieved with salts or ester formulations are in the range of 1 to 3 mM, which is similar to what can be achieved with a well-formulated ketogenic diet in humans sensitive to insulin, but well below -7 days of total fasting (Owen 1969). In humans more insulin resistant, the ester formulation can provide higher blood levels than a sustainable diet (as opposed to fasting in the short term). For example, in the Virta IUH study of more than 200 patients with type 2 diabetes, average ketone levels in the blood were 0.6 mM at 10 weeks and 0.4 mM at one year.
With regard to epigenetic signaling, initial studies of the effects of BOHB on the activity of class 1 histone deacetylase against oxidative stress (Schimazu 2013), the suppression of the NLRP3 inflammasome ( Youm 2015), mouse longevity (Roberts 2017) and other epigenetic regulatory effects suggest that levels as low as 1 mM have potent effects. In addition, the association between a very mild ketonemia and a reduction in coronary mortality with the use of SGLT2 inhibitors in patients with type 2 diabetes (Ferranini 2016) suggests that 39, there may be clinical benefits with chronic BOHB levels as low as 0.3 mM (Gormsen 2017. Vetter 2017).
The other potentially important distinction between nutritional ketosis and ketosis of chemical origin is the potential metabolic role played by the production of AcAc by the liver and the redox status. Although the BOHB / AcAc ratio in venous blood is generally between 80% and 20%, Cahill's (1975) classic studies have observed significant peripheral hepatic and arteriovenous venous gradients in this patient in patients keto-adapted. These observations imply that the liver produces a higher proportion of AcAc than that found in the peripheral blood and that this is due to the absorption of AcAc in the peripheral cells (mainly the muscles) with a new release in the form of BOHB . In the process, the reduction of AcAc in BOHB produces NAD +, which is beneficial for the state of mitochondrial redox and mitochondrial function (Verdin 2015, Newman 2017).
That said, there is also the question of the relative advantages of AcAc over BOHB, both as independent signaling molecules and as redox modulators in peripheral (or non-hepatic) tissues. Viewed in this light, the AcAc generated in the liver acts as a NAD + donor for the periphery, whereas the pure BOHB taken orally, to the extent that it is retroactively converted to AcAc (Sherwin 1975), would deprive potentially the periphery of NAD +.
Another factor to consider is that in cases of food ketosis, the liver regularly provides ketones and releases them permanently into the circulation. In contrast, most ketone supplementation protocols involve bolus intakes that do not replicate the endogenous release pattern. The extent to which this influences the metabolic and signaling responses of different tissues remains unclear.
Summarizing this section, it is clear that some of the benefits of nutritional ketosis can be attributed to circulating levels of BOHB, and some of these benefits can be achieved at blood levels of 0.5 mM or less. Therefore, it remains to define where we set the bar of the minimum level of ketone conferring a benefit.
Practical Considerations on Chronic Disease Prevention and Management
As long as there is no more precise information on the necessary blood levels and the different proportions of BOHB and AcAc in order to optimize cellular and organic functions, it will be difficult to specify the dosage and duration of additional ketones. However, for fuel use, and most likely for physical performance, sustained blood levels of BOHB between 0.5 and 1.0 mM are probably needed. This objective is achieved physiologically by a ketone production estimated at 50-100 grams per day in a keto-adapted human.
With current formulations of ketone salts, even 50 grams per day are likely to exceed taste tolerances and physiological minerals. Thus, for these products, their potential benefits are probably limited to increasing levels of ketones in the blood of people already following a low carbohydrate diet.
On the other hand, for ketone esters, repeated doses of 20 to 30 grams per day may be possible. Thus, these products may be able to maintain a modest level of ketonemia without food restriction in carbohydrates. Thus, some benefits of cardiac and brain nutrition may result, not to mention the epigenetic effects limiting oxidative stress and inflammation. But given the recent observation that ketone esters administered significantly reduce circulating free fatty acids (Myette-Cote 2018) – probably due to insulinotropic effect or direct suppression of lipolysis (Taggart 2005 – their sustained use in people with underlying insulin resistance may compromise their long-term benefits by promoting weight gain, except in the case of carbohydrate restriction.
Other barriers to the long-term use of ketone supplements are their low taste for esters and their cost. Currently, at around $ 1 per gram of ketones delivered, daily doses of between 25 and 100 grams add up quickly to exceed the most reasonably expected benefits, unless you win the Tour de France.
There are tantalizing anecdotes about the use of additional ketones to improve human physical performance during competitions, especially among elite cyclists. Since BOHB can provide more energy per unit of oxygen consumed than glucose or fatty acids (Sato 1995, Cox 2016, Murray 2016), this makes sense. But what we do not know, is there is a period of adaptation necessary to the use of exogenous ketones, and therefore how to use them for training. It is clear that exogenous ketones decrease adipose tissue lipolysis and the availability of fatty acids, as opposed to what happens with a well formulated ketogenic diet. This distinction between exogenous ketones and ketogenic diets between adipose tissue physiology and the human energy balance highlights an important reason why these two ketone enhancement strategies should not be confused.
Cognitive function, Alzheimer's and cancer
Again, there are some very interesting animal studies as well as some isolated cases and small uncontrolled trials in patients with neurodegenerative disease and cancers receiving ketogenic and / or exogenous ketones (Murray 2016, Poff 2015, Roberts 2017, Newport 2015, Cunnane 2016). In some cases where the patient does not have the cognitive resources necessary to comply with a well-formulated ketogenic diet, or when the target blood levels of BOHB that act in animals are difficult to reach in humans through diet only additional ketones can play an important role in preventing, managing or reversing these disease categories.
Ketone supplements rapidly and transiently increase blood levels of BOHB. At first glance, it seems that this should promote positive effects. Many new studies are reported, some positive, others neutral, others negative. However, there are still many issues to be resolved.
The different forms (salts vs esters), their co-ingestion (carbohydrates vs no carbohydrates, minerals), the basic diet (ketogenic vs. high carbohydrate) and the dosage, period and periods of adaptation are only some of the important factors that can determine the metabolic responses to ketone supplements.
The information we provide on virtahealth.com and blog.virtahealth.com does not constitute medical advice, nor is it intended to replace a consultation with a health professional. Please inform your doctor of any changes you make to your diet or lifestyle and discuss these changes with them. If you have any questions or concerns about your health problems, please contact your doctor.