Ketone supplements

I am pleased overall that various products are being marketed and discussed for promoting moderate ketosis. In another forum today, I’ve heard about Veech and Clarke’s ketone ester – not marketed yet, but throughly written up in peer-reviewed publications – and also heard from people using a currently avialable product based on beta-hydroxybutyrate salts and medium-chain triglycerides in combination. Whether based on MCTs and/or ketone salt mixtures, or based on ketone esters, all should get BOHB and AcAc into circulation to some degree, and all should be safe when properly manufactured. So no one is likely to be hurt by them, the first consideration in medicine. They may differ in efficiency, in chirality, or in concentration range achieved. The products various parties have been able to bring to market so far are all at an early stage of public experimentation and adoption. Time, experience, and more science will likely tell us what the differences among methods actually mean for health.

I’m not going to tackle in this post the various reasons to expect that ketosis may promote health and diminish risk for various chronic illnesses. The ketogenic diet, intermittent fasting, calorie restriction, and induced ketosis appear to me to be distinct but related alterations in diet, energy metabolism and therefore biochemistry. These likely form an overlapping set of interventions. If any of these techniques share common mediators, the ketone bodies would be principal candidates. For many of us there are good reasons to adopt a very low carbohydrate diet, and thus produce our own ketosis by lipolysis, beta-oxidation, and hepatic ketogenesis. Bear in mind that exogenous ketone bodies may downregulate our own lipolysis by the activity of BOHB at the GPR109a receptor on adipose cells.

I’ve been looking at my reference collection to find any documentation pertinent to the issue of BOHB racemic mixtures. This is an issue that conceivably could make a difference in the quality or efficiency of the products we are discussing.  Dr Veech’s ketone ester is designed to yield the native isomer only, d-BOHB. D-beta hydroxybutyrate, also described as (R)-3-hydroxybutyrate, is the predominant ketone body in circulation. It is enzymatically interchangeable with (non-chiral, less stable) acetoacetate in a redox reaction that occurs intracellularly and this reaction is the first step toward ketone body oxidation (which will yield acetyl-CoA leading to ATP production via the TCA cycle and oxidative phosphorylation).

So, is the other isomer, L-beta hydroxybutyrate, different in any important ways? It would be a component of certain synthetic racemic BOHB mixtures in use. So far I’ve found enough to make me want to continue research on this question. And I’m sure there are knowledgeable individuals who could tell us more. Here are two references.
1-“One of the KB, BHB, is optically active and as the chemically-manufactured form is an equal mixture of the D- and L-isomers. Endogenous BHB is the D-isomer and mammalian tissues have no recognized pathways for conventional oxidation of the L-form (Robinson & Williamson, 1980). This would suggest that half of any administered exogenous BHB may be metabolically useless. …All these studies have used the racemic mixture of BHB and must be interpreted with some caution because of uncertainty about the pathways available for the metabolism of the L-isomer (Robinson & Williamson,1980) which has constituted half the infused load.” from Ketone Bodies As Substrates, Rich AJ, Proceedings of the Nutrition Society, 1990, 49, 361-373.
2-“The ketone bodies enter extra-hepatic tissues on the same carrier, where other monocarboxylates can act as competitive inhibitors. Unphysiological isomers such as D-lactate or (S)-3-hydroxybutyrate can also act as competitive inhibitors to ketone body transport. Since ketone body transport across the blood brain barrier is a limiting factor to ketone body utilization in brain every effort should be made to keep the blood concentration of these unphysiological enantiomers at low levels during ketogenic therapy. When blood ketone body concentrations are elevated to levels found in starvation, heart, muscle, kidney and brain utilize ketone bodies as the preferred energy substrate.” from US2001/0014696A1, patent, RL Veech.

The patent is referenced but the footnote for this paragraph escapes me as yet; I’d like to know more about competitive inhibition between isomers at the monocarboxylate transporter. I’ll re-examine that reference list. And next, will review Robinson and Williamson, “Physiological Roles of Ketone Bodies as Substrates and Signals in Mammalian Tissues” (1980) as that paper is likely to be helpful.