My theme is that investigation into the potential benefits of moderate ketosis for many medical conditions is justified. Moderate ketonemia may be induced by extended fasting, sustained dietary modification, or administration of ketone body precursors. In order of efficacy, the precursors are 1) ketone body esters – these are esters of either of the principal ketone bodies, beta-hydroxy butyrate and acetoacetate, usually esterified with butanediol which is itself a KB precursor, 2) ketone body salts, or 3) medium-chain triglycerides. The esters are most direct and efficient, they have no sodium or potassium load as the salts do, and they do not require the stages of oxidative metabolism followed by hepatic ketogenesis that the MCTs must undergo.

For any ketone body supplement containing beta-hydroxybutyrate, be aware this is a chiral molecule, the D isomer only is produced in ketogenesis and that isomer is the substrate for further metabolism. The L isomer would also be present in BOHB  from a typical laboratory synthesis which would be a racemic mixture unless much care was taken for a stereospecific synthesis. The L isomer is at best not useful, possibly a detriment to ketone body transport and metabolism.

Usual fed-state circulating KB concentrations may be 0.1 mM. With prolonged fasting, concentrations may rise to 1 mM or so, and with KB precursor or supplement administation, the resulting elevated circulating ketone body levels may reach a  2-5 mM range. This is still physiologically normative although it is as if the body is in a prolonged fasting state. This range of concentrations is safe and fundamentally different from the dangerous and pathologic condition of diabetic ketoacidosis.

For decades, much of pharmacotherapy has focused on the more complex molecules that may interact with cell surface receptors, nuclear receptors, or enzymes. We haven’t heard much about these circulating small molecules, the ketone bodies, in medical applications.  But thanks to the work of many researchers, there is mounting evidence for their potential usefulness in many difficult conditions such as neurodegenerative diseases, inflammatory diseases, and metabolic disorders.

The ketone bodies were recognized early on as biologic “substrates and signals”. They are now known to function both as versatile and efficient cellular fuels, and as signaling molecules that deliver messages – promoting increases in cell antioxidant capacity, in mitochondrial biogenesis and the “browning” of adipose tissue, and decreases in inflammation, in overexcitation of neurons, and reactive oxygen species generation. When therapeutically employed, the KBs are also likely to support many intracellular functions in various tissues without interference or interaction with most of our commonly employed medications, as the mechanisms of action should be distinct.

In addition to the exogenous ketone approach, I also support similar broad research into ketogenic and other low-carbohydrate diets. These diets are already known to benefit epilepsy, obesity, mitochondrial diseases, and disorders of insulin resistance. Ketone bodies may be a principal mediator of some of these benefits, but the diet’s decreased reliance on carbohydrate intake and thus on glycolysis may also be vital in lowering excessive insulin secretion, preserving the NAD+/NADH ratio in cytoplasm to a range favorable for the epigenetic actions of sirtuins, and decreasing the potentially damaging “reductive pressure” placed on the mitochondrial respiratory complexes by typical “Western” diets that are high in both carbohydrate and fat. The low carbohydrate diets are actually not very difficult to follow; anyone interested may consult the published work of Dr Stephen Phinney and Dr Jeff Volek.

Rob Coberly MD
Albuquerque