Keto-Adaptation – Some Clues to Its Complexity

Human metabolism has evolved to be remarkably flexible in its ability to use a variety of dietary energy substrates. From a cultural history perspective, humans have demonstrated the ability to subsist for generations on up to 80% of dietary energy as carbohydrates at one end of the macronutrient spectrum to over 80% as fat (a ketogenic diet) at the other end. Given this wide range of dietary options, what is the optimum nutrient mix? Is one end of this spectrum better than the other? Or is it best to be somewhere in the middle? How long does human metabolism take to optimize its use of the dominant fuel provided? We know that a lot of disease symptoms and health indicators get much better soon after someone starts on a ketogenic diet.

Most people, including most nutrition scientists, appear to believe that the effects of a high fat diet can be determined after only a week or two. Thus most diet studies, particularly those assessing effects on physical performance, have typically been run for two weeks or less. And this is still the case, even though we published data over 3 decades ago showing that the process of adapting to a very low carbohydrate intake requires at least a month and likely quite a bit longer. How much longer? It depends upon what measure of adaptation one is following, and it is very likely that inter-individual variability is a factor as well.


How Long Does it Take to Optimize Ketone Metabolism?     Some assume that keto-adaptation occurs simultaneously with the build-up in the level of ‘ketones’ (beta-hydroxybutyrate) in the blood. This hypothesis is based on the assumption that all of the benefits of ketones are directly linked to the amount available in the circulation. But here’s the catch – in our controlled inpatient studies, blood levels of BOHB come up to a new steady state within a week of starting a ketogenic diet but one’s subjective and objective ability to do vigorous exercise takes anywhere from several weeks to a few months to recover and then stabilize. In other words, the process of keto-adaptation that allows for normal or increased exercise performance lags well behind the level of ketones in the blood.

The body’s ability to produce and defend muscle glycogen via gluconeogenesis can become finely tuned, but that this takes much longer than 4-6 weeks to occur.

Serum Uric Acid as a Biomarker for Keto-adaptation: An intriguing potential indicator of the body’s progress into keto-adaptation is the response of the serum uric acid content after initiation of a ketogenic diet. In healthy normal humans with initially normal blood uric acid levels, their values typically double in the first week of nutritional ketosis.

The figure below depicts the serum uric acid levels typical for a healthy person fed a moderate protein ketogenic diet for 12 weeks. The acute rise in the first week occurs simultaneously with the increase in blood ketones, but then the slow progressive decline occurs despite stable levels of dietary protein and blood ketones.

Blog May 31 keto chart -1.png

In other words, the initial rise in blood uric acid appears linked to the onset of nutritional ketosis, but then the body slowly adapts back to normal uric acid clearance despite sustained ketones in the blood.So what gives?

The best available answer to this question is the following: to protect the body’s acid-base balance against too much acid from the diet or produced by our metabolism, our kidneys have the capacity to identify and actively clear organic acids from the blood. To some degree, at the onset of nutritional ketosis, this seems to be indiscriminate – it treats uric acid and non-toxic levels of ketones all the same. So at the start of nutritional ketosis, these two organic acids compete for excretion, causing blood uric acid to rise despite no increase in its production.

Over time the kidneys adapt to normalize uric acid excretion in the presence of beta-hydroxybutyrate, this process takes a few months to occur.

During this recovery in the kidney’s handling of organic acids, other aspects of the body’s energy regulation and homeostasis are undergoing similar slow changes as well with the net effect resulting in the process of ‘keto-adaptation’.

Does Keto-adaptation Increase Mitochondrial Density?         Another potential structural change that might directly contribute to keto-adaptation would be an increase in mitochondrial density in muscle, brain, and other oxidative tissues. The dramatic shift in energy metabolism towards fatty acid and ketone oxidation would be expected to enhance mitochondrial function. This could occur by increased mitochondrial biogenesis (production of new mitochondrial), decreased mitochondrial damage and autophagy (mitochondrial breakdown).

It is understood that reactive oxygen species (ROS) cause structural and functional damage to mitochondria, and that nutritional ketosis decreases mitochondrial ROS production. This could result in a prompt increase in the lifespan of existing mitochondria.

Keto-adaptation as a Complex of Changes on Varying Timelines: To be sure, when someone initiates a well-formulated ketogenic diet, a number of changes are set in motion which may occur in parallel, but with widely varying rates of completion.  (For these changes click the Virta link below.)

Bottom line: Keto-adaptation will likely be defined as the net effect of many parallel responses to a well-formulated ketogenic diet, with these various responses occurring on differing timelines, and to differing degrees across individual phenotypes/genotypes. The timeline for full keto-adaptation will likely be measured in months rather than days or weeks.

Have more questions about nutritional ketosis? Check out Nutritional Ketosis and Ketogenic Diet FAQ

This Post has been condensed fromKeto-Adaptation by Stephen Phinney, MD, PhD and Jeff Volek, PhD, RD on January 23, 2018






May you Live Long Healthy.

Yours truly,

Lydia Polstra





Author: 2healthyhabits
