In Categories: Science & Research

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 for humans? Is one end of this spectrum better than the other? Or is it best to be somewhere in the middle? If adopting one end of the spectrum, how long does human metabolism take to optimize its use of the dominant fuel provided? Surprisingly, the truthful answer to all of these is ‘we really don’t know!’ Yes, we know that a lot of disease symptoms and health indicators get much better soon after someone starts on a ketogenic diet. What we do not yet fully understand are all of the underlying physiological process through which ketosis promotes metabolic healing, and how long that process takes to get the full benefits.

Part of the reason that we don’t know more about this issue is the lack of longer-term human research at the high fat end of this dietary spectrum. 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.

While a ketogenic diet can put you into a state of nutritional ketosis in a matter of days, it can take weeks to months to become fully keto adapted.

How Long Does it Take to Optimize Ketone Metabolism?

One simple assumption that we can dispose of right away is that keto-adaptation occurs simultaneously with the build-up in the level of ‘ketones’ (primarily 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 (Phinney, 1980; Phinney, 1983), 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.

Another indicator of how the body adapts to tight carbohydrate restriction may be the amount of glycogen that is maintained in muscles. Long ago, we noted that even when dietary carbohydrate is very low, muscle glycogen only drops to about half of its prior level after 4-6 weeks on a high fat diet (Phinney, 1980; Phinney,1983). But more recently, we studied highly trained runners who had followed a ketogenic diet for 6 months or longer. Despite impressive weekly training mileage, their glycogen levels had come all the way back up to those of a matched group of athletes following a high carb diet (Volek 2016). This implies that 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. Although this phenomenon was reported over half a century ago, its cause remains poorly understood. Some medical experts assume that carbohydrate restriction causes more purines from nucleic acids to break down to uric acid, either due to increased death of cells or from a higher dietary protein intake (i.e., meat containing nucleic acids). For reasons we won’t detail, neither of these mechanisms stands up to data in the published literature.

In short, 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. 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 that there is a somewhat murky understanding of how our kidneys deal with organic acids. 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 (which can be toxic when it builds up in the blood) 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. This was demonstrated long ago when two studies demonstrated sharp increases in blood uric acid levels when ketones were infused intravenously into human volunteers (Lecocq, 1965; Goldfinger, 1965).

But then, over time something seems to occur that slowly allows the body to efficiently rid itself of uric acid despite persistent blood ketones. In other words, the kidneys adapt to normalize uric acid excretion in the presence of beta-hydroxybutyrate, but for reasons we have yet to fathom, this process takes a few months to occur. One clue about how this occurs is the observation that during starvation ketosis, after 3 weeks the kidneys are excreting ketones at one third the rate than after just 4 days despite having the same blood ketone levels (Fery, 1985). This implies that over many weeks, the kidneys ‘learn how’ (i.e., adapt) to conserve ketones and get back to efficiently excreting uric acid.

In pointing out this slow recovery in the kidney’s handling of organic acids, we are not suggesting that this process itself is the limiting factor in keto-adaptation. Rather, perhaps 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 we long ago named ‘keto-adaptation’ (Phinney, 1980; 1983).

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. Although human evidence of keto-adaptation being linked with mitochondrial adaptations are lacking (we should be in a position to change that soon), mouse studies indicate a connection (Bough et al. 2006; Ahola-Erkkila et al. 2010). This could occur by either increased mitochondrial biogenesis, or decreased mitochondrial damage and autophagy.

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. Given estimates that mammalian mitochondria have half-lives in the 1-2 week range, and since it takes about 5 half-lives to reach equilibration after a change, an increase in mitochondrial lifetime might take 5-10 weeks to reach a new steady state for enhanced mitochondrial density, depending on the tissue or organ in question.

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. These may include:

  1. A prompt increase in ketogenesis resulting in BOHB becoming available as a major cellular fuel for oxidative metabolism, particularly in brain, heart, and skeletal muscle.
  2. Progressive adaptations in some tissues to prioritize fatty acid oxidation rather than ketones (e.g., skeletal muscle), allowing more ketone and less glucose use by the brain, and thus less need for gluconeogenesis from protein.
  3. Prompt reduction in ROS generation, resulting in reduced target tissue damage, but with the time to a new steady state depending upon the turnover rate of the target tissue.
  4. Fine tuning of glycogen conservation and 3-carbon substrate scavenging, allowing muscle glycogen content to return to ‘normal’. (Volek, 2016)
  5. Reduced inflammatory mediators, resulting from down-regulation of the NLRP3 inflammasome (Youm, 2015) and reduced isoprostane generation (Forsythe 2010, Kim, 2012).
  6. Improved power-to-weight ratio with body fat loss and improved body composition (McSwiney, 2017).

With the increasing availability of oral ketone supplements, we should also be able to learn more about both the short-term effects of ketonemia and the selective effects of exogenous BOHB in contrast to the mix of BOHB and AcAc that is released by the liver (Owen 1969). Given the observation of Cahill et al. that AcAc is selectively taken up by muscle, then reduced to and re-secreted into the circulation as BOHB, there is the added potential benefit of this process in regenerating NAD+ in peripheral tissue. This offers a point of study for inter-organ fuel exchange along with a shift in cellular redox state between the liver and peripheral organs (e.g., muscle and potentially brain).

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. These many variables aside, however, 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 our FAQ by Dr. Steve Phinney and the Virta team.

The information we provide at virtahealth.com and blog.virtahealth.com is not medical advice, nor is it intended to replace a consultation with a medical professional. Please inform your physician of any changes you make to your diet or lifestyle and discuss these changes with them. If you have questions or concerns about any medical conditions you may have, please contact your physician.

20 Comments

  1. Avatar

    very helpful- I have been focusing on ketosis for 6 weeks and frequently the urine strips remain pale – like Dr Hallberg’s Youtube presentation on LDLs suggested I may be one of those whose LDLs increases- my VLDLs improved, my HDLs improved- will retest with an NMR or Vap in 9 weeks-
    I am a FNP at a community clinic and am working with many diabetic and insulin resistant patients. Wanting to help them change their lives as well as mine….

    Reply

  2. Avatar
    wallace hodge May 6, 2018 at 6:05 pm

    You must blood test. the strips are useless

    Reply

  3. Avatar

    Dear virta team,

    I’ve been trying to do a ketogenic diet for almost 3 weeks, but i have been barely in ketosis (1,5 mmol) only 2 or 3 times, not days… I’ve found it difficult to remain in ketosis, a meal with slighty more of protein and i’m out…also once I got out of ketosis with a green tea! I was at 0.5 in the morning and 2 hours later after only have drunk a cup of tea the urine stripes marked none…i’m used to a 12-14 hours of IF every day, been doing LC for 3 years.
    I’m a “healthy” woman of 41, 56kg, 161 cm tall and 25% body fat, I can not exercise due to a back injury, I’ll be stopped for 3 months more at least…I’d like to lose % body fat and obviously not to put more fat on during this period, do you know any good practitioner in ketogenesis in Spain, where I live?
    So as it is frustrating not seeing results last thursday I fell out of the wagon and I ate some cereal…do this mean my body has to restart the path to ketosis from zero? although I’ve been merely in ketosis…But my body has noticed the changes: hair loss increased and cystic acne appeared…how could I bet theses symptoms?
    Thks for your advice,
    Best regards,

    Reply

    1. Avatar
      Virta Health May 7, 2018 at 5:41 pm

      We usually recommend the blood strips rather than the urine strips as they are more accurate. This FAQ on keto might help you troubleshoot your issues and optimize your nutrition plan: https://blog.virtahealth.com/nutritional-ketosis-faq/

      We don’t know any practitioners in Spain. Best of luck finding one!

      Reply

    2. Avatar

      Be careful of to much protine, your body can turn protine into sugar if you eat to much, its the biggest cause for not getting keto adapted.

      Reply

      1. Avatar

        That’s not correct. Gluconeogenesis is demand driven, not supply driven, meaning that the body will only convert the protein you eat to glucose when it needs it. No more than you need. Eat the protein you want, however be aware its consumption because of mtor and igf-1. Search these two words and their connection with protein eaten. (long story short, if you don’t lift and if you’re young, don’t eat too much proteins, as you lose the capacity to digest it with age)

        Reply

  4. Avatar

    Dear all,
    I forgott to say, that following your advice I increased the amount of salt, I also drink purified sea water, here is easy to find, as It provides quality minerals.
    thks

    Reply

  5. Avatar
    Michael Susano June 22, 2018 at 3:40 pm

    I began keto 5 wks ago. dropped 11#. Have been reading the ‘art and science of low carb living’ by Drs. Phinney and Volek. I’m a physician myself, have been overweight with high chol improved about 40% with statin. I took it upon myself to stop my statin within the past week. Had fasting labs done at office today. results showed TC much elevated from previous, 140 last reading within past year to 224 today, also, LDL increased to 132 today, I can’t remember previous, but, I know it was normal.
    HDL good, TG good. glucose good. one LFT was only mildly bumped, prob not significantj, but I thought it interesting and wondered if that was associated with keto at all.
    I did read in the book that LDL may go up, but, that it may be larger particles which are safer than smaller LDL particles, per the book, .
    Just can’t help but feel a little deflated with these results. Will they normalize with time, continued keto and exercise? I have a knee injury now and haven’t been active much, but, I can swim, so, that’s an option.
    I also read in the book that keto + statin gives best results. I was just hoping to leave it out, but, I suppose it’s best to restart.
    Just was hoping to if someone had seen anything similar and, is this just par for the keto course in initial stages, and, will it normalize with keto alone?
    thanks
    Michael Susano

    Reply

  6. Avatar

    Hi Virta team,

    One question that’s not clear to me is whether falling out of ketosis inadvertently (due to accidental slightly higher carbs on one day or even hepatic glucose output) halfway through the adaptation period resets the clock?

    For instance, if ketones are measuring >.5 or 1 mmol for 3 weeks, and then I eat a meal that had more carbs than I thought and get knocked out for a few hours, do I have to start the clock from 0 when measuring the time period for keto adaptation?

    Thanks,

    John

    Reply

    1. Virta Health

      Hello John! Thank you for your question. It varies based on the person, but a few hours out of ketosis will likely minimally affect your long-term goals if you’re sticking to a ketogenic diet. Keep in mind that keto-adaptation takes from weeks to months, so there’s no set time period for keto-adaptation. More on that here: https://blog.virtahealth.com/keto-adapted/

      Reply

  7. Avatar

    Just wanted to say that this is excellent research, and well presented. Hopefully, with an increase of adherents will come an increase in data and a better look at what long term ketosis does to alter the body. I am excited to learn what the end point looks like, and the pros and cons of sustained ketosis.

    Reply

  8. Avatar

    I have an extra 10 lbs and I’ve been on a strict keto diet for a week, using the Total Keto Diet app on my phone that tracks your food and ratios of carb/fat/protein. On day 5 I developed gout in my big toe which I’ve never had before and was so painful I could only walk on the side of my foot. I thought I had broken my foot but my orthopedic surgeon told me I had gout and asked what changed in my diet. A couple questions:

    – the TotalKetoDiet app calculates net carbs so for example- I eat an avocado a day and the app calculates the net carb subtracting the fiber which allows me to eat more than the 25 allocated carbs.
    – the MyFitnessPal app does not calculate net carbs.
    – I’m doing 8/16 intermittent fasting

    Questions:
    – Should I be using net carbs or total carbs? I’m on day 7, no alcohol at all and strict on the ratios and I’m still not in ketosis but was using the urine strips so will get the blood test. How long does this take to get there?
    – It looks like getting gout is a rare instance but any advice for getting rid of it?

    Thanks

    Reply

    1. Virta Health

      Hi Gaye, thanks for reaching out! We aren’t able to provide specific medical advice via this forum, however I can provide you with some resources.

      At Virta, we encourage our patients to start with 30 grams of total carbs per day. To learn more about how we develop a well formulated ketogenic diet, check out this post: https://blog.virtahealth.com/well-formulated-ketogenic-diet/

      There is a short-term increased risk of gout flares when initially entering into nutritional ketosis due to the competitive inhibition of ketones on kidney excretion of uric acid (Veech, 2004). This is transient, and once one is through the keto-adaptation process, the long-term risk of gout decreases (Hussain, 2012). To learn more, check out Dr. Phinney’s post on gout: https://blog.virtahealth.com/ketogenic-diet-gout/

      Reply

  9. Avatar

    I’m successfully using the keto diet for weight loss and will likely stay keto after I reach my goal weight. But in October, I’ll be traveling to a place where following keto will be impossible. I’ll be trekking for 6 weeks in Nepal where only rice and lentils are available. I’m not worried about gaining the weight back while in Nepal but it will probably take some time to adapt back to a high carb diet performance wise. When should I start the transition and what issues will I have switching back to a high carb died after almost a year in ketosis?

    Reply

    1. Virta Health

      Eric, what an exciting journey you have planned! Dr. Phinney has supplied the following response to your question:

      Straight Answer: It typically takes a week or two for most of the transition back to a carb-based metabolism, but this should be done SLOWLY, by sequentially adding 25-50 grams of carbs per day.
      Oblique Answer: My ketogenic friend and amazing 18-year reversed diabetic Dr. Jay Wortman and his medical student son Alex went on a 4-week trek in northern India up to 20,000 feet with an organized group. They planned carefully in advance, packing nuts and sausages as part of their baggage allotment. They also spoke with the trek leadership and arranged to have eggs, ghee, and full-fat cheese available in place of the rice, lentils, and nan. Alex wrote his senior thesis on their very successful trek, during which he and his dad Jay had reduced altitude problems compared to their fellow trekkers who ate the carbs. Note: depending on where you go in Nepal, you might be offered traditional butter tea for breakfast, which is made from dark tea, yak butter, and salt [https://en.wikipedia.org/wiki/Butter_tea].

      Reply

  10. Avatar

    Thanks for the answer. Yes, on a fully catered trek I might manage to stay in ketosis but that’s not my situation and I’m not concerned with that. I’ll be eating at tea houses where rice and lentils are the standard fare and my preferred choice. Besides, I’ve always lost 10-15 pounds when I go trekking in Nepal (it’s my 5th time) so gaining weight is not a concern. Nor am I diabetic or insulin resistant so neigher is staying in ketosis. I am concerned about endurance and aerobic performance though because at 61 years old I’m not able to do what I did at 45. Walking uphill at 18k to 20k feet is difficult at any age.

    BTW, I’ve seen many of your informative videos on YouTube but I’d like to see more videos for athletes. Best ways to train while on keto, etc.

    Reply

  11. Avatar

    Hi Vista team
    Greetings from Kenya! I’m really hoping you can answer this … Context: I’m two weeks into Keto and 6 months into training for a 7day 250km self-supported challenge in august… I’ve done two before and I’m super slow but finish happy and upright … My problem is that despite reading everything I can get my hands on, I can’t find any details anywhere about how to fuel long slow runs\walks during the transition period to keto adaptation…. I had a nasty experience last weekend at the 3 hour mark despite keeping my heart rate under 135… Heart palpitations, nausea, shaky, chills (it was 95 degrees!), Dizziness…. I had to use every shred of will power to stay conscious and call my husband to come and get me.
    So here’s the question: how do I fuel my long slow runs and walks (3-10hrs) to meet my mileage targets without this happening again, and without hampering the keto adaptation process? I’m assuming carbs are needed somehow? And how do I adjust volume of carbs over the next few months as I get into the fully adapted state?
    Thanks in advance!

    Reply

    1. Virta Health

      Hi Beth! Congratulations on such an undertaking! One of the most important aspects of keto adaptation is adequate electrolyte replacement. For details on the role of potassium and sodium, you can read more here: https://blog.virtahealth.com/potassium-sodium-ketogenic-diet/

      Also, you may find the book http://www.artandscienceoflowcarb.com/the-art-and-science-of-low-carbohydrate-performance/ by Drs. Phinney and Volek helpful in designing a training plan.

      Reply

  12. Avatar

    My blood ketones are very high, wjat could expkain that? I have been on keto and intermittent fasting for 8 weeks. I usually eat once a day, under 20 carbs. I never done longer fasts. Some days I eat 30 grams.
    I don’t have a need for more. Lost 22 pounfs, 39, healthy female

    My blood ketones are VERY high. I have never seen a reading under 3.4. Most often I am around 4.2, and I go up to 6.2. Last night I decided to eat tons of veges, sone raspberries, etc, and even a glass of wine. An hour after, my blood ketones were 3.4 and blood sugar 86.
    This morning before eating, back to 4.7 and glucose 68.

    Does this mean I am in starvation ketosis all day? Not keto adapted yet? I feel some blood circulation issues poping up, like leg cramps and I have very hard time getting any blood from my fingers.

    Do I need MORE than 20 carbs ?

    Reply

    1. Virta Health

      It is very possible that you aren’t receiving adequate nutrients and that you do need additional carbohydrates and meals. It is also important to make sure you are adequately hydrated as dehydration can also increase blood ketones. We cannot provide specific medical advice via this forum, but you may want to consider adding a meal and/or snacks as well as increasing carbohydrates.

      Reply

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