January 1, 2013


Ketosis – advantaged or misunderstood state? (Part II)

Read Time 12 minutes

When I wrote part I of this post, I naively assumed this would only be a two-part series. However, so many great questions and comments emerged from the discussion that I realize it’s worth spending much more time on this important and misunderstood topic. In terms of setting expectations, I suspect this series will require at least four parts.

So, back to the topic at hand…. (You may want to read or maybe reread part I for a biochemistry refresher before diving into part II.)

Is there a “metabolic advantage” to being in ketosis?

Few topics in the nutrition blogosphere generate so much vitriolic rhetoric as this one, and for reasons I can’t understand. I do suspect part of the issue is that folks don’t understand the actual question. I’ve used the term “metabolic advantage” because that’s so often what folks write, but I’m not sure it has a uniform meaning, which may be part of the debate. I think what folks mean when they argue about this topic is fat partitioning, but that’s my guess. To clarify the macro question, I’ve broken the question down into more well-defined chunks.

Does ketosis increase energy expenditure?

I am pretty sure when the average person argues for or against ketosis having a “metabolic advantage” what they are really arguing is whether or not, calorie-for-calorie, a person in ketosis has a higher resting energy expenditure. In other words, does a person in ketosis expend more energy than a person not in ketosis because of the caloric composition of what they consume/ingest?

Let me save you a lot of time and concern by offering you the answer: The question has not been addressed sufficiently in a properly controlled trial and, at best, we can look to lesser controlled trials and clinical observations to a make a best guess. Believe me, I’ve read every one of the studies on both sides of the argument, especially on the ‘no’ side, including this one by Barry Sears from which everyone in the ‘no’ camp likes to quote. This particular study sought to compare a non-ketogenic low carb (NLC) diet to a ketogenic low carb (KLC) diet (yes, saying ‘ketogenic’ and ‘low carb’ is a tautology in this context). Table 3 in this paper tells you all you need to know. Despite the study participants having food provided, the KLC group was not actually in ketosis as evidenced by their B-OHB levels. At 2-weeks (of a 6-week study) they were flirting with ketosis (B-OHB levels were 0.722 mM), but by the end of the study they were at 0.333 mM. While the difference between the two groups along this metric was statistically significant, it was clinically insignificant. That said, both groups did experience an increase in REE: about 86 kcal/day in the NLC group and about 139 kcal/day in the KCL group (this is calculated using the data in Table 3 and Table 2). These changes represented a significant increase from baseline but not from each other. In other words, this study only showed that reducing carbohydrate intake increased TEE but did not settle the ‘dose-response’ question.

This study by Sears et al. is a representative study and underscores the biggest problems with addressing this question:

  1. Dietary prescription (or adherence), and
  2. Ability to accurately measure differences in REE (or TEE).

Recall from a previous post, where I discuss the recent JAMA paper by David Ludwig and colleagues, I explain in detail that TEE = REE + TEF + AEE.

Measuring TEE is ideally done using doubly-labeled water or using a metabolic chamber, and the metabolic chamber is by far the more accurate way.  A metabolic chamber is a room, typically about 30,000 liters in volume, with very sensitive devices to measure VO2 and VCO2 (oxygen consumed and carbon dioxide produced) to allow for what is known as indirect calorimetry.  The reason this method is indirect is that it calculates energy expenditure indirectly from oxygen consumption and carbon dioxide production rather than directly via heat production.  By comparison, when scientists need to calculate the energy content of food (which they do for such studies), the food is combusted in a bomb calorimeter and heat production is measured.  This is referred to as direct calorimetry.

Subjects being evaluated in such studies will typically be housed in a metabolic ward (don’t confuse a metabolic ward with a metabolic chamber; the ward is simply a fancy hospital unit; the chamber is where the measurements are made) under strict supervision and every few days will spend an entire 24 hour period in one such chamber in complete isolation (so no other consumption of oxygen or production of carbon dioxide will interfere with the measurement).  This is the ‘gold standard’ for measuring TEE, and shy of doing this it’s very difficult to measure differences within about 300 kcal/day.

Not surprisingly, virtually no studies use metabolic chambers and instead rely on short-term measurement of REE as a proxy.  In fact, there are only about 14 metabolic chambers in the United States.

A broader question, which overlays this one, is whether any change in macronutrients impacts TEE.

Despite the limitations we allude to in the summary of this review, there is a growing body of recent literature (for example this studythis study, and this study) that do suggest a thermogenic effect, specifically, of a ketogenic diet, possibly through fibroblast growth factor-21 (FGF21) which increases with B-OHB production by the liver.

These mice studies (of course, what is true in mice isn’t necessarily true in humans, but it’s much easier to measure in mice) show that FGF21 expression in the liver is under the control of the transcription factor peroxisome proliferator-activated receptor a (PPARa), which is activated during starvation. Increased FGF21 promotes lipolysis in adipose tissue and the release of fatty acids into the circulation. Fatty acids are then taken up by the liver and converted into ketone bodies. FGF21 expression in liver and adipose tissue is increased not only by fasting but also by a high fat diet as well as in genetic obesity which, according to these studies, may indicate that increased FGF21 expression may be protective. Hence, ketosis may increase TEE either by increasing REE (thermogenic) or AEE (the ketogenic mice move more).  Of course, this does not say why. Is the ketogenic diet, by maximally reducing insulin levels, maximally increasing lipolysis (which dissipates energy via thermogenic and/or activity ‘sinks’) or is the ketogenic diet via some other mechanism increasing thermogenesis and activity, and the increased lipolysis is simply the result?  We don’t actually know yet.

Bottom line: There is sufficient clinical evidence to suggest that carbohydrate restriction may increase TEE in subjects, though there is great variability across studies (likely due the morass of poorly designed and executed studies which dilute the pool of studies coupled with the technical difficulties in measuring such changes) andwithin subjects (look at the energy expenditure charts in this post).  The bigger question is if ketosis does so to a greater extent than would be expected/predicted based on just the further reduction in carbohydrate content. In other words, is there something “special” about ketosis that increases TEE beyond the dose effect of carbohydrate removal?  That study has not been done properly, yet.  However, I have it on very good authority that such a study is in the works, and we should have an answer in a few years (yes, it takes that long to do these studies properly).

Does ketosis offer a physical performance advantage?

Like the previous question this one needs to be defined correctly if we’re going to have any chance at addressing it. Many frameworks exist to define physical performance which center around speed, strength, agility, and endurance.  For clarity, let’s consider the following metrics which are easy to define and measure

  1. Aerobic capacity
  2. Anaerobic power
  3. Muscular strength
  4. Muscular endurance

There are certainly other metrics against which to evaluate physical performance (e.g., flexibility, coordination, speed), but I haven’t seen much debate around these metrics.

To cut to the chase, the answers to these questions are probably as follows:

  1. Does ketosis enhance aerobic capacity? Likely
  2. Does ketosis enhance anaerobic power? No
  3. Does ketosis enhance muscular strength? Unlikely
  4. Does ketosis enhance muscular endurance? Likely

Why? Like the previous question about energy expenditure, addressing this question requires defining it correctly.  The cleanest way to define this question, in my mind, is through the lens of substrate use, oxygen consumption, and mechanical work.

But this is tough to do! In fact, to do so cleanly requires a model where the relationship between these variables is clearly defined.  Fortunately, one such model does exist: animal hearts.  (Human hearts would work too, but we’re not about to subject humans to these experiments.)  Several studies, such as this, this, and this, have described these techniques in all of their glorious complexities.  To fully explain the mathematics is beyond the scope of this post, and not really necessary to understand the point.  To illustrate this body of literature, I’ll use this article by Yashihiro Kashiwaya et al.

The heart is studied because the work action is (relatively) simple to measure: cardiac output, which is the product of stroke volume (how much blood the heart pumps out per beat) and heart rate (how many times the heart beats per minute).  One can also measure oxygen consumption, all intermediate metabolites, and then calculate cardiac efficiency.  Efficiency increases as work increases relative to oxygen consumption.

Before we jump into the data, you’ll need to recall two important pieces of physiology to “get” this concept: the acute (vs. chronic) metabolic effect of insulin, and the way ketone bodies enter the Krebs Cycle.

The acute metabolic effects of insulin are as follows:

  1. Insulin promotes translocation (movement from inside the cell to the cell membrane) of GLUT4 transporters, which facilitate the flux of glucose from the plasma into the inside of the cell.
  2. Insulin drives the accumulation of glycogen in muscle and liver cells, when there is capacity to do so.
  3. Least known by most, insulin stimulates the activity of pyruvate dehydrogenase (PDH) inside the mitochondria, thereby increasing the conversion of pyruvate to acetyl CoA (see figure below).
Image credit: Veech et al., 2001

The second important point to recall is that ketone bodies bypass this process (i.e., glucose to pyruvate to acetyl CoA), as B-OHB enters the mitochondria, converts into acetoacetate, and enters the Krebs Cycle directly (between succinyl CoA and succinate, for any biochem wonks out there).  I keep alluding to this distinction for a reason that will become clear shortly.

An elegant way to test the relative impact of glucose, insulin, and B-OHB on muscular efficiency is to “treat” a perfused rat heart under the following four conditions:

  1. Glucose alone (G)
  2. Glucose + insulin (GI)
  3. Glucose + B-OHB (GK)
  4. Glucose + insulin + B-OHB (GIK)

In fact, that’s exactly what this paper did.  Look at what they found:

Image credit: Kashiwaya et al., 1997

The upper two graphs in this figure show similar information, namely the response of cardiac output and hydraulic work to each treatment. (Cardiac output is pure measurement, as I described above, of volume of blood displaced per unit time. Hydraulic work is a bit more nuanced; it measures the mechanical work being done by the fluid.)

Adding insulin to a fixed glucose (GI) load increases both cardiac output and hydraulic work, but it’s only significant in the case of hydraulic work.  Conversely, adding B-OHB to glucose (GK) increases both cardiac output and hydraulic work significantly. Interestingly, combining insulin and B-OHB with glucose (GIK) increases neither.

Oxygen consumption was significantly reduced in all arms relative to glucose alone, so we expect the cardiac efficiency to be much higher in all states. (Why?  Because for less oxygen consumption, the hearts were able to deliver greater cardiac output and accomplish greater hydraulic work.)

The figure on the bottom right shows this exactly.  If you’re wondering why the gain in efficiency is so great (24-37%), the answer is not evident from this figure.  To understand exactly how and why adding high amounts of insulin (50 uU/mL) or B-OHB (4 mM) to glucose (10 mM) could cause such a step-function increase in cardiac efficiency, you need to look specifically at how the concentration of metabolic intermediates (e.g., ATP, ADP, lactate) varied in the rat heart cells.

This is where this post goes from “kind of technical” to “really technical.”

The figure below presents the results from this analysis.  The height of the bar shows the fold-increase for each of the three treatments relative to glucose alone.  To orient you, let’s look at a few examples.  In the upper left of the figure you’ll note that GI and GIK both significantly increase glucose concentration in the cell, while GK does not.  Why?  The GI and GIK treatments both increase the number of GLUT4 transporters translocated to the cell surface so more glucose can flux in.  GK does increase glucose concentration, but not significantly (in the statistical sense).

Image credit: Kashiwaya et al., 1997

Table 1 from this paper, below, summarizes the important changes from this analysis.  In particular, look at the last column, the Delta G of ATP hydrolysis.

I was really hoping to write this post without ever having to explain Delta G, but alas, I’ve decided to do it for two reasons:

  1. To really “get” this concept, we can’t avoid it, and;
  2. The readers of this blog are smart enough to handle this concept.
Image credit: Kashiwaya et al., 1997

Delta G, or Gibbs free energy, is the “free” (though a better term is probably “available” or “potential”) energy of a system.

Delta G = Delta H – Temperature * Delta S, where H is enthalpy and S is entropy. The more negative Delta G is, the more available (or potential or “free”) energy exists in the system (e.g., a Delta G of -1000 kcal/mol has more available energy than one of -500 kcal/mol). To help with the point I really want to make I refer to you this video which does a good job explaining Gibbs free energy in the context of a biologic system. Take a moment to watch this video, if you’re not already intimately familiar with this concept.

Now that you understand Delta G, you will appreciate the significance of the table above.  The Gibbs free energy of the GI, GK, and GIK states are all more negative than that of just glucose. In other words, these interventions offer more potential energy (with less oxygen consumption, don’t forget, which is the really amazing part).

To see what the substrate-by-substrate changes look like across the mitochondria and ETC, look at this figure:

Image credit: Kashiwaya et al., 1997

Though it is by no means remotely obvious, what is happening above boils down to two major shifts in substrate utilization:

  1. In one step the reactants NADH/NAD+ become more reduced (in the chemical sense), and;
  2. In another step the reactants CoQ/CoQH2 become more oxidized (in the chemical sense).

These changes, taken together, widen the energetic gap between the states and, in turn, translates to a higher (i.e., more negative) Delta G which translates to greater ATP production per unit of carbon. 

Additional work, which you’ll be delighted to know I will not detail here, in fact shows that on a per carbon basis, B-OHB generates more ATP per 2-carbon moiety than glucose or pyruvate.  As an aside, this phenomenon was first described in 1945 by the late Henry Lardy, who observed that sperm motility increased in the presence of B-OHB (relative to glucose) while oxygen consumption decreased!

Is there a reason to prefer GK over GI?

Yes. Recall that ketones make their way onto the metabolic playing field without going through PDH.  Adding more insulin to the equation forces more pyruvate towards PDH into acetyl CoA.  While B-OHB “mimics” the effect of additional insulin, it does so in a much cleaner fashion without the complex cascade of events brought on by additional insulin (e.g., decreased lipolysis) and, perhaps most importantly, avoids the logjam of impaired PDH due to insulin resistance (I’ll come back to this point in a future post when I address Alzheimer’s disease and Parkinson’s disease).  In essence, B-OHB “hijacks” the Krebs Cycle via a slick trick that lets it bypass the bottleneck, PDH.  All the glucose and insulin in the world can’t overcome this bottleneck.  It’s truly a privileged state and a remarkable evolutionary trick that we can utilize B-OHB.

Back to the original question…

Clearly, in the highly controlled setting of a perfused rat heart, ketones offer an enormous thermodynamic advantage (28%!).  But what about in aggregate human performance?  There is no reason to believe that therapeutic levels of B-OHB (either through nutritional ketosis or by ingesting ketone esters) would increase anaerobic power, since the anaerobic system does not leverage the Delta G improvement I’ve outlined here.  Same is true for muscular strength.  However, there is reason to believe that aerobic capacity and muscular endurance could be improved with sufficient B-OHB present to compliment glucose.

It turns out this has been demonstrated repeatedly in subjects ingesting ketone esters, developed by Dr. Richard Veech (NIH) and Dr. Kieran Clarke (Oxford). Because the results of their work have not yet been published, I can’t comment much or share the data I have, which they shared with me.  I can say the ingestion of B-OHB in the D-isoform (the physiologic isoform), resulting in serum levels between 4 and 6 mM, did lead to significant increases in aerobic power and efficiency in several groups of elite athletes (e.g., Olympians) across multiple physical tasks maximally stressing the aerobic system.

Once published, I believe these studies will be a real shot across the bow of how we view athletic performance.  It is very important to point out, however, that these studies don’t exactly address the most relevant question, which has to do with nutritional ketosis.  In other words, ingesting ketone esters to a level of 4 to 6 mM might not be the same as de novo producing B-OHB to those levels.  But, such trials should be forthcoming in the next few years.  Personally, I am most eager to see the results of a ketone ester alone versus nutritional ketosis versus combination treatment, all to the same serum level of B-OHB.

The Hall Paradox

For the really astute readers, you may be saying, “Waaaaaaaait a minute, Peter…if ketones increase Gibbs free energy while reducing oxygen consumption, should this imply TEE goes down?”  You’re right to ask this question.  It was the first question I asked when I fully digested this material.  If each molecule of B-OHB gives your muscles more ATP for less oxygen, you should expend less not more energy at the same caloric intake, right?

I was discussing this with Kevin Hall at NIH, an expert in metabolism and endocrinology.  Kevin pointed out the error in my logic.  I failed (in my question) to account for the energetic cost of making the ketones out of fat.  Remember, in the experiments described above, the B-OHB is being provided for “free.”  But physiologically (i.e., in nutritional ketosis or even starvation), we have to make the B-OHB out of fat.  The net energy cost of doing this is actually great. According to Kevin, it is not generally appreciated how making ketones from fatty acids affects overall energy efficiency. Nevertheless, this can be examined by comparing the enthalpy of combustion of 4.5 moles of B-OHB, which is about -2,192 kcal, with the enthalpy of combustion of 1 mole of stearic acid (about -2,710 kcal) that was used to produce the 4.5 moles of ketones. Thus, there is about 20% energy loss in this process.  Hence, the energy gain provided by the ketones is actually less than the energy cost of making them, at least in theory.

This suggests that being in nutritional ketosis may require more overall system energy, while still increasing work potential.  In other words, a person in nutritional ketosis may increase their overall energy expenditure, while at the same time increasing their muscular efficiency.  In honor of Kevin, I refer to this as the Hall Paradox.

Parting shot

Ok, if you’re still reading this, give yourself a pat on the back.  This was a bit of chemistry tour de force.  Why did I do it? Well, frankly, I’m tired of reading so much nonsense on this topic. Everybody with a WordPress account (and countless people without) feels entitled to spew their opinions about ketosis without even the slightest clue of what they are talking about.  As I said in part I of this series, there is no bumper sticker way to address this question, so to say ketosis is “good” or “bad” without getting into the details is as useful as a warm bucket of hamster vomit (unless you’re Daniel Tosh, in which case I bet you can find a great use for it).

Next time, I’ll try to back it out of the weeds and get to more clinically interesting stuff.  But we had to do this and we’re better for it.

Chemistry by Marcin Wichary is licensed under CC by 2.0

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.


  1. Ernst — the two prime factors in gall stone formation is genetics and diet. The former being hard wired as it were.. the latter a complex combination of overall diet choices and exercise level/sedentary lifestyle. HIGH insulin levels program the body into fat storage mode and start this cascade of stone formation which is genetically based. I’ve never read anything per diabetics staying on a low carb & higher fat content diet as being predisposed to stones per those diet choices. IMO.. gall stone formation is likely an epigenetic trait.. IE: sedentary lifestyle with long term high insulin levels trigger a genetic expression to form stones.

    Your weight loss on the high fat diet could mean your body is loosing muscle mass… using them as a source of protein… likely to a minor extent. Your system has adapted to your current ‘fueling’ level and adjusted the total weight downward… being now a little leaner. WISH.. I had your genes… !!

    Observe the people exiting any large grocery store.. I say large because one then gets the message quickly. So many of them actually WADDLE carrying those excess pounds. Go into the store then and observe their food choices.. carts loaded with processed foods loaded with wheat and various forms of sugar. This is the face of the looming health crisis coming in the country.. as this population ages the cost to our society will be enormous.

    Genetics.. a complex code with everyone’s being different. Your weight will vary as mine does per diet choices. Finding the balance that works best for your system isn’t dependent on what the scale reads.. rather how you feel per energy levels & mental functioning. Your body adjusts to your current feeding level… with no history of family gallstones there’s IMO no reason to be concerned with stone formation on a reduced carb diet.


    • NOTE: addition to this post.. last burb per my opinion and NOT med pro.

      Aladin February 21, 2015
      Your comment is awaiting moderation.
      Ernst — the two prime factors in gall stone formation is genetics and diet. The former being hard wired as it were.. the latter a complex combination of overall diet choices and exercise level/sedentary lifestyle. HIGH insulin levels program the body into fat storage mode and start this cascade of stone formation which is genetically based. I’ve never read anything per diabetics staying on a low carb & higher fat content diet as being predisposed to stones per those diet choices. IMO.. gall stone formation is likely an epigenetic trait.. IE: sedentary lifestyle with long term high insulin levels trigger a genetic expression to form stones.

      Your weight loss on the high fat diet could mean your body is loosing muscle mass… using them as a source of protein… likely to a minor extent. Your system has adapted to your current ‘fueling’ level and adjusted the total weight downward… being now a little leaner. WISH.. I had your genes… !!

      Observe the people exiting any large grocery store.. I say large because one then gets the message quickly. So many of them actually WADDLE carrying those excess pounds. Go into the store then and observe their food choices.. carts loaded with processed foods loaded with wheat and various forms of sugar. This is the face of the looming health crisis coming in the country.. as this population ages the cost to our society will be enormous.

      Genetics.. a complex code with everyone’s being different. Your weight will vary as mine does per diet choices. Finding the balance that works best for your system isn’t dependent on what the scale reads.. rather how you feel per energy levels & mental functioning. Your body adjusts to your current feeding level… with no history of family gallstones there’s IMO no reason to be concerned with stone formation on a reduced carb diet.

      Understand I am NOT a medical professional and am expressing my opinion per my experiences over time. I come from a family with many very obese individuals.. none of which formed gallstones. Apparently our genetics aren’t predisposed to gall stone formation.


  2. Hello,

    Thank you for this information. It must of taken you a very long and dedicated period to collect the panoply of research here. I am greatful for USEFUL information like this especially in the light of all the anactodtal responses to this question. I am relativley new to this topic and as a young medical student am only interested the more. What advice can you give for someone like me ( a novice) who has the relative scientific background to persue this question more in depth ( by that I mean with the science to back up the claims) what literature, if any can I read? Also 2) how does one get started in NK? are there useful dietery cookbooks– perferably general guidlines– that one can use?

    Thank you very much for this information again!

  3. **************(skip if in a hurry)**************
    I have already watched all your videos I could find and am currently working on reading through your whole blog. I could write pages about how great ketosis, your blog, your talks (and butter) are and how helpful they were for a wide array of questions I had so far, but I’ll have to skip that for brevity. I am currently experiencing a multitude of benefits from a very low carb diet and have successfully introduced several family members to this lifestyle. I would describe the feeling of having ketones for energy instead of glucose as “honey-peanut-butter flowing through the brain” and am sure many can relate.

    I would like to allow myself to ask for your opinion and maybe challenge you a bit (as you requested on your startpage) on two things, for which I could not find good answers yet:

    1. While looking for some Magnesium in a drugstore, I saw a supplement that is supposed to block the absorbtion of carbohydrates in the gut. Now, for people like you, who got their ketogenic diet figured out, this probably would not make a huge difference and of course I am not proposing that people use such a supplement to eat huge amounts of carbs and then artificially block them to be in ketosis (that would just be stupid) but this be of help for some people? Are they reasonable for people really struggling hard with their insulin resistance?
    Could they enable a wider range of people, especially morbidly obese people, who do not have necessary resources, to benefit from a ketogenic diet by increasing the carb threshold for ketosis?
    I would be interested to get your opinion on the idea of blocking excess carbs from affecting insulin.

    2. As I am most interested in the effects ketosis has on the brain, I read about some people experiencing a decreased need for sleep on a ketogenic diet. Assuming these experiences are related to ketosis, could you think of an explanation for this phenomenon?
    Could it be because of the decreased production of reactive oxygen species?
    Could it be because of the more efficient brain activity caused by ketosis which needs less rest at night?

    I would like to thank you in advance for answering comments in such an engaging way (which is astonishing considering the number of comments here) and wish low insulin levels to all!!

  4. Seeking recommendations for the best diet software.

    I have only recently begun to explore and experience a ketogenic nutritional approach. While seeking to learn more about the subject, I discovered the wonderful EatingAcademy website. I enjoy preparing my own food, and have adequate time to devote to it. So far, I have relied mostly on intuition to design meals that are healthy, and place me in a state of ketosis. I have been fairly successful to that extent.

    The thing I’m having a more difficult time with, because it requires a bit more than intuition, is how to monitor my caloric intake so that I can safely and reliably lose some of my excess fat, but make sure I’m not losing lean mass. I feel like my motivation to eat has definitely diminished, which would lead me to think I’m consuming enough calories, but I’m not sure.

    I have briefly searched for diet software to help me monitor my nutritional intake, and have found a few choices. But I’m not yet sure which of them might be best. I would like an application that meets the following needs:

    Multi-platform (Windows, Mac OS X, primarily)
    Easily input of complicated recipe ingredients, with ingredients / serving sizes in metric or English units
    Access to large and reliable food database
    Not too expensive

    Thanks in advance for any recommendations!

  5. Methods to test for presence of ketones.

    I embarked on the low-carb lifestyle very recently, and using KetoStix, have found that on each test, I seem to be in a state of ketosis to some degree. I’m wondering if someone might suggest a device/method to more precisely detect ketone levels, and where such a device can best be obtained.


  6. Peter,

    As you outlined in your IHMC talk there are multiple pathways the body can mobilize glycogen for ATP in muscle tissue dependent on the time/power dependent demand. Are there also multiple pathways for metabolizing adipose tissue for ATP other than by the lipolysis you outlined for ketosis. Also what is the pathway/cycle in which fat is mobilized for fuel when someone is not in a ketogenic state?

    Hoping this finds you,


  7. I’ve been on fruit only protocol for seven days now, been checking urine daily with a test strips.High ketones level every day, lost 8 lb in one week. I eat apples, pears, grapes, berries, melons,no citrus or bananas. Plenty glucose and ketosis without additional protein.


  8. “BHB converts to AcAc and generates succinate via Succinyl-CoA Tranferase (SCOT). The liver (where ketones are made) lacks SCOT, and thus spares ketones for other tissues.
    Most cancer cells lack SCOT, also.”
    I dont fully understand what you mean by this, doesnt AcAc generate succinate as it converts to AcAc-coa, which gets further metabolized into 2 molecules of Acetyl-coa by the addition of another coa ? Since succinate eventually gets metabolized into coa as well wouldnt BHB yield more acetyl-coa than glucose through its own metabolization. So why was the increase in acetyl-coa necessarily attributed to increase PDH activity? It simply could have been the result of direct BHB utilization. Wouldnt measuring the rate of glucose depletion in the medium be a better way of seeing if BHB activates PDH ?

  9. Hello there! I am a post menopausal women and have fought my menopausal weight gain for years–trying every diet/lifestyle change out there BUT nutritional ketosis/ketogenic diet–this is actually my last hope. Is this lifestyle change effective for a woman in my phase of the meno life? Also what is a good starting point for a book/website information on a step by step guide to get started. Thank you!!!

  10. Hi Peter. I saw someone else has already asked but couldn’t see a reply. What are your thoughts on a cyclical ketogenic diet? Going by what I’ve read, I can’t see the need for a 36 hour carb load over the weekend. Would the carb loading only be benificial for muscle hypertrophy as opposed to reducing body fat and getting lean? Great article BTW

  11. I’m struggling a lot with this article.

    why is it important to recall the acute effects of insulin? None of them seem to lead to the “complex cascade of events”, they all seem like benefits to me.

    GIK (glucose + insulin + ketones) resulted in the greatest increase of cardiac efficiency, so why is this not seen as the preferred state (for performance, at least)?

    in the table showing the delta G values, GIK (glucose + insulin+ ketones) and GI (glucose + insulin) had the lowest values (or highest negative values, if you will) – doesn’t that mean there was greater energy released, in comparison to GK (glucose + ketones)?

    why is more insulin forcing more pyruvate towards PDH into acetyl coA a bad thing? Isn’t good to have more acetyl coA??

    how does the anaerobic system not leverage the delta G improvement? Thus, why would nutritional ketosis not be advantageous for anaerobic power and/or muscular strength?

    I don’t understand the hall paradox – if ketones (B-OHB) can produce more energy for less oxygen, are they still a more efficient way of producing energy for athletes if there’s a large energetic cost involved in making ketones from fat? why/why not?

    I feel the finding from Henry Lardy on the efficiency of B-OHB contradicts the finding from the table 1 of that study shows a lower delta g value for GI (not ketones!).

    why do you talk about B-OHB in moles when the study you showed talked about them in millimoles? I found this made it difficult to compare the enthalpy of B-OHB and stearic acid to the delta G values of the study (I know enthalpy and delta G are different things, but I don’t see how else I can appreciate energy cost of converting fat to ketones).
    Also, how do you conclude that there is thus about 20% energy lost in that process?

    Thankyou so much for this post, it was pretty freaking awesome, even if it confused me. I am extremely grateful for the time and effort you put into your posts and this one has done wonders for how much I idolise you.

  12. Dr. Attia – I was wondering if you could help me with a keto biochem question? I’ve always loved your blog and I’m in NK (1.2 mmol/L this morning). I will add that I had four science majors in college (but that was a long time ago) and I used to be a professional triathlete (that was a long time ago, too).

    Some have touted MCTs as being converted to ketones. In fact, Dr. Mercola wrote an article along these lines this week (3/6/2016), saying:

    “MCTs are fats that are not processed by your body in the same manner as long-chain triglycerides. Normally, a fat taken into your body must be mixed with bile released from your gallbladder before it can be broken down in your digestive system. But, medium-chain triglycerides go directly to your liver, which naturally converts the oil into ketones (unless you are on a statin drug, which blocks the liver from converting them to ketones), bypassing the bile entirely.

    “Your liver then immediately releases the ketones, which are water soluble, into your bloodstream where they are transported to your brain to be readily used as fuel. Additionally they do not require L-carnitine to shuttle them into the mitochondria for fuel.”

    That doesn’t make sense with my science understanding. My understanding is that such a system DEPENDS upon whether one is, or is not, in a ketogenic (or starvation) state. The idea that if one eats MCTs, converting them to ketones depends upon the ketogenic (or starvation) state.

    My understanding is that triglycerides are broken down to FFAs and taken into mitochondria and turned into Acetyl-CoA and subsequently put through the Krebs Cycle and ETC to make NADH, FADH2, ATP, etc.

    In non-ketogenic people (glucose burners), the Krebs Cycle continues its steps to make ATP, etc. But, ONLY in ketosis (or starvation) will oxaloacetate be depleted in the Krebs Cycle, and, then, the metabolism switches to GNG AND the production of ketones. Thus, my understanding is that ONLY when you’re in ketosis will liver mitochondria produce ketones; not by simply ingesting MCTs in a non-ketogenic state.

    I also understood that ketone production doesn’t depend upon FFAs ability to enter mitochondria (i.e., whether they need the carnitine shuttle or not, or whether they need albumen as a carrier molecule to be water soluble in the blood). It’s whether oxaloacetate senses the depletion of pyruvate (from glycolysis) that initiates GNG and ketone production (again, not simply drinking MCTs).

    Am I missing something? Or can a non-ketogenic person simply consume some MCTs and they’ll be converted to ketones?!


  13. Broken links above – please provide the accurate links. I would like to read this information in looking for clinical basis for Keto. thanks

    “A broader question, which overlays this one, is whether any change in macronutrients impacts TEE. If you’re interested in the entire review of the literature on this topic, refer to this appendix (LINK BROKEN) from the exhaustive review we did at NuSI, along with this summary(LINK BROKEN) and narrative(LINK BROKEN). This review spans over 80 years of research and 1.2 million subject-days. ”

    GREAT WORK – thank you!

  14. Seven weeks into ketosis, no problems at all during adaption through a variety of sports/fitness activities. Any evidence out there to support the armchair theory that this might be due to the fact that I started (& never went excessively long periods without intense) weight training at 14 yrs of age (some 31 yrs ago), and perhaps developed “improved” insulin sensitivity?

  15. Great post. Is it possible to specify exactly where the lesser requirement for oxygen is? If fatty acid oxidation, the link reaction and the Kreb’s cycle are all anaerobic then does that indicate the oxygen savings are at the electron transport chain? Or am I completely off track?

  16. I have been *flirting* with NK for some months now. I like the science and I find the eating style fairly simple to follow. I am a RNY Gastric Bypass patient from 2000, when I had surgery I was around 550 lbs, now I am in the 250 range. I am working on this next 50 or so pounds and try to stick to a strict <30 carbs per day budget. I have not found any discussion around RNY patients and NK here and am wondering if you have any ideas around this population. NK has the potential for much greater calorie intake at much smaller volume. Since my volume is quite restricted, and absorption is kind of an unknown at this point… Do I modify anything? I find I cannot turn a pee stick much past "trace" for love or money, but I need to avoid going full eating disorder and getting my calories so low I just fall over dead – or kill someone … I am going to get a blood test kit, but what if I discover I just cannot get in to NK! I just wonder if there are details around my altered anatomy which I should pay attention to? My husband and son lost all their chub in under 6 moths on Keto (both with a fairly "normal" metabolic reality). I loose the initial water weight, but from there NOTHING. Even when I add exercise.

    There is only so far calorie restriction goes – what might I be missing?

  17. I am also interested in women’s hormone influence of low insulin. I also noticed a concern with some people who see elevated liver enzymes. I would believe this would only happen when you are NOT keto adapted. This was observed in the mouse studies where exogenous ketones were given to mice with a mixed diet….which would be similar to the average population. I’d love more studies on the use of exogenous ketones with zero diet changes and not being keto adapted on liver metabolism. Any studies on exogenous ketones in the sedentary SAD diet population?

  18. So my question is… if a population of people born with congenital heart defects need to focus on longevity, would diet (in this case ketosis) be the direct answer to the end game surgery or catastrophic event. Also I think you have shown in several of your posts that overall obesity trumps anything else, so would (or would not) the goal be to eliminate the obesity and worry about stressors on the heart after you have attained a better ground to stand on. I have heard two opinions from doctors or friends that go as such.

    Doctor # 1: Light cardio, standard american diet, high in fibre and low in cholesterol, the more you relax the less stress is placed on the cardiovascular system.

    Doctor #2: Interval cardio, LCHF diet, heightened cholesterol markers, focus hard on burning the adipose fat off to attain a better fitness level.

    Side note: Is there any data that you have seen for success rate of cardiac surgery for obese patients vs. normal or lean patients.

    This of course is anecdotal or hypothetical question, seems to be little shown for how best someone to manage a congenital disease vs. one of getting older. My question also doesn’t take into full effect the benefits of Ketosis and nearly asks from a predisposed cardiac example.

    And I love your blog its great reading for someone who never had the chance to go to medical school, etc. Please keep doing what your doing!


  19. Do you have any evidence that suggests that cycling in and out of ketosis is beneficial? What are the number of days in ketosis and number of days out of ketosis for the conditions (high athletic, moderate exercise, etc…). What were the carbohydrate and protein grams required to go out of ketosis?

    Thank you for your time and effort to help us understand ketosis.
    Roger Oesterling

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