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

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  1. Peter:
    Thank you for writing a thoroughly informative article. I apologize if this question has been asked before, but I couldn’t find it with the search function, so I will ask… if I am eating ketogenic diet (about 65% of calories coming from fat, the rest from protein, and about 20g of trace carbs) and I overeat where I am in a calorie surplus (at least what would be considered a calorie surplus prior to starting a ketogenic diet), what happens to the excess fat/protein? As an example, if on a 40-30-30 diet with my normal weight lifting workouts and daily activity my caloric maintenance is 2800 calories and on the ketogenic diet I eat 3800 calories, can I still gain fat since insulin is almost nil? I read so many conflicting theories that I don’t know what to think. Some say that you can absolutely gain fat in ketosis if eating a caloric surplus… others say there can be no caloric surplus in ketosis due to entropy and that bmr increases in ketogenic dieters to match the caloric intake, thereby making a calorie surplus impossible….still others say that excess calories are excreted. What is your take on this?
    Thank you. Can’t wait to hear your answer!

  2. Peter,
    I read the fat flux post today. I saw that you mentioned that the state of ketosis itself provides a metabolic “disadvantage” due to the process of making ketones out of fatty acid (both stored through lipolysis and dietary). I also noted that you were able to eat nearly 4500 calories on a ketogenic diet and lose fat whereas on a moderate/high carb diet you were eating quite a bit less calories just to maintain weight. I do have an additional question: what do you think would happen if you ate 15,000 calories per day on a ketogenic diet instead of the 4500. Assume that you could force-feed yourself every day with that exorbitant amount of food. I mean, at some point would a caloric surplus be created whereby your body would store the surplus as fat or do you think that theory by your friend Kevin would hold up and your body would match the exorbitant calories in by using all that extra energy (calories) to make ketones out of fatty acids?

    Also, what is your take on a carb cycling diet where you eat keto for 5 1/2 days and high carbs for 1 1/2 days?

    Thanks again.

  3. Peter,
    Many thanks to you for sharing this info. It has been revolutionary to say the least. What really got my attention was that your weight retention story is very similar to mine. After 7 years of triathlon training etc. and limited weightloss I needed a different approach. I have a picture of myself right after an Olympic distance tri and 8 months of training and so called “good eating”. I still had a gut. Not fair. I’ve been in NK for over 3 months and lost weight and inches. This is the easiest eating plan I have ever experienced and i’m moths ahead of my usual weight loss. The ability to cycle for hours without breakfast and not cramp; the ability to go most of the day without being ravenously hungry, is a dream come true. This works for me and my cholestrol panels are better than ever. I plan to do IM New Orleans next spring on this NK plan.

    I do have a question about proein intake and gluconeogenisis: I understand that my protein intake needs to be less than 140 grams daily or I risk producing glucose through the process of gluconeogenesis. I also have read many times that the body can only process approximately 30 grams of protein at a time. If this is the case and I eat two meals a day, each containing 70 grams of protein, am I then converting the extra 40 protein grams each meal back to glucose. If so, shouldn’t it make more sense to stretch out my protein allowance into additional meals throughout the day to ensure it gets uploaded for it’s beneficial use as protein and not an undesireable conversion.?

    I keep reading from most of the NK authorities, that you guys are only eating twice a day on average. Hoping you can clarify this for me Thanks again.

  4. Re – “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.”

    It doesn’t appear to me that B-OHB “enters” Krebs between succCoA and succ – it just accepts the CoA (and SuccCoA moves along the TCA cycle to become succinate) so that B-OHB can eventually become acetylCoA and enter through the same door as the as all FFAs which have undergone beta-oxidaton to acetylCoA . I am clarifying this in order to ask a question – what is the point of ketones (besides the brain), since the peripheral tissues have plenty of access to NEFAs, and both FFAs and ketones enter Krebs as acetylCoA? In other words, how to ketones enhance cellular metabolism if they are just increasing the “traffic congestion” at acetylCoA? Ketones don’t have a separate metabolic pathway.
    I know this is years after you posted this, but maybe you’ll see this biochem question and decide to answer it?

  5. I didn’t know where to post my question. I guess this is as good as anywhere. I was just watching Dr. Dominic D’Agostino on a TED presentation. He repeated a statement I believe you have made and I keep hearing repeated over and over. Basically it goes something like, “When drugs fail, it has been shown that a ketogenic diet can help control seizures in children with epilepsy”, and sometimes there are other types of seizures mentioned. My question is why wait until after drugs fail? Wouldn’t it make more sense to use the ketogenic diet first and then use drugs as a last resort instead of the other way around?

    • It’s actually a good question, you ask, George. The answer is multi-faceted, but it probably stems from 2 things: 1) the culture of medicine (drugs first), and 2) the fear of KD (e.g., heart disease)

  6. Hi again Peter,

    My question was put forth with complete sincerity and with due respect. I acquired an excellent knowledge base about cholesterol from reading your original series of articles, and I’m hoping you can clarify something else for me.
    I am having difficulty reconciling your explanation of ketones’ unique pathway with Chris Masterjohn’s piece on ketosis (https://blog.cholesterol-and-health.com/2012/01/we-really-can-make-glucose-from-fatty.html), specifically the section…
    “When large quantities of fatty acids flood the liver during fasting, caloric restriction, diabetes, or the consumption of a low-carbohydrate, high-fat, ketogenic diet, our livers produce so much acetate that the TCA cycle suffers heavy traffic. Any acetyl CoA with the foresight to listen to the evening traffic report would quickly decide to head straight for the Land of Ketogenesis, where the railways are open and the paths are free. This is where our livers turn acetate into ketones, sending the ketones out into the bloodstream so our other tissues can use them for energy.”

    If ketone bodies (made in the liver and sent out into the periphery) need to be converted back to acetylCoA to enter the Krebs cycle, how would that be of any help to the peripheral cells that are already overflowing with acetylCoA (from FFA beta oxidation)? I really would appreciate if you help me to understand where my thought process is incorrect. I do know you’re busy, I am hoping that the answer is short and simple. Thanks for your time.

    • 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.
      Remember, ketone oxidation is an another pathway (regulated tightly by insulin) that parallels beta oxidation of fatty acids.
      The main purpose, however, is to ensure high energy flow to the CNS when glucose is limited. Bigger brained animals have higher capacity to use ketones it seems.

  7. Thanks for a clear and concise answer – so the utility of the ketones is the brain, not the peripheral tissues, and hence your excellent talk on ketosis and the prevention of “bonking” vis-a-vis athletic performance.

    • No, peripheral tissue can use ketones (and seems to prefer it) also, as does the heart. The point is why we do it. That’s where the brain come ins, from an evolutionary perspective.

  8. With the availability of breath ketone meters I’m wondering how many kcals a keto adapted person loses through respiration. The vapor pressure of acetone is quite high, ~400mmHg at body temperature. The loss of ketones could explain the slightly lower RQ of keto adapted athletes than predicted by a simple minimization of the Gibbs Free Energy calculation.

    • It’s been measured and it turns out to be quite low in energy, given that acetone is not the dominant energy currency ketone body (AcAc and BHB are).

  9. Thank you Peter for all of your work and making it public. I have read Part I and II of Ketosis-Advantaged or misunderstood posts. As a WM63 who has lived with AS (Ankylosing Spondylitis) most of my life I was asked to read up on Embrel and consider doing the weekly injections. I was very interested in Embrel until the repeated word cancer kept popping up but on the bright side I learned about coconut oil for the first time and have a light bulb go off.

    I have been on organic virgin coconut oil for two months and use the $15 breath analyser of of eBay that uses three AAA batteries. Even after I got up to taking 8-12 table spoons 3-4 times a day nothing much happened. Readings like .005 to .02 %BAC was the best I could do for the first month. After two months I did hit .086 this morning.

    Now I am wondering if my liver was at first not doing a good job at burning fat or does it just take time to adapt? When I came in this evening I blew .008 and now four hours after taking 2 table spoons of VCO the meter just read .021 %BAC. I gather this cheap meter is actually measuring breath acetone level. By the way I have been doing a better job of staying away from carbs and food with added sugar. The pain level has decreased some too. For the past 10 years I have only been taking fish oil because the NSAIDS had did a number on my stomach, balance and mental clarity.

    Thanks again. Gale Hawkins

  10. I have recently been diagnosed with type 2 diabetes. I made the choice to cut out sugar and carbs from my diet independantly from any advice. After being told by many people that it was a dangerous thing to do and I could go into seizure and die, i searched around the internet and found this site. In the one month that I have stopped taking on board carbs I have lost nearly a stone. I dont seem to be having any ill affects and have been kind of waiting for them to kick in. I am overweight so figure that my body is now using my fat reserves to live. My question is as follows. I was prescribed Metaformin 500, should I still take this if my carb intake is just about zero? I have started being able to fast for up to 24 hours without any intake of food except for tea and coffee with milk and perhaps a couple of apples during the day. Is this causing me any harm? Any guidance would be appreciated

  11. Hi Peter,

    I will spare my story of T1D diagnosis 3 months ago, and having to confront the ‘system’ while putting myself on KD before even knowing what it is.

    I would like to thank you for providing all this invaluable crunched information that is nowhere else to be easily found. The time and effort you put into this blog is having a huge impact on my personal dietary choices.

    I have one question that I hope you will be willing to answer –
    I have been (and still am) repeatedly told by most ‘professionals’ (MDs, dietitians, trainers etc) how KD is dangerous for me, yet not one of them can offer me a convincing evidence (or even a theory for that account) as to why so.
    What are your biggest concerns about your dietary journey in the long run? And by concerns I mean hypotheses that have yet to be proven right or wrong by appropriate studies.

    Thanks again

    • Idan, T1D, as you know, is a pretty unique state and I share the concern of your doctors. While I probably have a different view from them on the ideal diet for T1D, I would agree that a diet producing ketones could be tricky to manage given the lack of endogenous insulin to feedback on the system.

    • Thanks for the reply,

      I assume (and please correct me if the assumption is wrong) that you’re referring to the danger of not being able to monitor for dka based on ketones (which is still manageable with constant BG monitoring). I was curious to know though if you had any concerns at all for long term effects regardless of T1D

      • The danger in T1D is that the feedback loop–high ketones stimulating insulin to in turn reduce ketones–doesn’t work, which is how someone with T1D can have BHB levels over 15 mM and resulting DKA.

  12. I’ve been vegan since March 2014, it’s December 2014. Previously, I was a half-assed, wanna be, lacto-ovo-vegetarian most of my life. I’ve very intentionally dropped 35+ pounds and am just 5 pounds away from my “ideal” weight for my height and age: 57, 5’8″ female. I currently weigh 144. God it feels so good to FINALLY be here!!

    I was wondering about my very definite state of euphoria and significantly increased energy. A girlfriend suggested ketosis. Naturally, my reaction was “YUK, NO WAY! Can’t be!” Last time I was in Ketosis was in my late teen years trying to lose weight on the horrible (IMHO) Atkin’s diet.

    I try to go raw as much as possible, but occasionally have some processed foods, like Tofurkey Pot Pies, for example. The more I stick to raw, no question, the better I feel. I KNOW when I feel this way (great euphoria and tons of energy) that the scale will be kind to me in the morning (stays even or tenths of a pound drop). The less I eat, the better I feel. I now LIKE that kind of empty feeling in my gut area. Having a full belly is no longer a good feeling. Usually means I just ate too much food. I pay a lot of attention to what I’m eating and drinking. But, for sure I get PLENTY of carbohydrates. I have to get the test strips again, but from reading above, I’m not sure they’ll be an accurate indicator of actually being in Ketosis. I swim every day and will be starting a weight work out very soon.

    I wondering if I’m in Ketosis and I was thinking from my past 40-year-old or so information if it’s a bad thing. Still hard for me to tell from the article. I guess I also wanted to weigh in with my experience of it (if that’s what it is) as a vegan and feeling great. Super great. Thank you!

  13. Hi Peter,
    I stumbled on one of your You Tube presentation a few months back and became an instant fan, what you said resonated with me. i don’t have any medical issues, but at sixty I figured that I better start paying more attention to my health. Anyway, long story short, I started my low carb high fat diet on Oct 27th of this year. i wish I can call it a Ketogenic diet, but it’s not been easy getting below 80g of net carbs with about 80 in protein and about 170 in fat… I won’t bore you with all the details, since my questions isn’t really about me but i figured a bit of background wouldn’t hurt. I also feel great, even though the rest of my family think i lost it and sure to explode any day now.
    In my wanderings on the internet, I kept seeing references the the Gerson Therapy. Seeing that it was more for cancer and degenerative disease therapy, I didn’t pay much attention until recently. Can you shed some light on their logic? While they do agree that sugar (white processed that is) and grains are bad, it seems like they are all for vegan, juicing, nearly raw foodist and against dairy, fat (animal or plant), salt, etc…
    I appreciate your comments. please keep up the good work.

    • Jason, no need to “wish” for ketosis…it’s not necessary for health/performance. It’s simply another manifestation of using diet to reduce insulin and trigger a different metabolic pathway. That said, the bigger point/question is complex one. I can’t speak for their logic, though it should be noted that if the dietary triggers of metabolic disease are sugars and highly refined grains (i.e., the foods we did not consume at all or in excess during our evolution)–and I do subscribe to this hypothesis–then two vastly different dietary strategies that remove the same triggers can both produce similar results in terms of disease prevention. That’s the short answer. The long answer I don’t have time for, but it gets into the nuance of individual variation and susceptibility. Maybe something for a podcast one day. I think Tim Ferriss is collecting comments/questions for our Part II podcast in January.

  14. Peter, are you still practicing medicine as a surgeon? I saw your TED MED presentation but then saw reference to your patients above. Just curious; I apologize if this is too personal.

    Thanks for time and passion with this blog,

    • Not too personal. I left surgery in 2006. I do practice (non-surgical) medicine now, but only ~10 to 20% of my time. Most of my time is spent on NuSI.

  15. Peter,

    I’ve tried to read through most of your information, but I apologize if I missed the answer to my question. I started a low carb diet seven days ago — eating somewhere between 10 and 20 net carbs per day — and so far it’s been fairly easy. However, last night I could not fall asleep and had what seemed like heart palpitations or at least an irregularly strong heartbeat. I’ve read several other websites that claim low carb diets can cause insomnia and hypoglycemia, yet I get the sense from reading your material that you disagree. Do you believe my difficulty sleeping / strong heartbeat will pass if I continue with 10 – 20 net carbs per day, or should I increase my carb intake to manage my heart irregularities? My heart has been beating harder today as well. Normally, my resting heart rate is around 45, but today it is at 70. I am a very active 33 year old guy in the Army who works out regularly. Thanks in advance for your help!


    • Hi Jason,
      How did it develop for you? I have more or less same situation: started low/no-carb ~7 days ago. Felt great, but also felt resting heart rate increasing (in my case 60 -> 70-75), very noticable at night but also during the day. Also found my blood pressure was lower… Basic stats: male, 43y, 6ft2, 82 kgs, body fat ~10%.
      Any thoughts?
      Kind regards,

  16. Hi there. Thank you for all of your sharing and informative and inspiring content.
    I’m writing because I’ve been following a Ketogenic diet for 134 days (trace ketones for 134 days in a row, per my Ketonix Sport) – and I have GAINED 13 pounds in the last 6 months.
    Excuse my language, but WTF??!!!
    I have never felt more energetic, alert or mentally better. However, I don’t wish to be packing on more weight and fat… Feeling great is not enough for me. I’m an adventure guide and I’m hired by corporations as a motivational speaker. How I look matters in how I show up and how effectively I can do my work and be myself. The inexplicable weight gain, especially when I’m doing lots of fasting and following a ketogenic diet makes no sense to me…
    A little backstory… I’m a leadership and wellness coach, and very much a self experimenter. I am 46, a mother, wife and entrepreneur. I am an Epic Adventurer and a very fit athlete. (I hike 1,000 miles a year)
    I don’t eat any grains… In May 2009, I gave up all grains. The results were staggering: I lost 30 pounds and 15% body fat in a single year after those changes. I burned the boats on the grains back then and have never looked back.
    Today, almost 6 years later, I’m 46. Until the last 6 months or so things were still going great and I had kept all the weight off. However, today, I am up 10-14 pounds (in the last 6 months.)
    This is crazy! How can this even be possible? Is there something wrong internally? I had some labs done via WellnessFx last May, and thyroid and other markers were normal… Nothing stood out…

    I would GREATLY APPRECIATE a response and a direction for where to turn for a consult. I am so excited about how the Ketogenic diet makes me feel, but I am not happy to be gaining so much weight and it doesn’t compute. I am at wit’s end and really needing some help here?
    Shelli Johnson

  17. What fantastic information you have here. I have stumbled on the site as I look for information on my teenage son’s acetone breath. He is a wrestler, at a weight I feel is too low and have been wondering if he is going into a state of Ketosis days before weigh-ins. If I smell strong odors of acetone on his breath (along with him barely eating or drinking) – is this alone enough to indicate the ketosis? He is very thin; it is hard for me to imagine where his stores of fat are hiding. I have been reading along looking for the clues about how dangerous this can be; the only danger I seem to be digging up here is the danger from ketosis related to diabetes. This is unrelated to diabetes. Is there danger from being in a state of ketosis when you do not appear to have any fat stores in reserve? What are the ramifications of him doing this? Thanks for any info

  18. Thank you Dr. Atia. I just wanted to share something and see if what’s happening to me might be happening to others. I pretty much started keto (Atkins) without doing any research. It wasn’t long before I did as I began to feel a tad “strange”. I noticed one day, as I was sitting in my truck, that I felt CALM. As if I had no more fear. It almost seems as if my body is not fighting with itself anymore. Has anyone else ever experienced this?

    • Only started one week ago… So very early, but experience some kind of ‘basic calm-ness as well. I’d say it’s a good thing.

  19. I read Gary Taubes “Good Calories, Bad Calories”. It was a brilliant read.
    I wasn’t even trying to lose weight. But out of curiosity I started eating a high fat / low carb diet.
    In a short while, my weight dropped from an already meager 68kg to 64.5kg.
    (I don’t know if I was ever in Ketosis, I don’t think so.)

    So, I’m personally convinced beyond a doubt that low carb makes you lose weight.
    I was just wondering. I’ve not found a single study , proving beyond a doubt that on the long run
    eating a high fat diet does not cause Liver-problems(like gall stones) or Atherosclerosis.

    Should I worry about the long term effects of eating a high fat diet? And, since you’re basically
    a living experiment of one, do you worry about the long term (say 20 years) effect of living in Ketosis?

    • Ernest, I don’t know what 20 years of consistently being in ketosis does and I’m not sure anyone does. I was in ketosis for a little over 2.5 years and couldn’t measure any downsides, though there may have been some. The question should be, however, a relative one. So it’s not is Dietary Pattern X “good” or “bad,” but is better than A or B for a given individual? In that context, 20 years of ketosis would have been better than 20 years of what I did before.

    • Question: effect of low-carb (or NK) on resting heart rate & blood pressure
      Hi – I also came across the work of Mr. Taubes and started, more or less cold turkey, to cut out carbs to see what happens.
      Base: male, 43y, 6ft2, 82kgs, body fat (estimate) around 10%.
      Previously I had already cut out ‘sugar’ (added glucose) from my diet, but I did still eat a lot of carbs (bread, muesli, potatoes).
      I’m now in for a week, still early stages. I feel great! No more the ‘hunger attacks’ that I used to have (and the ‘deal with’ eating carbs). I’m sligthly concerned about my resting HR – used to be around 60 and now seams to have climbed to 70-75. Also, my blood pressure has dropped (as I found out after donating blood). Was wondering if changes in resting heart rate & blood pressure could be attributed to eating a low/no-carb diet?

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