January 1, 2013

Ketosis

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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426 Comments

  1. Peter –

    Wait! I think I just found solid evidence that contradicts my theory about eating protein and fat separately – one that provides further support for eating meals with plenty of fat.

    This 2009 study (Am J Clin Nutr 2009;90:986-92) analyzed the insulin responses from eating different meals. One of the strongest correlations they found was a negative one between the fat content of the meal and the insulin response (r = -0.60, P = 0.03). This negative correlation was even stronger than the positive correlations found for either the carbohydrate content of the meal or its glycemic load.
    https://ajcn.nutrition.org/content/90/4/986.full.pdf

    I’ve often wondered why eating fat seems to help so much. (Even on a no-carb diet, one might think that fewer calories would help.) Here’s another possible reason why. When one eats other foods and fats together, the dietary fat helps to reduce the insulin response from those other foods!

    So, I think I’ll continue to eat plenty of fat with my protein, as I have been.

    Richard

    • Richard, it is truce that fat blunts the insulin response. But if you consume protein after the workouts, elevated insulin for a short time is exactly what you want. Also, if you eat real food, you can’t really separate protein from fat, can you? I did some climbing at noon today (1 hour of intense bouldering) and the had my ‘higher’ protein lunch: 3 eggs and a can of sardines on olive oil, ca. 45g of protein. I did not add any extra fat (e.g. butter, coconut oil, a salad with plenty of olive oil) and still I did get plenty of fat from eggs and sardines.

  2. Peter, I read your posts with great interest. I have recently changed my eating habits, decreasing carbs, and my health has improved dramatically. It is for me a new way of life, and a much better one! I like your writing approach because is scientific (and I have a science background myself) so it really makes sense to me. Many, many thanks for sharing your knowledge to the world, you made a real difference to my life.

    There is however a question that I am trying to find an answer to, and I thought you are the best person whom I can ask:

    What is your opinion about pure vs virgin coconut oil?

    It makes sense to me that the organic virgin coconut oil is indeed the best one to eat, if having it raw. However, which is best for cooking? I am currently cooking with pure coconut oil because it’s much cheaper, it imposes no flavour on the food, and I believe that it has a higher smoking point than the virgin one – but is this really true? (I tried to find an answer on the web but with no avail.) Or, if one is truly careful with what one eats, should stay away from the pure version as it is too processed, and should only use virgin coconut oil?

    Thank you. Miruna

  3. Thanks, Martin. I see your points.

    And to all…I’m embarassed that I got so excited about the study that showed a lower insulin response with higher fat meals. That could easily just be the substitution effect. (Since the calories for each meal were fixed and fats cause no insulin response, then of course the higher-fat meals will have a lower insulin response. That could be just because, or mostly because, those meals also have fewer carbs and proteins.)

    Peter, many of us often lament the fact that there are too few good studies done about the topics that we are most interested in. And I know researchers are always looking for meaningful topics to study. It would be interesting to see a list of the studies that you would most like to see done, grouped by topic and priority. That would certainly promote good discussion, and with your growing clout it might help get those studies done.

    For example, I’d like to see a good study done on this point, where subjects eat protein alone and their insulin response is measured. Then they eat the same amount of protein with fat, and their insulin response is measured. Seems simple enough. If we listed proposals like that somewhere, then perhaps others would take some of those ideas and run with them.

    Thanks to all.

  4. Hi,

    I am wondering if you think that the small amount of Corn Syrup Solids in Better Than Bouillon could drive insulin and suppress ketones in the blood. I have been following Paleo strictly while using Better Than Bouillon about 2-3 tsp a day for sodium. Blood ketones remain at .2 to .4. Eating about 85/15/5 daily with calorie deficit of about 500-1000 depending on exercise. Frustrated!

    PaleoDave

    • 85/15/5 and blood ketones 0.2-0.4?

      You don’t say which of the numbers refers to which macro-nutrient, but I’m thinking given that A. your ketones are low and B. you’re called “PaleoDave” that you mean 85% protein, 15% fat and 5% carbohydrate. And that’s probably your answer. Way too much protein, therefore glucogenesis in the liver and you’re not generating or fuelling on ketones. Reduce the protein, increase the fat, good calculator here – https://sweetgeek.net/food/protein_calculator.html

      If you meant 85% fat, then I’m stumped.

  5. Hi Peter,

    First off, I want to say that your recommendations have changed the course of my life. I’ve been a type 1 diabetic for 23 years and for the past several years, I checked my blood sugars dozens of times a day, ate a ‘healthy’ diet, and exercised regularly, yet my A1C’s always lingered around 7. During this past year, I started a low carb diet, and for the first time in my life, my A1C is 6.0. I have never felt better. I don’t even know how to begin to express my appreciation.

    Secondly, I have a question for you– I am getting treatment for a binge-type eating disorder. As you can imagine, this issue has wreaked havoc on my blood glucose control in the past. Things are much better on the low carb diet. However, I often feel the drive to eat past the point at which I am full. To try to prevent weight gain, I eat mostly low carb veggies at these times. Despite the intake of these low- carb and low-density foods, my blood sugars spike exactly as Richard Bernstein, MD describes as the ‘Chinese restaurant effect’ (the increased volume in the stomach causes stretching which signals receptors to increase glucose and/or insulin production/release). Therefore, I end up giving a larger bolus of insulin despite only taking in a limited number of carbs and calories. My question is this: when I give larger amounts of insulin, but eat a small number of calories (lots of low carb veggies), will I be more likely to gain weight than if I were to eat a larger number of calories (a high-fat, high-calorie, almost 0 carb meal) but give a smaller bolus of insulin? As an example, on a ‘low-density’ day, I give a total of around 30-35 units. On a day that I get about 30% more calories, but mostly from fat, I give a total of around 25 units.

    I realize that this specific question has probably not been addressed by studies, but I’d love your input on the subject. Thanks again for all of the excellent posts and for your work at NuSI!

    • Amanda, congrats on your great progress. I’m glad you’ve found the work of Bernstein. I don’t know the answer to your question. Seems like it’s worth experimenting under the careful observation of your endocrinologist.

  6. A thorough series, Peter, good work.

    First, for the record:: by no means am I afraid of (healthy) fat. (My nutrition follows the one described in Paul Jaminet’s excellent book ‘Perfect Health Diet’).

    However… Maintaining the body in a ketogenic state requires an extremely restrictive & unnatural nutrition (please, don’t tell me, that rejecting to eat a banana or adding coconut oil to coffee instead of a full-fat milk is something Mother Nature wants us to do). The short-term (3-6 months) results may be promising, admitted. But this means NOTHING long-term, really. Have you seeen the results of this 60-day 100% carb experiment?

    https://20potatoesaday.com

    How can you explain excellent blood markers and 21pound weight loss by eating the insulin-spiking starch-loaded potato?

    The goal here should be to strive a sustainable, affordable, enjoyable diet/lifestyle, not some hacko-experiments involving putting butter on full-fat chees for taste.

    Half of the World’s population (Asia & surroundings) lives on a high-carb diet and also happens to be among the healthiest on the Planet. Something’s clearly wrong here with a blind high-fat praise.

    I am lookking forward to seeing you addressing these nutrition questions.

    • Kamil, N of 1 experiments, including my own, are interesting any may generate hypotheses, but are by no means conclusive. My wife, for example, could live on M&M’s, Oreo cookies, and ice cream for 60 days and not gain an ounce (she has no weight to lose and is constantly trying to gain weight — unsuccessfully). You question about Asia and other parts of the world has been previously addressed on this blog. Should be easy to find, but I forget the exact title.

      Lastly, I’m confused by suggestion that I’m suggesting everyone should live in a ketogenic state? Are you taking this message away from this post?

    • Hello Peter,

      I do know your ‘Japanese phenomenon’ blog article (especially the honest ‘I don’t really know’ part, which is true – we have no idea why, and it would be extremely beneficial to find out the answer).

      Coming back to the ketogenic diet takeaway message: correct me if I am wrong, but it seems you are strongly in favour of a very low-carb, high-fat diet. Maybe you are right, maybe not, time will tell. But, for the NuSi project, one needs to reset and start unbiased ;), whereas all we hear so far is Gary Taubes’ high-fat appraisal and demonization of fructose.

      Paul Jaminet describes how reintroducing safe starches cured him from illnesses he had developed by following a strict LCHF diet. A topic worth investigation in the ketogenic series 😉

      Good luck!

      • NuSI is completely unbiased. Peter and Gary don’t do the research. As you say, time will tell. So until then, each of us needs to make up our own mind and do the best we can with current information. The only thing I know for sure is that Peter Attia does best without many carbs in his diet. That’s it. If your plan works for you, great. Paul is a thoughtful guy, and I don’t doubt what he says worked from him. But I’m not Paul. And he’s not me. Separate what I say population-wise from personally.

  7. Many thanks indeed for your detailed and thorough work Peter.
    My wife and I are currently experimenting with a low carb high fat diet. We have rigorously monitored kcal, protein, fat and carbohydrate intake daily for two weeks with weighing food and a spreadsheet, itself a very interesting insight and worth the time. We have measured blood ketones for the past week. My wife is age 44, weight 57 kg, exercise active, healthy. Average daily intakes for her last 7 days: 990kcal, 50g protein, 95g fat, 12g carb, well satiated. To cut to the chase, her ketones are consistently between 5 and 7, which are too high for optimal ketogenic state as I understand it. I take it from some of your previous comments that such levels are not of great concern but I am still a little unclear on how the insulin response to such levels is not counter productive to the very effects intended with ketogenic adaptation? I have not been able to find much on it apart from a few comments attached to your blogs. Appreciate the volume of e-traffic you must orchestrate daily, so any brief advice you have would be most gratefully received.

    • I would say, assuming you’re measuring blood ketones in the units of mM, this is the upper limit of what is typically seen, though it’s probably explained by her relative hypocaloric state. I’d say keep it up and be sure you’re following the guidance of Phinney and Volek (e.g., electrolyte replacement).

  8. Was in doctor’s lounge talking today about a 5’4 patient 300 lbs, trouble with Metformin, on “diet therapy” for years. I asked about low carb and the discussion began. One doc asked around if anyone had any Atkins patients who had stuck with it for a year and everyone said no. he said all his Atkins patients had rebounded, regained all the weight plus more.

    Not a bad discussion actually but what came out was a big issue in the real world with compliance. There is a whole psychology here overlayed on the actual physiology of ketosis. The same doc said his patients got “mean as snakes” when they were ketotic, which does not match my experience in any way. But he is a busy internist in the modern era and certainly does not have time or resources to help people through the adaptation phase.

    There is nothing unique about a low carb diet by the way; ALL diets seem to fail down the road. One study on Medscape showed that ongoing support led to better sustained weight loss, which should not be a surprise. But it seems logical to me that part of your NuSI study design should include counseling, support, etc on all arms of the study groups.

    • Completely agree. The question is WHY is long-term dietary compliance so poor? I believe there are 2 drivers:

      1. Mixed messages from surroundings (family, friends, doctors, media) that discourage the approach (this is largely true of folks on low carb diets).
      2. Poor surrounding infrastructure. How tough is it to eat in accordance with a diet (low carb, again, being a great example, but not the only one), when everywhere you go dietary offerings (e.g., stores, restaurants, other folks homes) are completely orthogonal to your “prescription?” It’s the rare person who can, in the long run, stay on the prescription, despite the forces to derail.

  9. I’d like to do my own experiment, so my question is: How long (how many days) would one need to go <50gCHO/day to get into ketosis? I'm a well-trained endurance athlete, and I'm training for Boston right now. My diet is about 55% CHO, 20% PRO, 25% FAT. I consume way too many simple sugars, which is a no-brainer to reduce, but I'm not convinced I'll feel better if I eliminate all CHO. I am thinking of doing a track workout (mile repeats x 5) and long run ~18 miles at a certain pace), each on my normal diet and each in ketosis. So how long will it take to go into ketosis from my normal high CHO diet?
    Thanks for all the information you're putting out there.

    • Typically, assuming all other kinks are worked out, only a few days. The adaptation (i.e., return to same level of functionality) can take weeks. For some, it’s 2 weeks, for other, like me, much longer. Generally, the more active, the longer it takes. It took me about 3 months to adapt.

    • Hi Jessica,

      Being very active myself I’ve also experienced that it takes a long month. It took months for me too. Anecdotally what really helped me was starting a food log, keep the carbs very low, keep the protein moderate (it surprised me how much protein I was actually eating), stay hydrated (this made a big difference for me) and supplement with sodium, potassium and magnesium (especially sodium). Besides that, read The Art And Science of Low Carbohydrate Performance by Phinney & Volek and remember their advice “when in doubt – eat more fat”.

      Good luck!

      Best,

      Hemming

    • On the same topic, let’s assume you went through 3 months of no carbs and became very adapt… but then you have a week of weakness that consists of a very poor diet. Does that essentially reset the adaption clock, or will it take less than 3 months to get to the same level of adaption?

  10. Just wondering the following: when in ketosis, are fatty acids still converted to Acetly Coa for the krebs cycle, or is it all converted to Ketones?
    Also, do you know if you are on a low carb, but non-ketosis diet, say around 100 grams of carbs a day, just enough to provide your brain with enough glucose, what will the rest of your body use for energy?

  11. Great blog Peter and I love reading your posts and studies.
    Wondering your take and experience on these issues that are often associated or reported with a VLC diet?

    Dry eyes
    Not having enough glucose to form mucus in the eyes. Also continuing a diet with near 0 carbs likely suffering gut permeability issues when running out of mucus to protect the lining of stomach from stomach acid.

    Poor sleep
    The brain starving for glucose and making sleep tough.

    Thyroid issues.

    Cholesterol.
    Extreme low-carb diet raising LDL levels.

    Thanks!

  12. Hi Peter,

    I’ve been doing LCHF for awhile now and have had a great experience. Prior to this I was low carb, high protein and thanks to you, Phinney, Volek and Rosedale, I went ahead and dropped my protein down by about half and started proactively adding in more fat. I was never fat phobic to start with, but the exercise of bumping it up significantly and having nothing, but positives come of it was a pleasant surprise and has opened up a great deal of meal options for me. I know from previous posts of yours that you are very familiar with Dr’s Phinney and Volek’s work, but I was wondering if you we’re familiar at all with Dr. Rosedale’s work. I only recently came across his work and found his perspectives to be very interesting and found that he shed light on other aspects/benefits of a low carb, high fat, moderate protein approach that I’d never heard mentioned. Particularly with regard to the broad influence of leptin in various maladies, but also in regards to mTOR. I come from a weight training viewpoint and have been bombarded for years now with the whole idea of the growth promoting effects of mTOR up regulation, and the benefits of post workout protein consumption used to help stimulate it as well as eating above threshold protein intake on a per meal basis to keep restimulating it. Dr. Rosedale is the first person I’ve ever heard come out and say that this is likely a bad idea in terms of overall long term health. After hearing out his views on the matter I gotta say that it makes a ton of sense to me and have now shifted my focus onto improving hormone signaling via improved sensitivity rather that high signaling levels. Something i was already doing with regard to insulin sensitivty, but now I’m finding more of a reason to not go protein crazy than just knocking myself out of ketosis. So far, a month into it I feel nothing but better. Currently 193 lbs and 11.3% bf at 6′ tall, counting only protein grams(average 85-100 grams per day) keeping carbs low and letting fat satisfy hunger. Still making gains in strength while getting leaner. Also, seem to be getting even better results than I used to despite training infrequently. Im attributing this to improved protein economy due to a slower turnover rate associated with sub mTOR stimulating protein doses. I could be totally wrong about that part though, just my gut feeling. I’m curious to hear your thoughts on my experience and Dr. Rosedale, particularly with regard to mTOR as this was the part that was completely new to me.

  13. Peter, firstly congratulations on a great website sharing all your experience and results. I’ll keep this brief as I want you to answer my questions…

    1) Do the less saturated dietary fatty acids, such as PUFAs, get oxidised preferentially over the saturated dietary fats? This would make sense in view of their differing shelf lives and susceptibility to peroxidation within the body.

    2) To what degree is ROS production reduced in KN compared with a standard diet?

    • As a follow-up question to 1). Does that mean that PUFAs are less likely to be stored as fat or just that oxidised preferentially to SFAs? I’m thinking that in the first case the SFA/PUFA ratio matters and in the second it doesn’t. Either Paul or Peter, do you have a view on this?

      Best regards,

      Hemming

  14. I find this subject fasinating. I am in ketosis and feel great. Stilll loosing weight but am very near goal. have lost 50 pounds sinse may 2012. started low carb and progressed to ketogenic diet around Oct. 2012. I am introducing more fat to my diet now and plan on living LCHF in weight maintenence. Full life with work, famlily and fitness regime; boot camp.
    Was high fasting sugar/hypogylcemic and now have stable sugars on the low end , stable moods and stable energy. my low iron issues are also resolved with this diet.
    I have recently read The Art and Science of LC Lifestyle and have a better understanding of the importance of salt and pottasium when eating LCHF.
    One resaon I can really see is that without eating any processed foods the only sodium I get is the sodium I physically add to my food. I have heard that as much as 5 grams of sodium a day is recommended. I have to admit that when iIstarted adding more sodium is when i felt 100 percent all the time. It was the missing piece for me.
    What are the other reasons for needing more salt or do you agree that 5 grams of sodium a day is needed when on a LCHF diet?
    love this blog and love this life style.

  15. Hi Peter,
    What an informative site!! My husband and I are considering lowering our carb intake. My only issue is that he (my husband) has had a couple of gall bladder attacks (he has “sludge”) and it was recommended that he limit fat intake. He does belch a lot after some meals, othertimes, he’s fine. The doctor recommended removing the gall bladder, which we were not intersted in pursuing. The high fat content of this style of eating is slightly concerning given his issue. Are some fats more difficult on the gall bladder than others? We are having trouble figuring this one out and would appreciate any guidance.
    Thank you!
    Jen

  16. I have been treating my 30 y/o daughter with ALS since 2007. The primary pathology in ALS is cells lack energy hence it is a metabolic disease. The patients, as in most neuro degenerative diseases, accumulate Glutamate. My hypothesis is since Glutamate accumulates its breakdown products are absent. One of the breakdown products is AKG [alpha ketoglutaric acid]. This is the basis for the Deanna protocol now over 1000 patients world wide have requested the protocol and most of the responses indicate that it stops or slows the progression of the disease. Symptoms such as fasiculations, twitching and tremors are reduced or absent. My daughter tried B-H-B which made her symptoms worse. Pyruvate had no effect on her.
    My question is since AKG plus complex 1 precede B-H-B would not utilizing AKG or Pyruvate supply more energy than B-H-B ? Any thoughts why she would get worse as manifest by an increase in symptoms when taking B-H-B?
    I also would appreciate any thoughts of how I might enhance energy delivery to the cells? At present we have no way of measuring blood levels of AKG hence I have no way of knowing whether sufficient energy is available when needed. My supposition is that the dying cells emitting abnormal potentials cause the muscle symptoms. We know that when energy is provided to apoptotic cells the mitochondria lose their crenelated appearance and become straight. Hence it is assumed that the abnormal energy potentials diminish when sufficient substrate is supplied to the cells? Your thoughts would be greatly appreciated.

    Vince

    • Vince, this is certainly the theory being explored with Veech’s ketone esters. Pull the papers I cite and you’ll see he comments on ALS as one possible disease that could be treated by ketone esters due the bypass of PDH and the supply of BOHB into the Krebs Cycle. The important question — to which I do not know the answer — is if a ketogenic diet can produce the same effect. This is important because ketone esters are not yet commercially available, unfortunately.

  17. Hi Dr. Attia,

    I thought I sent this question in but don’t see it so forgive me if I am repeating myself. Great information here it helps me to understand ketosis better. My question is is there a problem with cycling in and out of ketosis? For example I eat VLC/HF for fat loss but I find I want to up my carbs a little every 7-10 days or so. I assume this throws me out of ketosis, are there any potential health consequences from cycling in and out of ketosis regularly?

    Thanks

    • I don’t really know. Not sure anyone does, but it strikes me as a bit inefficient. Paradoxically, this may be better for weight loss, but worse for performance.

    • Hi Dr. Attia,
      Could you elaborate a little on how and why that is better for weight loss? Great blog btw, I’ve been following you for a little over a year after finding you through Gary Taubes’ site and I am a huge fan of what you all and what you are attempting to do!
      Thanks.

    • Sorry about that, let me clarify. I was asking a question in response to your response of the previous question about cycling in and out of ketosis every 7-10 days because of “cheating”. Its obvious why it’s not optimal for adapting and why it would hurt your performance. What I’m not clear on is why it can be more effective for weight loss? Especially in lieu of what was said in the post, that is that there can be an increase in overall RMR in someone who is in NK.
      Thanks again for your time Dr. Attia!
      Cheers!

  18. Peter,

    I was turned on to your blog/Gary Taubes/etc. a few months ago by a friend. Needless to say, I am consumed by it. While I do not yet have the details of all the science down, I am working to learn them. Obviously most people go into nutritional ketosis in order to lose weight/ be healthy/ promote fat oxidaton. I am an athlete and I am required to maintain a weight of around 250 + lbs. Since conforming my diet, in which I slip in and out of NK, depending on the day; sometimes I will eat nuts, sweet potato, occasional fruit, I have lost weight down to about 242 lbs. I would love to keep on this lifestyle change but cannot afford to be sub 250. Would you have any recommendations to keep weight on? I have thought about trying to eat more low-carb foods, thereby increasing caloric load. Or possibly bite the bullet and eat more complex carbohydrates. Any recommendations would be appreciated.

    Thank you,
    Zack

    • Yes, certainly possible, but I can’t really answer in this brief context. So many variables and highly dependent on complete “suite” of goals and objectives.

  19. Dr. Attia,
    Do you have an opinion or would care to comment on the ability of Type 1 diabetics to safely enter NK? I have been type 1 most of my life, have been eating 20-50g carbs/day for almost 2 yrs. I have slashed my insulin usage approx 70% but still can not enter NK, I either have increased blood sugar and ketone production, indicating DKA, or I still have to take too much insulin to produce ketone bodies.

    • It requires great care and the oversight of a very experienced physician. With looking at the book Richard Bernstein, who is himself a type 1 diabetic.

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