April 23, 2018

Ketosis & fasting

Ketosis – advantaged or misunderstood state? (Part I)

In part I of this post I will see to it (assuming you read it) that you’ll know more about ketosis than just about anyone, including your doctor or the majority of “experts” out there writing about this topic.

by Peter Attia

Read Time 12 minutes

If I held a crystal ball 10 years ago, I’m not sure I would’ve believed it if it showed me the increased interest in the ketogenic diet would look like the figure below. That’s 2 logs, folks.

 

 

Admittedly, I started my journey on this path in 2009, with a deep dive into ketosis in the Spring of 2011, but it seemed so obscure! (For a timeline of what I did, I think I covered it somewhere in this talk…yes I’m too lazy to actually confirm this by skimming through it.) All told I spent approximately 3 years in the strictest state of nutritional ketosis (NK) with one very memorable deviation when I had 6 or 7 full-sized and upsettingly decadent desserts circa September 2013. I believe the diet helped me transition from metabolic syndrome to metabolic health and I certainly thought it could benefit other people. This nutritional state could gain some steam, I thought.

I was well aware of the dearth of mainstream knowledge of NK, and particularly the conflation of NK with diabetic ketoacidosis (DKA), a pathologic state that results from the complete or near absence of insulin, which is what prompted my writing and desire to share my journey. And I was once in the wanker category of folks who spoke with “authority” about ketosis, despite knowing somewhere between zero and nothing on the topic. I remember exactly where I was sitting in a clinic at Johns Hopkins in 2002 during my residency explaining to (admonishing, really) a patient who was on the Atkins diet how harmful it was because of DKA. Not only that, the ketogenic diet could be seen as the antithesis of a “healthy” diet by conventional standards. I could see how this was a difficult proposition for many to acknowledge.

The beautiful part of good science is its self-correcting nature. The ugly part is this self-correcting nature often moves at a glacial pace—and it’s not linear. We often view history century-by-century and see what amounts to continual progress in medicine. But we live our lives—and consume information—day-by-day, exposed to the peaks and valleys of medical wisdom.

Looking back on my earlier posts on ketosis—and explaining what I eat, for example—makes me both chuckle and cringe. I remember how bizarre the diet seemed to many readers and the general public at the time. I also remember digging into the literature and learning, for example, that my alma mater, Johns Hopkins had been using the ketogenic diet to treat pediatric epilepsy for almost a century…and being so embarrassed about admonishing that patient I saw in my residency.

Since then, it’s safe to say I dove down the rabbit hole. The more I learned, the more I grew tired of reading so much misinformation on the topic. While there are more thoughtful people and articles on the subject of ketosis these days (e.g., here’s a thoughtful video on ketosis and ketogenic diets from one of my most important ketosis mentors, Steve Phinney, a co-founder of Virta Health1Disclosure: I’m an investor in, and advisor to, Virta Health.), there are still pieces like the one Vox published this month, that doesn’t exactly do the topic justice.

Like many variables in diet, health, and disease, it behooves us to look beyond the bumper sticker explanation. I want to highlight a couple of posts I wrote, to attempt to provide a little more nuance and understanding to the subject: “Ketosis — advantaged or misunderstood state?” Parts I and II. Part I follows below. I’m hoping to write more on the topic in the not-too-distant future since there’s been a number of intriguing papers published recently (certainly since 2012). But I also wanted to bring these back into focus in light of the information I’m seeing more of on the interwebz. (You can also visit the Ketosis section of the site to view more articles on the subject.)

Because I know people will ask, I have not been on a ketogenic diet “regularly” since about mid- to late-2014. The reasons are too nuanced to describe here, but my deviation is not because I lost confidence in its efficacy. With nearly a decade of clinical experience, I can safely say I was an outlier (in the best sense) with respect to my physiology and response. I was leaner, and more mentally and physically fit during this three year period than during any other period of time as an adult, and my biomarkers were as good as they had ever been. I’ve also seen the benefit of ketogenic diets first-hand on my patients and my own sister, a remarkable story I hope to share one day. But I’ve also been humbled by my inability to explain why some people have suboptimal or even negative responses to NK. I would say, all things considered, my knowledge of ketosis is greater today than when I was writing about it voraciously, but my confidence in my understanding of it, might actually be lower. As the saying goes, the further one goes from shore, the deeper the water gets.

—P.A., April 2018

§

(Part I: originally posted November 26, 2012)

In part I of this post I will see to it (assuming you read it) that you’ll know more about ketosis than just about anyone, including your doctor or the majority of “experts” out there writing about this topic.

Before we begin, a disclaimer in order: If you want to actually understand this topic, you must invest the time and mental energy to do so.  You really have to get into the details.  Obviously, I love the details and probably read 5 or 6 scientific papers every week on this topic (and others).  I don’t expect the casual reader to want to do this, and I view it as my role to synthesize this information and present it to you. But this is not a bumper-sticker issue.  I know it’s trendy to make blanket statements – ketosis is “unnatural,” for example, or ketosis is “superior” – but such statements mean nothing if you don’t understand the biochemistry and evolution of our species.  So, let’s agree to let the unsubstantiated statements and bumper stickers reside in the world of political debates and opinion-based discussions.  For this reason, I’ve deliberately broken this post down and only included this content (i.e., background) for Part I.

What is ketosis?

Ketosis is a metabolic state in which the liver produces small organic molecules called ketone bodies at “sufficient” levels, which I’ll expand upon later.  First, let’s get the semantics correct. The first confusing thing about ketosis is that ketone bodies are not all – technically — ketones, whose structure is shown below. Technically, the term ketone denotes an organic molecule where a carbon atom, sandwiched between 2 other carbon atoms (denoted by R and R’), is double-bonded to an oxygen atom.

Conversely, the term “ketone bodies” refers to 3 very specific molecules: acetone, acetoacetone (or acetoacetic acid), and beta-hydroxybutyrate (or beta-hydroxybutyric acid), shown below, of which only 2 are technically ketones.  (The reason beta-hydroxybutyrate, or B-OHB, is not technically a ketone is that the carbon double-bonded to the oxygen is bonded to an –OH group on one side, technically making B-OHB a carboxylic acid for anyone keeping score.)

Now, back to the real question at hand.  Why would our body make these substances? To understand why or when the body would do this requires some understanding of how the body converts stored energy (the food we eat or the energy we store in our body, i.e., fat or glycogen) into phosphate donors.  For a refresher on this process, please refer to the video in this post, specifically the section from 2:15 to 13:30.

The ATP issue

As you may recall, about 60% of the energy we expend, say 1,800 kcal/day for someone consuming 3,000 kcal/day in weight balance, is purely devoted to keeping us alive by generating enough ATP (“energy currency”) to do 2 things: allow ion gradients to function and allow muscular relaxation.  So, obviously, we can’t tolerate – literally even for one minute – insufficient ATP production.  In fact, one of the most potent toxins known to man (cyanide) exerts its effect on this process by inhibiting the electron transport chain which generates the bulk of the ATP our body produces.  Even the most transient interruption of this process is fatal.

Take home message #1: No ATP, even for 1 minute, equals no life.

The brain issue

The brain is a particularly greedy organ when it comes to energy requirement. To put this comment in perspective consider the following: though our brain represents only about 2% of our body mass, it accounts for about 20% of our energy expenditure.  (In children, by the way, this may be closer to 40-50% of basal metabolic demand.) So, beyond the ATP issue, above, there is a substrate issue with the brain as neurons derive most of their energy from glucose.  While there is emerging evidence that neurons can also oxidize fatty acids directly in small amounts and may even prefer lactate (over glucose), these two substrates do not approach the levels of consumption by neurons that glucose does.  So, for the purpose of this discussion, let’s just focus on the need of the body to provide glucose to the brain.

You’ll recall, from the point I made above, that my brain requires about 400 to 500 kcal of glucose per day (100 to 120 gm).  You’ll also recall (from the video, above) that I can store about 100 to 120 gm of glucose in my liver.  While I can store much more in my muscles, (on the order of about 300 to 350 gm), because muscles lack the enzyme glucose-6-phosphatase, glucose stored in muscle as glycogen is unable to re-enter the bloodstream and is meant for the muscle and the muscle alone to use.  In other words, muscle glycogen is a stranded asset of glucose in the body to be used only by the muscle.

So, if I’m deprived of a dietary source of glucose, I depend solely on my liver to release glycogen (a process known as hepatic glucose output, or HGO).  How long can HGO supply my brain with sufficient glucose? It depends on a few things that impact both the “source” and the “sink” of glucose.  Other competing sinks for glucose (e.g., activity level, thermogenic needs) and sources (e.g., glycerol and gluconeogenic amino acid availability) can make a difference for a while. But, in a state of starvation we’ve only got about one to three days before we’re in trouble.  If our brain doesn’t get a hold of something else, besides glucose, we will die quite unceremoniously.

Take home message #2: No glucose for 24-72 hours equals the need for something else the brain can use instead (that is not fat or protein, since neurons can’t oxidize fat and the last thing we want to do is start muscle wasting at a geometric rate).

The Krebs Cycle

This poses a real evolutionary dilemma.  We need an enormous amount of energy just to not die, but the single most important organ in our body (also quite energy hungry in its own right) can’t access the most abundant source of energy in our body (i.e., fat) and is, instead, almost solely dependent on the one macronutrient we can’t store beyond a trivial amount (i.e., glucose). Obviously our species wouldn’t be here today if this were the end of the story. But, to understand how we survived requires one more trip down biochemistry memory lane.  In the figure below (also included and described in the video) I gloss over a pretty important detail.

How, exactly, does our body take pyruvate (from glucose) or acetyl CoA (from fat) and generate so much ATP?  The answer lies in the beauty of the Krebs Cycle, which feeds into a process called the electron transport chain (or ETC), I alluded to above.  Since the adage ‘you can’t get something for nothing’ is as true in biochemistry as it appears to be in life, to get all that ATP (i.e., stored energy in the form of the phosphate bond), we need to give up something.  What the ETC does give up, as its name suggests, is electrons.  Through a series of redox reactions the ETC trades the stored energy held by electrons going from higher to lower energy states in exchange for the chemical energy stored in the bonds of the third phosphate group on an ATP molecule.

To think of it another way, if you start with stored energy – glucose or fat, for example, which if burned in calorimeter will give off varying amounts of heat – and you’re willing to convert their carbon, hydrogen, and oxygen molecules into another form with less energy – water and carbon dioxide which, if burned, produce very little heat – it’s a fair trade!  The ETC is simply the vehicle that allows our body to make the switch.

In a car, by contrast, it’s much simpler.  The engine combusts the hydrocarbon (e.g., gasoline) directly and in one flash liberates the heat contained within the hydrogen-carbon and carbon-carbon bonds in exchange for carbon dioxide, water vapor, and a few other things.

If you take a look at the figure, below, you’ll get a sense of the moving pieces involved in this cyclic transfer process.  Molecules shuffle back and forth, around the cycle, and kick off spent carbon (carbon dioxide, termed “waste”) and reducing agents (e.g., conversion from NAD+ to NADH) for the ETC.

By RegisFrey (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Under conditions of abundant glucose (and sufficient insulin sensitivity) the brain is primarily converting glucose to pyruvate (left side of figure).  Pyruvate is then shuttled into the mitochondria and converted into acetyl CoA with the help of a very important enzyme called pyruvate dehydrogenase (PDH).  I’m going to come back to this enzyme, in part II of this series, because this is where the story gets very interesting.  Acetyl CoA (which is also a direct byproduct of fatty acid breakdown) is then combined with oxaloacetate and so begins the Krebs Cycle, which generates all the reducing agents to feed the ETC and generate massive amounts of ATP.

Where do the ketones come in?

In the absence of acetyl CoA (several ways this can happen, including substrate shortage, as I’m describing here) we evolved a cool trick.  Our liver can make – out of fat or protein, though we much prefer to use fat so we can spare our protein and prevent severe muscle wasting – something called beta-hydroxybutyrate, one of the 3 ketone bodies I described above.

B-OHB and acetoacetate (see figure below from this paper by Cahill and Veech, 2003) are produced by the liver from long and medium chain fatty acids and released into the bloodstream.

Image credit: Cahill and Veech, 2003

Acetoacetic acid and B-OHB live in reversible equilibrium (on the left), but once acetoacetate is converted to acetone (on the right) there’s no going back.

Now take a look at the figure below, from this 2001 paper. This is another rendition of the figure above showing the Krebs Cycle, but here you can see where B-OHB and acetoacetate enter the picture.

Image credit: Veech et al., 2001

The reason a starving person can live for 40-60 days is precisely because we can turn fat into ketones and convert ketones into substrate for the Krebs Cycle in the mitochondria of our neurons. In fact, the more fat you have on your body, the longer you can survive.  As an example of this, you may want to read this remarkable case report of a 382 day medically supervised fast (with only water and electrolytes)!  If we had to rely on glucose, we’d die in a few days.  If we could only rely on protein, we’d live a few more days but become completely debilitated with muscle wasting.

The graph below, also from the Cahill and Veech paper, shows the blood chemistry of a person starving for 40 days.  Within about 3 days, a starving person’s level of glucose stops falling.  Within about 10 days they reach a steady-state equilibrium with B-OHB levels exceeding glucose levels and offsetting most of the brain’s need for glucose. In fact, the late George Cahill did an experiment many years ago (probably would never get IRB approval to do such an experiment today) to demonstrate how ketones can offset glucose in the brain. Subjects with very high levels of B-OHB (about 5-7 mM) were injected with insulin until glucose levels reached 1 mM (about 19 mg/dL)!  A normal person would fall into a coma at glucose levels below about 40 mg/dL and die by the time blood glucose reached 1 mM.  These subjects were completely asymptomatic and 100% neurologically functional.

The last point I’ll make on the starving patient is that, as you can see in the figure below, the glucose level normalizes at about 65-70 mg/dL (about 3.7 mM) within days of fasting, despite no sources of exogenous glucose.  Why?  Because with so much fat being converted into B-OHB and acetoacetic acid by the liver, a significant amount of glycerol (the 3-carbon backbone of triglycerides) is liberated and converted by the liver into glycogen.  As an aside, this is why someone in nutritional ketosis – even if eating zero carbohydrates – still has about 50-70% of a normal glycogen level, as demonstrated by muscle biopsies in such subjects.

Image credit: Cahill and Veech, 2003

Take home message #3: We evolved to produce ketone bodies so we could not only tolerate but also thrive in the absence of glucose for prolonged periods of time.  No ability to produce ketone bodies = no human species.

Last point of background: Everything I’ve just presented is based on data from starving subjects.  If one restricts carbohydrate intake, typically to less than about 20-50 gm/day (dependent on timing and carbohydrate composition), and maintains modest but not high protein intake (because protein is gluconeogenic – i.e., protein in excess will be converted to glycogen by the liver), one can induce a state referred to as “nutritional ketosis” with similar physiology to what I’ve just presented without resorting to starvation.  Why you’d do this is something I will discuss later.

One other housekeeping issue: Ketosis versus DKA?

In a separate post, I explained the difference between nutritional ketosis (NK) and diabetic ketoacidosis (DKA). If this distinction is not clear, I’d suggest giving this separate post a quick skim for a refresher.  DKA is a pathologic (i.e., harmful) state that results from the complete or near absence of insulin.  This occurs in the setting of type 1 diabetes or very end-stage type 2 diabetes, and often as the result of a physiologic insult (e.g., an infection) where the patient is not receiving sufficient insulin to bring glucose into his cells.  A person with a normal pancreas, regardless of how long he fasts (including the fellow I reference above who fasted for 382 days!) or how much he restricts carbohydrates, can not enter DKA because even a trace amount of insulin will keep B-OHB levels below about 7 or 8 mM, well below the threshold to develop the pathologic acid-base abnormalities associated with DKA. Let me reiterate, it is physiologically impossible to induce DKA in anyone that does not have T1D or very, very, very late-stage T2D with pancreatic “burnout.”

Embarrassing admission: I remember exactly where I was sitting in a clinic at Johns Hopkins in 2002 explaining to (admonishing, really) a patient who was on the Atkins diet how harmful it was because of DKA.  I am so embarrassed by my complete stupidity and utter failure to pick up a single scientific article to fact check this dogma I was spewing to this poor patient. If you’re reading this, sir, please forgive me. You deserved a smarter doctor.

In Part II of this post I’ll tackle the questions I know folks still have on their mind (below). Until then, re-read this post to make sure you really understand this physiology.  You’re already 10 steps ahead of the next person.

  1. Is there a “metabolic advantage” to being in ketosis?
  2. Are there dangers of being in ketosis?
  3. What are the most important things you need to know about getting into (or staying in) ketosis?
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574 Comments

  1. As usual, a great article. Had a lecture in endocrinology today and, although he conceded the difference between nutritional ketosis and DKA, he claimed that he had seen ‘severe CNS effects’ in those who attempted ketosis, and wouldn’t recommend it. I wonder if you’ve ever come across the use of a glucagon shot with high protein intake as a means for losing fat? Keep busting myths!

    • Not familiar with the glucagon injection strategy. Our body is pretty good at making it, though, but in theory very high levels of glucagon (for example, as seen in a rare tumor called a glucagonoma) do produce profound wasting. Problem is, the wasting is both of fat and muscle.

    • @Gus

      “he claimed that he had seen ‘severe CNS effects’ in those who attempted ketosis,”

      Bwah-ha-ha-ha! I eat 1650 calories a day (‘cuz I’m female) in the ratio of 85% fat (25% of saturated), 12% protein, 3% carbs. My blood ketones average 2.4 in the morning and about 4.1 at night. I have been eating this way since I read Volek’s Art of Performance in May. I lift weights once a week and right now am leg pressing 310.

      When not spending my days cavorting about in my size 9 Calvin Klein skirts and super-skinny True Religion jeans, I’m holding down a job as a tech executive, learning a foreign language, and spending time with one of my friends planning a book project about logic.

      So please tell your doctor that I have indeed observed “CNS symptoms” – mostly an increased ability to focus for long periods of time without getting mentally tired, improved memory, and an ability to think on my feet more quickly. In all day meetings everyone else is constantly snacking on the cookies & Mexican food – I’m eating coconut oil. At 5pm, I’m calm, ready to keep going, and want to finish the action items, whereas everyone else gets really cranky, complains how mentally tired they are and has to end the meetings so they can review the final numbers-based decisions the next morning. With more cookies.

      Even if I hadn’t lost a lot of weight eating like this, I would do it again in a heartbeat solely for the mental benefits alone. So that’s your “CNS symptoms” for you. 🙂

    • @melancholy aeon: Yes! Me too – exact same story (except I read Mark Sisson’s fat adaptation blog posts then bought the book). 1700 (give or take a few hundred) cals a day, 70% fat normally. I train hard (bodyweight and bar calisthenics) four or five times a week. Strength gains and recovery both excellent and the consistent energy is just the best. thing. evar. Don’t mind if I drift out of ketosis for a few days (social events, or just feel like eating a fat pile of sweet potato) but I mostly stay in it.

      I’m curious (I don’t know any women who are fat adapted so excuse the questions) – do you do carb ups? Have you noticed any change in your menstrual cycle or other hormone profiles? How did you eat before you changed? How have your family handled it? Do you get weird questions about your diet at work?!

    • @simik
      “Those ‘severe CNS effects’ could be just keto-flu.”

      A headache is a severe effect? Lawd luv a green-eyed duck! That’s exaggeration for sure. I myself have always had a cup of broth a day, so I never suffered from it. There’s absolutely no need to suffer to from it.

      @fi
      Don’t know any women? Hang out in the right places. 🙂 I guess a lot of ultramarathon people do it, tho’ that’s not my crowd obviously.

      ” do you do carb ups?”
      No, never. Why lose the mental advantage? Rosedale speculates about a lot of other benefits too.

      “Have you noticed any change in your menstrual cycle or other hormone profiles?”
      Yes, my PMS vanished, as Phinney said it would. Because PMS and menopause are both related to inflammation – he’s actually an expert on this topic, but no one hardly ever asks him about it. It also became shorter, lighter and now always arrives on the same day. It comes and goes unnoticed for me now, not the trauma it used to be.

      “How did you eat before you changed?”
      WAPF. I spent days and days making sourdough rye bread by hand to try to ferment out all the anti-nutrients. Each loaf of bread took 5 days to make. Tasted great, but really exhausting. Even then I had no energy. Only later did I learn I had the COMT & HLA-DQ gluten intolerance genes, even tho’ I don’t have classic celiac. I also switched from raw milk to goat kefir. I drink 1 oz kefir a day and have raw cream in my coffee.

      “How have your family handled it?”
      My husband went with me. He built a lot of impressive muscle doing the Total Immersion swimming at Stanford, eating right at 50 total carbs. ‘Cuz guys have that advantage. So he’s cool with it. He wears 30-inch raw Japanese denim.

      “Do you get weird questions about your diet at work?!”

      Of course not. Besides, my lunches look quite normal – 2 oz. tuna and 3 oz. green veggie or salad. No one would bat an eye. There’s nothing strange about this diet. I mostly eat like Julia Child now, actually.

      Like most Silicon Valley workplaces, we are very diverse and to comment on what other people eat would be extremely rude. We have Hindus, Sikhs, Muslims, Buddhists, Russian Orthodox Christians, Jains, Jews, vegans, Filipinos who eat pork skin, Cantonese & Taiwanese who eat duck feet. . . it would be career suicide to step into that minefield. 🙂

      Best wishes.

    • Use caution when “experts” lecture to you. Ask them to clarity. For example, what were the serious CNS effects. Many students complain that my biochemistry lectures give them serious CNS effects! I agree with Peter regarding the evolution among many of us who are experts by credentials, but not by experience. There is an old saying that “the physicians that really know about nutrition are the ones with a nurse who has a weight problem.” In my case, I didn’t really start learning real world biochemistry until I was diagnosed with prostate cancer (I’m OK, 10 yrs out from surgery) but especially last year when my lipid labs came back with particle (dense) LDL off the chart. That is when I found Peter’s work along with Volk, Phinney, Westman, etc. Needless to say my lectures are going to be considerably changed this year. I even have a suggested viewing guide to recommend for the students as outside learning. I believed I was teaching the right thing and much of what I have taught is pretty good stuff, very nutrition oriented. But, I no longer trust my expertise. Now, I am constantly digging.
      As a final thought about those “serious CNS effects.” I have found that since becoming ketoadapted that I started suffering cramps in my legs when sleeping. This never had happened during a history of running (I am 71 yo, runner for 30 years, bodybuilder, yoga, … you get the picture). It seems that the severe, and healthy, suppression of insulin release downregulates a protein called sodium/potassium ATPase that is needed for the kidney to conserve electrolytes, especially potassium and magnesium. The depletion of potassium from within muscle cells leads to the cramping. magnesium deficiency also contributes. But now to the CNS issues. The electrolyte depletion also produces CNS disturbance and accounts for much of the “off” feeling when becoming ketoadapted. Guess how easy this is to remedy? I take both bouillon and potassium supplements and magnesium and the cramps are gone and i feel great.
      Hope this helps those who are just learning this stuff. The world needs more physicians like Peter.

  2. Peter,
    Thank you for an excellent article.
    I wish you would have been my professor in grad school!!
    Looking forward to Part II

    • TO: john pelley July 10, 2014 above If you want a paradigm shift in exercise and health, checkout Dr. Doug McGuff’s book and youtube videos. Peter recently recommended the book. My paradigm shifts were caused by Dr. Bernstein three years ago that led to Gary Taubes and Peter. Dr. McGuff caused my shift 3 months ago. Living is being ready for the next one

    • Good question. I’ve never seen this specifically studied. Metformin inhibits HGO, but I’m not sure it’s directly enhances ketosis (in theory, if HGO is suppressed enough, you’d think it might help). But I do not know.

  3. Great post, an efficient trip down biochem memory lane. Look forward to part 2.

    “As an aside, this is why someone in nutritional ketosis – even if eating zero carbohydrates – still has about 50-70% of a normal glycogen level, as demonstrated by muscle biopsies in such subjects.”

    Didn’t know that before, very interesting. That explains why my performance in the gym doesn’t suffer that bad when I go extremely low on the carbs. After the initial ketoadaptation period I’m performing pretty near my previous higher-carb levels.

    • Yes, though we don’t know how much liver glycogen they have (since we can’t really justify liver biopsies). Indirectly, though, it’s clear that even without any carbs, HGO is preserved, so there must still be some glycogen turnover in the liver.

    • The site won’t let me reply to Peter’s comment (don’t you like me, Peter, or something?), but I mentioned the 50% glycogen retainment effect to a mate who is convinced ketosis is dangerous and asked for references. i’m struggling to find any, including using my university’s library. Will keep looking, but does anyone know of any studies that explain this?

      Have started with the cahill and veech paper, will have read it shortly, but I fear he may reject it because it’s on 40 day fasts and that seems to be a lot different to what we consider NK to be.
      I know you justified this near the end (NK has similar physiology, just without the acidosis, correct?) but again, not sure he, and many others, would take that as good enough.

  4. I had a lecture on anorexia a few days ago, and our (psychiatrist) teacher told us that she had a boy who was on “one of those primal diets, of meat and nuts, eating 500kcal a day”. (He had a mental disorder…and it was used to lambast my dietary preference). She went into a discussion of how we need a “balanced diet” of meat, vegetables, and grains.

    I spoke to her at the break and corrected her on what a “primal diet” was, but tried explained that there is no “need” for grains (let alone the possible GI dangers; let’s not try to convert someone in one fell swoop). I said I hover around 100g carbs a day as I put on weight and try to cut it down to 50g when I want to lose weight (I’m anywhere between 205-225, 5-10% fat…depending on the season and our test schedules). She said that’s dangerous, your body needs glucose, you’ll go into DKA, etc (need grains for insulin, balance, energy…)

    She said I should get a CBC and CMP because it’s probably not good for me. “Well I’ve been eating this way for about 4 years now, sleep great, never sick, and am doing well in medical school…so…um…could it be that you’re wrong?” We agreed to disagree.

    This mindset is pervasive…and oddly enough, I have only heard this rhetoric from physicians of at best average health and fitness levels admonishing their patients for being overweight on the exact same type of diet!

    • I blame the left wing. I know a lot of people are going to hate me for saying this, but it’s the left wing that has taken over most of our research and research labs. And while that wouldn’t necessarily be a bad thing because, hey, we always need to improve our science, and the right-wing isn’t going to invest in it as much, somebody needs too. Unfortunately, the left wing also if chalk full of all those special interest groups that have everything to lose when what they’ve been fighting for over the last several years, some even decades, suddenly find out they’re wrong, that the exact opposite is very plausibly true.

      They aren’t just going to take that science lying down. They’re going to do even what the good ole Thomas Eddison himself did, and that’s to use whatever political power and influence they can possibly muster to try and get that science either discredited or to come under question at least. They are going to use their political allies influence and power over research funding and labs and schools to do whatever they can to prove themselves right, their opposition wrong, and to make their opposition sound as psuedo-science, bought-out, and brainwashed as possible.

      It’s not that they’re necessarily greedy, evil, or selfish, although, by now, most probably are, it’s simply that they are threatened, and they’ve believed a certain way for so long, and have so much personal stake riding on this belief, that they cannot accept that it could be wrong. And some are just comfortable with the life, and have become greedy and scared of losing it. It’s how a lot of science regarding controversial things has gotten skewed. Look throughout history, modern societies of the day are often full of people trying to subvert, in some way, science that they feel will affect their place and power in society. That’s just part of the imperfection of mankind.

      Now that this research is beginning to see the light of day, not because it was in some textbook or learned in nutrition classes, or because the peer-reviewed journal entries made huge wide-spread public attention, but almost exclusively due to the number of common people who have looked at it’s science, tested it out on themselves, and have decided to follow it because of how well it worked and is working for them.

      Without all all of the common people benefiting and demonstrating the reality of this, it would still be considered pseudo-science by the leading scientific authorities of our day, and in fact, it sort of is. Bu inevitably, it seems to be working it’s way out in spite of all of that, and one day it’s going to hurt some left-wing special interest groups in a large way.

      Fortunately, the nutrition and anti-meat special interest groups are not as powerful as some others are, and they’re slowly giving way to the overwhelming abundance of evidence that is mounting up due to the everyday common people who are using this ketogenic idea.

      I imagine that inevitably, health classes in elementary, middle, and high schools all across the U.S. will be teaching this alternative diet as a healthy alternative to carb-based diets.

    • A saying of my H.S. football coach:

      Foolish is the man (or woman) who has absolutes! Wise is the man who understands his absolutes are his faith.

      You might also look up the work of Greg Ellis Ph.D.—–Bye Bye Carbs.com

    • The key sentence here is: “your body needs glucose”.

      If someone’s says this, you know they do not understand the least of how the body works, and they probably have never tried themselves to stay in ketosis state for a longer period.

      I’ve been running (nonprofessional) for 34 years, the last 5 years also marathons, I did about 20+ marathons, my body stayed the same since I was 18 years old (78 kg, ~10% fat), I experimented a lot with being in ketosis because I wanted to test my hypothesis that one can improve on a marathon by training in ketosis, because then you improve a lot of the mechanisms by training them already from the start of your work out, which otherwise would have started only after 32 kilometres of work out.

      I met a lot of people like your teacher, especially since I do running nonprofessional.
      I found people like your teacher a lot in average trainers and health instructors.
      The most dangerous ones are the ones who are utterly convinced they are right, because they are not open anymore for arguments that prove the opposite.
      There’s also the effect of cognitive dissonance, they don’t want to accept that their beliefs are incorrect because the implications would be very uncomfortable.

      I don’t know what is the best approach. Some times asking questions like: “how come the body and the brain keep on preforming really good after 32 kilometres of running though the glycogen reserves are completely empty?”, might arouse them to do a bit more research.

      Hope you started a little spark of being more open minded in your teacher.

  5. Peter,
    Once again you present an excellent and well written post. Thank you for all you do. I feel I learn something new everytime i jump onto your website. I have a question for you if you have the time. Hypothetically, if one were practicing nutritional ketosis for a few months and was fully adapted, could they then drop some dietary fat intake to speed up body composition changes(fat loss)?

    Thanks again for the blog.

    • @ Paul.
      That would constitute what is called a “fat fast.” For few days only, try to get up to 90% of your calories from fat, preferably saturated, of course, and consume only around 1,000 calories. This is surprisingly difficult to do, the 90% part, because protein accompanies fat almost universally. I use slices of pepperoni sausage with dabs of cream cheese on them. I say only a few days because you could get into a state of muscle wasting if you go much longer. However, melancholy aeon’s experience might indicate otherwise. This helped me and some other people I know to break through what the Atkins people call a plateau.

    • @Edward

      ” For few days only, try to get up to 90% of your calories from fat, preferably saturated, of course, and consume only around 1,000 calories. ”

      Wow, I would do recommend that. 🙂 But if it works for you. . . n=1. I personally have a strong feeling that women over 5’2″ should never eat less than 1500 cals a day and men never less than 1800. Love your body, don’t throw it into a starvation crisis. I myself eat 3 meals and at least 1 snack every day (usually olives & chicken broth). I want my body to be happy and not freak out or slow my metabolism.

      Like many women, I also don’t do well with this fasting stuff. Too Kate Moss for me. 🙂

      Jimmy Moore is a fine example of how eating this way will change your body composition, replacing fat with muscle easily. 🙂 He lost what? 40 pounds of fat and replaced with 6 pounds of muscle? He does skip lunch, but eats a truly enormous breakfast. . . .no calorie deprivation there. 🙂

    • @ melancholy aeon

      “I personally have a strong feeling that women over 5’2? should never eat less than 1500 cals a day and men never less than 1800. Love your body, don’t throw it into a starvation crisis.”

      Actually, I was reading somewhere online, you might have to google it, that doing 3 to 4 day fasts, like Biblical fasts, as in you eat nothing, is very possibly one of the most effective means of fighting cancer and preventing it.

      The article talked about the benefits to fighting and preventing cancer using a keto-dieting approach, saying that cancer survives best in a body with plenty of carbs, glucose, and proteins like glutamine found in many meats. It also talks about how the cancer can still survive in low-carb environment because of the glutamines and I think some other proteins that it can still use for energy. However, the article stated, I believe even quoted, (paraphrasing) that fasts like that make an almost impossible environment for cancer to thrive. The article went on to explain more specifics like that this and that forms or prevents the formation of, but the general message there was that there is potential being shown that having fasts like that can actually both prevent and fight cancer.

      It’s fascinating because much of science seems to indicate the reality of the what the Bible says. In this particular case, it reminded me of the fasting talked about in the Bible. Fasting was a part of the law that was finished and no longer necessary to be followed when the Messiah came. That’s the idea as spoken of by Paul behind why Christians no longer follow the law as the Jews were required too. Well, one of the aspects of the law was fasting regularly. It was actually more of a tradition than the law. However, the disciples who wrote the Bible after Christ ascended into heaven, they kept on with it and told all other Christians to continue fasting. In fact, Christ Himself stated that demons are cast out only by prayer and fasting. Now, fasting and prayer was for the sake of weakening the body and strengthening the spirit so that one’s body was not as strong as one’s spirit so that the spirit would win the battle, and one would have, essentially, the willpower to remain doing as is right in God’s eyes and not be led astray by their temptations.

      Well, interestingly enough, now it seems like there may also be a rather incredible health benefit from doing periodic fasting of a such magnitude, and that is the potential for making an inhospitable and deadly environment for any cells that happen to turn into cancers that perhaps we are unaware. After all, cancer is not detected on the DNA level. It’s detected by finding and abnormal growth that’s already been there for some time, and then testing it’s tissues for malignancy.

      I just thought that was fascinating and compelling enough to post along with the main idea of this post. I do hope I have not offended anyone, but as I would tolerate anothers trying to relate this to Atheism and the benefits inherent in an evolutionary evaluation of our current diet, i.e. the Paleo diet, I would hope to be given the same toleration.

  6. Dr. Attia,

    First, thank you all of the work you do in synthesizing the medical literature for “the rest of us.” I was really excited to see that you were starting a new series on ketosis! I’ve recently gotten my hands on some ketone urinalysis strips and a blood keto-glocometer, which I plan to use in measuring my fat-burning status while trying to lose weight.

    Will you by any chance be talking about the suitability of ketogenic diets for pregnant and postpartum women? My wife and I have both been utilizing low carb diets for some time now (though my wife doesn’t have any weight to lose and has a higher daily carb intake) and she is 8-months pregnant. On various websites I’ve seen it asserted, usually with little to no supporting evidence, that a ketogenic diet can have negative effects on the baby in utero. I think it was based on the assumption that the brain “needs” glucose and thus brain development could be affected by low glucose in the mother or something? We were also told by a lactation consultant that low carb intake is an issue for breastfeeding – that it can decrease milk production. This was also mentioned recently by a well-known paleo author/blogger, who suggested that ketosis during pregnancy can decrease prolactin levels. But, again, no sources for this were provided.

    Do you have any thoughts on these issues?

    • I do not have, or have at least, have not seen, data examining this question. I would safely say that a low GI diet is not only safe in pregnancy, but almost certainly beneficial. David Ludwig from Harvard is currently designing a very exciting trial to look at some of these effects, especially as they relate to the long-term risk of obesity in children.

    • Stay out of ketosis to reduce the chance of inadequate calorie and nutrient intake. Ketosis can be a helpful tool for weight loss, but, as you say, you don’t need to be losing weight right now. Besides, eating fewer calories means fewer chances to obtain the nutrients you and your baby need. I’ve also heard rumblings that a very low carb ketogenic diet can reduce prolactin. Prolactin is the “milk hormone”; it regulates your milk supply. For men trying to avoid gynecomastia (man boobs)? Sure, they’ll want to reduce prolactin, but in breastfeeding mothers, prolactin is normally quite high and it should stay that way. If you hope to grow a small human from infancy, you need to produce ample amounts of milk. It isn’t guaranteed that going into ketosis will depress your milk production, but it’s not worth the risk.

      Just eat your Primal carbs to stay out of ketosis. Though there are health benefits to ketosis in specific conditions (epilepsy, certain cancers, neurological disorders, obesity), I wouldn’t include “breastfeeding motherhood” among them. If you’re interested in the health benefits of ketosis, realize that simply breastfeeding – especially for longer than six months – is strongly associated with a bevy of health benefits for the mother, including weight loss, protection from breast cancer, protection from ovarian cancer, and lowered heart disease risk. So, providing ample milk to enable long duration breastfeeding is your safest bet.

      Read more: http://www.marksdailyapple.com/workout-break-raw-milk-banana-breakfast-ketosis-in-breastfeeding-and-bikram-yoga/#ixzz2DRpUynEg

    • @Dave

      “Do you have any thoughts on these issues?”

      Why not talk to any of the several women we all know who in fact have done this? Dr. Andreas Eenfeldt’s wife is breastfeeding their extremely healthy and amazingly calm baby now on 50 total carbs; during the pregnancy she was eating 30 total carbs.

      Dr. Jay Wortman’s wife also was low carb during her pregnancy and lactation; their little girl has been raised totally low carb. You should see her ski – at the age of 2.

      There are some quite prominent low-carb moms around and I suggest you talk to them. 🙂 Best wishes.

    • n=1, but my experience is that this isn’t something to be too concerned about. My wife is at between 50-100g CHO/day and breastfeeding. We don’t test for ketosis, so I do not know how much she’s in that state — I’m guessing she cycles in and out of it. But I can say that low-carb high-fat has been a-ok. Mom and baby are both healthy and happy. Baby won’t sleep, but I doubt that’s a ketosis thing 🙂

    • @melancholy aeon

      “Why not talk to any of the several women we all know who in fact have done this?”

      “There are some quite prominent low-carb moms around and I suggest you talk to them. Best wishes.”

      Did I miss a low-carb parent meet n’ greet or something? I was recently put in contact with Dr. Wortman but I don’t know any others. Feel free to introduce me.

      Dave

    • My wife and I have been low-carb about 8 years. When she was pregnant with our first child she was told by everyone that she should eat whatever her body wanted. Her doctors told her pretty much the same thing. So she started eating lots of french fries and pastries. She ended up with gestational diabetes. As soon as she had to start checking her blood a few times a day, she quickly cut out her carbs and went back to her normal 30g a day. The nurses couldn’t understand where her gestational diabetes went!

      For her second pregnancy she stuck to low carbs and the diabetes never came back.

      Oh and both of our sons have above average intelligence, but I might be biased 😉

    • @ Dave,

      As one person to another, I have no special qualifications to say one way or the other, but why even take the chance? We know from all of recorded human history, for certainty, no question, that a diet in everything, carbs, proteins, fats, vitamins, minerals, everything naturally food to us in more than ample supply is beneficial to a developing child. We all know this, so why even take a chance that maybe you might be depriving your child of something necessary.

      Two main ideas I wish people, especially women in the privileged free-world would learn regarding weight. Pregnant women are supposed to get fat and/or fatter, and babies are supposed to be fat little adorable tubs of lard. Now most seem to realize that babies are supposed to be fat, but many many seem not to realize that pregnant mothers are also supposed to get fat and/or fatter. After the child is born, and nursing won’t be affected or ideally when nursing is no longer and issue, then it doesn’t matter so much unless we’re worrying about starvation the next winter, but we’ve progressed out of that lifestyle for quite some time now.

      Just as a matter of common sense, I would recommend that no pregnant woman worry about diet at all except to ensure that they get every and all nutrients possibly provided in our food. Whether that means gaining weight or not, the focus shouldn’t be weight or even later weight loss, but instead solely on getting all of the nutrients possible, all of the vitamins, minerals, fats, carbs, and proteins that are offered in our wide world of natural foods. I say natural for obvious reasons. Our babies don’t need diacytal or color red 6, but they certainly need cholesterol, all the various fats, sugars, both complex and simple carbs, all the vitamins and minerals, all the proteins. And just to be safe, I’d stay on that focus until after nursing. Then, I’d get back on the keto-diet and watch my diet.

      But that’s just me.

    • Dave, I have read Gary Taubes’ book “Why We Get Fat” and I seem to recall him speaking about how obese kids get that from the high -carb intake of their mother during pregnancy. I cannot cite the page but it’s definitely in there. Perhaps you could get it online and look up some key words like “pregnancy”. HTH.

      Peter, Thank you for this article. One question if I may. Is there anything or any way (as in devices or testing equipment) to monitor the performance of this way of nutrition?

    • I can say from personal experience that a low carb diet (not low calorie, mind you) definitely hurt my milk supply as far as pumping. I could never get ‘ahead’ in storing milk, but baby nursing and gaining weight was a non-issue. However, the benefits for me health-wise (major auto-immune joint pain and inflammation) out-weighed being able to stock pile milk like I was able to with other my other children. So I don’t have a freezer stash – no big deal. If someone is already having trouble keeping up milk-wise, it would definitely be something to consider and watch.

  7. DOC! Great article. i think I mentioned this to you but when i did the Discovery channel show and was on day 8 of starvation they tested my blood glucose and it waas 33. they were shocked and re-checked it three times.

  8. Peter, just an FYI, when I was studying biochem in med school, I found the process of glycolysis and the krebs cycle you present above much more intelligible when the roles of pyruvate/acetyl CoA and NAD+/NADH were emphasized (as in this diagram from wikipedia: http://en.wikipedia.org/wiki/File:Catabolism_schematic.svg ). You hinted at the importance of pyruvate/acetyl CoA above, and I would love to see you expand on this point, as I found that the importance of this molecule cannot be over-emphasized in understanding metabolism in general and ketosis in particular. However, maybe it’s beyond the scope of an article intended for the general public; I remember sweating over this stuff for weeks until it made sense. Not sure if that’s encouraging or discouraging?

  9. I’m so glad you’re doing this series. You’re probably focused on ketosis for healthy people, but this seems like a good place to share my experiences, as my partner has Parkinson’s and this launched us into an in-depth exploration of ketosis as one possible way to halt or reverse neurodegenerative diseases. Dr. Mary Newport’s n=1 experiment feeding coconut oil to her husband who has had Alzheimer’s for 11 years now was our springboard, and from there I dove into Bill Veech’s voluminous published research on ketones – did you know he actually worked in Dr. Hans Krebs’s lab with the man himself and published a report about it? Veech also worked on a project with the US Department of Defense to explore using synthetic ketone esters as food for the troops (those MREs get pretty heavy to hump around). Oddly enough, DoD was the only place he could get funding to study ketosis; NIH sponsored a small trial but had no further interest. The epileptic children’s diet from Johns Hopkins was another touchstone, and Dr. Dominic D’Agostino has done some work with ketosis for ALS patients. The upshot is that there’s so much evidence that BhB fixes broken brains that I’m wondering why the scientific world isn’t all over it. I think most physicians fear ketosis, and my partner’s psychiatrist actually told him at their last appointment that brains can only run on glucose…sigh. Diet-wise we’ve settled on a low-carb approach (about 50 grams a day) with a ketogenic adjunct such as coconut oil, MCT oil, or AAKG (Arginine alphaketoglutarate) to correct for eating a normal protein intake. Without the adjunct, he’s unable to maintain the necessary 2.0 mmo/l or higher ketone level constantly enough to have a therapeutic effect on the PD. We use a handwriting test since it’s easy to compare and hard to overcome with placebo effect. The results have been very encouraging. Sometimes we ask ourselves, “so why isn’t everyone else doing this? Are we fooling ourselves? Or are they?” Neurodegenerative disease isn’t very pleasant so it’s hard to believe someone would refuse to give up crackers to avoid it. Thanks for letting me share, and I hope this isn’t too off topic.

    • Lacie, you’re actually touching on one of the topics I plan to explore in Part II. I’ve spent a lot of time with Veech and Clarke and the DOD exploring the opportunity of ketone esters to take nutritional ketosis to the next level, both for prevention (e.g., TBI) or performance enhancement. Definitely look forward to exploring this topic with folks. You’re definitely hitting on an important point.

    • @Edward, 12-15 grams of AAKG powder per day allows a 225-lb. male to eat 100g of protein and 30-50g of carb a day and still get 2 mmo/l ketones on the meter. 1/2 cup per day of coconut oil or MCT oil will do the same thing but with major stomach upset that you don’t get with AAKG.

      I don’t take a ketogenic adjunct; I prefer to just drift in and out of ketosis and eat my usual low carb diet. But my partner doesn’t have a choice – every day he’s not in ketosis, he’s losing brain cells. I’ve read some cautions about taking AAKG more than 60 days at a time on bodybuilding sites, but I can’t find any PubMed articles that say so. Plenty of articles that say it doesn’t work for building muscle, but that’s not what he’s using it for. Interestingly, several articles say that AAKG ramps up insulin secretion – I don’t get how it can do that and still induce ketosis.

    • Lacie, I was so happy to run across your comment. I have been searching for detail about ketosis and neurodegenerative disease. There is quite a lot of exciting information about brain-based disease like ALS, Parkinson’s, Alzheimer’s, and of course epilepsy, but very little concerning peripheral neuropathy like I have (multifocal motor neuropathy, which is assumed to be autoiummune; it’s often misdiagnosed as ALS).

      I was already low-carb for a year before my diagnosis (thanks to Good Calories, Bad Calories; I was not overweight), and after that, having read more and more about the neuroprotective effects of ketone bodies, I went zero-carb and have been that way for two years. At my age of 58 it’s supposed to be hard to generate high levels of ketones, and my ketostix usually indicate Trace or Small, despite generous amounts of coconut oil and some MCT oil on a daily basis.

      So your comments about AAKG and “therapeutic” levels of ketones are very intriguing to me, and I would love to find out more.

  10. Hi Peter,

    so when ingesting glucose, at what ratio does it get stored as glycogen into muscle vs the liver? Which of the two takes priority? Seems when attempting keto-adaptation we would only prefer it concentrated in the liver so that the brain can do its thing..

  11. Hi Peter,
    Thanks for such an informative article! I wonder if you have any ideas about whether low-carb-triggered migraines may be related to this shift in primary substrate that the brain uses. The first couple of times I did Atkins, I got a migraine headache the 1st couple of days, before starting to feel okay, and then after a couple of weeks, starting to feel great (probably ketoadaptation). (I do get migraines occasionally under other circumstances too.) I found this seeming triggering of a migraine by shifting to low-carb interesting (as well as annoying!). I wonder if these headaches are similar to the ‘Yom Kippur’ headache, and I think some people also refer to a ‘first day of Ramadan’ headache? I know these headaches might be due to dehydration or electrolyte changes, but maybe sometimes instead to a shift into ketosis transiently affecting brain metabolism in an annoying way? Anyway, I’ve been doing some form of low-carb now for most of the last 22 months- sometimes in ketosis, other times not (at least by measuring blood ketones). Now I find that if I indulge in more carbs for a week or 2 and then go back to strict low-carb, I don’t seem to get these headaches as much. I do try now to ‘ramp down’ my carbs over a couple of days, rather than going cold turkey. Maybe that helps? Or maybe I’m now more metabolically flexible? If anything, I’m less careful about taking in broth etc the first couple days of low-carb, so I don’t think it is some change along those lines. I’m curious to hear your thoughts.

    • Very interesting, Laura. There definitely are enough possible things going on that it would be hard to know for sure which change or set of changes in the culprit. I’m not an expert in migraines (vs. other headache mechanisms, for example), so that’s the first place I’d look to see what generally causes that particular type of headache, then see if there is a possible mechanism of action linking the change in substrate? Seems very testable, though.

    • this is a well known fact.
      it means that your body lacks minerals.
      quick fix is to drink water with a couple tablespoons of salt.
      and make sure you get your daily calcium.

  12. Dr. Attia,
    Thanks for another great post. I’ve been in nutritional ketosis for about a year now, and have lost over 40 pounds. I think my diet (80/20 fat to protein) and supplements (sodium and magnesium) are dialed in, and I feel great.

    I still have about 15-20 pounds of excess fat I would like to lose. Getting down to my current weight was effortless, but I think I’ve reached an equilibrium. Is there anything I can do to move the metabolic needle? Has metformin been studied for this purpose? Thanks for your help.

  13. Hello Dr. Attia,

    Thanks for your excellent ongoing work.

    I love wine. I also love ketosis. Can the two co-exist?

    Since first learning about all this a few years back I’ve been trying to read up and understand how ketosis is affected by alcohol. Is there new info about this? I’ve read a lot of what seem to be educated guesses, such as that alcohol pauses ketosis without throwing you out of it, and that it can give you a false positive read, at least with the urine strips.

    I’m asking not about sweet mixers and beer which I know have their own issues beyond just the ethanol, but more about the ethanol itself I guess. If ethanol is neutral in its effect, I would think that straight hard liquor would be the low carb drink of choice rather than dry wine. Is the only reason that dry wine is recommended over say vodka and lime as the go to “if-you-must-drink-on-low-carb-have-this” drink that wine has a health halo (whether deserved or not) compared with hard liquor?

    I’ve read that alcohol is a carb and also that it is not a carb but is like carb. (?) Also I know of “The Drinking Man’s Diet” and that Dr. Atkins said you had to cut out booze to lose, at least in the early stages. So many contradictions! Are the mechanisms just not yet understood? It’s something I’m really curious about above and beyond trying to find a way to justify drinking some wine. : >

    • Yes, in moderation. It does dependent on how sweet the wine is and how much you consume. A reasonably dry red wine might only be about 3-5% sugar by weight, so a glass or two isn’t going to take you out of ketosis.

    • My basic understanding is that alcohol puts a damper on GNG in the liver, possibly due to the liver dealing with metabolizing the alcohol and alcohol metabolites. This is a good read: http://ajpendo.physiology.org/content/275/5/E897.full

      I think a lower HGO when you aren’t eating much glucose leads to feeling really awful…a hypothesis I can confirm personally. If I carb-load before large amounts of alcohol consumption, I feel okay. If not, I feel absolutely miserable.

      • I think this is only the case if you’re not in “firm” ketosis. All the suppression of HGO in the world is not an issue if your brain has sufficient access to B-OHB. This gets to one of the questions someone posed about flirting with ketosis. This is one of potential drawbacks experienced by some (though not all).

    • In my experience I can have two or three glasses of wine (dependent on daily activity) without going out of ketosis. I normally drink dry red wine.

  14. Outstanding post once again Peter! I’ll be sure to promote this series to our dietitians at Life Time like I did for your Straight Dope on Cholesterol series. Thanks for taking the time to write these in ways that make them easy not just to understand but to use to explain to others.

  15. Peter,
    The laymen parts of this article are exactly what I had hoped to hear. I’ve been keto since May and have learned how to “depend solely on my liver to release glycogen” based on reviewed daily blood tests. I’ve seen a gradually steady glucose level as time endures. Foods I eat don’t spike my glucose nearly as much. Less than 5 carbs + 180 protien + fat. I’m still learning slowly the types of fat available. The list goes on of all the benefits keto has done for my life. Ok, enough venerating. I just wish I could find a good doctor who I don’t have to wrestle with on this topic.

    Geo.

  16. In the final, pre-references section (“Future Uses of ?OHB”) of the Cahill, Veech paper (“Ketoacids? Good Medicine?”), they address some problems that they have with the ketogenic diet. It’s only been a few months, but I don’t share their view that this diet is difficult to maintain. I’m not concerned about the serum cholesterol issue, but please speak to the the purported association with kidney stones.

    • Josh, I can speak to the difficulty of maintaining a truly ketogenic diet, as my Parkinson’s partner and I are veteran low carbers but had a hard time of it. The problem is to be therapeutic for illness, you have to stay above 2.0 mmo/l at all times. If you eat even a speck of protein or carb, you go out of ketosis and are right back where you started. The epileptic children’s diet is more or less devoid of protein, and although we like fat as much as any good caveman, life without protein is malnutrition, not to mention boring. Athletes and other healthy people can drift in and out of ketosis, which allows them to eat a steak once in a while.

    • @ Lacie

      “Josh, I can speak to the difficulty of maintaining a truly ketogenic diet, as my Parkinson’s partner and I are veteran low carbers but had a hard time of it. The problem is to be therapeutic for illness, you have to stay above 2.0 mmo/l at all times. If you eat even a speck of protein or carb, you go out of ketosis and are right back where you started.”

      Not so. I eat between 50-60g of protein a day (an egg every morning and then 2 2oz servings of fish or meat for lunch and dinner plus some chicken broth and cream) and reliably stay at 2.1 or above with ease. If you struggle with ketosis eating “even a speck” of protein or carb, you’re not eating enough fat. 🙂

    • @Melancholy, I think the ability get into dietary ketosis varies a lot between individuals, and there’s a lot we don’t know about it due to lack of studies. Particularly, I wonder how metabolic flexibility, age, and cellular damage from years of following conventional wisdom figure into the equation.

      At over 100 grams of fat per day for me and twice that for my partner, we’re not sparing the butter, but the ketone meter doesn’t lie.

    • @Josh, MCT oil works great but it’s really hard on the stomach. Coconut oil only slightly less so. AAKG has been fantastic, no side effects other than a slightly stinky odor, dissolves easily in water, partner’s ketones consistently above 2 mmo/l with up to 50g carb per day and 100g protein. Easy peasy. I heard about it from Dr. Dominic D’Agostino, Ph.D. researcher at University of South Florida; nobody else seems to know it’s such a potent ketogenic. I do wish there were more studies on it; lots of broscience but not much else.

  17. Hi Peter,

    Another good post that ties a lot of things together. Thanks for the technical deltail and the relevance.

    I have noticed a few posts now and again about alcohol. I have noticed especially posts on wine, and your replies. I hope I can add to the discussion:

    While I was using a blood tester to check my BOHB levels, I found that after a few days I could maintain about 3.0, which is well into ketosis. (I’ve always been able to go into ketosis easily.) At that level I would easily lose weight daily. However, if I had more than a glass or two of red wine per day, my BOHB would stay about the same, but the weight loss would stop. This was a reliable connection, which I tested several times (all in the cause of science, of course… 🙂 )

    Clearly, since my BOHB level was NOT affected, but my rate of weight loss was, I was not being knocked out of ketosis by the wine, but I was certainly being knocked out of weight loss. I would say that the small amount of sugar in the wine was not the culprit, since I was still measurably well into ketosis. If the problem were the residual sugar in wine, it would have taken me out of ketosis.

    So, provisionally, I am advancing the hypothesis that the moderate ethanol level in dry red wine has the effect, in ketosis, of stopping net body fat loss even though it does not stop ketosis. This is odd, because being in ketosis means you’re using fat from somewhere. That opens up a world of speculation:

    – This may only be me. That’s the problem with any n=1 experiment: I may just be weird.
    – We know that ethanol gets converted in the liver to triglycerides (which are fats) that get sent out to the rest of the body. Does that offset the fat-burning effect of ketosis on other fat stores? I think that would take a lot of triglycerides, perhaps more than accountable for from the ethanol (I’m not drinking THAT much wine), but maybe not.
    – Many papers have reported that ethanol increases insulin resistance, including in the liver; liver insulin resistance would affect (increase) liver release of glucose (HGO). Does increased liver release of glucose play a part here, even though the body is, overall, still in ketosis? That’s an odd balancing act, since more glucose output should lower ketosis, but, maybe….
    – There may another liver-related phenomenon at work, since ketones are produced in the liver in the first place. Why fat stores are not being used in that case is still not clear.
    – Of course, there’s the usual option that we may have something here that is observed, but is not yet understood.

    I certainly don’t know. I just know that if I drink very much wine while in ketosis (more than 2 glasses of very dry red), it will flat stop my weight loss; if I don’t then the weight loss is pretty reliable. And I also know, from direct BOHB testing, that the red wine intake is not stopping my ketosis (BOHB level). So I, at least, can still be solidly ketotic but not lose weight if I am using more than a fairly small amount of [red] wine (which is all that I have tested for); but if I am not using the wine, and if I am ketotic, the weight will come off.

    (Note: wine has a surprising amount of calories; a bottle of wine — which is quite a lot of wine, of course — has about 500 calories (kcal’s). So it could creep up on you.)

    This is just meant to be an additon to the general converstation… I don’t think that any of this definitively settles any question. A NuSI-style trial, with the proper controls and protocols, is necessary to get a real handle on this, and many other, questions. But I hope it helps someone besides me to address the issue, and maybe adjust their intakes with this in mind.

    Thanks for your time,
    Bob.

    • Bob,

      Thanks for your insight about drinking wine while in ketosis. I too seek scientific truth through running an adequate number of clinical trials on myself. 🙂 I have been in nutritional ketosis for the past couple of months. My B-OHB levels are not as high as yours (avg. around 1.5) but I have consistently lost weight during this time. I do drink 2 glasses of white wine most every night. I know there is some commentary to be inserted here, but I digress. My understanding regarding alcohol is that the liver will stop any fat burning until the alcohol (aldehydes) are metabolized. Hence the increased levels of acetones on urine ketone strips after ingestion. But this should only be a relatively short period (depending on the amount of alcohol consumed) I would think. Would I probably lose more weight and have higher blood ketone levels if I did not consume alcohol on a consistent basis? My sense is most likely. My question to you is how long a period of time did you consume alcohol before you noticed a halt in weigh loss? And secondly, how long did it take for the weight loss to resume after eliminating the alcohol? You must keep very accurate tallies of your weight every day. I do not weigh myself often as there can be many variables involved. It would drive me crazy to worry about a pound here and there. But that is just me. I can just tell by the way I look and feel and how my clothes fit. Maybe I should do a more scientific approach to really see if my weight loss will increase sans alcohol. Right now, for me, it’s about carb restriction (obviously) and the type of exercise I am doing. Let me know if you have anymore insight. Thanks, Michael

    • Michael,

      While losing weight I would weigh and record myself every morning, and check BOHB a couple of times during the day. Naturally, I didn’t necessarily lose weight every day, but the trend was evident.

      On a day when I had, let’s say, more than about 2 glasses of wine at night, the next morning my weight usually would not have changed, or sometimes would have ticked up a bit. If I kept that up for several days running, the downward trend in weight would be stopped until I backed off on the wine. Then weight loss would resume almost at once. It was just that simple. I seem to be OK with 1 or 2; above that and I’m above my threshold. Experimenting with just skipping wine entirely worked better in weight-loss terms, but has a downside…

      Your mileage may vary.

      I have no real idea why this works this way, but it seems to, for me.

      Bob.

    • One hypothesis would be that we have evolved a hepatic cell priority system for getting rid of toxins like ethanol. If the liver’s metabolic capacity is 100% dedicated to clearing ethanol from the blood, this would probably prevent it from performing ketotic production. Once the industrial spill is taken care of, it happily resumes ketotic duty. I get a feeling this is just a question of resource allocation priority.

    • Great stuff here, thanks Peter.

      Bob,

      I wonder what you would find if you were monitoring body fat and “water” percentage throughout your wine trials. I wonder if the weight pause is just water weight.

      When I do my own n=1 wine studies, I always feel bloated in a few days, like my liver is swollen, and I’ll gain 5 pounds. Stop studying, and I will lose the weight in a few days.

      Its nice to think that we could enjoy our wine, stay in ketosis, and just gain temporary water weight.

      Further “study” is required 🙂

    • Bob thanks for interesting post, In my N=1 experience When I have wine and being in optimal ketosis before, and I have maximal like 100-200ml of very dry wine, but of course I usually eat also more protein because I am at restaurant when I drink wine, what I am seeing is that my weight goes up immediately even a 1-2 kg of water weight, but not fat. I am using normal tanita personal weight 4 points, What weight are you using? I think dexa scan would be needed to make some relevant conclusion …. the water goes of the day after … or two days after 🙂

      what I am seeing is that after I started ketogenic diet I have ZERO tolerance for alcohol, even a one sip of wine ( I don’t know 20 ml ) I am suffering from headaches all the other day, and at night after the dinner I am hot or cold, I have sore throat I have to drink a lot of water because I am very thirsty, my sleep is not continuos, and also I feel like my nose is clogged, the next day I am swollen and I see water weight goes up, and doesn’t matter how much I have the symptoms occur every time, but If I have more its worse so I don’t drink at all any more. Before ketogenic state ( for me eating 2x a day, 50-60 proteins, 20-30 carbs ( fiber included) 60kg, 26 years, 160 cm ) I was more liberal low carb like 50g of carbs and more protein like 100-120 g wine wasn’t such a problem for me …

      petr do you have some suggestions where is the connection? I am nutritionist in czech another 2 clients on strict low carb are experiencing the same … ( and we drink enough of water and salt 🙂

    • It probably plays a very small role outside of starvation (unless you’re a bear or a whale). During nutritional ketosis, most glycogen formation probably comes from the limited glucose ingestion and gluconeogensis of amino acids.

  18. Very interesting article, doc!
    I can’t wait to show this to my collegue who was telling me how dangerous my diet was because sometimes went in to the “nutritional ketosis state” and then out (I love fruit too much).
    I tried to explain the difference between ketosis and DKA, but he wouldn’t believe me, because his doctor said it differently.

    Later in the discussion we touched a different subject. That fat cells, once created, never disappear. They just change in size (volume of TG). I’ve tried to google around and I’ve found some, not very reliable sources, which say you can only reduce the size of your fat cells, not the total number. This was the reason why obese people who lost great amounts of body fat easier falls back to obesity compared to naturally thin people.

    Are you planning an article or paragraph in an article devoted to this subject?

    Looking forward to part II

    • Not in the immediate future, as this issue of fat cells is a bit tangential to this topic (which I’m struggling like crazy to explore in less than 10,000 words). Hope this post can help you have an honest discussion with your friend.

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