Ketoadaptation and physiological insulin resistance

This is where the magic happens.

Rat pups, fed a flaxseed oil-based ketogenic diet from weaning onward – note the drop-off in ketones after 2 weeks (Likhodii et al., 2002):

flaxseed ketogenic diet

What happened on day 17?

Patient history: these rats have been “low carb” their whole lives.

Side note: flaxseed oil is very ketogenic! (Likhodii et al., 2000):

ketogenic rodent diets

Flaxseed oil-based ketogenic diet produced higher ketones than 48h fasting; the same can’t be said for butter or lard.  PUFAs in general are more ketogenic than saturated fats in humans, too (eg, Fuehrlein et al., 2004):Saturated polyunsaturated ketones

Crisco keto (adult rats) (Rho et al., 1999):

shortening-based ketogenic diet

suspect those two rogue peaks were experiment days…

 

At this point, please just note the stunning consistency in the drop-off of ketones.

Experiment 1 & 2 (above) are adult rats; they went through a period of high carb chow dieting, unlike experiment 3 and the rats in the first study, who were weaned onto ketogenic diets.  Still same phenomenon: ~few weeks after initiation of ketogenic diet = breakpoint; ketones decline.

Ketoadaptation: why do ketone levels decline?  This happened in both rat studies above, Phinney 1983, and in many “n=1” practitioners.

Possible explanation 1 (ketoadaptation): rat milk is kind of like a low carb diet; high in fat, but not low enough in other stuff to be ketogenic.

Milk fat

-Hooded seal milk is practically heavy cream: imagine the amount of suction pups must need to apply.  Poor mom, that’s gotta hurt; fortunately, lactation only lasts 4 days

-Rat milk is super-high protein.  

milk protein

Therefore, weaning to the flaxseed oil-based keto diet is what really initiates ketoadaptation… which seems to take 2-3 weeks (judging by the decline in ketones [this is explained further below]).

Possible explanation 2 (physiological insulin resistance): free fatty acids released faster then they’re burned, accumulate in skeletal muscle, induce mild physiological insulin resistance.  This is evidenced by glucose levels trending upward at this time, and the modest increase in insulin still works in adipocytes just fine.

These aren’t mutually exclusive:

Phase 1: first few days of ketosis, rapid increase in ketones & fatty acids, and drop in glucose; may share some features in common with starvation.

Carbohydrate restriction is not starvation.  Just google “urea cycle” if you don’t understand the differences; it’s regulated completely differently in both contexts…

Phase 2: 2-3 weeks in these studies, may take longer in humans (ie, 3-4 weeks).  Mitochondria are proliferating.  Ketones high.

Phase 3: ketoadapted + physiological insulin resistance; circadian ketosis: ketones decline, reach steady state at a lower level.  .  In early starvation, skeletal muscle runs on ketones as they become increasingly available, but then switches to fatty acids, which is how ketones are able to reach > 6 mM in this context.

 

Theory: during nutritional ketosis, muscle doesn’t make this switch, and the decline in ketones occurs because that’s how long it takes for muscle mitochondria to catch up.  KETOADAPTATION!  Ketones in starvation usually reach > 3x higher than those in nutritional ketosis (part of this is because non-fat fuels are more abundant when you’re eating [eg, dietary protein] than when you’re not [eg, muscle protein]).

Starvation:

Starvation Cahill

Muscle ketone use would also be in agreement with increased power output and capacity for high intensity physical performance once ketoadapted.  Ie, ketonez are the super-fuel (cite any paper by Richard Veech).

Phinney 1983:

Phinney 1983 beta-hydroxybutyrate

From weeks 3 to 4, ketones drop from 2.82 mM to 1.58 mM… ketoadaptation or physiological insulin resistance alone might explain why they don’t continue to rise, but not necessarily why they decline; that part of the equation may require both.

Recap (part speculation): during starvation, muscle starts on ketones but then switches to fatty acids, in part, to prevent wasting and spare ketones for the brain.  This is how ketones get so high, and it doesn’t happen when you’re eating [keto].  While on a ketogenic diet, muscle uses ketones and does so increasingly so after ketoadaptation, when mitochondrial capacity is up to snuff <– that’s the speculative bit; but it could explain: 1) why ketones routinely decline in humans & rodents after ‘ketoadaptation;’ and 2) how physical performance is restored (ie, Veech).

 

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  • Dan Ordoins

    Great write up again.
    ‘Recap (part speculation): during starvation, muscle starts on ketones but then switches to fatty acids, in part, to prevent wasting
    and spare ketones for the brain. This is how ketones get so high, and
    it doesn’t happen when you’re eating [keto]. While on a ketogenic diet,
    muscle uses ketones and does so increasingly so after
    ketoadaptation, when mitochondrial capacity is up to snuff <– that’s
    the speculative bit; but it could explain: 1) why ketones routinely
    decline in humans & rodents after ‘ketoadaptation;’ and 2) how
    physical performance is restored (ie, Veech).'

    I noticed for myself when I first started keto diet and adaption my sweat, breath and even urine would smell of amonia… Now after more that 3 years of full time ketosis and adaption I no longer have that smell…. Perhaps apart of the adaption or better use of ketones….? I have upped my seafood more along the way as well which may play a part.
    interesting stuff….

  • “So adding shots of coconut oil and flax oil should speed up keto adaptation? Or just ketogenesis to help with performance in the adaption period?” -Justin Wisor, on Facebook

    Flaxseed (or preferably fatty seafood) *might* speed up ketoadaptation by increasing PPARa activation. Coconut oil is a good ketogenic substrate (might help performance?) but doesn’t activate that pathway…

  • Thomas Hemming Larsen

    Do you know if the breath acetone/blood beta-hydroxybutyrate data from the rats can be transferred to humans? If so, do you have the full data set? Yes, I want to know how my Ketonix correlates to blood beta-hydroxybutyrate.

    • I have a blog on this coming soon. In the meantime, here’s the full data set: http://www.clinchem.org/content/48/1/115.full.pdf+html

      • Thomas Hemming Larsen

        Thanks Bill. They have fitted a function mapping breath acetone to beta-hydroxybutyrate, but they have accounted for body weight. The formula doesn’t make any sense for humans.

        Speaking of that blog post Can I ask you a favor and see if you can get the full data set for this study http://www.hindawi.com/journals/bmri/2014/869186/ I’ve tried contacting the researchers with no luck.

        Btw, how come you always seem to have a blog post coming up on whatever I ask 🙂

        • CynicalEng

          The body weight thing is odd, as the acetone is a concentration. g/h/kg BW would make sense, but not g/litre/kg BW. I think it’s an artefact of measurement to account for the volume of rat in the chamber, but don’t really get it – perhaps the concn in the chamber is effectively a grams emitted over a fixed time. I would multiply out by the average BW to get back to concn and see how that looked.

          • Thomas Hemming Larsen

            Yes. The rats were in a collection vessel where they measured the concentration of acetone so they had to take body weight into account.

  • “The real question is what speeds mitochondrial biogenesis besides KD dieting… HIIT?” -Justin Wisor, Facebook

    An acute bout of high-intensity interval training increases the nuclear abundance of PGC-1? and activates mitochondrial biogenesis in human skeletal muscle http://www.ncbi.nlm.nih.gov/pubmed/21451146

  • Bill, I can just imagine all the bros’ eyes lighting up as they see your rat milk table.

    Probably slightly easier to milk a rat than a cat, but I may be over-thinking things. As usual.

    Have a good one.

    • hardcore keto-dieters will be looking for Hooded Seal Milk. It’ll be the next big thing.

  • Dustin Sikstrom

    Bill I’ve been ketogenic for a year and a few months. I never got to test with a blood meter early on but I used a breathalyzer. If you’re interested in some of my results I posted them here: http://www.reddit.com/r/keto/comments/1ox7z5/dae_use_a_breathalyzer_with_their_keto_i_have/ As I said, I was able to reach .10% BAC without a single drink. That was pure acetone release. I have since been able to correlate a few blood ketone readings to breathalyzer results, and one reading I got was .05% BAC correlated to about 1.1 mmol/l blood ketones. That was after exercise. Most of my readings were eventually .01-.02 % and that gave me about .1-.3 mmol/l, so my n=1 input shows for every .01% you get about .2 mmol increase.

    Also, FWIW I made a write up that gets thrown around /r/keto any time someone says “OH GOD I WAS IN KETO AND NOW AFTER 2 MONTHS I’M NOT ANYMORE. DO I NEED TO EAT MORE FAT?!” http://www.reddit.com/r/keto/comments/1w8cbs/science_dont_fall_victim_to_ketone_envy_ever/

    Regarding this post, agreed entirely. I noticed the same thing in myself and have a hard time reading any ketones anymore unless I actually do start fasting or doing long bouts of aerobic exercise (see jogging for 1+ hour, which to me is long lol, not hard but long). Even then, they don’t really go that high, which makes me agree with your theory of mitochondrial adaptation.

    Perhaps this means that even though a NK diet has fewer blood ketones, it induces far more health benefits than a starvation KD does? Well, obviously starvation isn’t preferred, I just mean if the mitochondrial adaptation actually does occur in NK, then that would mean there is a clear distinction in the impact it has on the body and therefore many of the things that are argued about starvation *must* either be thrown out or retested in the context of a calorie balanced NK diet (adequate energy).

    I’m not entirely sure if your data on flaxseed is suggesting to consume flaxseed to increase ketones or what, but that seems counter-intuitive to your point that ketones drop post-adaptation. Care to elaborate a bit more? Do you think DHA would provide a better adaptation? I’ve currently been trying to consider iodine and DHA as “essential supplements” for keto adaptation. On /r/keto we talk about using sodium, magnesium, and potassium, as recommended by Lyle McDonald. This made a difference for me when adapting for sure, but I think there is more to it. I’m not sure how it would work entirely, but it seems in terms of context of “paleo theory”, fewer plants means a colder season, which also means fewer land animals in some regard, but marine life is abundant. Plus considering Cunanne’s theory, it really seems like iodine + DHA make brains happy, especially a ketogenic brain. Thoughts?

    • This Old Housewife

      I have a thought about r/keto: if they’d quit wrapping every freakin’ thing in bacon, they’d probably find no need to hang out at that pizza-fest. Also, cutting corners by using artificial flavoring, colorings, and off-the-shelf products (whatever it takes to get to that magic 5 grams net carb/serving) is probably doing more harm than good.

      Trying to”keto-fy” once-loved junk food recipes isn’t helping either.

    • Hi Dustin, thanks for the info & links! Most of the literature on this confirms your Reddit article: strong correlation between blood beta-hydroxybutyrate, breath acetone, and seizure protection. Latter part suggests “important” or “meaningful” ketosis… not just spillover.

      As to the flaxseed thing – it’s just a quirk of metabolism; saturated fats are slightly more IR-inducing, but not pathological in this context. I think ketones are gonna decline no matter what, after ketoadaptation… they might just settle at a slightly higher level if you’re on a PUFA-rich diet.

      I would actually wager a guess that marine PUFAs (eg, DHA) might actually facilitate/expedite ketoadaptation, due to PPAR alpha activation, enhanced mitochondrial biogenesis.

  • Neeraj Engineer

    Bill, I’m sure you read this but in “art and science of low carb perf”, it is mentioned that after keto adaptation, skeletal muscles switch to primarily burning FFAs and adapt away from using ketones possibly to spare them for brain and heart.
    Could this explain the drop in blood ketone readings after adaptation? Is it possible that some signalling mechanism down regulates ketone mechanism based on lower demand?

    • Lol Neeraj! Did you read any of this blog post? 😉

      • Neeraj Engineer

        Ok, maybe this is beyond my pay grade; I’m looking at this paragraph specifically …
        “While on a ketogenic diet, muscle uses ketones and does so increasingly so after ketoadaptation, when mitochondrial capacity is up to snuff <– that’s the speculative bit; but it could explain: 1) why ketones routinely decline in humans & rodents after ‘ketoadaptation;’ and 2) how physical performance is restored "
        so when in NK, muscles continue to use ketones after ketoadaptation?
        Trying to understand this. Help!

        • Ketones rise in starvation because muscles switch to fatty acids. Volek & Phinney assume the same thing happens in nutritional ketosis. I don’t. Otherwise, 1) ketones wouldn’t decline and 2) performance wouldn’t recover, after ketoadaptation.

  • rs711

    Good on you for making the much needed point that starvation ? ketosis. However, ketosis is the evolutionarily adaptive shift our species experience during starvation.

    Apologies for oversimplifying some of this, but ==> during keto-adaptation new mitochondria are built, dysfunctional ones recycled, resulting in an increased mitochondrial density in tissues. Like many processes, this building process reaches an equilibrium of sorts – or at least slows down considerably – at some point (a la “day 17”?). Why? Putatively because tissue is now in more of a mitochondrial maintenance phase than in a rapid building one. It is logical to expect a drop in circulating substrates levels geared towards B-oxidation, i.e. to readjust accordingly. Why? Economy. Economy ‘makes sense’ in a scenario of: caloric sufficiency + more machinery with better efficiency (http://goo.gl/QZxOcL). This scenarios is quite distinct from starvation, where the body scrambles to readjust its basic energy producing machinery without sensing incoming calories & structural components. During starvation, economy in terms of circulating substrate levels is not desirable as the higher priority is the maintenance of basic life functions (starting with the brain & so on down – organ wise).

    From what I can tell, physiological insulin resistance in a calorically-sufficient keto-diet or starvation is very welcome! It tells the story of how your body is partitioning fuel according to specific tissue demands. Unsurprisingly, when the body fails to adapt to its environmental cues with inappropriate insulin signalling, tissues suffer from energy fluctuations. This can be seen with basic microscopes in diseases like MERRF (myoclonic epilepsy with ragged-red fibres): tissue with defective mitochondria unable to properly oxidatively phosphorylate stain red.

    To better understand the why’s & how’s behind your speculation, “mitochondrial capacity is up to snuff”, I think a stronger grasp on the bodies ability to sense calories would be helpful.

    • “I think a stronger grasp on the bodies ability to sense calories would be helpful.”

      There are many systems in play which sense, not necessarily “calories” per se, but nutrients… for example, as mentioned in this post, urea cycle enzymes respond to dietary protein. Also, carbs/insulin. And fats/PPARs. Plenty of sensing 😉

      • rs711

        You’re right – biologists speak of calories whilst our bodies simply take stock of how much of X, Y or Z there is via epigenetic feedback. Or at least, that’s the story I’ve come to understand.

        Theoretically, even if we knew the levels of all the enzymes that interested us in a person, moment to moment, we’d still be left with the question “How does the body integrate these signals into a decision regarding [insert favorite process here]?”. This is further complicated by the fact that we have…..2 genomes (aka bidirectional genomic flow) which is directly relevant to ketoadaptation dynamics.

        At the moment, your speculation is the most astute. I’m simply uncertain whether or not an ‘enzyme count’ is in & of itself a sufficient metric/signal for our bodies to prompt significant short-term changes in gene expression. Might the brain have a larger say in what it does with this signal & become the proximate arbiter?
        [More likely, I’ve dove off the deep-end :p…]

        • unknown-unknowns >> known-unknowns!!

          changes in enzyme level/activity are a crude indicator; certainly not the whole picture. Brain definitely has a say!

  • Thomas Hemming Larsen

    The table with protein content of breast milk is very interesting. It really supports your case of getting adequate protein for growing muscle mass 🙂

    • interestingly, hooded seal pups also double in weight in just a few days, although it’s nearly all blubber!

  • newbie

    Probably get myself into hot water commenting on this item – “Muscle ketone use would also be in agreement with increased power output and capacity for high intensity physical performance once ketoadapted. Ie, ketonez are the super-fuel”

    My understanding of ketones is that they are are put through Kreb’s to make ATP. So, HIT is a glycolytic activity, anaerobic.
    Ketones aren’t getting involved. Link to Peter Attia’s post – http://eatingacademy.com/nutrition/ketosis-advantaged-or-misunderstood-state-part-ii
    To cut to the chase, the answers to these questions are probably as follows:
    Does ketosis enhance aerobic capacity? Likely
    Does ketosis enhance anaerobic power? No
    Does ketosis enhance muscular strength? Unlikely
    Does ketosis enhance muscular endurance? Likely

    Your thoughts?

    • Yes, “ketones are put through Krebs to make ATP.” In general, much of what you said is correct [in the context of non-ketoadapted biology]. But the increased mitochondrial number & function that occurs in ketoadaptation change the landscape.

      Here are more studies showing this is true: http://caloriesproper.com/more-on-physical-performance-and-ketoadaptation/

      Here’s a more thorough explanation of “ketoadaptation:” http://caloriesproper.com/ketoadaptation/

      • Check out Richard Veech’s work on ketones. He showed very clearly how this happens.

      • newbie

        Will read on Veech, thanks.

        Been following your blog for a while, did read those posts previously. Have a question, just asking for your thoughts. This is in reference to your”ketoadaptation” post – Take a group of mice and jack up their plasma free fatty acid levels to those seen in Phinney’s ketogenic dieters for a short while and you get a similar effect. Increased mitochondrial everything. You’ve written on IF before – would you think that if someone practices IF 16/8 (Leangains style) and likely has lots of FFA in the morning, but then eats a mod CHO nonketogenic diet, would they still have the mitochondrial biogenesis advantage?

        • The mitochondrial overhaul seems specific to ketoadaptation in this context… if you’re moderate carb and glycogen replete, you don’t really need it; also, having full access to both pathways doesn’t seem like a good idea… increased oxidative stress?

          That said, there’s probably a balance between duration of fast & level of carbs, which determine the extent of autophagy. As Jack mentioned above, more autophagy may lead to more mitochondrial adaptations.

  • Raymund Edwards

    Bill – “The real question is what speeds mitochondrial biogenesis besides KD dieting ”

    BCAA ? ( in the context of adequate protein intake ) ?
    Donald Layman’s papers make this connection between protein intake and mitochondrial biogenesis also.

    • Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice.

    These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals.

    http://www.ncbi.nlm.nih.gov/pubmed/20889128

    Also commentary here

    http://www.lef.org/magazine/mag2011/may2011_Can-a-Power-Booster-Also-Be-a-Longevity_Booster_01.htm

    • BCAAs – sure (can’t hurt?), but there’s much more human data supporting HIIT for mitochondrial biogenesis.

      • also, as per Dr. Kruse’s comment above (http://disq.us/8k5lbb), intermittent fasting may work as well due to increased autophagy.

        • Jack Kruse

          nothing is better than IF for improving autophagy besides sleep

  • Thomas Hemming Larsen

    FWIW. I’ve noticed that my ketones are higher when I eat more fat. I also feel better this way. If I just eat enough protein and cut fat and carbs my ketones will be low and I’ll feel like crap. What I’m thinking is that I need some fat to produce ketones (since I don’t have much body fat). Besides that I might have settled on a specific ketone level it seems like the level cycles in response to my diet (and workout).

    • Hahaha you’re the skinniest “keto-guy” I know… and the most ketogenic, given the degree of ketosis you achieve even during carb back-loads 🙂

      • Thomas Hemming Larsen

        Haha, I’m not sure of the correlation between ketones and body weight – although I have a theory that its negative and that that might be part of the reason why some people are lean.
        It has really surprised me too how many carbs I can eat and still get those ketone readings. That’s why I’m trying to find more data on breath acetone and blood ketone levels.

    • Dan Ordoins

      I feel the same…. When I have enough fat I feel great running of ketones…. When I try and cut the fat and up the protein like in a protein refeed I feel like crap and often crave more food. The extra protein and less fat tends to make me crave fat. I definitely don’t crave carbs when I get this way…. perhaps due to my long term adherence and adaption to ketosis.. When I get these cravings from eating lots of lean protein keep the macadamia nuts, coconut butter and bacon away from me…… I can do some serious damage with these LOL
      I am pretty lean myself aournd 6% BF or so…..

      • I don’t know about the % or incidence or anything, but there’s definitely a sub-population of people who experience high protein-induced hunger (it’s *almost* “Taubsian,” in a way).
        It’s the minority, I think, because most people experience high levels of satiety on high protein diets.

        • Thomas Hemming Larsen

          I know what you mean but I think that goes for a different population than Dan and I. I would be close to calling our experiences rabbit starvation.

      • Thomas Hemming Larsen

        Its not as such eating more protein, its more when I don’t get enough fat. In some way I think its like when carb people get hungry (I don’t give a shit about if Peter Attia says that even the leanest person has God knows how many calories of fat, I still get hungry being in ketosis).
        I don’t crave carbs either and its not hunger in the hangry sense. I’m exactly like you, I just want fat! Its interesting how I don’t care at all about pastry etc. now. I guess its just because people running on carbs want carbs and people running on fat want fat.

        Thanks for sharing Dan. I’m happy to hear I’m not the only one needing to be mindful of eating enough to feel good.

        • Gašper Grom

          Same for me. To much protein I am hungry. To little fat I am not as I could be as on lot of fat.

  • This Old Housewife

    You might want to scan this page for viruses–every time I come here, my antivirus picks up a new virus, quarantines it, then kills it off. Each day is a new virus, so someone has it out for your readers. I’m guessing a pro-carb person.

  • This Old Housewife

    Monday morning @ 10:08 EST–another virus. Earlier, I checked in around 6, and nothing.

  • Long-Term Effects of a Very Low-Carbohydrate Weight Loss Diet on Exercise Capacity and Tolerance in Overweight and Obese Adults

    http://bit.ly/ZJnGfQ

    Aim: Compare the long-term effects of an energy-restricted very low-carbohydrate, high-fat (LC) diet with an isocaloric high-carbohydrate, low-fat (HC) diet on exercise tolerance and capacity in overweight and obese adults.

    Methods: Seventy-six adults (25 males; age 49.2 ± 1.1 years; BMI 33.6 ± 0.5 kg/m2) were randomized to either a hypocaloric (6–7 MJ/day) LC diet (35% protein, 4% carbohydrate, 61% fat) or isocaloric HC diet (24% protein, 46% carbohydrate, 30% fat) for 52 weeks. Pre- and postintervention, participants’ body weight and composition, handgrip, and isometric knee extensor strength were assessed and participants performed an incremental exercise test to exhaustion.

    Results: Forty-three participants completed the study (LC = 23; HC = 20). Overall, peak relative oxygen uptake increased (+11.3%) and reductions occurred in body weight (?14.6%), body fat percentage (?6.9% [absolute]), isometric knee extensor strength (?12.4%), handgrip strength (?4.5%), and absolute peak oxygen uptake (?5.2%; p ? 0.02 time for all) with no diet effect (p ? 0.18). During submaximal exercise, rating of perceived exertion did not change in either group (p = 0.16 time, p = 0.59 Time × Group). Compared to the HC diet, the LC diet had greater reductions in respiratory exchange ratio (LC ?0.04 ± 0.01, HC ?0.00 ± 0.01; p = 0.03), and increased fat oxidation (LC 15.0 ± 5.3% [of energy expenditure], HC 0.5 ± 3.9%; p = 0.04).

    Conclusion: In overweight and obese patients, an LC diet promoted greater fat utilization during submaximal exercise. Both an LC diet and an HC diet had similar effects on aerobic capacity and muscle strength, suggesting that long-term consumption of an LC weight loss diet does not adversely affect physical function or the ability to perform exercise.

  • Victoria

    It has been shown that triglycerides interfere with leptin crossing the blood brain barrier. They or another molecule may have a similar effect on beta-HBA. Triglycerides increaes with starvation, but decrease on a low carb diet. A molecule with this kind of behavior could explain the drop in ketones–because without the molecule inhibiting ketones from crossing the blood brain barrier, the brain can get all it needs at lower concentrations.

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