40 years ago a group of researchers turned ketosis into poetry.

But first, a brief primer.  In red.

“The glucose muscle-sparing effect of fat-derived fuels” 

or, the Randle Cycle 2.0.  it’s like a course in life enhancement.

Part I.  Intermediary metabolism

The glucose-fatty acid cycle
The Randle Cycle, as originally proposed, states that fatty acid oxidation inhibits glucose oxidation.  This is good because during starvation, every tissue than can survive on fatty acids instead of glucose should do so, sparing as much precious glucose as possible for the brain.

The glucose-sparing effect of fat-derived fuels
A critical vital horcrux to this is in the oh-so-humbly-disguised phrase “fat-derived fuels.”  The fat-derived fuels are ketones, and they are rescuing the brain from starvation (ie, neuroglycopenia); they do so by supplementing glucose as a fuel source.  Ketones are good at this; many tissues are happy to oxidize ketones when they are available.

The glucose muscle-sparing effect of fat-derived fuels
Ketones are derived from fat.  During prolonged starvation, glucose comes from skeletal muscle amino acids (eg, alanine).  Ketones spare glucose.  Thus, ketones spare muscle.  QED.

Part II. The brain
Even the brain loves ketones!  Who it loves more is unknown (glucose or ketones), but what is known is that when blood ketones get high enough, the brain will happily utilize them for fuel.  Happily.  Whether or not it was known by Randle at the time, the glucose-fatty acid cycle could work just as well as the muscle-n-ketone cycle.  

End background.  Enter best keto study. EVER.

Resistance to symptomatic insulin reactions after fasting (Drenick, Alvarez, Tamasi, and Brickman, 1972)

Starved-obese but otherwise healthy men who hadn’t had anything to eat for two months.  TWO months.  Down ~73 pounds, and what do they get?  jabbed by a syringe filled with insulin! (p.s. <– read that link if you’ve got the time)

Flashback two months.

A group of obese but otherwise healthy men volunteer for a weight loss study, and they undergo an insulin tolerance test.  ~0.2 U/kg insulin injected, and plasma insulin shoots up from 30 to about 1000 mU.  As expected, blood glucose plummets:before fast

and surprise, surprise, they experienced:hypo

Ie, clinical hypoglycemia.

Then oddly enough, the men agreed to stay in the study, which consisted of two months of total starvation.  They lost 73 pounds on average; and what do they get for this astounding accomplishment?? jabbed again!  2 months starvation, then another insulin tolerance test.  Blood glucose started out a little lower than pre-fasting (not surprising), and it went down a little further:after fast

However,no hypo

After the fast, the same nine subjects had no insulin reactions.


Blood glucose at 2 mM, or about 36 mg/dL, and absolutely no clinical symptoms whatsoever.

what is known is that when blood ketones get high enough, the brain will happily utilize them for fuel.  Happily.

Prior to ketosis, if you deprive the brain of glucose, you get shaky nervous sweaty confusion.  During ketosis, the brain is all like: “whatever sugar, I don’t need you.”

all because of THIS

After two months of starvation, you’re right about here:fuels

(Cahill 2006)

when blood ketones get high enough, the brain will happily utilize them for fuel.  Happily.  (see that line at the very tippy top of the graph above?  yeah, that’s ketones)

Even after getting jabbed with insulin, their ketones were above 6 mM (which is “high enough” by any definition):

ketones post fast


Starvation and survival (Cahill and Owen, 1968)

brain fuels

In NORMAL, take away the glucose and get all shaky nervous sweaty confusion.  In STARVATION, however, take away that paltry contribution of glucose and everything runs A. O. K.

Sans ketones:hypo

Avec ketones:no hypo


next time someone says you need to eat carbs to fuel your brain…


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  • Miodrag Mili?

    Ha ha… u r awesome 🙂

    Question, however, as always.

    One of the obvious difference between fat released from the adipocytes and fat that comes from the outside is the endotoxemia. As such, results of this study do not support your conclusion just like that.

    Recently we had this report about doubling of endotoxemia after single hight fat coconut oil meal vs other fats.

    While this is interesting I don’t think its relevant as pigs were not let to adapt to this diet, like on this 2 older studies: http://goo.gl/wRrVf

    So, is this concern, in your opinion ? People often point to increased endotoxemia on high SFA diets because LPS are one of the most potent toxins around. Could it induce hormetic effect ? What about antioxidants… AFAIK, C completely abolishes effects in various creatures.

    • As usual Miodrag, you bring a lot to the table.

      Firstly, those studies on coconut oil are very interesting- what do you think: acute SFAs impair intestinal barrier, but chronic n6’s are more proinflammatory?
      Also, hormesis is a complicated concept, IMO; care to elaborate? (SFAs/antioxidants/hormesis/ascorbate???)
      low sugar environment might reduce Vit C requirements…

      • Miodrag Mili?

        Actually, if you read the study, you will see that they hypothetisize that Coconut Oil (CO) actually stabilizes the lipid raft and allows better trans cellular pathways for endotoxins to move trough but also other things like vitamins (so its unfortunate constelation) while w-3 (not w-6) do the opposite. Combined with antibacterial effects of CO its probably what happens after acute exposure. After longer run I expect flora and immune system to recalibrate to new endotoxin levels.

        Hormesis could be defined as such level of stress that your body will successfully overcome it without visible damage and become stronger after it as it adapts to new scenario. You should know… but in this context could sub-lethal or sub-serious-damage CO endotoxemia improve your immune system?! Or the level of endotoxemia is simply to high for that and only damage is left.

        No, low sugar do not decrease vit C requierements, thats not correct way to put it. High sugar (particularly int he form of cerials) induces vitamin C deficiency (marginal or full – subclinical scurvy) is a better way, you still need C in both cases, this endotoxemia might be very well one of them but also cholesterol gets stucked with marginal C status (and you have lots of it on high fat diet) and so on… Furthermore, the situation is not that clear as before – its recently disocovered that GLUT receptors can switch preference from glucose to C in RBCs and that in gut, the competition doesn’t seem to take place like in other parts of the system. I am still, presonally, on the megadosing side, given no toxicity of C.

  • john

    Common wisdom tells us to eat at least 120 g of carbs a day to keep the brain running. Does that mean if you’re eating low-carb, but not in ketosis, that you are sparing muscle (aa’s) to get that 120 g of glucose for the brain? Or do some ketones make up for that? If it’s the former, how does a low-carb proponent reconcile that?

    • if by sparing you meant degrading, then not really. Muscle sparing will occur in proportion with ketosis and dietary fat level. There is still some ketosis in low carb diets even if they aren’t ultra-ketogenic. WRT to your last question: hopefully, with data.

  • Wenchypoo

    Common housewife here–just wanted to say that the brain is SOOOOO happy with ketones, even hot flashes are completely diminished to zero by defying the CW of “eat your soy and go on HRT” and going on a keto diet instead.

    Along with epilepsy and other brain malfunctions, menopausal hot flashes also seems to be cured with large amounts of fat that turn into ketones. Blame the blood-brain barrier!

  • Justin Wisor

    Mat Lalonde may disagree with that last statement. On Robb Wolf’s podcast, he explains how he was doing a MetCon while Ultra Keto and nearly passed out. His brain was apparently starving, but I guess under complete starvation is the best way to ensure highest B-OHB levels? Eating protein pre-workout may have affected his levels. I have no idea. He’s all for keto under right conditions, just not during highly glycolytic exercise. Guess it can’t work for everyone

    • Hi Justin,
      might have something to do with the extreme level of intensity…

      Marathon runners (who are burning tons of fat but aren’t necessarily ketoadapted) experience a similar phenomenon… by the end of the race, some try to “finish strong” and sprint to the finish line. In general, sprinting requires glycogen, which is depleted toward the end of the marathon. Muscles take up blood glucose instead, the runner gets hypoglycemic, wobbly legs, and can pass out. I suspect proper ketoadaptation can help this, but only to a degree… those MetCons sound like hell.

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