Ketosis advantaged or misunderstood state?

(Part I)

eatingacademy.com

Ketosis advantaged or
misunderstood state? (Part I)
As The Eating Academy approaches its first birthday in about a
month, I figured it was as good a time as any to put together some
thoughts on a subject I get asked about with great frequency. (For
those wondering when Ill get to Part X of The Straight Dope on
Cholesterol, the answer is, hopefully before the end of the year.) A
few months ago I was planning a post along the lines of the 10
things you need to know about ketosis, but Im now thinking that
might be putting the proverbial cart before the horse. So, lets start
with a more fundamental set of questions. In part I of this post I will
see to it (assuming you read it) that youll 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 dont 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 its
trendy to make blanket statements ketosis is unnatural, for
example, or ketosis is superior but such statements mean
nothing if you dont understand the biochemistry and evolution of
our species. So, lets agree to let the unsubstantiated statements
and bumper stickers reside in the world of political debates and
opinion-based discussions. For this reason, Ive deliberately
broken this post down and only included this content (i.e.,
background) for Part I.
What is ketosis?

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Ketosis is a metabolic state in which the liver produces small

organic molecules called ketone bodies at sufficient levels, which
Ill expand upon later. First, lets 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

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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 cant 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, lets just focus on the need of
the body to provide glucose to the brain.

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Youll recall, from the point I made above, that my brain requires
about 400 to 500 kcal of glucose per day (100 to 120 gm). Youll
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 Im 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 weve only got
about one to three days before were in trouble. If our brain doesnt
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 cant 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) cant
access the most abundant source of energy in our body (i.e., fat)
and is, instead, almost solely dependent on the one macronutrient
we cant store beyond a trivial amount (i.e., glucose). Obviously our
species wouldnt be here today, blogging for example, if this were
the end of the story. But, to understand how we survived requires
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Ketosis advantaged or misunderstood state? (Part I)

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 cant 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 youre 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
its a fair trade! The ETC is simply the vehicle that allows our
body to make the switch.

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In a car, by contrast, its 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, youll 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.

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). Im 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.

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Where do the ketones come in?

In the absence of acetyl CoA (several ways this can happen,
including substrate shortage, as Im 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.

Acetoacetic acid and B-OHB live in reversible equilibrium (on the

left), but once acetoacetate is converted to acetone (on the right)
theres 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.

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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, wed die
in a few days. If we could only rely on protein, wed 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 persons 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 brains
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.

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The last point Ill 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.

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 Ive just presented is based
on data from starving subjects. As most of you reading this know, if
one restricts carbohydrate intake, typically to less than about 20-50

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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 Ive just
presented without resorting to starvation. Why youd do this is
something I will discuss later.
One other housekeeping issue: Ketosis versus DKA?
In an earlier post I explained the difference between nutritional
ketosis (NK) and diabetic ketoacidosis (DKA). If this distinction is
not clear, Id suggest giving this earlier 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 their
cells. A person with a normal pancreas, regardless of how long
they fast (including the fellow I reference above who fasted for 382
days!) or how much they restrict 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 youre reading this,
sir, please forgive me. You deserved a smarter doctor.
In Part II of this post Ill tackle the questions I know folks still have
on their mind (below). Until then, re-read this post to make sure you
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really understand this physiology. Youre 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?
26
NOV

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Ketosis advantaged or misunderstood state? (Part II)

eatingacademy.com

Ketosis advantaged or
misunderstood state? (Part II)
When I wrote part I of this post, I naively assumed this would only
be a two-part series. However, so many great questions and
comments emerged from the discussion that I realize its worth
spending much more time on this important and misunderstood
topic. In terms of setting expectations, I suspect this series will
require at least four parts, after which I hope to get back to finishing
up The Straight Dope on Cholesterol series.
So, back to the topic at hand. (You may want to read or maybe
reread part I for a biochemistry refresher before diving into part II.)

Is there a metabolic advantage to being in

ketosis?
Few topics in the nutrition blogosphere generate so much vitriolic
rhetoric as this one, and for reasons I cant understand. I do
suspect part of the issue is that folks dont understand the actual
question. Ive used the term metabolic advantage because thats
so often what folks write, but Im not sure it has a uniform meaning,
which may be part of the debate. I think what folks mean when they
argue about this topic is fat partitioning, but thats my guess. To
clarify the macro question, Ive broken the question down into more
well-defined chunks.
Does ketosis increase energy expenditure?
I am pretty sure when the average person argues for or against
ketosis having a metabolic advantage what they are really arguing
is whether or not, calorie-for-calorie, a person in ketosis has a
higher resting energy expenditure. In other words, does a person in

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ketosis expend more energy than a person not in ketosis because

of the caloric composition of what they consume/ingest?
Let me save you a lot of time and concern by offering you the
answer: The question has not been addressed sufficiently in a
properly controlled trial and, at best, we can look to lesser
controlled trials and clinical observations to a make a best guess.
Believe me, Ive read every one of the studies on both sides of the
argument, especially on the no side, including this one by Barry
Sears from which everyone in the no camp likes to quote. This
particular study sought to compare a non-ketogenic low carb (NLC)
diet to a ketogenic low carb (KLC) diet (yes, saying ketogenic and
low carb is a tautology in this context). Table 3 in this paper tells
you all you need to know. Despite the study participants having
food provided, the KLC group was not actually in ketosis as
evidenced by their B-OHB levels. At 2-weeks (of a 6-week study)
they were flirting with ketosis (B-OHB levels were 0.722 mM), but
by the end of the study they were at 0.333 mM. While the difference
between the two groups along this metric was statistically
significant, it was clinically insignificant. That said, both groups did
experience an increase in REE: about 86 kcal/day in the NLC group
and about139 kcal/day in the KCL group (this is calculated using
the data in Table 3 and Table 2). These changes represented a
significant increase from baseline but not from each other. In other
words, this study only showed the reducing carbohydrate intake
increased TEE but did not settle the dose-response question.
This study by Sears et al. is a representative study and
underscores the biggest problems with addressing this question:
1. Dietary prescription (or adherence), and
2. Ability to accurately measure differences in REE (or TEE).
Recall from a previous post, where I discuss the recent JAMA
paper by David Ludwig and colleagues, I explain in detail that TEE
= REE + TEF + AEE.

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Measuring TEE is ideally done using doubly-labeled water or using

a metabolic chamber, and the metabolic chamber is by far the more
accurate way. A metabolic chamber is a room, typically about
30,000 liters in volume, with very sensitive devices to measure VO2
and VCO2 (oxygen consumed and carbon dioxide produced) to
allow for what is known as indirect calorimetry. The reason this
method is indirect is that it calculates energy expenditure indirectly
from oxygen consumption and carbon dioxide production rather
than directly via heat production. By comparison, when scientists
need to calculate the energy content of food (which they do for
such studies), the food is combusted in a bomb calorimeter and
heat production is measured. This is referred to as direct
calorimetry.
Subjects being evaluated in such studies will typically be housed in
a metabolic ward (dont confuse a metabolic ward with a metabolic
chamber; the ward is simply a fancy hospital unit; the chamber is
where the measurements are made) under strict supervision and
every few days will spend an entire 24 hour period in one such
chamber in complete isolation (so no other consumption of oxygen
or production of carbon dioxide will interfere with the
measurement). This is the gold standard for measuring TEE, and
shy of doing this its very difficult to measure differences within
about 300 kcal/day.
Not surprisingly, virtually no studies use metabolic chambers and
instead rely on short-term measurement of REE as a proxy. In fact,
there are only about 14 metabolic chambers in the United States
(and I will be spending a day inside one next week, but thats
another story).
A broader question, which overlays this one, is whether any change
in macronutrients impacts TEE. If youre interested in the entire
review of the literature on this topic, refer to this appendix from the
exhaustive review we did at NuSI, along with this summary and
narrative. This review spans over 80 years of research and 1.2
million subject-days.

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Despite the limitations we allude to in the summary of this review,

there is a growing body of recent literature (for example this study,
this study, and this study) that do suggest a thermogenic effect,
specifically, of a ketogenic diet, possibly through fibroblast growth
factor-21 (FGF21) which increases with B-OHB production by the
liver.
These mice studies (of course, what is true in mice isnt necessarily
true in humans, but its much easier to measure in mice) show that
FGF21 expression in the liver is under the control of the
transcription factor peroxisome proliferator-activated receptor a
(PPARa), which is activated during starvation. Increased FGF21
promotes lipolysis in adipose tissue and the release of fatty acids
into the circulation. Fatty acids are then taken up by the liver and
converted into ketone bodies. FGF21 expression in liver and
adipose tissue is increased not only by fasting but also by a high fat
diet as well as in genetic obesity which, according to these studies,
may indicate that increased FGF21 expression may be protective.
Hence, ketosis may increase TEE either by increasing REE
(thermogenic) or AEE (the ketogenic mice move more). Of course,
this does not say why. Is the ketogenic diet, by maximally reducing
insulin levels, maximally increasing lipolysis (which dissipates
energy via thermogenic and/or activity sinks) or is the ketogenic
diet via some other mechanism increasing thermogenesis and
activity, and the increased lipolysis is simply the result? We dont
actually know yet.
Bottom line: There is sufficient clinical evidence to suggest that
carbohydrate restriction may increase TEE in subjects, though
there is great variability across studies (likely due the morass of
poorly designed and executed studies which dilute the pool of
studies coupled with the technical difficulties in measuring such
changes) and within subjects (look at the energy expenditure charts
in this post). The bigger question is if ketosis does so to a greater
extent than would be expected/predicted based on just the further
reduction in carbohydrate content. In other words, is there
something special about ketosis that increases TEE beyond the

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dose effect of carbohydrate removal? That study has not been

done properly, yet. However, I have it on very good authority that
such a study is in the works, and we should have an answer in a
few years (yes, it takes that long to do these studies properly).
Does ketosis offer a physical performance advantage?
Like the previous question this one needs to be defined correctly if
were going to have any chance at addressing it. Many frameworks
exist to define physical performance which center around speed,
strength, agility, and endurance. For clarity, lets consider the
following metrics which are easy to define and measure
1. Aerobic capacity
2. Anaerobic power
3. Muscular strength
4. Muscular endurance
There are certainly other metrics against which to evaluate physical
performance (e.g., flexibility, coordination, speed), but I havent
seen much debate around these metrics.
To cut to the chase, the answers to these questions are probably as
follows:
1. Does ketosis enhance aerobic capacity? Likely
2. Does ketosis enhance anaerobic power? No
3. Does ketosis enhance muscular strength? Unlikely
4. Does ketosis enhance muscular endurance? Likely
Why? Like the previous question about energy expenditure,
addressing this question requires defining it correctly. The cleanest

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way to define this question, in my mind, is through the lens of

substrate use, oxygen consumption, and mechanical work.
But this is tough to do! In fact, to do so cleanly requires a model
where the relationship between these variables is clearly defined.
Fortunately, one such model does exist: animal hearts. (Human
hearts would work too, but were not about to subject humans to
these experiments.) Several studies, such as this, this, and this,
have described these techniques in all of their glorious
complexities. To fully explain the mathematics is beyond the scope
of this post, and not really necessary to understand the point. To
illustrate this body of literature, Ill use this article by Yashihiro
Kashiwaya et al.
The heart is studied because the work action is (relatively) simple
to measure: cardiac output, which is the product of stroke
volume (how much blood the heart pumps out per beat) and heart
rate (how many times the heart beats per minute). One can also
measure oxygen consumption, all intermediate metabolites, and
then calculate cardiac efficiency. Efficiency increases as work
increases relative to oxygen consumption.
Before we jump into the data, youll need to recall two important
pieces of physiology to get this concept: the acute (vs. chronic)
metabolic effect of insulin, and the way ketone bodies enter the
Krebs Cycle.
The acute metabolic effects of insulin are as follows:
1. Insulin promotes translocation (movement from inside the cell
to the cell membrane) of GLUT4 transporters, which facilitate
the flux of glucose from the plasma into the inside of the cell.
2. Insulin drives the accumulation of glycogen in muscle and
liver cells, when there is capacity to do so.
3. Least known by most, insulin stimulates the activity of

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pyruvate dehydrogenase (PDH) inside the mitochondria,

thereby increasing the conversion of pyruvate to acetyl CoA
(see figure below).

The second important point to recall is that ketone bodies bypass

this process (i.e., glucose to pyruvate to acetyl CoA), as B-OHB
enters the mitochondria, converts into acetoacetate, and enters the
Krebs Cycle directly (between succinyl CoA and succinate, for any
biochem wonks out there). I keep alluding to this distinction for a
reason that will become clear shortly.
An elegant way to test the relative impact of glucose, insulin, and
B-OHB on muscular efficiency is to treat a perfused rat heart
under the following four conditions:
1. Glucose alone (G)

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2. Glucose + insulin (GI)

3. Glucose + B-OHB (GK)
4. Glucose + insulin + B-OHB (GIK)
In fact, thats exactly what this paper did. Look at what they found:

The upper two graphs in this figure show similar information,

namely the response of cardiac output and hydraulic work to each
treatment. (Cardiac output is pure measurement, as I described
above, of volume of blood displaced per unit time. Hydraulic work is
a bit more nuanced; it measures the mechanical work being done
by the fluid.)

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Adding insulin to a fixed glucose (GI) load increases both cardiac

output and hydraulic work, but its only significant in the case of
hydraulic work. Conversely, adding B-OHB to glucose (GK)
increases both cardiac output and hydraulic work significantly.
Interestingly, combining insulin and B-OHB with glucose (GIK)
increases neither.
Oxygen consumption was significantly reduced in all arms relative
to glucose alone, so we expect the cardiac efficiency to be much
higher in all states. (Why? Because for less oxygen consumption,
the hearts were able to deliver greater cardiac output and
accomplish greater hydraulic work.)
The figure on the bottom right shows this exactly. If youre
wondering why the gain in efficiency is so great (24-37%), the
answer is not evident from this figure. To understand exactly how
and why adding high amounts of insulin (50 uU/mL) or B-OHB (4
mM) to glucose (10 mM) could cause such a step-function
increase in cardiac efficiency, you need to look specifically at how
the concentration of metabolic intermediates (e.g., ATP, ADP,
lactate) varied in the rat heart cells.
This is where this post goes from kind of technical to really
technical.
The figure below presents the results from this analysis. The height
of the bar shows the fold-increase for each of the three treatments
relative to glucose alone. To orient you, lets look at a few
examples. In the upper left of the figure youll note that GI and GIK
both significantly increase glucose concentration in the cell, while
GK does not. Why? The GI and GIK treatments both increase the
number of GLUT4 transporters translocated to the cell surface so
more glucose can flux in. GK does increase glucose concentration,
but not significantly (in the statistical sense).

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Table 1 from this paper, below, summarizes the important changes

from this analysis. In particular, look at the last column, the Delta G
of ATP hydrolysis.
I was really hoping to write this post without ever having to explain
Delta G, but alas, Ive decided to do it for two reasons:
1. To really get this concept, we cant avoid it, and

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2. The readers of this blog are smart enough to handle this

concept.

Delta G, or Gibbs free energy, is the free (though a better term is

probably available or potential) energy of a system.
Delta G = Delta H Temperature * Delta S, where H is enthalpy
and S is entropy.
The more negative Delta G is, the more available (or potential or
free) energy exists in the system (e.g., a Delta G of -1000
kcal/mol has more available energy than one of -500 kcal/mol). To
help with the point I really want to make I refer to you this video
which does a good job explaining Gibbs free energy in the context
of a biologic system. Take a moment to watch this video, if youre
not already intimately familiar with this concept.
Now that you understand Delta G, you will appreciate the
significance of the table above. The Gibbs free energy of the GI,
GK, and GIK states are all more negative than that of just glucose.
In other words, these interventions offer more potential energy (with
less oxygen consumption, dont forget, which is the really amazing
part).
To see what the substrate-by-substrate changes look like across
the mitochondria and ETC, look at this figure:

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Though it is by no means remotely obvious, what is happening

above boils down to two major shifts in substrate utilization:
1. In one step the reactants NADH/NAD+ become more reduced
(in the chemical sense), and
2. In another step the reactants CoQ/CoQH2 become more
oxidized (in the chemical sense).
These changes, taken together, widen the energetic gap between
the states and, in turn, translates to a higher (i.e., more negative)
Delta G which translates to greater ATP production per unit of
carbon.
Additional work, which youll be delighted to know I will not detail
here, in fact shows that on a per carbon basis, B-OHB generates
more ATP per 2-carbon moiety than glucose or pyruvate. As an
aside, this phenomenon was first described in 1945 by the late
Henry Lardy, who observed that sperm motility increased in the
presence of B-OHB (relative to glucose) while oxygen consumption
decreased!
Is there a reason to prefer GK over GI?
Yes. Recall that ketones make their way onto the metabolic playing
field without going through PDH. Adding more insulin to the
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equation forces more pyruvate towards PDH into acetyl CoA.

While B-OHB mimics the effect of additional insulin, it does so in a
much cleaner fashion without the complex cascade of events
brought on by additional insulin (e.g., decreased lipolysis) and,
perhaps most importantly, avoids the logjam of impaired PDH due
to insulin resistance (Ill come back to this point in a future post
when I address Alzheimers disease and Parkinsons disease). In
essence, B-OHB hijacks the Krebs Cycle via a slick trick that lets
it bypass the bottleneck, PDH. All the glucose and insulin in the
world cant overcome this bottleneck. Its truly a privileged state
and a remarkable evolutionary trick that we can utilize B-OHB.
Back to the original question
Clearly, in the highly controlled setting of a perfused rat heart,
ketones offer an enormous thermodynamic advantage (28%!). But
what about in aggregate human performance? There is no reason
to believe that therapeutic levels of B-OHB (either through
nutritional ketosis or by ingesting ketone esters) would increase
anaerobic power, since the anaerobic system does not leverage
the Delta G improvement Ive outlined here. Same is true for
muscular strength. However, there is reason to believe that
aerobic capacity and muscular endurance could be improved
with sufficient B-OHB present to compliment glucose.
It turns out this has been demonstrated repeatedly in subjects
ingesting ketone esters, developed by Dr. Richard Veech (NIH) and
Dr. Kieran Clarke (Oxford). Because the results of their work have
not yet been published, I cant comment much or share the data I
have, which they shared with me. I can say the ingestion of B-OHB
in the D-isoform (the physiologic isoform), resulting in serum levels
between 4 and 6 mM, did lead to significant increases in aerobic
power and efficiency in several groups of elite athletes (e.g.,
Olympians) across multiple physical tasks maximally stressing the
aerobic system.
Once published, I believe these studies will be a real shot across
the bow of how we view athletic performance. It is very important
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to point out, however, that these studies dont exactly address the
most relevant question, which has to do with nutritional ketosis. In
other words, ingesting ketone esters to a level of 4 to 6 mM might
not be the same as de novo producing B-OHB to those levels. But,
such trials should be forthcoming in the next few years. Personally,
I am most eager to see the results of a ketone ester alone versus
nutritional ketosis versus combination treatment, all to the same
serum level of B-OHB.
The Hall Paradox
For the really astute readers, you may be saying, Waaaaaaaait a
minute, Peterif ketones increase Gibbs free energy while
reducing oxygen consumption, should this imply TEE goes down?
Youre right to ask this question. It was the first question I asked
when I fully digested this material several months ago. If each
molecule of B-OHB gives your muscles more ATP for less oxygen,
you should expend less not more energy at the same caloric
intake, right?
A few months ago I was discussing this with Kevin Hall at NIH, an
expert in metabolism and endocrinology. Kevin pointed out the
error in my logic. I failed (in my question) to account for the
energetic cost of making the ketones out of fat. Remember, in the
experiments described above, the B-OHB is being provided for
free. But physiologically (i.e., in nutritional ketosis or even
starvation), we have to make the B-OHB out of fat. The net energy
cost of doing this is actually great. According to Kevin, it is not
generally appreciated how making ketones from fatty acids affects
overall energy efficiency. Nevertheless, this can be examined by
comparing the enthalpy of combustion of 4.5 moles of B-OHB,
which is about -2,192 kcal, with the enthalpy of combustion of 1
mole of stearic acid (about -2,710 kcal) that was used to produce
the 4.5 moles of ketones. Thus, there is about 20% energy loss in
this process. Hence, the energy gain provided by the ketones is
actually less than the energy cost of making them, at least in theory.
This suggests that being in nutritional ketosis may require more
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overall system energy, while still increasing work potential. In other

words, a person in nutritional ketosis may increase their overall
energy expenditure, while at the same time increasing their
muscular efficiency. In honor of Kevin, I refer to this as the Hall
Paradox.

Parting shot
Ok, if youre still reading this, give yourself a pat on the back. This
was a bit of chemistry tour de force. Why did I do it? Well, frankly,
Im tired of reading so much nonsense on this topic. Everybody with
a WordPress account (and countless people without) feels entitled
to spew their opinions about ketosis without even the slightest clue
of what they are talking about. As I said in part I of this series,
there is no bumper sticker way to address this question, so to say
ketosis is good or bad without getting into the details is as useful
as a warm bucket of hamster vomit (unless youre Daniel Tosh, in
which case I bet you can find a great use for it).
Next time, Ill try to back it out of the weeds and get to more
clinically interesting stuff. But we had to do this and were better for
it.
Have a happy New Years everyone.
1
JAN

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