The Ketogenic Diet's Effect on Cortisol Metabolism

The Ketogenic Diet for Health

One of the myths surrounding ketogenic diets comes from misunderstanding the role of cortisol — the "stress hormone".

In a previous post, we addressed one of the arguments behind this myth: the idea that to activate gluconeogenesis (to make glucose out of protein), extra cortisol must be recruited.
That is just factually incorrect, as we showed in the post.


The other argument, which we address here, is more complex.


Like the previous cortisol myth, it involves a faulty chain of reasoning.
Here are the steps:

1. Ketogenic diets may raise certain measures of cortisol.
2. Chronically elevated cortisol is correlated with metabolic sydrome,
   and therefore higher cortisol measures may indicate the onset of
   metabolic syndrome.
3. Therefore, ketogenic diets could cause metabolic syndrome.

Metabolic syndrome is a terrible and prevalent problem
today.
It is that cluster of symptoms most strongly identified with diabetes —
excess abdominal fat, high blood sugar, and a particular cholesterol
profile — but also correlated with other life-threatening conditions
such as heart disease and cancer.


In this post, we're going to explain some of the specifics of cortisol metabolism.
We'll show how this argument is vague, and how clarifying it leads to the opposite conclusion.
The confusion may all stem from misunderstanding one important fact:
different measures of cortisol are not equivalent.

First, though, there is an important reason why the argument doesn't make sense.

We already know that a ketogenic diet effectively treats metabolic syndrome.
As we will describe below, it turns out that certain cortisol patterns
are strongly linked to metabolic syndrome, and might even be a cause of
metabolic syndrome.
If the cortisol pattern that develops in response to a ketogenic diet
were the kind that was associated with metabolic syndrome, then we would
expect people on ketogenic diets to show signs of abdominal fat gain,
rising blood sugar, and a worsening cholesterol profile, but we see the
opposite.
This by itself makes it highly unlikely that ketogenic diets raise
cortisol in a harmful way.


In other words, because cortisol regulation is so deeply
connected to metabolic syndrome, the fact that ketogenic diets reverse
symptoms of metabolic syndrome is itself strong evidence that they improve cortisol metabolism.

In Brief

• There are many different measures of cortisol,
  because researchers have identified many different processes in cortisol
  metabolism.
• Increases in some of those measurements are consistently linked to metabolic syndrome, and others are not.
• Some researchers believe that cortisol dysregulation is a key underlying factor in metabolic syndrome.
• The cornerstone of this connection may be the activity of an enzyme, 11β-HSD1.
  It converts from the inactive form cortisone to the active cortisol.
• In metabolic syndrome, 11β-HSD1 is underactive in liver tissue and overactive in fat tissue.
  This results in a high rate of cortisol clearance, and low rate of regeneration.
• These symptoms of cortisol dysregulation associated with metabolic
  syndrome were found to be reversed by a keto diet in a study that made
  the necessary measurements.

Does a ketogenic diet raise cortisol?

Boston Children's Hospital graphic (with our markup in black). Click for the original.

In a widely-cited study [1], from the Harvard-affiliated Boston Children's Hospital, published in the Journal of the American Medical Association,
three different diets were tested: a low-fat diet, a low-carb diet, and a low-glycemic-index
diet.
The study showed that the different diets had substantially different
metabolic effects, with the low-carbohydrate diet having the best
results.
To our surprise, the researchers then recommended the low-glycemic-index
diet instead.
As they explained in the accompanying press release:

“The very low-carbohydrate diet produced the greatest improvements
in metabolism, but with an important caveat: This diet increased
participants' cortisol levels, which can lead to insulin resistance and
cardiovascular disease.”

The Boston Children's Hospital then went on to produce a graphic advising patients to follow the low-glycemic-index diet,
and giving this as the primary reason not to choose the low-carb diet.
Here is that graphic, which we've marked (in black) to show our disagreement. (Click for the full version without our markup.)


The cortisol levels are an understandable concern, because high
urinary cortisol has been epidemiologically associated with a greatly
increased risk of death from heart attacks [2].


However, because a ketogenic diet effectively treats metabolic syndrome, we should expect that it also reduces those specific cortisol patterns that are associated with metabolic syndrome (and therefore heart disease).
As we show below, this has, in fact, been found.

How is cortisol associated with metabolic syndrome?

Just as we
now understand that measuring an individual's total cholesterol without
looking at its component parts is inadequate for assessing
cardiovascular health, there are different ways to measure cortisol, and only specific patterns of measurements are found with metabolic syndrome.


Cortisol can be measured in fluids, such as urine, saliva, or blood.
Within those fluids, the amount of free cortisol can be measured, but so can cortisone,
the inactive form, or the metabolites that are the result of enzyme
action, and the ratios of any of these to the others can be measured
(see Figure 1).
Moreover, these measurements have a diurnal rhythm, being higher and
lower at different times of the day.


The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) can convert back and forth between cortisol and cortisone.
11β-HSD1—a subtype of 11β-HSD—converts cortisone to cortisol.
When inactive cortisone is converted to the active cortisol, it is called regeneration.
The other enzymes in the illustration break cortisone or cortisol down into metabolites.
That process is called clearance.
It turns out that measurements of these enzyme are important for evaluating cortisol metabolism.


The cortisol profile that has been associated with metabolic syndrome includes the following characteristics:

• high cortisol production rates [3].
• high cortisol clearance rates [4], [5].
• high 11β-HSD1 expression in fat cells, and low 11β-HSD1 expression in the liver [6], [7], which determines when and where cortisol is regenerated.

Similarly to the way total cholesterol measurement is correlated with heart disease, but only because it is roughly
correlated with more informative cholesterol measurements, 24-hour
urinary cortisol may be a proxy for production or clearance, but a poor
one [3], [4], [7].


Cortisol levels are affected by production, but they are
also affected by regeneration and clearance.
In other words, if regeneration were increased, or clearance decreased,
levels could go up even if production stayed the same or went down.
(We previously discussed a similar situation with blood glucose and faulty inference about glucose production rates.)
This means that levels can look similar, even when cortisol metabolism is very different.



Implication for those following the “adrenal fatigue” hypothesis:
if you measure your cortisol, and it is high, you can't conclude that
your adrenal glands are working correspondingly hard. It could be due to
increased regeneration and reduced clearance by enzyme activity. Higher
cortisol could actually mean the adrenals are working less!
In obesity, it appears that production goes up to compensate
for high clearance and impaired regeneration, although sometimes not
enough to compensate; blood cortisol is sometimes actually lower in
obese subjects [8].

How does a ketogenic diet affect the relevant cortisol measures?

In [9], investigators put obese men on either a high-fat/low-carb (fat 66%, carb 4%) or a moderate-fat/moderate-carb (fat 35%, carb 35%) diet ad libitum
(eating as much as they wanted).
Note that both diets had the same protein percent, and both were lower
carb than a standard American diet, but only the high-fat/low-carb diet
was at ketogenically low levels.


For the high-fat/low-carb group, “the metabolic syndrome pattern” was
reversed: blood cortisol went up, clearance went down, and regeneration
went up.
This was apparently due to an increase of 11β-HSD1 activity in liver
tissue.


(Activity of 11β-HSD1 did not go down in fat tissue of those
subjects, but the authors point out that the activity in fat tissue
tends to go down when more fat is eaten, and the high-fat/low-carb group
weren't actually eating more fat in absolute terms than at baseline,
only lower carb.)


This reversal didn't happen in the moderate-fat/moderate-carb group, even though they lost a similar amount of weight.


So the ketogenic diet actually improved the cortisol profile of
the participants, making it less like the cortisol profile seen in
metabolic syndrome.

Summary

There is some reason to believe that cortisol dysregulation is a key underlying factor in metabolic syndrome [10], [11].
The dysregulation has a particular pattern that seems to be caused by a tissue-specific expression of the enzyme 11β-HSD1.


There is a belief among some researchers that ketogenic diets worsen
cortisol metabolism (which could lead to metabolic syndrome and heart
disease),
but an examination of the specific pattern of cortisol metabolism
related to metabolic sydrome shows the opposite.


This is what should have been expected in the first place, since
ketogenic diets have already been shown to improve insulin sensitivity
(the defining symptom of metabolic syndrome) in repeated randomized
controlled trials.


One mechanism by which keto diet improves metabolic syndrome may be its beneficial effect on cortisol metabolism.

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Further Reading

For a review of 11β-HSD1, see:

11β-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects.

Gathercole LL, Lavery GG, Morgan SA, Cooper MS, Sinclair AJ, Tomlinson JW, Stewart PM.

Endocr Rev. 2013 Aug;34(4):525-55. doi: 10.1210/er.2012-1050. Epub 2013 Apr 23.