The World Turned Upside Down: The Second Low-Carbohydrate Revolution (42 page)

Targeting Cancer
Through Insulin Inhibition.

Much of the valuable work on cell
biology was informed by an
approach to disease that tended to downplay the biochemistry at the
upstream-stimulus level, namely, what you eat.  The major goal
was to
characterize the individual components in the inner working of the cell
and to
search for those components that were specifically malfunctioning in
pathological states.  These agents, primarily proteins, could
then be
targeted with drugs, either directly or indirectly, sometimes through
their
synthesis at the genomic level. With the important observation that
calorie
restriction could ameliorate or prevent cancer, a link with obesity was
established and, in some way, excess calories became interchangeable
with
weight gain. The obesity-cancer link became a serial link and it was
assumed,
as it is assumed in nutrition, that preventing obesity was part of
preventing
associated pathologies. In this way, successes of carbohydrate
restriction
in improving cardiovascular risk factors, for example, have frequently
been
dismissed as due to the attendant weight loss. This, despite the
evidence that
the improvements in risk factors or other outcomes persist even in the
absence
of weight loss or even when benefits were demonstrated in eucaloric
trials.

The rationale, then, was that calorie
restriction, the
recognized approach to obesity, would point to those intracellular
components
that could be targeted for drug development. In many cases, this was a
conceptual error.  In nutrition, it is likely that the
doctrine of "a
calorie is a calorie" is the single greatest impediment to
understanding. The
identification of obesity with excess calories, and the failure to look
beyond
this effect, that is, the failure to ask how the separate nutrients,
carbohydrate, fat and protein individually affected cellular metabolism
and how
these effects interacted – there is, after all, no calorie receptor –
compromised
otherwise sophisticated and informative experiments. Similarly, we and
other
workers in carbohydrate restriction failed to see how important it was
to look
at downstream cellular signaling.

Gene's study treated ten seriously
ill cancer patients with
low-carbohydrate ketogenic diets and showed that it was a safe and
feasible
regimen for such patients. The rationale followed from the fact that
rapidly growing tumors have a requirement for glucose (cannot
metabolize fat or
ketone bodies) but simply reducing carbohydrates to give the host an
advantage
was unlikely to be effective since blood glucose is regulated to stay
fairly
constant and the cancers are also good at getting whatever glucose is
there,
over-express GLUT1 receptors, the non-insulin-dependent glucose
receptor.

Ketosis, the state associated with
very low energy or very
low-carbohydrate intake, held some promise. Fine's hypothesis was that
if we
think of cancer in terms of genetics, we could think of cancer cells as
having
evolved through the life of the individual, an individual whose
systemic
environment, in a modern setting, would be unlikely to have any
significant
level of ketosis, that is, would be unlikely to provide any selective
pressure
for adaptation to use of ketone bodies as a fuel source. The host, on
the other
hand, was well-adapted to this substrate – it is unlikely that our
ancestors
regularly had three squares a day. Some fraction of cancer lines, then,
might
not deal well with a ketotic environment.

Figure
26-2
. Ketonemia versus insulinemia: the
lowest insulinemia
correlated with the highest ketonemia levels. Uniquely colored symbols
represent values for each patient.

In the experiment, it turned out that
those patients who
became stable or showed partial remission had the highest level of
ketone
bodies.
Figure 26-2
shows individual time points
with different symbols for each patient. As expected, there was a
correlation
between ketone bodies and insulin levels.

Although this was a small sample,
Figure
26-3A
shows that the patients were divided in terms of
outcome into
those who had progressive disease or those who became stable or showed
partial
remission. The level of ketone bodies was the best predictor of this
outcome.
Figure 26-3B
calories
or weight loss. Patients who
demonstrated stable disease or partial remission had a three-fold
higher
average ketotic response compared to those with continued progressive
disease.
In distinction, both groups showed similar calorie deficits or, as
shown,
degree of weight loss, suggesting that the well-established benefits in
caloric
restriction reflect an underlying mechanism beyond the energy itself.

Figure
26-3
.
A.
Ketosis versus disease progression. Patients who demonstrated stable
disease or
partial remission had much greater ketotic response compared to those
with
progressive disease.

B.
Calorie deficit
vs
outcome: the stable
disease/partial remission and
progressive disease groups showed no difference in calorie reduction.

Summary

A small study in advanced cancer
patients might be considered
only a minor step forward but, in fact, it ties into a vast area of
research on
the downstream signaling in both cancer and normal cells – that is, the
changes
in the cell following stimulation by an external food or hormones. Of
particular
interest is the well-known effect of calorie restriction. It was widely
understood that dietary calorie restriction would have a therapeutic
effect on
animals with cancer and, in addition, reducing calories was the only
way to
prolong life in animals. Studies following this idea showed that it was
an
insulin pathway that was involved. Gene Fine's study nailed the link
for us. It
is an encouraging situation, because if this is the worst of times in
nutrition, it is also the golden age of biology and bringing all of the
science
to bear on the problem has great promise indeed.

Chapter
26

Summary
and the
second revolution

Where are we now?

The low-carbohydrate revolution of
2002 was precipitated by
the popular exposés of the low-fat-diet-heart hypothesis and its failed
tests.
The well-armed forces mustered by diet-heart fared poorly in the early
confrontations with the actual experimental evidence. The loose band of
revolutionaries let them set up the battle as they chose. Without
belaboring the
analogy, the literature was along the lines of wartime reports and as
in many
revolutions, success was short-lived, done in largely by resistance
from the
medical and nutritional community. Scientific developments, however,
have
continued to reinforce the idea that control of metabolism by insulin
and other
hormones is the key factor in weight loss, diabetes and the metabolic
syndrome.
Now classic, well-controlled experiments nailed the idea. Carbohydrate
restriction is the best treatment for all of the features of metabolic
syndrome
and, consistent with the nature of a disease of carbohydrate
intolerance,
carbohydrate restriction is the "default" treatment for diabetes (the
one to
try first). At the same time, tests of the diet-heart hypothesis
continue to be
done and continue to "underwhelm." Bias against publishing studies of
low-carbohydrate diets may also be as strong as ever. A
low-carbohydrate paper
submitted to New England Journal of Medicine, British Medical Journal
or other
major journals will be treated with superficial politeness but palpable
disdain.

For the scientist and consumer alike,
the situation has
become more confusing, more ambiguous. A major factor appears to be a
near
disintegration of standards. Epidemiologic studies trying to show the
risks in
saturated fat (good fats-bad fats), in red-meat, in sugar (good
carbs-bad
carbs) continue to proliferate. In the absence of critical peer review,
they
are accepted for publication and their conclusions are presented at
face value
in the media, notably online medical publications which distill their
essence
for physicians. The same journals and sometimes the same popular
medical sites
publish papers describing how bad the obesity epidemic is and directly,
or by
implication, blame the patient. These same journals also ironically
publish
articles describing the breakdown in standards in the medical
literature.

The effects of carbohydrates
per se
are
generally ignored. If they are
mentioned at all, it is always to point out the dangers in their
"refined" state.
Wild, exaggerated effects are attributed to sugar but these are seen as
separate from carbohydrates and the lipophobes seem to have maintained
control
of the market – `low-fat products are the major form of every kind of
product
in the supermarket including "half and half." And yet, there is a sense
that it
is all over. The accumulating failures of low-fat and the popular books
and
articles are finally taking their toll. The publication in May of 2014
of Nina
Teicholz's "The Big Fat Surprise"
[11]
may be the
second low-carb revolution's "Common Sense" but whatever it is that
deals the
death blow, the nutritional establishment has cracked. Squabbling among
themselves is a sure sign. Walter Willett, head of Harvard School of
Public
Health calling for retraction of a published paper is embarrassing to
us all
(http://bit.ly/1znPrs8).

The Future.

"...it is, perhaps, the end
of the beginning." –
Winston Churchill.

Nutrition, however serious a health
issue, is not at the
same moral level as civil rights but it is clear that, paraphrasing
Martin
Luther King on Jim Crow: Low-fat is dead. It is just a question of how
long and
expensive you want to make the funeral. Continual failures of large
trials and
what must be reasonably seen as a refusal to accept outcomes, in
combination
with the success of alternative approaches, control of metabolism
through the
glucose-insulin axis makes a new method of thinking inevitable.

Surprisingly, the key scientific
focus of the second
low-carbohydrate revolution may be cancer. It has long been recognized
that
total caloric restriction, at least in animals, was of benefit in
slowing
progression of disease and extending life. While this led to the
questionable
paradigm of identifying calories with obesity and identifying obesity,
in turn,
as stimulating physiologic effects, the primary observation is real and
the
study of downstream cell signaling that follows from it has been very
productive. The extent to which the effects of calorie restriction are
due to
the
de
facto
reduction in carbohydrate is an important question not yet fully
examined. The
picture of the internal workings of the cell has, in any case, pointed
to the
critical role of insulin.

Research in carbohydrate restriction
has probably
under-estimated the importance and value of detailed downstream
stimulus-response coupling in cells, while cell biology has been remiss
in
insufficient attention to the nature of upstream signaling, that is,
the effect
of diet. It is not calories but carbohydrate that stimulates insulin
release
and obesity is largely a response, not a stimulus. In addition, ketone
bodies,
originally considered primarily a marker for fat breakdown is now
understood to
be a more global cell signal.

The possibility of cancer treatment
based on the theory that
tumors may be more poorly adapted to use this energy source (because of
their
evolution within the lifespan of the individual)
[13]
is one specific approach tested in a small pilot study. More generally,
the
long-overdue tests of carbohydrate restriction as a cancer therapy may
be the
important battleground in the second low-carbohydrate revolution. The
new
scientific paradigm may also be better received in the area of oncology
due to
the failure to otherwise contain it. In obesity, diabetes and metabolic
diseases,
it may be necessary to clear out the backlog of biased, unscientific
and
statistically flawed studies that have so far impeded progress. New
standards
will have to be implemented to improve the future literature.
Scientific truth
is its own justification but in this area, relief of much human
suffering makes
it of importance in the society at large. Progress may be slow but it
it is
necessary that the nutrition world be turned upside down.