ERD

Examine.com

Research Digest

Issue 4

February 2015

Table of Contents
05
14
17
25
33

Mood, dieting, and macros

What If There Were No Dietary Guidelines?
The iPad Hangover
Can mice get cancer from steak?

Sodium phosphate: a potentially underutilized

ergogenic aid

39

On the whey to getting lean: one more round of

whey vs. soy

45

Its (not) all in your head: how sodium intake

affects headaches

51
59

Diets, fast and slow

66
69

INTERVIEW: Ivan Oransky

Is the glycemic index actually useful for

making food choices?

INTERVIEW: Jessica Richman

From the Editor

Lets play a little game of Choose Your Own Adventure,

(B) You pull the full paper

Health Research Edition. Itll only take a few minutes, but I

You cant actually access the full paper. Your significant

hope it gets you thinking.

other is a student, so eventually you pull the full paper and

get all the details. The researchers used three different ques-

Youre going to be playing the role of someone scouring the

tionnaires and took some blood draws, and out of all those

web for evidence on a condition youve just been diagnosed

measurements, only one was significantly better in the

with. The title is The Case of the Misleading Abstract.

alpha lipoic acid group. You look up one of the references

Foreshadowing? Yes.

mentioned in the paper, and it actually concludes that alpha

lipoic acid isnt likely to impact autoimmunity by itself.

On a random weeknight, youre supposed to be sleeping

Also, the most convincing studies have been conducted on

but are instead doing health research (hey, it should pay off

diabetic mice.

eventually, right?). Since you havent read the February issue

of ERD, you dont yet know how nighttime web-browsing is

You dont buy the alpha lipoic acid. You have a little bit of

affecting your brain. Anyway, you stumble across an inter-

nonbuyers remorse, but forget about it the next week. The

esting abstract on pubmed. Apparently, alpha lipoic acid can

$25 you saved becomes $436 by the time you retire.

help treat symptoms of a certain autoimmune disease. Not

only is p less than 0.05, its less than freaking 0.001! Boom.

Neither of these scenarios is uncommon. Most of us have

bought way too many supplements based on either anec-

This is quite the useful bit of knowledge, because youve

dotes or tantalizing p-values. Granted, its really tough to

just been diagnosed with that autoimmune disease, and

face a health condition without an easy treatment, and that

your doctor wants to put you on an unpleasant medication.

can make an abstract sound more promising than the full

Should you (A) go buy the supplement on Amazon, or (B)

paper or body of research reveals. Money spent on ineffec-

try to pull the full paper?

tive supplements can really add up, and sometimes it may

be a better idea to focus on high-yield lifestyle habits like

(A) You buy the alpha lipoic acid on Amazon

plenty of sleep and methods to combat stress. Dont take

It arrives in two days. You dont mention this to your doctor

abstracts and their p-values as gospel, and best of luck on

because hes a bit close-minded, but youre sort-of banking

choosing your own adventure.

on the supplement helping, and hence delay starting your

medication for a few weeks. A few weeks later, the pain hasnt
gone away, youre still fatigued, and you have a new-found
hate for alpha lipoic acid.

Kamal Patel, Editor-in-Chief

Contributors
Researchers

Trevor Kashey
Ph.D(c)

Alex Leaf
M.S(c)

Courtney Silverthorn Zach Bohannan

Ph.D.
M.S.

Anders Nedergaard
Ph.D.

Jeff Rothschild
M.Sc., RD

Katherine Rizzone
M.D.

Spencer Nadolsky
D.O.

Editors

Gregory Lopez
Pharm.D.

Pablo Sanchez Soria Kamal Patel

Ph.D.
M.B.A., M.P.H.,
Ph.D(c)

Reviewers

Arya Sharma
Ph.D., M.D.

Natalie Muth
M.D., M.P.H., RD

Mark Kern
Ph.D., RD

Gillian Mandich
Ph.D(c)

Stephan Guyenet
Ph.D.

Sarah Ballantyne
Ph.D.

Mood, dieting, and macros

Transient decrements in mood during
energy deficit are independent of dietary
protein-to-carbohydrate

Introduction

Weight loss is big business. Some authorities estimate that 45

million Americans are trying to lose weight each year and
spend upwards of $33 billion annually to do so. And it has
been suggested that overweight and obese people experience
significant improvements on a range of subjective symptoms
after weight loss, regardless of diet composition.
However, dieting is also common in healthy-weight people looking to improve body composition and/or athletic
performance. Consuming high-protein diets has become a
popular method to aid in weight loss, as research has shown
high-protein diets suppress hunger and preserve lean body

mass during energy restriction in sedentary and athletic populations. These benefits are important for dietary adherence
and long-term success, but they are only a piece of the puzzle.
Dieting can be psychologically complex. The brain and nervous system communicate through small chemicals called
neurotransmitters. Collectively, these neurotransmitters are
what allow us to be aware, have emotion, remember things,
move our body, regulate body temperature, sleep, and do or
feel anything that our brain allows for. In fact, many diseases like Parkinson's, Alzheimers, depression, insomnia,
ADHD, and anxiety have been linked to neurotransmitter
imbalances.

Figure 1: Select roles of

mood-related neurotransmitters

acids (BCAAs) have been shown to alter brain neurochemistry through basic competition. That is, these amino
acids all share the same transporters that allow access into
the brain, and thus they all compete for entry. Since the
transporters are not specific to any one of the amino acids,
the largest determinant of which enters the brain is their
concentrations. Thus, if the plasma level of the BCAAs
increases, then brain concentrations of tryptophan, tyrosine, and their respective neurotransmitters is reduced.
Theoretically, this may have negative consequences for
mood, sleep, hunger, and overall liveliness.
On the other hand, carbohydrate intake has been observed
to increase serotonin production secondary to insulin promoting tryptophan uptake in the brain. Theoretically, this
may benefit mood. > The study under review aimed to compare the effects of different dietary protein-to-carbohydrate
ratios on cognitive performance, mood, and sleep quality
during short-term energy restriction.

Who and what was studied?

The outcomes presented in this study were actually secondThere are many ways to classify neurotransmitters, but for
our purposes its especially important to understand the
role that amino acids play in different neurotransmitters.
Some amino acids, such as glycine, taurine, and glutamate,
serve directly as neurotransmitters, whereas other amino
acids like tyrosine and tryptophan serve as precursors for
neurotransmitter synthesis. Tyrosine is the precursor for
the synthesis of the catecholamines: dopamine, adrenaline
(epinephrine), and noradrenaline (norepinephrine). These
neurotransmitters play a central role in attention, learning,
motivation, and alertness. Tryptophan serves as the precursor for serotonin, which can have an indirect effect on
well-being and happiness, and plays a variety of other roles

ary outcomes that were collected in a previous controlled

trial. That trial aimed to evaluate the effects of protein
intake on body composition, protein balance, and calcium
homeostasis during a short-term energy deficit.
Thirty-nine volunteers (82% men) with an average age of 21
years and average BMI of 25 completed the study. Despite the
technically overweight BMI, the inclusion criteria required
study participants to be recreationally active (defined as
three to four days a week of aerobic and/or resistance exercise) and physically fit (VO2peak of 4060 mL/kg/min).
The volunteers spent 31 days in a metabolic ward under

as well.

constant supervision to ensure compliance to the prescribed

There is some controversy surrounding high-protein diets

design, they were divided into three groups differing in pro-

because the consumption of a lot of large neutral amino

acids tyrosine, tryptophan, and the branch-chained amino

diets and physical activity. Using a randomized block

tein and carbohydrate content, but matched for total caloric
intake and fat:

 Low-protein (LP) group consuming 0.8 g/kg/day protein

Moderate-protein (MP) group consuming 1.6 g/kg/day
High-protein (HP) group consuming 2.4g/kg/day
The increase in protein was accommodated by an equal reduction in
carbohydrates. Throughout the entire 31-day study period, protein was
held constant at the assigned amount, fat was roughly 30% of total energy
intake, and carbohydrates made up the remainder. Alcohol and smoking were forbidden, and all the subjects had lights out by 11:00 p.m. to
ensure similar and adequate sleep between the groups. Nutritional supplements were also forbidden, with the exception of a daily multivitamin
provided by the researchers.
The first ten days of the study served as the control period, with subjects
practicing weight maintenance. Their energy expenditure was estimated
from pre-study indirect calorimetry measurements and physical activity
logs. During the subsequent 21 days, energy intake was reduced by 30%
(through reductions in fat and carbohydrates) and physical activity energy
expenditure was increased by 10%, for a total daily deficit of 40% compared to weight maintenance.
All diets were prepared by research dietitians and protein was provided as
mixed, high-quality proteins (e.g. dairy, lean meats, and vegetable-based
proteins). The subjects all performed regular physical activity. This included
three days a week of low-volume resistance training, where the participants
performed one single-joint movement per major muscle group (three sets
of 15 repetitions) using workloads determined during the pre-study period,
plus daily steady-state endurance activity at a low- to moderate-intensity
(4060% VO2peak) pace on a treadmill or stationary bicycle.
A battery of cognitive tests were administered on days 11, 20, and 30 in
the afternoon, about four hours after lunch. These time points were selected to represent the beginning (day 11), the midpoint (day 20), and end
(day 30) of the dieting period. During the control period, three practice
sessions were allowed for familiarization and to help reduce the potential
of a learning effect (performing better because of practice rather than
the variable of interest). During the cognitive testing, self-reported mood
state was also assessed, utilizing the Profile of Mood States questionnaire.
This questionnaire asks the question, how are you feeling right now?
and has the responder rate 65 mood-related adjectives on a zero to four
point scale.

Stratified block
randomization
Randomization methods are very
important for avoiding potential
sources of bias, yet often are not
reported adequately in journal articles.
When it comes to designing clinical trial groups, balance is key. If two groups
are tested, and one of the groups is
a good deal healthier than the other
one, the results are likely to be biased.
Randomization solves much of this
problem, by giving each subject an
equal likelihood of being in different
study groups. But what happens when
the sample size is small (as it often is
in trials, as huge intervention studies
require huge amounts of money)?
The smaller the sample size, the more
likely it is that groups will differ in characteristics that affect the outcome.
You can statistically control for known
factors, but you cant control for factors that arent measurable or that you
dont know about.
As opposed to simple randomization,
randomization through a stratified
block design allows the researchers to
statistically remove variables of the
study subjects that could potentially
influence the study results but arent
being studied. When randomly allocating the subjects into the experimental
and control groups, the researchers
first stratify them into blocks based
on traits they wish to hold constant

Self-reported sleep quality was assessed every morning

groups compared to the low-protein group. The diets during

upon waking using a questionnaire asking how long it

both the energy balance (first 10 days) and energy deficit

took to fall asleep, alertness at bedtime and upon waking,

phases can be seen in Figure 2.

number of awakenings during the night, restedness upon

waking, and four questions used to calculate an overall

Total mood disturbances, anger, and tension significant-

index of sleep quality.

ly increased in all groups from day 11 to day 20, but were

not significantly different from day 11 to day 30 and were

Finally, blood samples were collected following an overnight

not significantly different between any of the groups.

fast on days 10 and 31 to quantify plasma amino acid levels.

Additionally, confusion and vigor tended to increase during

the energy deficit with no difference between groups.

In this study, 39 people were kept under observation for a month while progressively consuming
fewer calories and engaging in more physical
activity as the study went on. Researchers administered cognitive tests and measured plasma amino
acid levels.

What were the findings?

The original trial that provided data for this study assessed
the impact of protein intake on body composition. All three
groups lost weight during the energy deficit, but the total fat
loss as a percentage of weight loss was greater and the total
fat-free mass loss smaller in the moderate- and high-protein

Depression and fatigue were the only mood-states that did

not differ throughout the intervention.
There was also a lack of differences between any groups on
the cognitive tests throughout the intervention. Although
there were nine cognitive tests administered, only one test
(the Four-Choice Reaction Time test) differed in any of the
group comparisons, with the high protein group performing better than the moderate protein group.
While all groups tended to improve on cognitive tests during
the energy deficit period, the improvements were observed in
tests that also happened to improve during every practice session within the energy balance phase. This suggests that the
improvements through the energy deficit period were a result
of a learning effect rather than being due to the energy deficit.

Figure 2: Protein & carb intake by study period

There were also no significant differences in sleep quality

was a slight trend for the high- and moderate-protein groups

throughout the intervention in any group or between the

to retain their difference relative to the low-protein group.

groups, with the one exception being a significant reduction

in alertness upon waking in the low-protein group from day
11 to day 20, which returned to normal at day 30.
Finally, plasma BCAA concentrations were significantly higher and tyrosine concentrations significantly lower
in the moderate- and high-protein groups relative to the
low-protein group on day 11, but the difference between
the high- and moderate-protein groups was not significant.
Moreover, upon entering energy deficit (days 20 and 30), all
groups showed significant elevations in plasma BCAA and
reductions in tyrosine concentrations, with the between-

The biggest shift in mood happened after day 11.

Study participants felt significantly more anger
and tension, though depression and fatigue were
not affected. Mood did not change much after
day 20. The results were fairly consistent between
groups eating different amounts of protein,
though the high- and moderate-protein groups
had higher BCAA concentrations and lower tyrosine levels than the low-protein group.

group differences losing their significance. However there

Total mood
disturbances,
anger, and
tension [...] were
not significantly
different between
any of the groups,
suggesting that
diet composition
had no effect on
mood changes.

What does the study really

tell us?

The purpose of this study was to examine how the dietary

protein-to-carbohydrate ratio influenced cognitive performance, mood, and subjective sleep quality. The premise is
that manipulating dietary protein and carbohydrate intake
would modulate neurotransmitter synthesis (primarily
serotonin and dopamine). It was indeed shown that plasma
BCAA and tyrosine, but not tryptophan, concentrations
were impacted by the dietary treatments in a relatively short
period of time, as the differences were noticeable by the end
of the ten-day control period. However, at this time there
were no differences between the groups in cognition, mood,
or sleep.
At the end of the dieting period, the differences in plasma
BCAA and tyrosine concentrations became insignificant.
However, there was a trend towards significance, suggesting
that a larger sample size or longer duration may have been
needed to detect the differences. Regardless, mood changes
were not different between the groups and were transient,
returning to pre-dieting levels by the end of the intervention. This suggests that it may have been the caloric deficit,
not the plasma amino acid concentrations, that increased
anger, tension, and total mood disturbances.
9

Similar things can be said for cognition, with all but one

levels by shuttling them into skeletal muscle and organs,

change occurring without difference between the groups.

and consequently also reduces competition for entry into

Finally, subjective sleep was mostly unaffected during the

the brain. Blood amino acid measurements were done after

entire study. The one exception was the low-protein group

an overnight fast, when insulin is minimal. Similarly, the

feeling less alert upon waking during the first ten days of

cognitive tests and mood questionnaire were completed

the dieting period only. Seeing how dopamine and nor-

roughly four hours after lunch, when insulin levels would

adrenaline play a central role in alertness, this outcome

be expected to have returned to baseline. Thus, it is possible

could be the result of the reduction of plasma tyrosine con-

that different outcomes would have been seen if the tests

centrations when the dieting period began. However, this

were administered closer to lunch when the subjects were in

would not explain why the sleep effects were not seen in the

the postprandial state.

other groups.
Another limitation of the study is that it was originally
So overall, what does this study tells us? It shows that a 40%

powered to detect changes in muscle protein synthesis and

caloric deficit in lean and recreationally active young adults

body composition, not cognitive outcomes. Also, without

[...] boosting protein probably wont help

you avoid the doldrums of starting a diet.
The initial ten days of beginning a diet
may be the most psychologically difficult,
but that this will pass with time.
may have a transient effect on mood regardless of the pro-

an energy-balance control group for comparison, it is not

tein-to-carbohydrate ratio. It also tells us that the dietary

possible to separate the effects of the energy deficit from the

protein-to-carbohydrate ratio does impact plasma concen-

effects of learning or the environment.

trations of BCAAs and tyrosine, but not tryptophan. This

could be owed in part to the dietary supply of amino acids,

When interpreting this study, its important to keep certain

with all groups consuming 16 times more BCAAs and seven

caveats in mind. This study does not tell us how the dietary

times more tyrosine and phenylalanine than tryptophan.

protein-to-carbohydrate ratio would impact mood and

Nonetheless, this suggests that downstream effects of the

cognition in obese people or in individuals who diet while

dietary protein to carbohydrate ratio would be limited to

already extremely lean. Nor does this study tell us how the

the catecholamines and not serotonin.

ratio would impact performance in physique athletes such as

bodybuilders or wrestlers. It also doesnt tell us how the ratio

However, tryptophan entry into the brain is facilitated by

interacts with the absolute caloric deficit, as both groups in

insulin, which acts to reduce plasma BCAA and tyrosine

the study had an identical 40% reduction in energy intake.

10

nutritional counseling provided makes trials even harder to

The results of this study suggest that mood is

affected during caloric restriction, regardless of
the specific macronutrient breakdown. However,
since the participants of this study were slightly overweight young people, further research is
needed to confirm whether this association holds
true for other populations.

compare.
Energy deficits have also been explored in several studies.
One found that two days of near 100% caloric deprivation
had no effect on mood in healthy young men, and a study
in physically active soldiers found a 30-day energy deficit
(40%) to not significantly affect mood-state in comparison
with a calorie-adequate diet.
In overweight and obese men and women, a six month long

The big picture

This study is one of many that examine differences in cognition and mood between low- and high-carbohydrate
weight-loss diets that use different durations, study populations, and magnitude of energy deficit.
For instance, in an eight week study of overweight or obese
subjects, nearly all cognitive outcomes showed no difference
between low or high carbohydrate groups. In a separate
year-long study, obese subjects had similar mood improvements from both low-carb and low-fat diets in the first two

25% energy deficit was shown to improve depression scores

at three and six months, but participants who followed a
67% energy deficit for three months followed by a weight
maintenance diet only showed improvement at the end of
the intervention. In all three of these energy deficit studies,
results also showed no significant changes in cognition as a
result of dieting.
Perhaps surprisingly, energy deficits have often been shown
to not impact sleep. In the short-term near 100% caloric

months, but after a year

the low-fat group had
greater improvements.
Cognitive outcomes
werent different between
groups.
For these types of studies, outcomes have to
be taken with a grain
of salt. Mood improvements may be due
to weight loss rather
than diet composition.
Study results also differ
depending on how mood
was measured, and compliance with the diets
as well as the type of

[...] overweight
and obese people
experience significant
improvements on a
range of subjective
symptoms after weight
loss, regardless of diet
composition.

deprivation study mentioned earlier, sleep was

also unchanged, and a
previous study in overweight premenopausal
women found that four
weeks of an 800kcal/day
diet (energy deficit of
1460 kcal/day) did not
affect sleep quality.
Increasing the dietary
protein-to-carbohydrate
ratio has been shown to
result in some cognitive
improvements in other
studies, but typically for
only certain selected
outcomes rather than
cognition or mood as
11

a whole. For example, one trial compared the effects of a

normal (1.5g/kg) or high (3g/kg) protein diet in healthy
normal-weight young adults. For three weeks, all foods and
beverages were provided by the research staff. Cognitive
performance improved in both groups, but only the high
protein group significantly reduced reaction time. The

The results of this study support the idea that

changes in mood may be influenced more by the
duration and magnitude of a diet, rather than its
macronutrient composition.

high-protein group ended up with significantly higher plasma concentrations of the BCAAs, which the authors suggest
may have been the cause of the improved reaction time
Collectively, the above suggests that changes in mood are
reliant on a variety of factors, such as the length of the diet,
magnitude of caloric restriction, and occasionally composition of the diet. Although the evidence is somewhat

Frequently Asked Questions

Would BCAA supplements impact these neurotransmitters?

Since BCAAs are the problem in regard to competition for
entry of neutral amino acids into the brain, it stands to reason that supplementing high doses of BCAAs would have
similar if not worse effects on brain chemistry.

mixed, these studies

A recent study evaluat-

also suggest that dieting

may improve mood in
overweight/obese people more so than in lean
people.
Importantly, while these
other studies had differing fat intakes, the
current study controlled

Bottom line: Mood

and depression issues
rarely have quick fixes
in the form of pills.

for fat intake so that the

only dietary manipulation was the protein to carbohydrate ratio. It was also highly
controlled, with subjects being housed in a metabolic ward
and given all meals and beverages. Thus were able to derive
a fairly specific conclusion: boosting protein probably wont
help you avoid the doldrums of starting a diet. The initial
ten days of beginning a diet may be the most psychologically difficult, but that this will pass with time. Additionally, it
appears that cognition and sleep is likely to remain relatively unchanged throughout a dieting period. Its important
to keep in mind that the results were in non-obese young
people, so they cant be generalized to athletes with much
greater caloric demands or to people who are pushing the
boundaries of leanness.

ed the administration
of a BCAA, essential
amino acids (EAA), or
a milk EAA mixture on
brain amino acid and
neurotransmitter concentrations. It found that
the BCAAs in an amount
similar to many low
dose BCAA supplements
that are currently being
marketed does indeed

blunt increases in serotonin by competitively inhibiting the

uptake of tryptophan from the bloodstream.
Can I just take supplemental tryptophan to increase serotonin levels and improve my mood?
If only it were so easy. While serotonin levels are associated
with mood, many other factors are involved. In studies where
people are purposely deprived of tryptophan, some show a
markedly worse mood. However, this is highly dependant on
who the subject is, and those who have a history of depression are more likely to experience the effect.
Tryptophan supplements have been widely studied, and do

12

improve mood (as well as sleep) in certain subjects. People

often face choices between medicating for moderate depression with SSRIs, or taking a supplement such as tyrosine or
5-HTP (the precursor to serotonin). Mood is an incredibly
complex phenomenon, and unfortunately studies rarely if ever
compare medications to supplements. And lifestyle factors
such as stress and sleep can be as or more important than what
youre putting in your mouth.
Bottom line: Mood and depression issues rarely have quick
fixes in the form of pills. Supplements that can increase serotonin can also have side effects from too much serotonin being
present throughout the body. Its usually best to take a step
back and consider a variety of angles rather than a singular
amino acid or other supplement.

What should I know?

Jumping into a 40% energy deficit may result in mood disturbances for the first ten or so days, which return to pre-dieting
levels by the third week, regardless of the protein-to-carbohydrate ratio. This matches up quite nicely with what many refer to
as the low-carb flu. The lack of differences between the groups
of the current study suggests that perhaps it should be called
the dieting flu, as it appears that these effects are not isolated to
low-carbohydrate diets. Similarly, cognition and subjective sleep
quality showed minimal changes, some of which were transient.

When considered in conjunction with the benefits of higher

protein diets during times of caloric restriction for muscle
preservation and satiety, it seems prudent to not worry about
the hypothetical problems that a high protein to carbohydrate
ratio would have on brain chemistry and neurotransmitters, as
these changes do not appear to significantly impact cognitive

Any mood
or cognitive
disturbances
that do occur
appear to be
transient and
may be owed
to the caloric
deficit itself
rather than the
macronutrient
ratios.

function. Any mood or cognitive disturbances that do occur

appear to be transient and may be owed to the caloric deficit
itself rather than the macronutrient ratios.

In the mood for diet analysis? Join us at the Facebook ERD

forum to talk about low-carb flu, low-calorie blues, and how
the evidence matches experience.
13

What If There Were No

Dietary Guidelines?
By Adele Hite

A recent episode of South Park lampooning Americas

stickI have no fondness for the Food Pyramid in any ori-

epidemic of gluten anxiety features the Secretary of the

entation, nor its replacement, MyPlate. Both shapes reflect

USDA agonizing over the realization that his agency has

the advice of the Dietary Guidelines for Americans (DGA),

been recommending Americans consume large quantities

recommendations which divide the world of food up into

of this dangerous substance as part of a high-carbohy-

two groups: healthy food Americans should eat and

drate, reduced-fat diet. Determined to make amends, an

unhealthy food Americans should avoid. The basis for this

animated version of Tom Vilsack asserts the importance

division has little to do with beneficial nutrients food may

of the nutrition guidance his agency dispenses: We are

or may not contain, but is instead based on the presence or

the USDA! Without us, people would be eating dirtand

absence of components thought to impact chronic disease.

chairs. Vilsack ultimately saves the day by turning the

For the past 35 years, DGA guidance telling Americans

Food Pyramid upside down, and while some would applaud

what to eat and not eat in order to prevent chronic disease

this transformationeveryone ends up eating butter on a

has remained remarkably consistent.

14

Problem is, it hasnt worked very well.

political document, and they regulate a vast array of federal

programs and services, influence health-related research,

During that time, rates of hypertension, high serum cho-

and direct how food manufacturers respond to consumer

lesterol, and heart disease mortality have dropped. Some

demand. Virtually no aspect of our food environment is

researchers attribute these positive changes to dietary

unaffected by the DGA. It is worth considering what impact

improvements in line with DGA recommendations. Other

their absence would have on these other areas.

researchers blame the fact that obesity rates have doubled

and diabetes rates have tripled on our lack of adherence to

From the beginning, the DGA created clear winners and

DGA recommendations. It's a neat trick, giving the DGA

losers in our food system. Winners were processed food

credit for the good outcomes, but absolving them of the

manufacturers who could reformulate products to meet

negative ones.
If Americans have indeed
shifted their diets to align
more closely with the
DGA, the results are not
what was originally intended. On the other hand,
if the U.S. government
has been unable, for the
past 35 years, to convince
Americans to follow its
dietary advice, maybe its
time to quit trying.

DGA standards; losers

It's a neat trick,

giving the DGA
credit for the good
outcomes, but
absolving them of
the negative ones.

were farmers who produced eggs and meat,

which couldnt be easily
modified. When the DGA
directed consumers to
avoid saturated fats, manufacturers replaced them
with trans fats. Pink
slime emerged from the
beef industrys efforts
to produce lower fat
products.
Olestra, high-fructose

If there were no DGA tell-

corn syrup, polydextrose,

ing Americans what to eat,

soybean oil, and other

would heart disease mortality spike? Unlikely, since heart

products of the food science laboratory were used to make

disease death rates had been in decline for over a decade

food healthier, giving food manufacturers the opportunity

before the DGA were created. Would rates of obesity and

to plaster health claims on labels and directing consumer

diabetes climb even further? Under current conditions,

attention away from whole foods, which carry no labels and

i.e. DGA recommendations being followed or ignored

no such claims. The disappearance of the DGA would help

depending on who you ask, the predictions are by 2030,

level the playing field and perhaps begin to eliminate some

more than half of Americans will be obese and, by 2050,

unwanted additives from our food supply.

one in three Americans will have diabetes. As obesity and

diabetes rates did not begin their rapid ascent until after

Because the DGA influence research agendas, they have

the DGA were created, it is not likely eliminating them

imposed their shape on emerging science; its outcomes

would make matters worse.

reflect the policy in whose image it is made. Without the

DGA, government-funded nutrition science would operate

In fact, the DGA are far more than health prescriptions

without the ideological constraints created by govern-

that Americans do or do not follow. They are a powerful

ment-backed dietary advice. Without the DGA, a diabetes

15

prevention trial using a reduced-carbohydrate diet might not just

be an idle fantasy, but an NIH-funded reality.
Without the DGA, federal nutrition programs could tailor their
programs and practices to the needs of the individuals and communities that they serve, instead of being directed by remote,
one-size-fits-all, top-down dietary guidance.
Finally, the DGA assert that science has unquestionably established links between diet and chronic disease. It hasnt, but the
DGAs list of good and bad foods implies chronic disease
is entirely under the control of the consumer. This assumption
places the burden for prevention and cost of care on individuals,
relieving the government and other institutions of the responsibility to improve economic, environmental, and social conditions
related to health. Eliminating the DGA would open up the possibility for rethinking this approach to public health.
In many ways, the DGA were a big fat mistake. It is time we
acknowledge that and move on, not by turning the current DGA

Would
Americans
starting eating
dirtor chairs?
I dont think so.
Maybe, they
might just start
eatingbetter.

upside down, but by throwing them out altogether. Would

Americans starting eating dirtor chairs? I dont think so. Maybe,
they might just start eatingbetter.

Adele Hite is director and co-founder of Healthy Nation Coalition, a

non-profit health advocacy organization dedicated to promoting critical
nutrition literacy, individualized and community-based approaches to
food and essential nutrition, and an understanding of food-health relationships that goes beyond nutritional and caloric content of food. She
is also a registered dietitian and PhD student in communication, rhetoric, and digital media at North Carolina State University. She has masters
degrees in English education and public health nutrition and has pursued graduate studies in nutrition epidemiology.
Prior to her graduate studies, she worked as the patient educator at Duke Lifestyle Medicine Clinic.
Her current research involves a critical examination of the U.S. Dietary Guidelines for Americans, particularly their history, their scientific underpinnings, their effects on the food-health environment,
and the implications of these recommendations as a structure of power in the sociopolitics of food
production and consumption.
16

The iPad Hangover

Evening use of light-emitting
eReaders negatively affects
sleep, circadian timing, and
next-morning alertness

Introduction

Within the last few decades there have been massive developments in portable technology. High-powered devices have now become lightweight, convenient, and affordable.
Many activities, like book reading, have been digitized. With the development of this
technology, what once had been a common pastime to help get us to sleep may now
actually be doing the opposite by causing a shift in our circadian rhythm for sleep.
A circadian rhythm is essentially an organism's daily internal clock. In humans it
accounts for many of our physiological fluctuations throughout the day. A major molecule that affects our sleep biorhythms is melatonin. Many have heard of melatonin
used as a sleep aid, and for good reason. Melatonin is a hormone that is released by the
pineal gland in the brain and is involved with sleepiness and sleep regulation.
Melatonin production is heavily influenced by sunlight interacting with retinal pigments. When light hits the retina, arylalkylamine N-acetyltransferase production is

17

depressed. Arylalkylamine N-acetyltransferase is an enzyme that catalyzes

a crucial step in melatonin biosynthesis. Therefore, when light is absent,
melatonin concentration builds and sleepiness ensues.
What happens when the retina is exposed to light during sleepy time hours?
Research has shown that exposure to artificial light at night suppresses melatonin levels and increases alertness. When melatonin is suppressed, the
body is tricked into thinking it is still daytime and the circadian rhythm can
shift, especially when this happens repeatedly. This shift makes it difficult
to fall asleep. When a person cant sleep due to (light-induced) melatonin
suppression, that signals there has been a shift in the biological clock, relative to the normal 24-hour circadian cycle. As seen in Figure 1, levels of
hormones in the body such as melatonin and cortisol fluctuate throughout
the day. If the time course of one hormone is thrown out of whack, sleep
and other physiological outcomes may be shifted as well.

Figure 1: Variation in melatonin and

cortisol throughout the day

The
International
Agency for
Research on
Cancer, an
agency
directly
related the
World Health
Organization,
has classified
shift-working
as a probable
carcinogen.

But why is this a problem? There is no definitive explanation as to why we

need sleep, but we know that chronic deprivation is detrimental to our
immune system, ability to perform, memory, and a laundry list of other
things in regard to general health.

18

Without question, sleep is important. In fact, chronic sup-

1. Used an Apple iPad on maximum brightness

pression of melatonin via evening light exposure has serious

2. Read a print book

implicated health risks, such as cancer. Such conditions are

frequently seen in shift-workers, like nurses and fire fighters.

Lighting conditions were kept tightly controlled through-

The International Agency for Research on Cancer, an agency

out the duration of the study. The iPad was at a fixed angle

directly related the World Health Organization, has classified

and distance (about 1.5 feet away) from the participants

shift-working as a probable carcinogen. Shift work represents

face to ensure equal light exposure between participants.

an extreme of altered sleep patterns, but the mechanisms

Study participants were able to pick whatever literature they

behind cancer incidence due to altered melatonin secretion

wanted, with the exception of comic books (possibly due to

and circadian rhythm shifts have been widely researched.

different light reflections with colorful comics) and technical reading (possibly sleep inducing). Participants remained

Cancer risk aside, there are other legitimate reasons to study

in their beds at a fixed angle for the entirety of their reading

this phenomena, as it directly relates to performance (both

period, except for a 15 minute break at the 2.75 hour mark.

mental and physical) and general health. The aim of this

study is to quantify the effects of light-induced melatonin

The research group measured:

suppression, caused by iPad use before sleep, on sleep quality and feelings of lingering sleepiness after waking up.

1. How long it took the participants to fall asleep and

sleep activity.

Who and what was studied?

The title of this paper includes light-emitting eReaders,

but it is important to note that the experimental arm of this

study was conducted exclusively with Apple iPads.
This was an inpatient randomized crossover study that
included twelve healthy individuals who had all abstained
from stimulants (which was lab-verified), and were otherwise free of any disorders that affected sleep quality and
sleep patterns. Three weeks before the study began, the
participants adhered to a strict sleep schedule of 10:00 p.m
to 6:00 a.m, which was verified by logs, call-ins, and wrist
actigraphy (which measures movement patterns).
The study participants lived on the premises for the duration of
the study. Sleep schedules were fixed at 10:00 p.m to 6:00 a.m.
For five days in a row, four hours before lights out, but in
otherwise dim light, the study participants either:

a. Polysomnography (PSG) was performed on

nights four and five. PSG records all biophysical
activity and patterns during sleep.
b. Electroencephalography (EEG) concurrently
measured brain activity.
2. Melatonin levels
a. On the fifth night, blood was drawn hourly and
suppression was measured by comparison to
starting measurements.
3. Alertness and sleepiness
a. Self reported: participants completed a dimly-lit
computer generated survey both one hour before
sleep and approximately six times during their first
waking hour.
b. Physical measurements: EEG was taken upon
waking under reproducible conditions. Study
participants were asked to be still and stare at
a black dot for 3 minutes. Riveting.
4. The group measured the spectral output of several
commercial e-reader devices at the same distance the
face was placed from the e-reader during the time of
the experiment.

19

in a variety of conditions such as multiple sclerosis and

Study participants adhered to a strict waking and

sleeping schedule during the study. Before bed,
each participant read for several hours, using
either an iPad or a print book.

Alzheimers disease.
Keeping in mind the suppressed melatonin levels and decreases in REM sleep, iPad users reported lower levels of sleepiness
in the evening. EEG readings confirmed this by showing less
power in the delta/theta frequency ranges (associated with

What were the findings?

iPad use consistently suppressed night-time levels of melatonin, which were significantly lower than when paper
books were used. In fact, reading paper books resulted in no
suppression. Once the lights were dimmed, the melatonin
onset peak was shifted to a later time period with iPad use

when compared to paper book use. Effectively, the iPad

artificially inflated the length of the day perceived by the
brain, by about an hour and a half! This shift in circadian
rhythm for iPad users happened even though the room
lights were dimmed.
These changes in melatonin were associated with changes in
sleep patterns of the participants. On average, the iPad users
took about 10 minutes longer to fall asleep when compared
to paper book readers (at around 25 minutes, compared to
15 in the paper book group).
Coincidentally, there was also a decrease of Rapid Eye
Movement (REM), or dream-inducing sleep, by about the
same amount of time. However, the total amount of time
spent sleeping, the efficiency of that sleep (defined as the
percentage of time in bed spent actually asleep), and time
spent in non-REM sleep were not significantly different
between groups. While the exact function of REM sleep is
not fully known, one theory is that its involved in memory consolidation. As an analogy, computer hard drives can
accumulate fragmented segments of memory after long
periods of usage, and defragmenting the hard drive is a
function of the Windows operating system to remedy that
(or at least it was in the 2000s). A reduction in REM could
have a multitude of impacts, including potential disruption
of the blood brain barrier, which is theorized to be involved

sleep and drowsiness) when compared with print book readers. The following morning, iPad users were much sleepier
than print readers. It took iPad users on the order of hours to
fully recover from their sleep episode and gain full alertness
after waking in the morning. Chronic use of these devices
before bed may impair wakefulness, to the point where iPad
users might not feel truly awake until late morning.
Data for the print book readers was essentially the opposite, with greater feelings of tiredness in the evening and
increased wakefulness in the morning. This increase of
tiredness in the morning experienced by iPad users is likely
related to decrease in REM sleep, and might be explained
by the circadian phase shift. Since the wake times were set
between the groups, and the phase was shifted to a later
time, the study participants who used iPads essentially woke
up when their body thought they should still be sleeping. If

Effectively, the
iPad artificially
inflated the length
of the day
perceived by the
brain, by about an
hour and a half!
20

sleep and wake times were not regulated, its possible that this may not have been
observed. However, since most people must wake at a particular time (but not go
to bed at a particular time) its easy to see how these issues quickly compound.
The iPads peak light output is in the blue range of the visible spectrum at 452 nm.
The physiological effects from this blue light makes sense given the light output of
humans original light source: sunlight also peaks under 500 nm, and melanopsin
pigment in the human eye absorbs in a peak range of about 480 nm. Its not unrealistic to posit an artificial sun response when exposed to these higher energy
photons. Even though this wavelength may not seem as bright to humans when
exposed to an equal power of white light (which peaks at 612 nm), what mostly
matters to the brain is the excitation of the correct eye pigments to depress the
production of the arylalkylamine N-acetyltransferase, which in turn decreases
circulating melatonin.
In the short term, a person may get acute sleep onset insomnia due to a shift in
circadian rhythm. However, using electronic devices that emit blue light may
have biological ramifications in the long term, especially since chronic melatonin
suppression had been linked to an increased risk of various types of cancers.
Unlike in this study, though, most people self-select their bedtimes (and to a
lesser extent wake times). If a self-selected bedtime and wake time are not aligned
with the bodys natural circadian rhythm, this, combined with blue-light exposure, may further exacerbate the phase-shift phenomenon and lead to chronic
issues associated with sleep deprivation.
Lastly, a four-hour read time was established in this study, when many people
may spend even longer times in front of a screen (either TV, computer, tablet,
or phone) from afternoon to bedtime. The effects of longer exposure times are
unknown, while tablet and phone displays continue to get brighter each year.

Study participants using iPads before bed took about ten minutes
longer to fall asleep, experienced less REM sleep, and found it much
harder to feel fully awake in the morning than people that read print
books before bed.

The big picture

The findings are somewhat scary for the average person who loves the Internet,
which houses a vast collection of research on nutrition and health issues (and cat
pictures) that can easily keep you up for hours. Back-lit tablets suppress and delay
21

melatonin, affect EEG, negatively affect sleep quality, and

The study participants also had to adhere to regular eating

hinder the ability to wake up in the morning. But do the

and sleeping times. Taking these things into account, it is

findings of this rigorously controlled study apply to free-liv-

likely that the negative effects of this study may even be

ing humans?

understated. This study only had people in a phase shifted state for five days, where a person may be chronically

At first glance, it may seem difficult to translate the data

phase shifting for years. This may lead to chronic infections,

to the typical person not staying in such controlled con-

general malaise, premature fatigue/overtraining, and even

ditions. But this is not the case. On the one hand, study

precursors to metabolic syndrome.

participants remained in a bed (in a reclined position) for

almost the entire duration of the study with an IV insert-

The use of blue-light emitting devices is growing at a consis-

ed and electrodes stuck to their heads. On the other hand,

tent rate. The use of these devices near bed time is likely to

this may actually be a decent model system for the typical

interfere with the bodys natural sleep patterns. Continued

inactive adult.

interference may lead to chronic sleep issues, which are

linked to a host of negative conditions listed above. The

If you have to
use a tablet/
laptop/phone at
night, it may be
helpful to dim
the screen as low
as possible, while
still being able
to read.

study is not clear about how quickly this phase shifting

takes place and how quickly it can be corrected. Since there
are quantifiable differences between the two experimental
groups, and both groups went through each condition, it is
safe to say that these phase transitions can be altered over
the course of days.
Take note that there is nothing uniquely bad about iPads or
even tablets in general. Phones, laptops, and televisions are
all devices that emit blue light at substantial levels.

Frequently asked questions:

If I wanted to time my iPad use to avoid a phase shift, what

is recommended?
If a four hour exposure (from 6:00 p.m. to 10:00 p.m.) leads
to a 1.5 hour phase shift, then presumably a substantially
shorter exposure time ending much earlier in the evening
would lead to less phase shifting and more appropriately
timed melatonin secretion. But further research would be
needed to know specifics. Keep in mind that if the four hour
exposure occurred much earlier, in the daytime hours, mel-

Assuming a person works for eight hours per day at a desk

(staring at a light emitting screen), sleeps for eight hours per
day (but probably less) and then spends four plus hours per
day using electronic devices for entertainment rather than
work, its probably not much different than the lab setting.

atonin would already be suppressed by sun/light exposure

and you wouldnt have to worry.
If you have to use a tablet/laptop/phone at night, it may
be helpful to dim the screen as low as possible, while still
being able to read. One way to get around this is using blue22

light blocking glasses, which have amber lenses and hence

melatonin isnt the only determinant of circadian rhythm,

make you look quite silly (but also smart and innovative

so artificially restoring melatonin levels probably wont

compared to friends/mates that may mock you.) As seen

eliminate all the negative effects of bright electronic devices.

in Figure 2 these have been shown to allow for melatonin

production, and hence improve sleep quality and potentially

So while the specific efficacy of melatonin for phase shift

even mood. If you cant or wont use these glasses, but still

caused by iPads hasnt been researched, there is a cheaper

want to use your device at night, consider free programs

and simpler solution. Occams razor dictates that the sim-

such as f.lux for laptops or other alternatives for mobile

plest answer is often correct -- rather than putting a bandaid

devices. These automatically make the screen dimmer and

on the problem of shifted sleep, you could work on enforcing

more red as the sun sets. Some apps can even lower screen

a habit of natural light exposure. Some sunlight during the

brightness more than a device allows on its own.

day, and no bright light in the hour or more before bed. It

sounds tough, but starting slow (for example, shifting device

Can supplementing melatonin help to restore altered sleep

use a bit earlier each week) can make the transition easier.

rhythm?
If melatonin is used as a sleep aid in order to fall asleep

The study authors noted that the relatively easier time print-

during the time of maximum sleep propensity, this is plausi-

ed-book readers had in falling asleep is actually similar to

ble. Examine.com has a very extensive article on melatonin

the effect size of the popular insomnia medication Lunesta.

and its proper supplementation protocol. Melatonin may be

Simply constraining bright light to earlier hours could be an

an option for artificially attenuating the down-shifted mel-

effective and side effect free treatment option for those with

atonin peak if an iPad is used before bed. That being said,

sleep issues.

Figure 2: Effect of light and blue-light blocking glasses on melatonin

23

 Even being exposed to low intensity

blue light, like those blue LEDs on power
cords, can make you more drowsy the
next morning.
Should I have any issues with my e-ink device?

Will using a blue-light emitting device during the day inter-

No, the spectrum of the e-ink device is comparable to a

fere with my sleep patterns?

regular paperback book. However, some e-ink devices now

This is unlikely, as the mechanism of this phenomena is

have front-lit capacity, where light is directed on to the

associated with delayed melatonin accumulation. Melatonin

screen, rather than projected through it. There is no peer

is at imperceptible levels during the day, so there would be

reviewed data on spectral emission from those devices in

no quantifiable effect of inhibiting its synthesis with blue

this study, but anecdotally some of these devices appear to

light. The sun emits the very same wavelengths in apprecia-

have somewhat bluish hues (as opposed to the yellow of cer-

ble amount.

tain lightbulbs). Reading these devices on a dim brightness

setting with room lights turned off may be comparable or
even better than reading a print book with dim room lighting, since less of your field of vision will be lit. This has not
been formally studied though.
Bulbs that can change color and brightness automatically,
such as the Philips Hue, are increasingly popular. While you
dont have to go out and buy fancy smartphone-controlled
light bulbs (although they are kind of cool), at least dimming your room lights at night can greatly help melatonin
secretion. What about the lucky people who can sleep with
lights on, maybe falling asleep to the TV or while your partner is awake? Theyre not so lucky after all -- sleeping with
the lights on causes sleep to be shallow with more likely
arousals in the middle of the night.

What should I know?

Most all modern back-lit portable electronic devices emit

high-energy blue light. The human eye is sensitive to blue
light exposure, leading to suppressed melatonin production.

This suppression of melatonin production causes a shift in

sleep patterns. Hence, sleeping out of line with your natural
endogenous sleep patterns may lead to chronic sleep deficiency. Chronic sleep deficiency and consistently impaired
melatonin production may increase the risk of many inconveniences, disorders and diseases.
While other health topics (such as low carb vs high carb) may
be subject to many more studies, one of the most important but undercovered health issues may be the downstream
effects of poor sleep caused by using these devices at night.

Even being exposed to low intensity blue light, like those

blue LEDs on power cords, can make you more drowsy the

Dont you dare read this past 10pm. But if you choose to

next morning. So it can pay dividends to be more aware of

anyway, head over to the ERD private Facebook group to

what kind of light surrounds you throughout the evening all

talk about how to improve your light-related sleep habits.

the way into slumber time.

24

Can mice get

cancer from
steak?
A red meat-derived
glycan promotes
inflammation and
cancer progression

Introduction

Red meat is one of the foods the media loves to hate, perhaps while still secretly loving it. Any time new research
is published that deals with red meat consumption and X
(where X might be cancer, heart disease, diabetes, etc.) the
major news outlets pick it up, running scary headlines to
attract clicks. The science, however, is typically a bit more
nuanced than the bold claims of news headlines would lead
the average reader to believe. So is there actually anything
to worry about when eating red meat?

There is a modest but consistent correlation between diets

high in red meat and cancer risk in human epidemiological
studies. Scientists havent been able to figure out why this
link exists yet, or if the risk is increased by red meat directly
or through some other related factor. A number of hypotheses have been proposed: grilling red meat creates dangerous
compounds, the iron in red meat generates free radicals, or
people that eat more red meat are more likely to engage in
other diet and health behaviors that promote cancer, such
as a high fat or low vegetable diet (which is largely based on
correlational findings). So far, there isnt enough substantive

proof to hold any of these reasons up as the definitive cause

of the increased cancer risk.
Although there is no definitive proof, the collection of
mechanisms, human biomarker RCTs, animal studies, and
observational studies do see to support the hypothesis that
red meat increases digestive cancer risk. Since there probably will never be a human RCT with red meat as a variable
and colorectal cancer as an outcome, were unlikely to be
able to assess causality in humans.
This particular paper attempted to explain one possible
mechanism involved in the meat-cancer correlation from
an immune response standpoint. Our simplified images
of a cell typically depict a roundish circle denoting the cell
membrane, with a bunch of stuff inside the cell. In reality,
cell surfaces are covered with different kinds of molecules sticking out from the cell membrane. Many of these
molecules are long sugar chains made up of units called
monosaccharides. The researchers looked at a particular
group of monosaccharides called sialic acids, which are
linked into larger structures known as glycans.
25

The two sialic acids of interest were n-acetylneuraminic acid

would have provided a resistance advantage for these dis-

(denoted Neu5Ac) and n-glycolylneuraminic acid (denoted

eases many millennia ago.

Neu5Gc), which are seen in Figure 1. Structurally, these two

molecules are identical except for an additional hydroxyl

Despite this genetic change, Neu5Gc is still found in low

(-OH) group on Neu5Gc. These molecules are found in a lot

levels in normal human tissue - so any molecules would

of animal-based dietary sources in different levels, with beef

have to come from dietary sources and then be incorporat-

and caviar having the highest levels of Neu5Gc.

ed into our own cell membranes. Its also found in higher

levels in malignant tissue. The researchers speculated

Neu5Gc is interesting, because its not something that

that because this molecule is foreign to our bodies, our

humans can synthesize from Neu5Ac - the gene that codes

immune systems would react to it by producing antibodies

for the enzyme needed to add on the hydroxyl group had

to attack it. Indeed, it has been shown that 85% of people

a sequence deletion several million years ago and thus is

tested had antibodies against Neu5Gc. It is not known why

nonfunctional. This likely conferred several evolutionary

15% of the people tested did not possess the antibodies.

advantages. First, it may have been a factor in our ability to

increase our brain development beyond that available to our

An immune system that is constantly turned on results in

primate cousins. Second, certain pathogens such as select

inflammation. Markers of inflammation increase when the

strains of malaria as well as an E. coli toxin bind to Neu5Gc,

immune system is fighting off a foreign pathogen. In acute

so lacking the enzyme necessary to synthesize Neu5Gc

situations, inflammation is beneficial! However, were learn-

Figure 1: Humans and Neu5Gc

26

ing that chronic inflammation does not do a body good.

Chronic inflammation has been linked to heart disease,

Figure 2: Neu5Gc in common foods

various bowel syndromes such as irritable bowel syndrome

(IBS) and Crohns, and yes, cancer.
So, we finally have a hypothesis: A) red meat consumption
leads to B) incorporation of a foreign molecule into our
bodies, which leads to C) an immune response to the foreign molecule, which leads to D) systemic inflammation,
which leads to E) an increased incidence of cancer. The
researchers used simulations of A and C, and evaluated
their hypothesis in mice.

Though the media often links red meat consumption to an increased risk of cancer, scientists are still
trying to determine what aspect of red meat results
in cancer, or if this link exists at all. Researchers in
this study tried to determine if red meat consumption results in systemic inflammation due to the
presence of foreign, meat-derived molecules.
phospho-N-acetylneuraminic acid hydroxylase (CMAH)

Who and what was studied?

To confirm and quantify previous findings, the research-

ers used a new analytic method to determine the amount

of Neu5Gc in different foods. The results are summarized
in Figure 2. Neu5Gc was absent in fruits and vegetables,
most seafood, poultry, and butter. It was found in low lev-

enzyme needed to convert Neu5Ac to Neu5Gc. Unlike most

of our mammalian friends, including primates that are still
very genetically similar to us in other ways, humans do not
produce a functional CMAH enzyme due to a deletion in
the gene sequence for the enzyme. So like in humans, any
Neu5Gc in these genetically modified mice would have to
come from dietary sources.

els in milk and cheeses, bison, lamb, and pork. In beef, the
Neu5Gc content was approximately 2-30 times higher than
in other red meats and ranged from 0.025-.231mg/g, the
highest of any of the tested foods other than caviar. The
Neu5Gc content of beef varied greatly however, and the
lower range was more in line with other foods. By contrast,
poultry, dairy, and seafood were all high in Neu5Ac.
The researchers used a genetically modified mouse model for their experiments, as is often done in initial in vivo
studies. This particular mouse had the Cmah gene removed,
meaning that they could not produce the cytidine mono-

Keeping the notations straight: All gene symbols

are italicized (ex. Cmah) while all protein abbreviations are all caps and non-italicized (ex. CMAH).
Human gene symbols are written in all caps, while
mouse and rat gene symbols capitalize only the
first letter. So the full length mouse Cmah DNA
sequence produces the CMAH enzyme, while the
truncated human CMAH DNA sequence would
produce no functional enzyme.
27

 [...] most epidemiological data in

humans has linked diets high in red
meat to an increased risk of colon and
colorectal cancer. [...] the organ of interest
for spontaneous tumor formation was
the liver.
Male mice were fed a normal diet, or a normal diet supple-

animals to mount their own immune response against the

mented with porcine submaxillary mucin (PSM). Translation:

Neu5Gc.

pig salivary gland excretions, yum. PSM has a high

concentration of Neu5Gc and was meant to simulate the con-

Two additional experiments created the anti-Neu5Gc

sumption of red meat in humans. The PSM-supplemented

immune response prior to feeding and looked at HCC

mouse diet contained 0.25mg of Neu5Gc per gram of feed,

tumor formation. One tested the specificity of the immune

which is similar to the highest concentrations seen in red

response by feeding the mice the PMC enhanced diet,

meat. After being fed this diet for several weeks, the levels

which created elevated levels of Neu5Gc, or a diet enhanced

of Neu5Gc in the mouse were similar to levels observed in

with the unhydroxylated precursor molecule Neu5Ac. A

humans adhering to a red meat rich diet for several years.

second experiment compared pre-immunized wild-type

mice that had a functional Cmah gene to the genetically

Its important to note that most epidemiological data in

modified mice without the Cmah gene.

humans has linked diets high in red meat to an increased

risk of colon and colorectal cancer. In this particular mouse
model, however, the organ of interest for spontaneous tumor
formation was the liver (hepatocellular carcinoma, or HCC).
The researchers used liver cancer as an outcome because this
mouse strain is naturally susceptible to spontaneous liver
tumors. So the choice of liver cancer was somewhat arbitrary
-- if the strain had been susceptible to pancreatic cancer, they
may have used that as the outcome instead.
To create models of inflammation similar to humans, PSMand control-fed mice were immunized against Neu5Gc by
injecting red blood cell ghosts (which are empty red blood
cells) that did or did not contain Neu5Gc. This caused the

What were the findings?

The first experiment showed that elevated markers of

inflammation were only seen in the mice that were fed
PSM-enhanced food for 12 weeks prior to receiving an
injection of Neu5Gc antigen. Compared to mice that were
fed standard food for the same time period, or fed PSMenhanced food but received a control injection, levels of
interleukin-6, serum amyloid A protein, and haptoglobin
were all elevated at highly statistically significant levels. This
was also confirmed to happen in a dose-dependent manner;
as the injected antigen concentration increased, so did the
levels of inflammation markers.

28

HCCs (9% and 7% respectively) but 47% of the genetically

Scientists crack
why red meat is
linked with cancer
- and SUGAR may
be to blame.
- Headline on the Daily Mail, 12/30/14
In the second experiment, the test mice were first exposed
to Neu5Gc immunogens (which are able to induce an
immune response in addition to an antibody response)

modified mice exposed to the Neu5Gc immunogen had

developed HCCs.

Mice fed diets high in a cell surface sugar molecule found in red meat had higher levels of
inflammation markers. The inflammatory
response was specific to Neu5Gc and not the similar Neu5Ac precursor molecule. The combination
of consuming that sugar molecule and manipulating the mouse immune system to make antibodies
against that sugar molecule caused mice to develop more liver tumors than control groups.

The big picture

Scientists crack why red meat is linked with cancer - and

through injections of red blood cell (RBC) ghosts. The mice

SUGAR may be to blame - Headline on the Daily Mail,

were then fed either PSM-enhanced diets, or diets rich in

12/30/14

Neu5Ac through supplementation with edible birds nest

(EBN). Translation: the salivary secretions of the swiftlet

Contrary to media assertions claiming that scientists now

bird, highly prized as a culinary delicacy. Yum?

know why red meat causes cancer, this study actually had
some limitations. First off - there is no human data present-

Because the mice lacked the Cmah gene, they were unable

ed. There is an interesting mechanism proposed and a very

to convert the dietary Neu5Ac to Neu5Gc. Here, elevated

carefully designed model created to ask a specific mecha-

interleukin-6 levels were seen only in the PSM-fed mice

nistic question, but this may just be the first baby step on

and not in the EBN-fed mice. Additionally, 2 out of 7 mice

a long journey to knowing the true cause, if a single one

(29%) in the PSM feed group developed HCCs over the

even exists, for the increased incidence of cancer seen in

course of 55 weeks, whereas none of the mice in the EBN

consumers of red meat in large quantities. Mice models are

feed group developed tumors.

almost always the first starting point for asking a question

about biological cause and effect, but results should nev-

The final experiment compared the genetically modified

er be taken as conclusive or directly applicable to humans

mice with their wild counterparts. Mice were pre-ex-

at this stage. Cancer has been caused and cured in mouse

posed to either chimpanzee RBC ghosts with cell surface

models a dozen times over, in ways that have turned out to

Neu5Gc immunogens, or human RBC ghosts with cell

be completely inapplicable in humans.

surface Neu5Ac immunogens. All mice then received the

PSM-enhanced food. After 85 weeks, a comparable num-

The study design itself, aside from being only conducted in

ber of wild type and genetically modified mice that had

mice, had its own limitations. Studies in genetically similar

been exposed to the Neu5Ac immunogen had developed

mice provide nowhere near the applicability of data that a

29

large scale human study that includes a wide variety of population factors (age,
sex, race, weight) would. Also, the PSM-enhanced food intervention was meant
to simulate only red meat consumption, not to simulate a typical human diet that
is usually full of varied food products other than red meat. For example, a recent
small study in humans suggested that consumption of a certain type of starch
may counteract some of the cancer risk effects of red meat consumption. And the
immune exposure to the Neu5Gc immunogen in the final experiment introduced
an external factor at a single point in time, instead of a lifetime of immune system
exposure that likely has varied and currently unknown effects. The immune system is incredibly complex, and there are examples of immune system responses
having both pro- and anti-cancer effects.
As the study authors note, there is currently no published research that examines
the correlation of anti-Neu5Gc antibodies in humans with cancer risk. So it will
be important for future research to examine the mechanism found in this study
in a human sample. Finally, there is the question of organ system relevance. This
particular mouse model was used because there is a low level background incidence of spontaneous tumor formation in the liver over time, which more closely
resembles the spontaneous formation of tumors in older humans rather than
tumors that are artificially implanted in mouse organs for research purposes.
However, red meat consumption has not been correlated with increased liver
cancers. Some of the primary non-genetic risk factors for that disease are certain
viral infections and alcohol consumption, both of which may also involve some
aspect of chronic inflammation, but have never been linked to Neu5Gc. Cancer is
a complex disorder, so its difficult to draw direct comparisons between a tumor
that forms in the liver in one species versus one that forms in the colon in another species. The tumors in the mouse did show incorporation of Neu5Gc into the
tissue, but Neu5Gc has been found in a number of different malignant tissues in
humans (as well as in healthy tissue), so there may be non-specific incorporation
of the molecule into tumors in general.
The results of this study suggest a possibly novel explanation for the correlation
between red meat consumption and cancer, and might be able to explain some of
the contradictions with previously proposed explanations. The jury is still out on
whether this is relevant to humans. The research team believes in the importance
of this study, however. The last two authors listed on the paper have licensed
anti-Neu5Gc antibody technology from their institution and co-founded a company that is investigating targeted antibodies as a potential cancer therapeutic. Its
possible that regardless of any mechanistic explanations, Neu5Gc still might be
an interesting new target for cancer drugs, or perhaps a biomarker that can be
used in additional research.
30

no other related factors such as other dietary patterns and

This study provides evidence to support a molecular link between meat consumption and cancer
caused by inflammation, but since no human
evidence was gathered in this trial, much more
research is needed before these results can be
applied to people.

exercise were evaluated. And then theres the question of the

differing effects of a sudden immune trigger by introducing exposure to an antigen or immunogen, compared to a
lifelong antibody exposure in humans that likely begins as
soon as a child begins eating solid foods. Finally, the organ
of interest in the mice was completely different than the
organ of interest in humans, so drawing any direct comparisons at this point is challenging.

Frequently asked questions

How applicable are these results to humans?

The fact that the genetically modified mice lacked the gene
that is also non-functioning in humans did make this
mouse model more human-like for the purposes of this
studys aims. The quantity of the food exposure is at least

Should I change my diet?

Probably not solely as a result of this study. While there
are some interesting mechanistic correlations in the data,
there is too little evidence to be able to draw conclusions
from these experiments alone. This particular study was
not attempting to add to the body of knowledge that shows

Cancer has been caused and cured in

mouse models a dozen times over, in
ways that have turned out to be
completely inapplicable in humans.
somewhat similar to human intakes, unlike some studies
that show that a particular chemical or food is carcinogenic when fed to rats in 100 or 1000 times the quantity
a human could ever possibly consume. That being said,
it would be nearly impossible for a human to consume
a 100% beef diet consisting of the highest-Neu5Gc beef,
except for the small number of people who eat only red
meat and no plant products.
There are several reasons why the results may not apply to
humans. Mice were consuming only the enriched feed in
the experiments, whereas humans typically have a much
more varied diet that does not include only red meat. Also,

a slight but consistent correlation between red meat consumption and elevated cancer risk in humans, but rather
attempting to tease out a possible molecular cause for the
effects seen, given that previous theories such as mutagens
created by grilling and generation of free radicals may not
explain the whole story.
Even one of the study authors commented in an interview
that dietary changes are probably not necessary for everybody, and if this line of research does bear out it may be
more useful for people with either a previous personal history of cancer, or a family history of cancer.

31

Should I be concerned about inflammation? What can I do

about it?
Possibly - a lot of studies have shown that chronic inflammation in general has a lot of negative health effects. As
mentioned previously, even low levels of inflammation have
previously been correlated with a number of negative health
effects. Regardless of any specific connections that may come
from further inquiry of this data, making efforts to reduce
systemic inflammation is likely a healthy long term choice.
Quite a few supplements have been touted as reducing
inflammation, but here too much more research is needed.
A number of diet and lifestyle changes can be easily made
though. Many of the things that reduce inflammation, such
as reducing tobacco and excessive alcohol use, improving sleep, consuming more plant-based foods, increasing
exercise and utilizing stress reduction techniques, promote

What should I know?

In a very carefully designed and controlled experiment,

genetically modified mice were fed a diet meant to simulate
consumption of red meat (and only consumption of red
meat, rather than red meat in the context of a much broader and varied diet). After being exposed to an immune
challenge against a cell surface molecule found in red meat,
the mice had increased markers of inflammation and an
increased occurrence of liver tumors.
More research is warranted into this possible mechanism, as
there isnt yet human data, so applying these results directly
to humans is more speculative at this time. In terms of red
meat and protein in general, Examine.com has looked at the
human science behind the observed increase in cancer risk
multiple times, most recently here and here.

general health outside of any inflammation concerns as well.

To discuss mouse models, in vivo experiments, and recipes
with and without red meat, visit the ERD Private Forum on
Facebook.

32

Sodium phosphate:
a potentially underutilized
ergogenic aid
Effect of sodium phosphate supplementation
on repeated high-intensity cycling efforts
Introduction

Phosphate doesnt get much attention in the nutrition and

supplement world, but it performs many important functions during exercise and everyday life. These include acting
as an intracellular buffer and enabling the release of oxygen
from hemoglobin. It also plays a critical role in energy production as a part of the basic structure of phosphocreatine
and adenosine triphosphate (ATP). Phosphocreatine serves
as an energy store that is available immediately during exercise, and can release energy without the need for oxygen.
ATP contains three phosphate groups and is often referred
to as the bodys energy currency.

Sodium phosphate has shown promise as an ergogenic aid

for endurance athletes thanks to a growing body of research,
though it is relatively unknown whether supplementation
improves performance outside of a lab, in the context of the
ever-changing demands of athletic competitions. Previous
research has found improvements in maximal aerobic
capacity (VO2 max) after supplementation, though mixed
results have been found for lower intensity endurance
performance.
The purpose of the study under review was to investigate
the effects of sodium phosphate supplementation in a

33

research setting that's a more realistic reflection of real-life cycling conditions (repeated maximal sprint and short time-trial efforts), after six days
of sodium phosphate supplementation, as well as four days after stopping
supplementation, to determine any lasting effects.

Who and what was studied?

Seventeen competitive male cyclists with an average age of 34.7 completed

this study. As seen in Figure 1, these are elite level athletes who ride about
200 miles per week, with an average of 5.4 years of racing experience and
VO2 max of 71 ml/kg/min.

Figure 1: Elite male competitive cyclists in the study

After an initial familiarization session and assessment, baseline performance was measured, followed by six days of supplementation with either
sodium phosphate or a placebo. The performance testing was then repeated
on day one and day four after stopping the supplementation.

Why do study
results differ for a
given ergogenic
supplement?
One reason that sports supplements
can show benefit in some studies
but not others is because there are
many different testing procedures
that researchers can use to determine if there is an effect from the
supplement trial.
For example, studies can test
participants using a time-trial (covering a pre-set distance as quickly
as possible), time to exhaustion
(maintaining a pre-set pace for as
long as possible), or repeated sprint
tests (generating as much power as
possible each time). Within these
different protocols there is a lot of
potential variability, like the distance of the time trials, the intensity
for the time to exhaustion tests, or
the number of repeated sprints to
be measured, as well as rest time
between efforts, whether the participants are recreational athletes or
trained professionals, etc.

This was a double-blind placebo-controlled study. Participants were given either 50 milligrams per kilogram of fat-free mass per day (about 3.3
grams) of sodium phosphate or placebo (mix of glucose and table salt),
divided into four doses and taken with meals (every four to five hours) for
six days.
Great care was taken to replicate the potential confounding variables before
each test. Participants did not exercise for 24 hours before each trial, and

Underlying all of these variables

are gender differences, as men and
women can differ significantly when
it comes to fuel sources, metabolism, and specific adaptations to
exercise. And most studies, including
this one, have been in males only.

testing took place at the same time of day (within an hour) to control for
34

circadian variation. Participants also kept a 24-hour diary

as overall power output during sprints (5%) and time trials

of all food and drink intake prior to the initial test and were

(4%) in the sodium phosphate group. Supplementation had

required to replicate that energy intake as closely as possible.

no impact on performance during the first set, but it led to

performance improvements in the second, fourth and fifth

The test protocol was modified from cycling race simula-

set, effectively reducing the fatigue seen in the later sets

tions used in previous research, and attempted to emulate

of sprints. No differences were seen in the placebo group

the constant up and down effort of actual racing. This test

during any set of sprints.

took 43 minutes to complete, which is substantially shorter

than cycling road races. The test was, however, similar to

Similarly, supplementation led to an improvement of 9%

criterium and certain track cycling races.

compared to baseline during the second time trial, which

was set six. It is hard to say why the power output in set six

The protocol itself was a mix of four sets of 6 15 second

was higher than set three, but it may be due to psychologi-

maximal sprints (with 45 or 15 seconds recovery in between

cal factors related to the final section of the test. Again, no

sprints) and two sets of five minute time-trials. Active

differences were seen in the placebo group during either of

recovery for three minutes (pedaling at 100 W) separated

the time trial sets.

each set.
Another important aspect of this study is that no differences

Seventeen competitive male cyclists supplemented sodium phosphate or a placebo for six days.
Performance tests were done on the first and
fourth day after supplementation stopped.

What were the findings?

Increases were seen for overall power output (5%), as well

in power output were found between day one and day four
in the sodium phosphate group, meaning the effects of the
supplementation were still present four days after supplementation had ceased. No changes in power output were
observed in the placebo group throughout the testing.
No differences in serum phosphate concentrations were
reported between the groups at baseline, day one, or day
four. However, compared with baseline, serum phosphate

What the heck is the smallest worthwhile change?

P-values are used in research in order to establish statistical significance, i.e. the
probability of whether or not a relationship between two variables has occurred
by chance and how strong the relationship is. But often there isnt a way to make
inferences about the clinical or real-world significance of the effect.
Sometimes, useful effects may not be statistically significant, while statistically
significant effects may not always be actually useful. Using an alternative statistical model, researchers can establish the smallest change that would still be
beneficial (or harmful) and use the confidence limits to make a qualitative statement about the real-world significance of the changes. This study also classified
outcomes for the smallest worthwhile change as beneficial, trivial, or harmful.
35

 [...] it is reasonable to think that

sodium phosphate would benefit
endurance athletes competing in events
lasting not only from 15 minutes to one
hour, but likely into the four to seven hour
window of elite road races.
actually decreased in the sodium phosphate group on day

endurance athletes. Six days of supplementation resulted in

one and day four, while serum phosphate concentrations in

improved performance (greater work and power outputs)

the placebo group remained unchanged.

during a simulated cycling road race, which included a mix

of repeated short-duration sprints and five-minute maximal

Total work (measured in kilojoules) increased in the sodium

efforts. Impressively, the benefits still existed four days after

phosphate group on day four, while the increases seen on

supplementation had stopped.

day one were not statistically significant. However, analysis

for the smallest worthwhile change indicated that improve-

Since the test used in this study took 43 minutes to com-

ments in overall power output and overall sprint power

plete, it is unclear how these benefits would translate to

output (but not time trial power output) would likely still

a road cycling race lasting three to seven hours. However,

be of benefit in competition. No changes were seen in the

because of the lingering effects of the supplementation, it

placebo group.

is reasonable to think that sodium phosphate would benefit endurance athletes competing in events lasting not only

Cyclists supplementing sodium phosphate experienced a 5% boost to power output during the
performance test. Most of the benefits were
observed later in the tests, suggesting sodium
phosphate can reduce fatigue.

What does the study really

tell us?

This study adds to the growing evidence that suggests

sodium phosphate may be an effective ergogenic aid for

from 15 minutes to one hour, but likely into the four to

seven hour window of elite road races.
There are a number of proposed mechanisms behind these
improvements, which the study did not specifically explore.
These include:
Increased phosphate availability contributing to creatine phosphate synthesis, phosphate-stimulated
glycolysis, and enhanced oxidative metabolism (even
with no changes in serum phosphate levels).
Enhanced red blood cell 2,3-diphosphoglycerate

36

(2,3-DPG) synthesis, promoting a decreased affinity

road cycling protocol incorporating repeated-sprints and

of hemoglobin for oxygen and resulting in great-

short duration time-trial efforts. These benefits were still

er unloading of oxygen to the peripheral tissues.

evident four days after supplementation had finished, with

Previous research has shown that it took approxi-

no performance differences found between day four and

mately two weeks for RBC 2,3-DPG concentration to

day one post-loading.

return to baseline following only three days of sodium

phosphate loading.
Improved myocardial efficiency, providing a great-

The differences here were small (about 5% improvements)

but highly significant in the world of competitive sports,

er stroke volume (and cardiac output), leading to

where fractions of a second can make the difference

increased and more efficient oxygenation of the mus-

between winning and losing. Sodium phosphate appears to

cles during exercise.

be an effective supplement for trained endurance cycling

Improved hydrogen ion buffering capacity, which is

athletes looking for improvements.

important for repeated sprint ability.

There are still many unknowns in regard to sodium phosAll of these factors may have played a role in this study, con-

phate supplementation, such as how long the optimal

sidering this protocol would have engaged multiple energy

dosing period is, how long the effects will last upon stop-

systems (creatine phosphate, anaerobic glycolysis, aerobic

ping the supplement, effects of repeated loading periods,

glycolysis) during the course of the test.

whether gender differences exist, and precise mechanisms

of action.

This study adds to the growing body of evidence

that supports the use of sodium phosphate as an
ergogenic aid for endurance athletes.

Keep in mind that energy demands differ between sports,

and sodium phosphate supplementation may affect athletes
in various non-cycling endurance sports, such as running
and swimming, differently.

The big picture

Six days of sodium phosphate supplementation resulted in

enhanced performance during a simulated high-intensity

Frequently Asked Questions

What type of sodium phosphate did the study use?

This study (and many others) used tribasic dodecahydrate

The differences here were small (about

5% improvements) but highly significant
in the world of competitive sports, where
fractions of a second can make the
difference between winning and losing.
37

sodium phosphate. Previous research using dicalcium phosphate or calcium phosphate has failed to find performance
improvements. It is possible that the lack of performance
enhancements were due to using a different loading protocol (in some cases only giving a single dose), or possibly
lower bioavailability. However, further research is needed to
confirm this hypothesis.
How much sodium phosphate should I supplement?
Studies have generally used three to five grams or 50 milligrams per kilogram of fat-free mass, per day. However,
different dosages havent been compared much against each
other. And as mentioned previously, studies tend to be in
males only. Along with the limited sample size of many studies, and their inclusion of highly-trained endurance athletes,
the results may not apply as well to a typical active individual.
Will sodium phosphate supplementation cause GI distress?
It is possible that high doses of sodium phosphate can cause
gastrointestinal distress. To minimize this side-effect, sodium phosphate is best ingested in smaller doses spread in
three to four doses throughout the day, with food.
What about the association between serum phosphorous
and cardiovascular disease?
There is an association between serum phosphate and
cardiovascular disease, however this study showed that supplementation does not raise serum levels and paradoxically
may even decrease them.

What I should know?

Sodium phosphate may be an effective supplement to

improve cycling performance in highly trained athletes, but

exact dosing strategies, performance benefits, and mechanisms of action remain to be elucidated.

Cyclists, endurance athletes, and sodium phosphate aficionados (do they exist? maybe they should) can check out the
private Facebook ERD forum for more discussion on this
paper.
38

On the whey to
getting lean: one
more round of
whey vs. soy

Whey Protein Supplementation

Preserves Postprandial
Myofibrillar Protein Synthesis
during Short-Term Energy
Restriction in Overweight and
Obese Adults
Introduction

Stuart Phillips group at McMaster University has been conducting research on

all things protein for close to two decades, with particular emphasis on how

protein feeding affects protein synthesis at the whole-body level, as well as specifically in the muscle tissue (obtained from muscle biopsy specimens).
Measuring protein synthesis (or degradation) in muscle is the best biomarker of
ongoing muscle anabolism or catabolism that exists. Protein synthesis during
weight loss is important since keeping muscle on helps regulate blood
sugar and keeps metabolism higher. Obtaining information about
fat or protein turnover at a particular point in time can tell us
how well the body is conserving lean mass during weight loss,
which is what this study intended to do.

39

Who and what was studied?

The purpose of this study was to examine the effects of whey

and soy supplementation on protein synthesis and biomarkers of lipolysis during weight loss, with carbohydrate
supplementation as the control. Even though body compo-

which is the major factor proteins ability to stimulate protein synthesis.

Figure 1: Grams of amino acids per 100

grams of whey isolate or soy isolate

sition was measured during this study, the effect of whey

or soy protein supplementation on body composition was
not a major endpoint of the study. This was likely due to the
relatively short duration of the study, as small body composition changes would not be detectable even with DXA
(Dual X-ray Absorptiometry) measurements, which the
study uses and is considered the gold standard for body fat
measurement. Previous research has shown the error from
DXA to be around 1.2%, which would eclipse the relatively
minor body composition changes from this study.
There have been many studies comparing the effects of
soy and whey protein in stimulating protein synthesis and
affecting body composition in a range of conditions, but few
that have looked specifically into the effect on protein synthesis and lipolysis during weight loss.
The studies that have previously compared whey to soy in
their ability to stimu-

Essential
Amino Acid

Whey Protein
Isolate

Soy Protein
Isolate

Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine
Total BCAAs
Total EAAs

6.1
12.2
10.2
3.3
3.0
6.8
1.8
5.9
24.2
49.2

4.9
8.2
6.3
1.3
5.2
3.8
1.3
5.0
18.1
36.0

In order to examine the effects of soy or whey on protein

synthesis during weight loss, 40 healthy, overweight and
obese participants (19 males and 21 females) were included and randomized to to receive either a twice daily whey
supplement (27 grams per supplement), soy protein supplement (26 grams per supplement) or carbohydrate (CHO)
controls (25 grams per supplement), resulting in a total
daily protein intake

late protein synthesis

and stimulate gross
muscle hypertrophy
in other contexts have
generally found whey
to be superior to soy.
As seen in Figure 1,
this is probably due to
whey having a more
complete amino acid
profile (most soy is
very low in two of
the essential amino
acids, methionine and
lysine) and especially
due to wheys higher leucine content,

[...] research has

shown the error from
DXA to be around 1.2%,
which would eclipse the
relatively minor body
composition changes
from this study.

of 1.3 grams per kilogram of bodyweight

in the protein-supplemented groups and 0.7
grams per kilogram
of bodyweight in the
CHO group. All food
was provided by the
research team in the
form of prepackaged
meals, to increase
compliance.
During the study, all
participants were first
put on a three-day
40

maintenance diet (given maintenance calories and 1 gram

significantly higher after ingestion of whey protein than

per kilogram of body weight of protein), subjected to the

after soy. Soy still outperformed the CHO control supple-

first test day, and then put on 14 days of a hypocaloric diet,

ment. In fact, the plasma leucine release (measured by the

followed by the second test day. The purpose of the main-

area under the curve [AUC]) from whey was almost three

tenance diet was to equilibrate the subjects and put them

times higher than that for soy, whereas the essential and

on even ground, metabolically speaking. The hypocaloric

total amino acid AUCs were approximately twice as high.

diet was calculated to provide an energy deficit of 750 kcals

per day, which should result in a weight loss of one to three

Not surprisingly, there were also differences in insulin and

kilograms over the course of 14 days. On both of the test

glucose concentrations following ingestion of the supple-

days, the subjects received stable isotope infusions with

ment between protein groups and the CHO control group,

isotope-labelled phenylalanine and glycerol, were DXA

both before and after the dietary intervention. Ingesting the

scanned, and had blood and muscle samples taken.

glucose control supplement resulted in higher glucose and

insulin levels than ingesting either protein supplement, with

Body composition (total, fat and lean mass) was obtained

no difference between soy and whey protein supplementa-

from DXA scans. Muscle protein synthesis was calculated

tion groups. As amino acids are absorbed more rapidly into

from tissue enrichment of stable isotope labelled phenyl-

the bloodstream from whey protein than soy protein, it is

alanine in muscle samples. Lipolysis (fat burning) was

plausible to expect higher blood glucose and insulin levels

calculated using the appearance of the isotope-labelled glyc-

after whey supplementation.

erol in the blood. Glucose and insulin levels were obtained

from blood samples.

There was also a significant difference between the amount

of circulating glycerol between the protein groups and the

Overweight and obese participants were randomized to receive either soy or whey protein,
or a carbohydrate control, and put on a hypocaloric diet. Body composition measurements and
muscle protein synthesis were measured and compared between groups.

What were the findings?

The researchers found no significant difference in body

composition between the groups. This was actually the expectation for a study of this duration and diet
composition.

CHO control group. Glycerol was lower in the CHO group

than in either protein group. This indicates that lipolysis is
suppressed following CHO ingestion relative to both of the
protein groups. In the post-prandial
condition, the amount of glycerol
in the blood is a measure of the
rate of ongoing lipolysis. Fat is
stored as triglycerides, and
when fat stores
receive neuroendocrine
signals to
mobilize
fat, tri-

It has been shown numerous times that whey is a so-called

fast protein, which means that the amino acids in it are
absorbed faster than other proteins with a similar amino
acid content. In this study we see this yet again, as release
of leucine, essential amino acids and total amino acids were
41

 [...] this study actually does not prove

that whey is superior for maintaining
lean mass during weight loss. [...] whey
probably is better, but that cannot be
determined from these results because
this study lacks statistical power to find
such differences.
glycerides are hydrolyzed into fatty acids and glycerol, both
of which are released to the circulation. The fatty acids
are metabolized in most of the body, whereas most of the
glycerol is used for gluconeogenesis. The most likely explanation for the lower glycerol levels observed following CHO
ingestion is probably that insulin strongly inhibits lipolysis.
Since it was shown that the CHO supplement resulted in
higher insulin, this further reinforces this hypothesis.
The main finding of the study was the effect of the protein
supplements on protein synthesis in the myofibrillar protein fraction of muscle (the so-called Fractional Protein
Synthesis, FPS), before and after the dietary intervention.
The researchers measured FPS before and after protein
ingestion, as well as before and after the dietary intervention. The baseline FPS was around 0.02-0.03%/hour, but
upon stimulation it increased to 0.06-0.07%/hour for whey
and 0.03-0.04% for soy. When the FPS was expressed as the
change in FPS from before to after supplement ingestion,
soy scored higher than the CHO control supplement and
whey scored higher than both. This means that whey stimulates the protein synthesis in muscle more efficiently than
soy protein does.

Whey protein was absorbed more quickly than

soy protein, and stimulated muscle protein synthesis by roughly two times the amount that soy
supplementation did. However, no differences in
overall body composition was observed between
the groups.

The big picture

The results regarding amino acid, glucose, insulin, and glycerol concentrations were in line with numerous previous
observations.

When it comes to the findings for body composition, this

study actually does not prove that whey is superior for
maintaining lean mass during weight loss. Theres a fair
chance that whey probably is better, but that cannot be
determined from these results because this study lacks statistical power to find such differences.
In order for differences between groups to manifest as statistically significant, a sufficient number of subjects must
42

be enrolled. If the between-group difference we are looking

degradation is just as important as modulation of protein

at is small relative to the variation in the observations, this

synthesis. This is supported by the results of some studies,

calls for more subjects. The study duration was short (14

which have shown that different protein sources may have

days) and therefore the changes in lean and fat mass are

different influences on protein synthesis and degradation.

small compared to the margin of error using a DXA scanner, meaning that if any difference did exist between groups,

The reason that protein synthesis is more frequently report-

it would have taken more participants or a longer study

ed is that the technology for measuring protein synthesis

duration for significant changes to manifest.

is much better than the technology available for measuring

protein degradation. All of these factors make it difficult

If you know the variation in the measurement you are doing,

to conclusively state wheys superiority over soy based on

you can actually calculate

this study. The protein

the number of subjects

synthesis measurement

needed to detect a group

difference of a given size.
This is called a power
analysis. The researchers
actually describe that
they knew they had inadequate power to detect
between-group differences, which was acceptable
as this was not part of
the primary objective for
the study. Alternatively,
this may be a real and

[...] whey stimulates

protein synthesis in
myofibrillar proteins
much more efficiently
than soy protein
supplementation.

valid finding. It is possi-

used in this study is a

surrogate for the effect
on muscle mass. But
changes in muscle
mass can be measured
directly with something
like DXA, albeit this
requires a more challenging study setup,
meaning more subjects
for longer time and a
higher study cost. Of
course, studies can
always be better or

ble that although one protein source may be more effective

more detailed, so maybe this study will be the springboard

than another in a short window of time for measuring FPS,

for the next, more detailed study.

overall dietary intake may be most important for producing

long-term adaptations in body composition.

Lastly, funding for this study was provided by the Dairy

Research Institute through the Whey Protein Research

What the study did show, however, was that whey stimu-

Consortium. However, the reported findings are in

lates protein synthesis in myofibrillar proteins much more

agreement with the literature and with other studies not

efficiently than soy protein supplementation. How this

supported by dairy farmers associations.

translates into lean mass sparing during weight loss is very

hard to derive for numerous reasons. FPS is normally used
as a surrogate biomarker for a snapshot of hypertrophy processes. However, hypertrophy or atrophy is the result of net
protein synthesis or degradation, which is again the product of gross protein synthesis and net protein degradation.
Therefore, it should be apparent that modulation of protein

Frequently asked questions

How much daily protein synthesis and degradation happens

normally, and under weight loss or muscle gain conditions?
Baseline fasted FPS in this study was around 0.02-0.03%/
hour, whereas the fed FPS was two to three times higher.
Based upon these numbers, and MPS and FPS data record43

ed elsewhere in the literature, we

can assume an average total protein synthesis of 1.0-1.5%/day.
This means that 1.0-1.5% of the
protein of the muscle protein
is built up and broken down per
day at muscle mass equilibrium.
The amount of muscle made out of
protein is constant, at around 20% of
the wet weight of muscle. As a normal
adult (60-80 kilograms / 130-175 pounds)
carries 30-40% of his or her body weight as
muscle mass, this corresponds to 200-400 grams
of muscle (or 40-80 grams of muscle protein) that is
built up and broken down, daily.
In the context of changes in muscle mass during sustained
weight loss or resistance training, the net changes in muscle mass are generally on the order of 10-50 grams per day.
These can be bigger at the onset of weight loss or weight
gain, but it still underscores that much more protein is
being built up and broken down on a daily basis, than that

protein synthesis measurements and several molecular

biology biomarkers, such as insulin signaling through the

which is ultimately gained or lost as hypertrophy or atrophy.

Akt/mTOR signaling cascade or FOXO transcription factor

Has there been research connecting muscle protein synthesis

by the poor reliability of the molecular biology biomarkers,

to the end result of muscle hypertrophy?

A previous paper from Phillips research lab compared the
protein synthesis measured following a resistance exercise
bout in a part of a chronic resistance training study with the
gross hypertrophy measured after 16 weeks of the resistance
exercise program. The researchers found no correlation
between the two measures. Even though that was in a training study, the result underscores that maybe using protein
synthesis is not as good of a biomarker as we sometimes
would like to think.
What about molecular biology markers of muscle gain and
loss -- do they have similar findings as muscle protein synthesis?

expression. In this case, however, this is more likely caused

as they can display anabolic signaling even in grossly catabolic cachectic subjects.

What should I know?

Ingestion of whey protein stimulates myofibrillar protein

synthesis during weight loss more efficiently than soy protein and naturally better than carbohydrate. This indicates
that protein obtained from whey may more efficiently spare
muscle mass than protein from soy, but the actual impact is
outside the capabilities of this study to assess.

To dig into the science of protein synthesis a bit more, head

over to the Facebook ERD forum.

It is also worth noting that there is a disconnect between

44

Its (not) all in your

head: how sodium
intake affects
headaches

Effects of dietary sodium and the DASH

diet on the occurrence of headaches:
results from randomised multicentre DASHSodium clinical trial

Introduction

Though headaches are very common, very little is known

about what causes them. Obviously, certain dietary choices
(namely too much alcohol or not enough water) can cause
headaches, so it makes sense that other foods could also
cause headaches. However, the evidence for this claim is
spotty at best.

For example, it was once believed that monosodium glutamate (MSG) could cause headaches. This belief was largely
the result of a doctor who wrote a letter to the New England
Journal of Medicine on Chinese restaurant syndrome, his
term for the physical effects of his own overindulgences.
The link between MSG and headache has not been proven
in rigorous studies, and the evidence is covered on Examine.
com. Yet that single letter was enough to make MSG the
most researched dietary factor related to headaches.
45

Headaches have been linked to other health and lifestyle

needs and compliance with the study protocol.

factors too. One of the most common factors is hypertension. Because hypertension is associated with headaches,

Compliance is critical for a detailed trial like this, so par-

and blood pressure levels have a well-known dietary com-

ticipants were required to eat at least one meal at the study

ponent, it is reasonable to believe that dietary factors that

site, five days per week. All of their other food was provid-

influence hypertension may also influence the occurrence

ed when they came for their on-site meal. The participants

of headaches. Therefore, the authors of this study set out to

were asked to record any uneaten food as well.

examine the links between headache occurrence and two

dietary factors known to reduce hypertension: the Dietary

After the run-in period, participants were randomized to

Approaches to Stop Hypertension (DASH) diet and reduc-

either the DASH diet or a typical American diet. Each

ing sodium intake.

participant stayed on the same diet during the entire study.

They were then further randomized to one of three different

Who and what was studied

This study on headaches was part of a much larger study of

the DASH diet and reduced sodium intake in hypertensive
or prehypertensive individuals. The original goal of that
study was to analyze whether the DASH diet and reduced
sodium levels have synergistic effects on blood pressure.
This study is a secondary analysis of 390 participants from
the original trial, being the roughly 95% of participants who
completed side-effect questionnaires.
Since the original study was a major trial designed to test
interactions between multiple dietary interventions, it was
extremely well controlled, and that feature carried over into
this study. Participants had three separate baseline visits
separated by at least seven days, and during that time (about
two weeks), they were fed a run-in diet to assess caloric

sodium levels (low, medium, or high), with the highest level

being equivalent to the typical American sodium intake.
Every 30 days, each participant was switched to a different
sodium level after a seven-day washout period, until each
participant had received all three sodium levels.
During the last week on each sodium intake level (at the
end of every month), the participants were tested for blood
pressure, body weight, and via urinalysis, and were surveyed for a variety of adverse events such as headaches
and fatigue. The urinalysis served a dual purpose of both
assessing metabolic factors and ensuring compliance (by
measuring sodium secretion). This study design is a great
example of a well-designed randomized crossover study
because it has strict adherence policies, multiple assessments of compliance, and blinded data collection staff.

Are secondary analyses second-class

citizens in the research world?
Secondary analyses are often treated the same as analyses from the original study, at least in the
media. But they probably shouldnt be. The original study that this was based on wasn't designed to
examine the headache issue, so it's not quite as convincing as a study that was.
The reason has to do with statistics. When you state a primary hypothesis before launching the study,
conclusions are more statistically reliable than doing post hoc hypothesis testing. This is because
you can fish around for significant results and make a paper out of whatever you find (which may or
may not be due to chance, despite a significant p-value), as opposed to being forced to focus on your
main hypothesis no matter what the outcome was when you state it a priori.
46

Study participants were split into two groups: eating a diet designed
to reduce hypertension, or a typical American diet. Then, each
participant spent a month eating at each of three different sodium
levels: low, medium, or high. Researchers measured blood pressure
and body weight, as well as tracked when headaches occurred.

Figure 1: Incidence of
severe headaches by
diet and sodium intake

What were the findings?

The high sodium diets (whether typical or DASH) had a significantly greater
incidence of headaches compared to the low sodium diets.
Going from low to intermediate to high sodium levels steadily increased headache
odds in both the DASH diet (36% to 38% to 43%) and control diets (39% to 41% to
47%). However, the difference in headache risk between the intermediate sodium
intake group and the lowest and highest sodium intake groups was not statistically significant. This may be related to the fact that this is a secondary analysis of a
study not specifically designed to analyze headache occurrence. Headaches were
were only measured once in each study period, and the study didnt collect data on
previous headache prevalence, among other design limitations.
Interestingly, the association between headache occurrence and sodium intake
persisted regardless of hypertension status or blood pressure. As one might
expect in a trial of hypertensive individuals who were fed the DASH diet, some
participants experienced a decrease in blood pressure below hypertensive levels.
However, even in these individuals, the correlation between headache risk and
sodium intake remained.
Perhaps most surprisingly, there was no overall difference in headache occurrence between the healthy DASH diet and the typical American diet. There
was however a difference between DASH dieters eating low sodium (36% had
headaches) and control dieters eating high sodium (47% had headaches).
The study participants also classified their headaches as mild, moderate, or severe.
Most headaches were classified as mild, and higher sodium intakes generally were
associated with a bit higher (although not statistically significant) mild-to-moderate headache rates. Despite the small number of severe headaches, Figure 1 shows
that high sodium seemed to have an association with severe headache incidence.
This association trended toward significance in both diet groups.

47

What does this tell us?

The Big Picture

hypertension affects headaches, and this study indicates

well-established. Similarly, the correlation between dietary

that sodium affects headaches in hypertensive individuals.

factors and hypertension is well-known, in part thanks to the

However, diet and hypertension status did not play a role

grandfather of this and many other dietary trials: the DASH

in the interaction between sodium intake headaches, which

study. On the opposite side of these famous and well-de-

suggests that sodium intake and headache risk may be

signed studies is the largest body of evidence for dietary

linked even in people who are not hypertensive.

factors that contribute to headache: a bunch of studies that

It is well-known that sodium affects hypertension and that

The correlation between hypertension and headaches is

refute anecdotal evidence linking headache to MSG conThis is supported by the data that show that hyperten-

sumption. Some believe that diets high in fruits and veggies

sion status was not correlated with the effects of sodium

are a panacea of sorts, and can curb pretty much any malady

on headache risk, but it is also worth mentioning that the

including headache. This study doesnt support that notion.

hypertensive participants had significantly more headaches

than the people with normal blood pressure. So there may

This study does show that sodium intake and headache

be more to the interactions between hypertension, sodi-

are probably correlated, but its still not known how. The

um, and headaches than can be revealed by the design of

simplest theory is that headaches are related to sodiums

this study. Its possible that sodium may impact headaches

effect on blood pressure. This study provides relatively weak

through mechanisms unrelated to blood pressure.

evidence, since it shows that sodium intake and headache

correlate regardless of blood pressure levels, diet, or hyper-

It is important to remember that this trial, no matter how

tensive status. Were left with a situation thats as promising

well-designed, was not originally intended to study the

as it is frustrating. Its relatively certain that sodium intake

effects of sodium intake on headache. Therefore, these analy-

(or intake of sodium-rich foods) affects headache occur-

ses are based only on reports of headaches while on the study

rence, but theres no good explanation as to how that

protocol. Headache frequency was not assessed at baseline,

happens. Regardless, this study still makes the case for lower

which may be one of the reasons that this studys findings are

sodium consumption than is typical in modern diets, if one

only significant for the high and low sodium intake groups.

is trying to reduce headaches.

This is an important factor to consider when comparing

these data to other studies on headache occurrence.

However, other merits of reducing sodium intake have been

heavily debated recently. A recent study in the Journal of the

Perhaps most surprisingly, there

was no overall difference in headache
occurrence between the healthy DASH
diet and the typical American diet.
48

American Medical Association (JAMA) that found no associ-

Heart Association recommends <2.4 grams sodium and

ation between sodium intake and mortality or cardiovascular

says 1.5 is even better. The US Centers for Disease Control

disease. Though headaches are not the same as death, the

recommendations are similar to those of the AHA.

differences between the studies are still worth mentioning.

Notably, the JAMA study analyzed data from a much longer

Generally speaking, if you have cardiovascular disease or

time frame in a much larger cohort of patients, but it did so

hypertension, less than 1.5 grams of sodium per day is a

using self-reported data. In contrast, this study followed a

smaller group of patients (but still sizeable by trial standards)
with much more rigorous requirements and assessments.
The World Health Organization (WHO) and other groups
already recommend a diet with significantly lower sodium
than the average American consumes, due to the interaction
between sodium and hypertension. A reduction of headache
occurrence may be an added benefit. The typical American
consumes ~182.7 mmol sodium per day, which is similar to
the 150 mmol received by the high sodium intake group in
this study. The current WHO recommendation is 87 mmol/
day. However, it should be noted that the WHO recommendation is still higher than the intake of the low sodium
group in this study (50 mmol). So although there may be a
general consensus of eat less sodium, there is not nearly
enough evidence to offer a firm recommendation beyond a
general upper limit. And that is besides the recent controversy about whether sodium reduction actually has benefits,
which could turn decades-old diet advice on its head.
For headache sufferers, this study provides a tantalizing bit
of well-controlled evidence, especially since effective prevention for some people can seem quite elusive. But dont
equate the results with causation -- its still possible that
high-sodium foods eaten in the study could cause headache
independent of their sodium content. The data on headaches resulting from foods and nutrients is unfortunately

Its relatively
certain that
sodium intake
(or intake of
sodium-rich
foods) affects
headache
occurrence, but
theres no good
explanation
as to how that
happens.

quite sparse.

Frequently Asked Questions

There are many different recommendations for sodium
intake (WHO, AHA, etc). Which should I follow?
Thats hard to answer definitively. The WHO recommends

good goal. If youre otherwise healthy, you can probably get

away with eating up to 2.4 grams, but that is based on governmental and organizational guidelines, which may change
as evidence is changing.

<2 grams sodium (so <5 grams/day salt). The American

49

Its important to note, however, that none of these recom-

MSG has sodium in it. Could that possibly explain the

mendations are based on headaches at all. They are strictly

effects observed in some individuals consuming MSG?

related to the research on interactions between hyperten-

Most MSG health effect reports are anecdotal. The effects of

sion and sodium.

MSG may be overstated, as blinded trials havent identified

any adverse events associated with MSG consumption, even

Is this study sufficient to recommend or adopt a reduced

in individuals who self-identify as sensitive to MSG.

sodium diet for people who suffer headaches?

Its impossible to make a definitive statement about recom-

In fact, in one study, individuals who claimed to be sensitive

mendations based on one or even a few studies, no matter

to MSG were repeatedly randomized in four separate trials,

how well-designed. However, if you struggle with head-

and only two out of 130 responded appropriately to their

aches, reducing sodium consumption may be worth a try

treatment in all four trials. Furthermore, regularly con-

because its a relatively easy intervention without any known

suming enough MSG to notably affect sodium intake levels

side effects and multiple potential benefits.

would be a substantial feat because a gram of pure MSG

equates to only 150 mg of sodium. It would take over 13

Is there any good reason to increase sodium intake?

grams of MSG to reach the maximum intake recommended

It is often recommended that individuals engaged in very

by the WHO (2 grams).

strenuous activity (for example, ultramarathon runners)

should consume something with added sodium to prevent
hyponatremia, but there isnt that much evidence to support
this assertion, and it may be more important to limit excessive fluid intake.
Oral rehydration therapy (for people with major GI illnesses or severely dehydrated individuals who need to recover
electrolyte levels) has sodium as one of its major components, but the effects of that therapy are related to the
interplay between glucose, sodium, and water absorption in
the small intestine rather than sodium alone. Furthermore,
if a person experiences a GI illness that severe, they are
likely already receiving medical care that includes a comprehensive rehydration protocol. Individuals who engage in
extreme weight cuts for sport performance may consume

What should I know?

This study was very well-designed and had a rather strong

conclusion. It showed that sodium intake likely influences
the prevalence of headaches irrespective of other dietary or
demographic parameters. However, its important to note
that the effect size was not large, which implies that reduced
sodium consumption may reduce the frequency of headaches, but its rarely the sole cause and unlikely to be the
sole solution.
However, most people can stand to reduce intake of junk
foods that are often high in salt, and its unlikely to cause any
negative effects, except possibly reducing your consumption
of delicious and addictive snacks you ate as a child.

extra sodium to rehydrate, but it is likely more effective

when combined with glucose.

If all this analysis is giving you a headache, take a load off

on the Facebook ERD forum.

Lastly, those with low blood pressure can also find salt to be
useful when facing hypotensive episodes.

50

Diets, fast and slow

The effect of rate of weight loss on

long-term weight management: a
randomised controlled trial
Introduction

Many people say that dieting is hard, and that keeping the lost weight off is even harder. But

we dont need to take their word for it, the science of weight loss backs up their claims. One
review, containing evidence gathered during most of the 20th century, found that only about
15% of obese people were successful in keeping a significant amount of weight off long-term
through dieting!
Why is dieting so hard? Maybe its because the way we go about dieting isnt quite right.
Government agencies in the U.S., U.K., and Australia all recommend an initial, gradual weight
loss strategy of one to two pounds a week. Gradual weight loss is recommended for several
reasons. It allows more time for people to form the habit of eating fewer calories. Also, crash
diets with very low daily caloric intake can sometimes lead to nutritional deficiencies. Plus, its
claimed that crash diets lead to larger rebounds after the diet is over, which makes sense considering that very low calorie diets have been seen to lower basal metabolic rate.
51

But is this true? There is certainly some evidence to suggest

the relative lack of evidence comparing rapid and gradual

that it is. For instance, one study found that counselling

weight loss. By randomizing rapid versus slow weight loss,

overweight and obese women to make small changes in

the researchers hoped to answer whether or not the speed of

their diet with the goal of 1800 calories per day succeeded

initial weight loss actually affects keeping the weight off.

in slow, steady and sustainable weight loss that persisted

even after a year. A control group that provided counselling
encouraging a 1200 calorie/day diet ended up with regaining weight after a year.
However, there is disagreement about whether or not slow
weight loss actually leads to better outcomes. One review of

Guidelines currently suggest that slow weight

loss is preferred to rapid weight loss, since rapid
weight loss may not lead to sustainable results
over time. The evidence, however, is not clear-cut
on this matter.

the literature suggests that faster initial weight loss was associated with better long-term weight maintenance, as long
as proper support is provided. A recent trial, which encouraged older, obese women to decrease daily caloric intake
to 1200 while increasing physical activity, found that the
people who achieved more rapid weight loss both lost more
weight and kept more weight off. However, this trial was not
randomized, so its hard to say whether the rapid weight loss
caused the increased success in weight maintenance or not.
Sustained rapid weight loss is a bit more common in clinical
settings. Protein-sparing modified fasts (PSMFs) are sometimes prescribed to very obese patients, and have calorie
intakes of 500-600 kcal per day. For these patients, PSMFs
can have better long-term weight loss than other approaches. While there is a
rebound, as with any
diet, adherence is fairly
high and people remain
motivated because they
can see the scale moving. These patients, as
they tend to be very
heavy, also tend to face
substantial and often
immediate health risks
if weight is not lost.
The purpose of this
study was to address

Who and what was studied?

Participants were recruited via advertisements in

Melbourne, Australia. To be included in the trial, the participants had to be obese (defined as a BMI between 30 and
45) but otherwise healthy adults between 18 and 70 years
old. People who smoked, were on medications that could
affect weight, had any clinically significant disease (such as
diabetes), or who used weight-loss drugs or adhered to a
very low calorie diet three months prior to recruitment were
all excluded.
The 204 participants were studied in two different phases.
The goal of the first phase was to have participants lose 15%

[...] only about 15%

of obese people were
successful in keeping
a significant amount
of weight off long-term
through dieting!

of their weight, either

quickly or slowly. The
second phase took only
people who met this
goal, so they could
be observed to determine how well their
weight loss could be
maintained.
The first phase was performed by randomly
assigning participants
to either a fast or slow
weight loss program.
52

Both programs had the aim of a 15% loss in weight using an

overall caloric deficit of 105,000 calories, but over different time
frames and using different methods. The fast program consisted of replacing three meals a day with Optifast, a commercial
meal replacement. The total caloric intake for this group varied
between 450 - 800 calories a day, depending on the individuals
needs to reach their 15% weight loss goal over 12 weeks. This
rate of weight loss is about equal to 1.5 kilograms or 3.3 pounds
per week.
The slow groups diet consisted of a 400 - 500 calorie deficit achieved by using one or two Optifast meal replacements,
alongside a diet concordant with the Australian Guide to
Healthy Eating from 1998 (which has since been updated to
allow for more protein), which suggests that 15% of daily calories come from protein, 2530% from fat, and 5560% from
carbohydrates. The aim of the slow diet was for each participant
to lose 15% of their weight over 36 weeks, which would average
out to about 0.5 kilograms or 1.1 pounds per week.
Both groups were given the same educational material and
assigned to biweekly meetings with a dietician, who provided
feedback on their progress. Both groups were also encouraged
to exercise at a mild or moderate intensity for at least 30 minutes a day. Study participants who succeeded in losing at least
12.5% of their weight in both groups moved on to the second
phase of the study.
The purpose of the second phase was to determine whether
the rate of weight loss affected the ability to maintain the losses. Each participant received an individualized plan, which
again adhered to Australian Guide to Healthy Eating. Each
participants goal was to maintain their weight. They met with
a dietician four and 12 weeks into phase 2, and every 12 weeks
thereafter, for 144 weeks. Their adherence to the diet was monitored via self-reported food intake logs. If a participant was
gaining weight, they were advised to change their diet to create a
400 - 500 calorie deficit.
In addition to weight, fasting ghrelin (a hormone that induces

Random samples,
random assignment
This study was a randomized trial. But what
exactly was randomized, and why does randomness matter in the first place? There are two
types of randomness that pertain to trials like
this: random sampling and random assignment.
Random sampling is when each member of a
population has an equal chance of being selected for a study. It allows you generalize the result
of a study from the subset included in the study
to the entire population. Why cant you do this
without a random sample? Because there may
be bias otherwise. For instance, if we put a poll
up on Examine.com to ask people Do you care
about the evidence behind abstracts? wed
probably get a large number of yes responses.
You Examine.com readers exceptionally curious,
and definitely not a random and representative
sample.
This study did not use a random sample of people, but instead enrolled people who answered
an ad or heard about the study through word of
mouth. Since this sample could be biased (for
instance, perhaps those who answered the ad
were very motivated to lose weight), it would be
hard to generalize the results of this study to all
people.
However, this study used another kind of randomness that is also important: they randomly
assigned participants to groups. This helps to
infer causality in a study because it helps to get
rid of confounding factors.

hunger) and leptin (a hormone that induces satiety) blood levels

53

 One of the
biggest findings
from this study
is that the rate of
weight loss does
not affect weight
regain in the tested
population

What were the findings?

Almost 90% of participants completed phase 1 (the weight

loss phase) of the study, with significantly more people
dropping out of the slow weight loss group (18% vs. 3%).
The biggest reason cited for dropout was difficulty of sticking to the diet.
As seen in Figure 1, more people in the fast weight loss
group achieved their goal of reducing their weight by 12.5%,
and the result held up whether all subjects were considered
or just those that completed phase 1. There was no significant difference in changes in fat-free mass in either group.

Figure 1: Rate of weight loss

and subjective hunger assessments were also measured at

the start of the study, the end of phase 1, and weeks 44 and
144 of phase 2. A subgroup of participants also had their
3-beta-hydroxybutyrate levels drawn, which is a measure of
ketosis. Activity was measured with a pedometer.

This trial was implemented in two phases. In

phase 1, obese adults were randomized into two
diets designed to reduce their weight by 15% over
either 12 weeks (the fast group) or 36 weeks (the
slow group). In phase 2, participants who succeeded in losing at least 12.5% of their weight
were put on a maintenance diet designed to maintain the weight loss. Researchers intended to
determine if rapid weight loss leads to rebound
weight gain, and what role hunger plays in the
rebound process.

There were some biochemical differences between the

groups in phase 1 as well. The fast weight loss group had
significantly higher levels of 3-beta-hydroxybutyrate (indicating ketosis) partway through phase 1, but there was
no difference between groups at the end. Leptin (which
promotes satiety) decreased throughout phase 1 for both
54

groups, but decreased significantly more in the fast weight

loss group. Ghrelin (a hormone that induces hunger) rose
equally for both groups throughout phase 1. Both groups

Figure 2: Success rate during weight loss

phase (12.5% or more weight loss)

reported an increase in subjective hunger, although there

was no difference between the groups.
The fast weight loss group tended to walk about a thousand steps more per day than the slow weight loss group,
even though they were both given the same exercise advice.
However, the amount of steps taken did not differ between
groups when only participants who succeeded in losing
12.5% of their weight were examined. People who walked
more were not more likely to meet their goal, as there was
no significant difference in number of steps taken per day
between people who met the weight loss goal and people
who didnt.
Overall, 51 participants from the slow weight loss group and
76 from the rapid group moved on to phase 2 of the study in
order to determine if the weight loss could be maintained.
There was no significant difference in the dropout rate
between groups in phase 2 of the study. All but six people

Leptin rose at a similar rate in both groups in phase 2, but

(one from the slow group and five from the fast group)

participants who regained less than 25% of the weight lost

started regaining weight, and so were put on a 400 - 500

in phase 1 had much lower leptin levels than those who

calorie per day deficit, as per the experimental protocol. As

gained more than 75% of it back. Ghrelin levels decreased

seen in Figure 2, during phase 2, no significant difference

a little during phase 2, but still remained elevated, with no

in weight gain was seen between groups; both regained

significant difference between groups. However, subjective

over 75% of the weight they originally lost on average. This

hunger was higher in the group that lost weight quickly

put both groups at a total of about 5% weight loss over the

than in those who lost it slowly.

course of the study. The pedometer measurements also

didnt differ between groups.

There were also some differences in adverse events between

the groups. During phase 1, one person developed acute

Also, crash diets with very low daily

caloric intake can sometimes lead to
nutritional deficiencies.
55

cholecystitis, a condition known to occur with rapid weight changes, where the bile
duct of the gallbladder is blocked, which leads to inflammation. The authors of the
study considered this to likely be caused by the rapid weight loss. Two other serious
adverse events occurred in the rapid weight loss group (cancer) that the authors do
not think was caused by the rapid weight loss. One person in the rapid weight loss
group also withdrew due to worsening depression, on which the authors did not
comment. There were no adverse events in the slower weight loss group.

Its quite
apparent
that the
body fights
losing
weight and
keeping it
off.

The fast weight loss group had an easier time sticking to the diet
than the slow weight loss group. The fast weight loss group was also
more successful in losing at least 12.5% of their weight in phase 1 of
the study. Both groups gained back about 30 pounds during phase 2
while trying to maintain their weight loss, with no significant difference between the two groups. Hormonal and subjective measures of
hunger rose throughout phase 1, and only dipped slightly in phase 2.

What does the study really tell us?

One of the biggest findings from this study is that the rate of weight loss does not
affect weight regain in the tested population: obese nonsmokers, who dont take
any weight loss drugs and who dont have diabetes. This puts a dent in the idea

that rapid weight loss leads to greater weight gain down the road. It also tells us
that rapid weight loss can be even more successful than gradual weight loss, since
more people were able to stick to the rapid weight loss plan than the gradual one,
while also meeting their weight loss goal.
It also tells us something many of us already know: dieting is hard. The total
weight loss for both groups ended up being about 5%. Most of the weight lost
during the dieting phase of the study was regained during the maintenance phase,
although that phase was an incredible 144 weeks long, so its not like the weight
was regained right away. Its also important to note that results reflect averages for
the sample -- some may have been wildly successful, while for others life events
may have gotten in the way, as they often do. In other words, there can be quite a
bit of human variation when trying rapid vs gradual weight loss.
Its quite apparent that the body fights losing weight and keeping it off. Hunger
was observed to increase and persist in both groups throughout both phases,
boosted by a rise in ghrelin (a hunger hormone) that persisted for at least three
years (the length of this study), and which doesnt level off much, even as weight
is regained. Leptin levels (a satiety hormone) also remained low in people who
56

kept weight off, but rose in people who put significant

weight back on, suggesting that the body is attempting to
get its weight back to where it started.
Keep in mind, the people in this study had access to nutritional counseling and were under medical supervision
throughout the course of the study. The authors note that
because of this, the results of this study may actually be
better than what could be expected in the real world, where
people are not under such strict supervision. This was also
one conclusion of a systematic review of weight loss studies,
and suggests that the methodology of rigorous clinical trials
like this may make their results less generalizable outside of
the context of a controlled study environment. The fact that
the studys participants did not have diabetes and did not
smoke, and that a specific brand of meal replacement was
used, may further limit the generalizability of these results.
But, since this was a randomized trial, a pretty strong conclusion can be drawn: fast weight loss does not necessarily
cause fast regain, and can be a relatively effective method for
weight loss for some people.

This study found that losing weight quickly does

not lead to any more weight gain than losing
weight more slowly, and in fact can be more effective. However, it may be difficult to generalize
these results to different populations outside of a
clinical setting.

Making more
choices drains
willpower, which
has been shown
to affect food
choice.
meal replacements that use high-quality protein and are fortified with nutrients have a better safety record when used
under medical supervision. Early PSMF diets employed for
rapid weight loss used fairly incomplete proteins like collagen, along with very few micronutrients, and thus do not
apply to modern PSMFs.
There are some aspects of the rapid weight loss plan that
may have helped the participants of this study be more
successful. First, participants in the fast group in this study
didnt have to measure portions, as they completely relied
on meal replacements to lose weight, whereas people in the
slow group still ate some conventional meals. Measuring
portions to count calories isnt always accurate and can be
hard to learn, which may explain some of the fast groups
success. Also, the use of meal replacements eliminates

The big picture

Despite the fact that some government agencies and common sense dictates that losing weight more slowly is more
sustainable, this study showed that rapid weight loss can be
a more effective method of losing weight, and doesnt necessarily lead to more weight gain. Very low calorie diets have
had a history of safety concerns, primarily caused by poor
nutrition. At such a low calorie intake, youre unlikely to
get the nutrients you need to be healthy. However, modern

variety in the diet, which helps satiety and leads to less food
eaten, and has been seen to increase diet compliance and
weight loss in another study. The psychological phenomenon of decision fatigue may also play a role here. Making
more choices drains willpower, which has been shown to
affect food choice.
While caution in extrapolating the results of this study to
other populations is warranted, this study is an important

57

contribution to the science of dieting. According to the

5% drop in weight can help significantly lower the risks of

authors, there were no randomized, controlled trials specifi-

developing many of the chronic diseases associated with

cally studying the effects of the rate of weight loss on weight

obesity.

maintenance. Due to the relative lack of evidence for the

widespread belief that rapid weight loss can lead to stron-

Keep in mind that the study participants regained weight

ger rebound weight gain, this belief has been questioned in

over three years. After one year, they had still retained more

some recent papers. The current study adds to the evidence

than half of their initial weight loss. Maybe if the study

supporting that, at least for some people, some of the time,

implemented a one-year anniversary kick-in-the-butt to

slow and steady does not always win the race.

get participants back on track, the results might have been

different. But as it stands, the study protocol was the same

This study suggests that while very low calorie

diets have been shown to be be potentially harmful in the past, they may be a viable weight loss
option for obese people if done under proper
nutritional and medical supervision. There are
several behavioral reasons why modern meal
replacements may have contributed to the success
of the fast weight loss group in this study.

throughout the three years of maintenance, and that didnt

really work out.
Can crash diets be harmful?
Yes, in some circumstances they can be. In this study, one
person suffered from an inflamed gallbladder, which was
attributed to the diet. The American Association of Clinical
Endocrinologists mention several other dangers, such as
uric acid buildup in the blood from very low calorie diets,
which can lead to severe complications, including kidney
damage. These kinds of diets, with calories under 1000 kcal

Frequently asked questions

How much of the weight loss came from muscle in this

study?

per day, should be done under medical supervision.

What should I know?

Fat-free mass was measured at the end of both phases

This study found that medically-supervised, rapid weight

using bioelectrical impedance, and it did not significantly

loss in obese individuals leads to no more weight gain after-

decrease in either group. While bioelectrical impedance

ward than slower weight loss. This method also had a higher

is often considered a worthless, garbage, waste-of-time

success and compliance rate. This runs counter to current

measurement among those who are really into fitness, its

recommendations, which suggest that rapid weight loss is

actually not a bad way to measure changes in a single indi-

harder to achieve, and can lead to greater weight gain down

vidual over time.

the road.

However, it is important to point out that muscle loss was

not measured throughout the weight loss phase. But while
we cant really say too much about muscle loss from this

Hungry for more? Whet your appetite for discussion in the

private ERD readers Facebook group.

study, a large change in muscle loss would have likely shown

up in the group means.
The people in this study only lost 5% of their bodyweight by
the end of the study. Thats not much, right?
Modest weight loss can still have several benefits. Even a
58

Is the glycemic
index actually
useful for making
food choices?

Effects of High vs Low Glycemic

Index of Dietary Carbohydrate
on Cardiovascular Disease Risk
Factors and Insulin Sensitivity
Introduction

Foods that contain similar amounts of carbohydrates may differ in the amount and
speed at which they raise blood glucose levels. This quality is referred to as the
glycemic index (GI), and is based upon the blood glucose response (total
area under the glucose curve) over two hours to 50 grams of its carbohydrate content, as compared with 50 grams of glucose.
The higher a GI value is, the more the food raises blood sugar in a
way similar to pure glucose. Lower GI carbs are those that digest
more slowly and dont raise raise blood glucose to the same degree.
However, GI can also be a function of insulin response, and not
just a function of carbohydrate digestion or meal composition.
It has become common practice among healthcare professionals to
suggest an individual consume low glycemic index carbohydrates.
However the effects of GI on diabetes and cardiovascular disease (CVD)
risk factors have been equivocal in trials, as well as meta-analysis of
observational studies.

59

Further complicating matters is the fact that carbohydrates

Over half (52%) of the participants were women and

are not eaten in isolation, but generally as part of mixed

51% were black. The authors oversampled black partici-

meals containing fat, fiber, potassium, polyphenols, and

pants because of their disproportionate burden of insulin

other nutrients that can affect health measures. It is still

resistance and other risk factors that result in high rates

uncertain what (if any) practical significance there is for

of diabetes and cardiovascular disease. Signs of metabol-

manipulating GI in the context of an otherwise healthy diet.

ic dysfunction were present in many of the participants,

including hypertension (26%), obesity (BMI 30) (56%),

The DASH diet, or Dietary Approaches to Stop

LDL cholesterol at or above 130 mg/dL (68%), triglycerides

Hypertension, is an eating plan recommended for people

at or above 150 mg/dL (17%), and elevated (100 mg/dL)

with hypertension or prehypertension. The DASH diet has

fasting blood glucose (30%).

been shown to reduce blood pressure, lower risk of coronary heart disease, and improve bone mineral status. The

Four possible diets were provided based on the DASH-diet

diet puts a big emphasis on increasing fruit and vegetable

guidelines. Participants were provided all of their meals,

consumption, controlling sodium intake, and reducing pro-

snacks, and calorie-containing beverages throughout the

cessed food.

study. The intake of key factors such as total carbohydrates,

fiber, fatty acids, potassium, and sodium was controlled for.

The objective of this randomized controlled crossover feed-

While GI values do not take mixed meals into account, the

ing study was to determine the effects of GI and amount of

meals used in the study for high and low glycemic index

total dietary carbohydrate in the context of a DASH-type

were put together using similar types of foods according to

diet, on various risk factors for diabetes and CVD.

their values (for instance, white bread versus whole wheat

bread). The four diets were:

Who and what was studied?

A total of 163 overweight adults with above-normal blood

pressure completed this trial, which was performed at Johns

Hopkins Medical Institution (Baltimore, MD) and Brigham
and Womens Hospital (Boston, MA). Participants were
at least 30 years old, had elevated blood pressure (120-159
mmHg systolic and 70-99 mmHg diastolic), and were classified as overweight or obese by having a BMI of 25 or higher.

1. Highglycemic index (65% on the glucose scale),

high-carbohydrate (58% of total energy)
2. Lowglycemic index (40% on the glucose scale),
high-carbohydrate
3. Highglycemic index, low-carbohydrate (40% of total
energy)
4. Lowglycemic index, low-carbohydrate

A sample guide to the DASH diet

Type of Food
Grains
Fruits
Vegetables
Low fat dairy
Lean meats/seafood
Nuts/seeds/legumes
Fats/sweets

Examples
Whole wheat bread,
rice, quinoa
Apples, bananas, oranges
Spinach, tomatoes, carrots
Milk, yogurt, cheese
Beef, chicken, salmon
Almonds, cashews, beans
Avocado, olive oil

Number of Servings/day
6-12
4-6
4-6
2-4
1.5-2.5
3-6/week
2-4
60

 It is still uncertain what (if any) practical

significance there is for manipulating GI in
the context of an otherwise healthy diet.
Each participant completed at least two of the study diets for
five weeks each, with a two-week break consuming self-selected foods separating the diet interventions. Body weight
was maintained by adjusting calorie intake, and participants
recorded any additional foods as well as foods they did not
eat. Maintaining body weight was important because simply
losing weight can independently improve CVD risk factors.

What were the findings?

Figure 1 shows the primary outcomes at baseline and after

each diet.

Figure 1: Primary Outcomes at Baseline

and at the End of Feeding on Each Diet

Despite these efforts, participants still lost an average of 1

kg from baseline until the end of each diet period. However
there were no differences between groups. The main outcome measures were insulin sensitivity, LDL-cholesterol,
HDL-cholesterol, triglycerides, and systolic blood pressure.
Daily
intakes

Low carb,
high GI

Low carb,
low GI

High carb,
high GI

High carb,
low GI

Kcal

2011

1993

2011

1998

Protein (%)

23

23

16

16

Carbs (%)

41

40

58

57

Fat (%)

37

37

27

27

Fiber (g)

29

33

32

37

Potassium
(mg)

3949

4026

39663

4103

Glycemic
Load

112

64

172

104

Area under the glucose curve (AUC) this is a way to measure how much and for how long a persons blood sugar is

Study participants consumed at least two of the

four available diets during the course of the study.
The different diets contained either low or high
carbohydrate meals, using either high or low glycemic index foods. Researchers measured insulin
sensitivity, LDL-cholesterol, HDL-cholesterol,
triglycerides, and systolic blood pressure.

elevated. On the high-carb diet, eating low GI reduced the

12-hour AUC by 17% compared with high GI. However,
on a low-carb diet there was no difference in glucose AUC
between high or low GI diets.
The low-carb, high GI diet reduced AUC by 19% compared
with high-carb, high GI, but there were no differences
between high or low-carbs diets with low GI. Finally, the
AUC was reduced by 20% in low-carb, low GI compared
61

with high-carb, high GI. To summarize, either low-carb or

lowered with both low-carb diets, and increased on both

low GI will lower blood glucose through a 12-hour period,

high-carb diets.

but choosing both will not provide additional benefits.

To summarize:
Insulin sensitivity - On the high-carb diet, the low GI diet
unexpectedly reduced insulin sensitivity by 20% compared
with the high GI diet. There was no difference in insulin
sensitivity on the low-carb diet between high and low GI,
but another unexpected result was that the low GI diet
increased fasting glucose levels compared with high GI.
Insulin sensitivity was not different between high and lowcarb diets (at either high or low GI).
Lipids and Blood pressure LDL-cholesterol increased by
6% on a high-carb, low GI diet compared with high-carb,
high GI. Glycemic index had no effect on HDL cholesterol
level, systolic blood pressure, or diastolic blood pressure. However, a low-carb compared with high-carb diet
increased HDL-cholesterol by 4% at high GI level.
Regardless of GI value, low-carb decreased diastolic blood
pressure by 1 mm HG compared with high-carb diets. On
the low-carb diet, plasma triglycerides decreased by 5%
with low GI compared with high GI. When comparing the
low-carb diet to high-carb, plasma triglycerides were lower
by 18% and 20% with high and low GI, respectively.
Consuming the low GI, low-carb diet lowered triglycerides
by 23% compared to the high GI, high-carb diet, but did
not affect insulin sensitivity, systolic blood pressure, LDLcholesterol, or HDL-cholesterol. There were no additive
effects (of carb level and GI) on any of the outcome measures. Additional analysis showed the effects of the diets
were in the same among men/women, race (black and nonblack), presence of metabolic syndrome, and BMI.
Changes From Baseline. All diets were successful in lowering blood pressure (systolic by 7-9 mm Hg and diastolic by
4-6 mm Hg). LDL-cholesterol was lowered with the highcarb, high GI diet and both low-carb diets by 9-10% and
with the high-carb, low GI diet by 6%. Triglycerides were

Low-GI,
low-carb diet
vs
High-GI,
high-carb diet
Triglyceride levels
decreased by 23%

Low-GI,
high-carb diet
vs
High-GI,
high-carb diet
Insulin sensitivity
decreased by 20%
LDL-cholesterol
increased by 6%

Low-GI,
low-carb diet
vs
High-GI,
low-carb diet
Triglyceride levels
decreased by 5%

What does the study really

tell us?

In line with the prevailing opinion in the medical community, the authors of this study expected that consuming
foods with a lower GI would lead to improvements in insulin sensitivity and CVD risk factors. Unexpectedly, the low
GI, high-carb diet compared with the high GI, high-carb
diet actually decreased insulin sensitivity and increased
LDL-cholesterol and LDL apo-B levels.
It has been well established that a DASH-type diet can successfully lower blood pressure, and the same authors have
previously shown that a lower-carb DASH diet can reduce
plasma triglycerides, VLDL levels, and diastolic blood pressure. Varying the glycemic index of the carbohydrates in the
DASH-type of diet had yet to be studied. This study suggests that in the context of a DASH diet, low GI foods do
not improve CVD risk factors and may actually have some
detrimental effects compared with higher GI foods.
On a high-carb diet (58% of daily energy intake), choosing
foods with a lower GI had no effect on levels of HDL cholesterol, triglycerides, or blood pressure, and led to small
but unfavorable changes in LDL-cholesterol and insulin
sensitivity. On a low-carb diet (40% of daily energy intake),
choosing foods with a lower GI had no effect on levels of
HDL-cholesterol, LDL-cholesterol, insulin sensitivity or

62

blood pressure, but did lead to a small (5%) but favorable

Both a lower GI value and a lower carb content were able

decrease in plasma triglycerides. When compared to a high-

to lower the AUC compared to a high GI, high-carb diet.

carb, high GI diet, a low-carb, low GI diet had no effect on

Interestingly, there were no additional benefits on blood

insulin sensitivity, systolic blood pressure, LDL-cholesterol,

glucose from lowering both the GI and the carb content.

or HDL-cholesterol but did lower triglycerides by 23%.

This can be referred to as a plateau effect.

It is important to remember that this study was composed

Insulin index is another part of this equation, which refers

of overweight and obese people with elevated blood pres-

to the insulin response a particular food generates. While

sure (prehypertension or stage I hypertension), who were

this is highly correlated with carbohydrate content, Figure 2

consuming variations on a very healthy diet that included

shows that some types of foods have either lower or higher

a large number of fruits and vegetables. This study did not

insulin responses than would be predicted from their glyce-

address the effects of glycemic index on a typical western

mic responses. Specifically, foods that are high in protein, as

diet, or in normal weight people.

well as refined bakery products, may cause a disproportionately high insulin response.

While it is obvious that the GI values of foods will change

when combined into meals, this studys diets produced the
expected differences in blood glucose AUC over 12 hours.

Focusing dietary
recommendations
simply on the
glycemic index
appears to be an
oversimplification
of the multifactorial
process involved
in healthy blood
sugar control.

Figure 2: Mean insulin index vs glycemic

index of different food types

Additional research has suggested that glycemic index values may be related as much to clearance of glucose as they
are to entry of glucose into the bloodstream. Focusing
dietary recommendations simply on the glycemic index
appears to be an oversimplification of the multifactorial
process involved in healthy blood sugar control.
Although LDL-cholesterol was higher in the high-carb, low
GI group, the researchers did not measure LDL-particle

63

Furthermore, high GI foods may even be favorable to low

In the context of
a diet rich in fruit
and vegetables
and low in
processed foods,
glycemic index
may not matter a
whole lot.
size or LDL-particle number. It is possible that these changes in LDL-cholesterol could be benign or even favorable.
Additionally, the low carb diets contained higher amounts
of protein than the high carb diets (23 vs 16% daily kcals),
and the high carb, low GI diet had the greatest amount of
fiber (37 g/day vs 29-33 g/day for the others). It is certainly
plausible that these factors could affect results, though one
might expect the effect of high fiber to be the opposite of
what was observed.

The big picture

GI for certain outcomes when eating a DASH-type diet. It

remains to be seen whether or not using glycemic index to
select foods in the context of a typical western diet (and in a
well controlled study such as this) would improve CVD risk
factors.

Frequently asked questions

Protein and fiber levels were different between groups. Does

that change interpretation of the results?
It is possible, however the study was designed to make
comparisons between high and low GI, within the context
of either a high or low-carb diet. Because the protein was
the same within low-carb or high-carb groups, this should
not affect the outcomes. Fiber was highest in the high-carb,
low GI group, which was inevitable to some degree as fiber
content is a contributor to lower GI values.
How does this relate to glycemic load?
Glycemic load is glycemic index that has been adjusted to
reflect typical serving size. This is useful because we rarely
consume 50 grams of every food. Some foods (like grains,
for many people) are consumed in greater amounts, while
something like a carrot will have a high glycemic index but
low glycemic load. Here is a thorough resource for glycemic
load values.
How was the participant adherence to the protocols?
The researchers reported very high adherence, as all of
the food was provided to the participants and they were
instructed to write down any additional foods they may

In the context of an overall DASH-type diet, using glycemic

have consumed and any of the food given to them that they

index to select specific foods may not improve cardiovascu-

did not eat.

lar risk factors or insulin resistance.

All food was consumed and no additional foods were eaten
This quote from the study sums the findings up nicely.

on 96% of person-days on each diet. Although this was not

However, the importance of the first part of that sentence

intended as a weight-loss study, participants lost about one

should not be underestimated. In the context of a diet rich

kilogram of body weight from baseline, with no differences

in fruit and vegetables and low in processed foods, glycemic

in weight loss between any of the groups.

index may not matter a whole lot.

64

Ive [got a history of diabetes in my family] [am prediabetic] [am diabetic]. Should I eat low glycemic? Should I try
the DASH diet?
There are arguments on both sides. On the one hand, the
DASH diet has been shown in meta-analysis to improve
certain markers of blood sugar control. While evidence is
mixed, long term observational data suggests that a lower
GI diet can reduce the risk of some chronic diseases, with
trials also showing a reduction in inflammatory markers.
However, the randomized trial under review suggests that
theorized benefits may be overblown. Observational data
may not mean much, as people who eat lower GI could
have a variety of other characteristics that help them with
disease prevention.
Also, micromanaging every meal based on glycemic index
of specific foods is likely to be more annoying than helpful.
Fat and fiber are typically present in meals consisting of
minimally processed foods, and can blunt high blood sugar
responses. The glycemic load of a mixed meal can be hard
to estimate. If you are diabetic and on medication, listen
to your physician and other health professionals, and dont
rely solely on your own research. But following a named
diet isnt a prerequisite for controlling your blood sugar.

micromanaging
every meal based
on glycemic index
of specific foods is
likely to be more
annoying than
helpful.

What I should know?

In the context of an overall healthy diet that is rich in

fruits and vegetables, the glycemic index of foods is not
something to be very concerned about. This results of this
study even suggest that in the context of a higher-carb diet,
high-GI foods may be preferable to low GI foods from the
standpoint of their effects on insulin sensitivity and LDLcholesterol levels.

Got some thoughts on this study, or the glycemic index in

general? DASH over to the ERD Facebook group and let us
know what you think.

65

INTERVIEW:
Ivan Oransky
Ivan Oransky, MD, is the vice president and global editorial director of MedPage Today,
co-founder of the MacArthur Foundation-funded Retraction Watch, and founder of
Embargo Watch. He previously was executive editor of Reuters Health and held editorial positions at Scientific American and The Scientist. A 2012 TEDMED speaker, he was
awarded the 2015 John P. McGovern Award for excellence in biomedical communication from the Southwest Chapter of the American Medical Writers Association. He has
authored or co-authored four books and written for numerous publications, including
Nature, The New Republic, and The New York Times.
I believe Retraction Watch is turning five later on this year. Considering the massive number of retractions
you've reported on, what are a couple of your favorite ones? Like ones that might make for a good made-forTV movie (with "good" loosely defined).
Retraction Watch does indeed turn five in August. Good memory! My favorite stories often change over
time, but right now those that involve fake peer review often reviewed by the very authors who wrote the
papers are still at the top of my list. It might be difficult to turn those stories into a made-for-TV movie, but weve turned them into a longer feature for Nature. Theyre a perfect mix of pressure to publish and
ingenuity, in the same way someone might construct a perfect crime but then get caught. For a more
typical made-for-TV movie script, though, Id go with the story of Karel Bezouska, who broke into a lab one
night to tamper with an investigation into his work, or Jatinder Ahluwalia, who sabotaged his colleagues
and later turned out to have been dismissed from an earlier PhD program for the same reasons he eventually had to leave a second university.
Why do you think the number of retractions has been going up over time?
Youd expect to see more retractions as there are more papers published, but as Nature pointed out in 2011,
the rise in the rate of retractions from 2001 to 2010 far outstripped the growth in papers. Part of that was
definitely due to the advent of plagiarism detection software, and the fact that there are more eyeballs on
66

papers now that journals are all online. Theres also at least

I'm not sure how often meta-analyses account for included

circumstantial evidence that the amount of misconduct is

studies that have been retracted. Do you have any sense

going up, too. Thats less clear, though.

of how that issue is dealt with? After all, there isn't a duty
for meta-analysis authors to follow-up on included studies,

Examine.com was plagiarized last year, and the authors

especially if they are numerous.

became extremely defensive. Have you interacted much

Thats a critical issue, but Im not aware of anyone looking

with authors of retracted articles? What are these interac-

at it systematically, so to speak. It came up in meta-analyses

tions like?

performed after anesthesiology researcher Joachim Boldts

We always try to contact the authors of retracted papers.

fakery came to light. Most Cochrane meta-analyses are

Some get back to us. When theyre retracting for hon-

regularly updated, so perhaps there should be a mechanism

est error, those conversations show the best of sciences

that alerts meta-analysis authors to retractions and helps

self-correcting nature. We often add them to our doing the

them figure out whether they need to follow up. In fact, we

right thing category. Among those authors retracting for

were just awarded a $400,000 grant from the MacArthur

misconduct, or what sounds like misconduct, some dont

Foundation to build a retraction database that we hope will

respond to our requests, while others dont have much to

be linked to personal libraries authors use for referenc-

add, or give us a few details that flesh out the story. Most

es. That would make it impossible to cite a retracted paper

of the time with those kinds of retractions, we have to rely

without first knowing that it had been retracted.

on other sources for information. And then there are the

handful of authors who try to keep themselves out of the

If you were magically given authority over retraction poli-

limelight by threatening to sue us. Its never worked quite

cies for all journals, what changes would you implement?

the opposite. Just Google Streisand Effect.

This seems unlikely, but since youve invoked magic, Ill

Karel Bezouska, who broke into a lab

one night to tamper with an investigation
into his work, or Jatinder Ahluwalia,
who sabotaged his colleagues and later
turned out to have been dismissed from
an earlier Ph.D. program for the same
reasons he eventually had to leave a
second university.
67

make pretend: First, Id insist on clear notices that detailed

but in the long run its going to erode trust. Better to be

why exactly a paper had been retracted. No more opaque

forthright about cases of fraud, which are still uncommon,

This paper has been withdrawn by the authors. Of course,

then pretend they dont exist and then have to defend sci-

that would probably require hiring different lawyers than

ence when news breaks.

the ones many publishers seem to employ today when they

cave to legal threats from fraudsters. Id also do away with

We've lightly touched on journals and information dis-

the mulligan of retractions, the unexplained withdrawal

semination in previous issues, talking about predatory

of papers that are published online but not in print yet. The

publishing and exaggeration in press releases. What's on

idea that such a paper doesnt exist enough to warrant a

your mind these days concerning information dissemina-

full retraction notice is a quaint but ridiculously outdated

tion from journal articles? For example, I've read some of

notion some publishers insist on.

your writings on embargoes and the Ingelfinger Rule.

Ive more or less said my piece on how to use embargoes, if

Do high-impact journals deal with retraction in a more

journals must, but I remain concerned that the Ingelfinger

transparent manner? Are there any journals that do an

Rule prevents journalists from telling the real stories of

exemplary job of it?

science. Ive said more about this elsewhere, but basical-

High-impact journals generally provide more informa-

ly it keeps researchers from talking to reporters for fear

tion than others in retraction notices, but they also have

of having their work rejected by top journals. Youd think

more retractions per thousand papers published. Id say the

the rough-and-tumble world of online journalism would

Rockefeller University Press journals such as the Journal of

have eroded some of Ingelfingers power, but if anything

Cellular Biology do a consistently above-average job. Keep

its strengthened it as reporters look for the next minutes

in mind, though, that how well a given journal investigates

scoop. Still, Ive seen some chinks in the Ingelfinger armor,

allegations is usually a black box, unless we happen to learn

and that makes me happy.

of it from a source, and weve seen lots of journals stubborn-

ly refuse to correct the record, so its hard not to think that

the notices we see are just a tip of the iceberg phenomenon.
Back to the human angle: I can't imagine being the author
of a particularly egregious retracted article, and then
attempting to procure more grant money and get more articles published. For academics who live and die by their CV,
how can they continue in academia?
Thats an excellent question, and we have to say were always
surprised by a vocal minority of our readers who object
strenuously when we ask it by following up on cases of
fraud. In fact, more than half of researchers found to have
committed misconduct by the Office of Research Integrity
are still in the positions they had when they did the deed.
That strikes us as strange, given how competitive grants are.
It is a reminder, however, of how reluctant many researchers
are to blow the whistle or air sciences dirty laundry. They

Dr. Oransky earned his BA at Harvard and his MD

at the New York University School of Medicine.
While a student, he served as executive editor of
The Harvard Crimson and as co-editor-in-chief
of the medical student section of the Journal
of American Medical Association. In addition
to his work as a medical writer and editor, Dr.
Oransky teaches medical journalism at New York
Universitys Science, Health, and Environmental
Reporting Program, and he is a clinical assistant
professor of medicine at New York University
School of Medicine. Dr. Oransky currently serves on
the board of directors and as vice president treasurer of the Association of Health Care Journalists.

may think thats a good way to minimize the effects of fraud,

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INTERVIEW:
Jessica Richman
Jessica Richman started and sold her first company after high school. At Stanford
University she earned degrees in Economics and Science, Technology and Society
(with a computer science focus). Along the way, she worked for Google, McKinsey,
Lehman Brothers, the Grameen Bank, and top-tier Silicon Valley venture firms.
Jessica arrived at Oxford University as a Clarendon Scholar and completed an MSc at
the Oxford Internet Institute. She is currently a DPhil student at Oxford with a focus
on innovation, social networks, and collective intelligence.
In layman's terms, how does uBiome go about testing for bacteria? What can you detect and what
can't you detect? And also...is the testing technology changing from year to year?
Great question, and a warm hello to all inquiring Examine.com readers. uBiome offers kits for people to sample the bacterial populations anywhere on the body and do personal experiments to learn
about themselves.
Sampling is done from the comfort and privacy of your own home, with a simple and non-intrusive
procedure. For the gut sample, all we need is a swab of your toilet paper; for the skin sample, its just a
swab behind your ear. We also sell kits for nose, genitals, and mouth.
Each site has a unique microbiome that is home to a specific balance of flora. With the samples from
each of these body sites we can tell you about the bacteria that inhabit that microbiome. You also get
access to our ever-expanding database of bacteria, to see the role those bacteria play in keeping your
microbiome balanced.
You can track the results of probiotic usage, diet and supplement experiments, and antibiotic treatments,
so you can see how they affect your microbiome over time. You can also compare your results to other
participants, to see how you compare to users who have made similar dietary or lifestyle choices.

69

This is an exciting, emerging field. Our team keeps up to

For people who are new to this area, we want to help them

date on the many studies that are published about the

understand that the microbiome is influenced by both

microbiome and constantly works on ways to make this

health and lifestyle choices. What you eat impacts not only

data accessible to our participants - regardless of their sci-

your gut flora but your microbiome at other sites too.

entific background. We want to help people engage with

their data in the most meaningful way possible.

More than 1.4 billion adults worldwide are overweight, with

more than 500 million clinically obese. Over the past two

We've covered a couple rodent studies looking at microbi-

decades, there has been a marked rise in allergies, autoim-

ome effects on health and performance. Conclusions from

mune, and neurological disorders. Autoimmune disorders

human research are a bit more limited, due to complexity

now aect 23 million Americans alone; Asthma in western-

and inability to control as many

ized societies has risen steadily,

parameters. Where does uBiome

doubling in the last 20 years.

fit into the research picture?

uBiome is the largest citizen
science research study looking
at the microbiome. We aim to
contribute significant findings
to this relatively nascent frontier
of scientific research. While our
test is not diagnostic, we do want
to empower our community of
knowledge-seekers with detailed
information and personalized
visualizations that will help them
understand how their microbial

What you
eat impacts not
only your gut
flora but your
microbiome at
other sites too.

There is overwhelming scientific evidence that the human

microbiome has profound consequences for our health, and is
implicated in diseases ranging
from obesity, diabetes, and IBD
to heart health, anxiety, and
depression.
uBiome is designed to help
explore the scientific ramifications of the microbiome and to
better understand this landscape
for the novice and expert alike,

balance relates to other data sets.

but we cant give people specific recommendations on what

One of the most exciting ways uBiome fits into the micro-

to eat based on your microbiome.

biome research picture is by equipping people with tools

to create their own scientific studies so they can explore

What can people currently learn by having their various

the issues most important to them. We want to see people

microbiomes sampled? What might they be able to learn

engaging with their microbiome in ways that might not

five years down the road (especially with continued testing)?

have been possible before. We want to learn what they learn.

With uBiome sampling, people can learn:

The microbiome is much more complex than most people

can fathom. Some bacteria can be "bad" in one context

What proportions of different bacteria are in their

microbiome

and not so bad in another. So recommendations are likely

How they compare to the microbiomes of other rel-

to be more complicated than for things like vitamins and

evant groups, such as healthy omnivores, vegans,

minerals. What advice do you give to gut novices about gut

smokers, and people who exercise regularly.

health? What about people who are already somewhat educated on the subject?

How their data compares to peer-reviewed studies of

the microbiome
70

 Papers show that antibiotics or a

drastic change in diet can alter a persons
microbiome in as little as three days.
Testing provides participants with a snapshot of their micro-

are currently examining the role of bacteria such as

biome at a single point in time. However, we so want to

Streptococcus mutans in tooth decay. A healthy mouth

keep our community informed about the studies that scien-

microbiome can help fight off the bacteria that cause cavi-

tists are only now beginning to develop. Sampling now and

ties or gum disease.

at regular intervals will allow people to have early access to

emerging studies, and give them the means to understand

The vaginal microbiome is also a rich area of research, with

how lifestyle or dietary choices may have changed their

new insights being generated frequently.

microbiome over time.

The FDA cracked down on 23andme last year. What sort of
How quickly can people change their gut microbiomes? For

regulatory issues does uBiome face, if any?

example, after a couple courses of antibiotics. Have you

uBiome is a research study, and we do not give any diagnos-

seen any particularly interesting success stories?

tic information to consumers.

Studies are just beginning to explore how susceptible the

microbiome is to change. Papers show that antibiotics or a

One of the most frequently asked questions we receive is

drastic change in diet can alter a persons microbiome in as

if we are IRB approved. For anyone not familiar with the

little as three days.

term, an Institutional Review Board is a committee that

approves, oversees and reviews biomedical and behavioural

Our participants are not just simply learning about their

research involving humans. They conduct analysis to deter-

bacterial balance - many are setting out to explore the

mine whether or not research should be done. Their priority

extent to which they can hack their own microbiome. We

is to advocate for the individual participant.

are doing some internal studies on this -- stay tuned! And

definitely let us know if any of you would like to join in, by

To answer that question here: uBiome has received research

writing to us at studies@ubiome.com.

study approval from E&I Review Services. To be completely sure that we had our participants privacy, security and

Most people focus on the gut, but uBiome samples five sites

well-being in mind, we have in fact consulted with our IRB

on the body. What are some things people should know

every step of the way. Under their advice, we completed the

about these other microbiomes?

final stages of their analysis and received approval immedi-

The important thing to realize is that your microbiome

ately after we had reached our initial funding goals.

functions differently at each of these sites.

Readers of ERD are often scientists or wannabe scientists.
For example, scientists who study the oral microbiome

Lots of information junkies. With so many different sourc-

71

es of information, and so many things that can be tracked,

what are some of the most interesting developing microbiome topics that we should keep in mind? Any must-read
gut-centered websites or blogs?
There is a wealth of information available for people who
want to learn more about the human microbiome. With
websites such as Google Scholar becoming increasingly popular, it is becoming easier for people to access that
information all the time.
Institutions like MIT also offer excellent courses online
for free. People who are interested in learning more about
human biology, before they dive into their microbiome,
might be interested to take their courses here.
The National Institutes of Health is a great source for
gut-centered material. For a lighter read, check out
MindBodyGreen.com. And Paleo Magazine has some
interesting articles and podcasts.
Were also firing up the uBiome blog, and would love to end
with a question to your readers: what are the most burning
microbiome-related questions on your mind, or whats the
number one thing youd want to learn from looking at your
microbiome?
Thanks so much for this opportunity to share our project
with the ERD community.

[...] question
to your readers:
what are the
most burning
microbiomerelated questions
on your mind, or
whats the number
one thing youd
want to learn from
looking at your
microbiome?

Jessica is a co-founder of uBiome, the world's largest successful citizen science

project. UBiome has been featured in Wired, MIT Technology Review, Scientific
American, NPR, FoxNews, ABC News, and dozens of other media outlets. Jessica is
also founder of Sciencecitizen.org, an organization that helps researchers incorporate the public into their work.

72

ERD
Until Next Issue...

The next issue of ERD will come out the

first week of March. In the meantime:
Comments? Questions?
Concerns?

Join the
Discussion Online

Send your thoughts to

erdeditor@examine.com

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