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METABOLIC SYNDROME AND RELATED DISORDERS

Volume 2, Number 1, 2004
Mary Ann Liebert, Inc.

Review
The Zone Diet: An Anti-Inflammatory,
Low Glycemic-Load Diet
BARRY SEARS, Ph.D., and STACEY BELL, D.Sc., R.D.

ABSTRACT
The Zone Diet was developed on the concept that the hormonal responses of macronutrients
could be orchestrated to maintain key hormones within therapeutic zones to control inflammatory responses. In particular, the two hormonal systems that are directly affected by dietary
macronutrients are (1) the insulin/glucagon axis and (2) eicosanoids. Each of these hormonal
systems can have a significant impact on the inflammatory process. This hormonal approach
to optimizing an anti-inflammatory diet has significant ramifications in treatment of those
chronic diseases (obesity, type 2 diabetes, and cardiovascular disease) that are known to produce inflammatory responses. On the other hand, an inappropriate balance of macronutrients
(especially high glycemic- load carbohydrates) can lead to increased inflammation. A primary
example of this is the promotion of the United States Department of Agricultures Food Guide
Pyramid. Since its adoption, the prevalence of obesity and type 2 diabetes has risen substantially. Both conditions also demonstrate a significant increase in inflammatory markers. The
purpose of this article is to review the historical factors that led to the development of the
Zone Diet, to understand how the Zone Diet can alter inflammatory responses, and to review
the published literature on its ability to affect hormonal and metabolic responses.

INTRODUCTION

sequences of the macronutrients in any such

proposed diet. It is the lack of attention to the
hormonal consequences of the diet that has resulted in the continuing debate of what Americans should eat for improved health.
A science-based diet approach to achieving
a healthy diet began in the early 1900s and
continues today.1 Dr. W. O. Atwater was the
first scientist to develop a scientific basis for
connecting food composition, dietary intake,
and health. Since that time, there has been a

ETERMINING what a healthy diet is remains

more of a philosophical discussion than
an evidence-based inquiry. Part of the reason
lies in the lack of articulation of what is the goal
of a healthy diet. Obviously, one goal is to
supply adequate levels of macronutrients and
micronutrients. However, this alone does not
necessarily qualify as a healthy diet since
one has to take into account the hormonal con-

Zone Labs, Danvers, Massachusetts.

24

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ZONE DIET

constant evolution of government dietary

advice culminating with publication of the
United States Department of Agricultures
(USDA) Food Guide Pyramid in 1992.2
The Food Guide Pyramid recommends
types and quantities of foods to eat from five
major food groups. It also suggests using fats,
oils, and sweets sparingly. If followed, the
American diet should contain about 30% of the
energy from fat, protein should provide about
15% of caloric intake, with carbohydrates (primarily grains and starches) providing approximately 55% of total calories.
Since the introduction of the USDA Food
Guide Pyramid, the prevalence of obesity and
chronic disease has increased at rates higher
than ever before.37 For children and adolescents the prevalence of overweight by age
is now: 10.4% for 25-year-olds, 15.3% for
611-year-olds, and 15.5% for 1219-year-olds.3
These percentages represent between a 26%
and a 32% increase for each age category since
19881994. Similarly for adults, 64.5% of Americans are overweight, 30.5% are obese, and 4.7%
are considered extremely obese (body mass
index [BMI] $ 40 kg/m2).4 The percentage increase over the past decade was 13% for those
overweight, 25% for the obese, and 38% for the
extremely obese. This represents an epidemic
of major proportions.
At the molecular level, increase in body
weight also generates a significant increase in
inflammation. This is the most likely linkage
between the increase in weight and the significant adverse health consequences that come
from it, such as the increased likelihood of
type 2 diabetes and cardiovascular disease.
Likewise the risk of developing cancer, high
blood pressure, arthritis, and asthma also increase significantly.5,6 As a result, life expectancy can be shortened as much as 22%.7
The increase in weight, chronic disease, and
inflammation has prompted some investigators to question whether the present USDAs
Dietary Guidelines for Americans and the
Food Guide Pyramid are best serving the public.813 Much of the criticism launched against
the USDA Food Guide Pyramid has been on
the glycemic load of the diet. Only secondarily
has the impact of glycemic load on hormonal
consequences and the corresponding increase

25

in inflammatory responses been discussed. It

is this increased inflammation that appears to
underlie the acceleration of the chronic disease
conditions associated with increased body fat.
The failure to appreciate the inflammatory implications of the USDA Food Pyramid led one
of us (B.S.) to propose a new dietary approach
based on hormonal modulation to reduce inflammatory responses in 1995.14 The purpose
of this review is to understand the role of the
glycemic load of the diet in terms of hormonal
responses that can lead to increased inflammatory responses. Then, the clinical data are
summarized that support the benefits of an
anti-inflammatory, low-glycemic diet.

THE CONCEPT OF THE GLYCEMIC LOAD

In the 1980s, the concept that all carbohydrates might not have the same impact on
blood glucose was controversial.15 It was assumed that simple carbohydrates would have
a more rapid impact on blood glucose levels
than complex carbohydrates. Unfortunately,
experimentation proved otherwise. This insight led to the development of the glycemic
index.
Glycemic index (GI)
The GI provides a way to assess the quality
of dietary carbohydrate in terms of the rate of
entry as glucose into the bloodstream.15,16
After ingestion of 50 g of a test carbohydrate
(after subtracting out the fiber content), the
blood glucose is monitored for a 2-h period.
The area under of the curve (AUC) of serially
measured blood glucose levels is compared
to a known AUC of either the same amount
of glucose, or the newer, and more preferred
measurement, white bread.17
This AUC of the test carbohydrate is then
was divided by the AUC of 50 g of a standard
carbohydrate, such as glucose or white bread,
and then multiplied by 100 to give the GI for
that carbohydrate. The results of these experiments were that some simple carbohydrates,
such a fructose, had a much lower GI than
complex carbohydrates, such as potatoes, rice,
or bread. The implication was that a higher GI

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26

would give rise to increased insulin secretion,

and thus have important implications in obesity, diabetes and heart disease. This last fact
was important as studies as early as the 1980s
were demonstrating a strong association between increased insulin levels and the development of heart disease.18
However, the GI is not a practical application since rarely does anyone consume a 50-g
portion of any given carbohydrate. Thus, a
more useful term emerged known as the
glycemic load (GL).
Glycemic load
The GI only refers to a single, 50-g serving of
a single carbohydrate source. Since multiple
foods in varying amounts are consumed during
the day, the concept of the GL captures the effect of usual servings on blood glucose concentrations.1922 The GL is defined as the amount of
the given carbohydrate in a serving size times
the GI of that particular carbohydrate and then
divided by 100. The GL takes into account both
the amount of insulin-stimulating carbohydrate
consumed and the rate at which that insulinstimulating carbohydrate will enter the blood
stream.
Using the GL concept, one can approximate
how the carbohydrate composition of a particular meal would affect insulin responses. The
GL (in grams) of some commonly consumed
carbohydrate-containing foods is shown in
Table 1.17 There can be significant differences
among a variety of foods between the grams of
carbohydrates in a serving and the GL.
By summing the GLs of all the foods consumed throughout the day, the daily GL of the
entire diet can be calculated.20 The USDAs
Food Guide Pyramid recommends 611 servings of breads, grains, and cereals.2 This would
create a GL of the entire diet of at least 200 g.
Grains, whether they contain fiber or not, have
high GLs because of the total amount of carbohydrate per serving, which contributes to the
daily GL.
The daily GL of the low-GL diet would be
between 50 and 70 g, because it includes only
small amounts of high-GI and high-GL grainbased foods. On the other hand, diets with a
very low GL (less than 20 g) would be insuffi-

SEARS AND BELL

TABLE 1.

THE GLYCEMIC LOAD OF COMMONLY CONSUMED

CARBOHYDRATE-CONTAINING FOODSa
Food

Glycemic load per

usual serving size (g)

Peanuts
Soy beans
Milk
Ice cream
Lentils
Apple
Baked beans
Kidney beans
Chick peas
Whole grain bread
White bread
Waffles
Potato chips
Banana
Orange juice from concentrate
Baguette
Pizza
Coca Cola
Pretzels
Corn chips
Doughnuts
Fruit Loops (Kelloggs)
Rice (white or brown)
Pasta (white or durum wheat)
Jelly beans
French fries
Macaroni
Pop Tart
Corn flakes
Bagel
Baked potato
Mars bar

1
1
3
3
5
6
7
7
8
9
10
10
11
12
13
15
16
16
16
17
17
18
20
21
22
22
23
24
24
25
26
27

aBased

on glucose as the standard.17

cient in the intake of carbohydrates to prevent

the generation of ketosis.
The daily GL represents both the quantity
(total grams of carbohydrate) and the rate of
entry of glucose into the blood post-prandially
(GI) of the diet. Thus, the GL provides a better
marker of insulin secretion than either total
carbohydrate intake or GI alone. Epidemiological studies support this because several have
shown that high GL diets are associated with
increased risk of several chronic conditions related to hyperinsulinemia.1922
Although the concept of the GL is an important one in the development of the Zone Diet,
it is not by any means the only factor. The
Zone Diet was developed to reduce chronic
inflammation associated with cardiovascular
disease by controlling those hormones (eico-

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ZONE DIET

sanoids) that ultimately control the inflammation process at the molecular level.14,23 The
daily GL of the diet is only one factor that has
an impact on the overall inflammatory response of the diet.

THE DEVELOPMENT OF THE ZONE DIET

The Zone Diet was originally developed as a
therapeutic intervention to reduce inflammation, and specifically for the treatment of heart
disease.14 There has been a controversy for the
past 150 years whether the primary cause of
heart disease is increased inflammation or elevated cholesterol. Virchow first postulated in
the mid 19th century that atherosclerosis was
an inflammatory disease.24 However, studies
by Anitschow in 1913 demonstrated feeding a
large amount of cholesterol to rabbits induced
atherosclerotic lesions.25 As a result of this experiment, the cardiovascular community became more focused on elevated cholesterol as
the primary causal factor as opposed to inflammation.
Forgotten in the rush to embrace the cholesterol hypothesis were studies in the 1930s
that demonstrated cholesterol feeding to rabbits also induced hypothyroidism, and if a
thyroid hormone was supplemented to a highcholesterol diet in rabbits, then no such lesion
development occurred.26,27 This initial observation by Anitschow was finally understood
in 1964 when one of his students repeated his
1913 experiment and found that high cholesterol feeding depressed thyroid function in
rabbits to nearly the same extent as surgical
removal did.28 Finally, it was also known
from primate studies that required intimal irritation by balloon angioplasty (and hence
causing inflammation) would dramatically
accelerate lesion development in hypercholesterolemic animals.29
Although these reported studies should
have put a damper on the primacy of the cholesterol theory and given more credence to the
inflammation theory, this was not the case as
epidemiological studies in the 1950s convinced many researchers that high animal-fat
diets (and therefore high-cholesterol) diets
were associated with heart disease.30 The fact

27

that such diets might also be pro-inflammatory diets never seemed to be considered.
The turning point in primacy of cholesterol
hypothesis began with the work of Brown and
Goldstein and the molecular nature of the LDL
receptor in the 1980s.31 Because one could easily measure cholesterol and because homozygotes deficient in the LDL receptor rapidly
developed heart disease, the focus on reducing
cholesterol levels became not only the numberone treatment for heart disease, but also the
clarion call for prevention of heart disease.
Inflammation and eicosanoids
The development of the Zone Diet started
when one of us (B.S.) became involved in this
controversy between inflammation and cholesterol in heart disease during the mid 1970s.
In this time period, epidemiological studies
demonstrated that Greenland Eskimos consumed a high-fat, high-cholesterol diet, yet
their incidence of heart disease was incredibly
low.32 One reason appeared to be the high levels of long-chain omega-3 fatty acids in their
diet.
The understanding of the importance of
these observations emerged with the growing
understanding of the role of eicosanoids in the
inflammatory process.23 Eicosanoids derived
from arachidonic acid (AA) were pro-inflammatory, but those derived from the long-chain
omega-3 fatty acid, eicosapentaenoic acid
(EPA), had little, if any inflammatory actions.
This presented the possibility to use high
enough levels of fish oil to modulate the inflammatory process, and thus alter the development of cardiovascular disease.
The ideal choice for maximizing the antiinflammatory potential of eicosanoids would
require more than just high-dose fish oil since
the eicosanoids derived from EPA were still
weak pro-inflammatory agents. On the other
hand, the eicosanoids derived from dihomo
gamma linolenic acid (DGLA) were powerful
anti-inflammatory eicosanoids. The problem
was how to manipulate the flow of omega-6
fatty acids to maximize the ratio of DGLA
to AA, thereby increasing the ratio of strong
anti-inflammatory to strong pro-inflammatory
eicosanoids as shown in Figure 1.

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SEARS AND BELL

Omega-6 Fatty Acids

Omega-3 Fatty Acids

Linoleic acid

Alpha Linolenic acid

Delta 6 Desaturase

Gamma Linolenic acid (GLA)

Steardonic acid
Elongase

Dihomo Gamma Linolenic acid (DGLA)

Strong Anti-inflammatory

Eicotretaenoic acid

Delta 5 desaturase

Eicosanoids

Arachidonic acid (AA)

Eicosapentaenoic acid (EPA)

Strong Pro-inflammatory

Weak Pro-inflammatory

Eicosanoids

Eicosanoids
FIG. 1.

Enzyme systems

Eicosanoid flow from fatty acids.

tion was to find the adequate levels of EPA to

reduce the activity of delta 5 desaturase suffiThe enzymes required for the synthesis of ciently to simultaneously significantly reduce
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the production of AA from DGLA. Finding the
the actual precursors of eicosanoids (DGLA,
AA, and EPA) are common to both the omega-6 correct ratio of supplemented EPA and GLA
and omega-3 fatty acids metabolism path- would thus theoretically offer maximum conways.23 This gives rise to the potential to trol of the inflammatory process by controlling
modulate the activities of these enzymes by the ratio of DGLA to AA.
nutritional interventions. For example, inThe complexities of this otherwise elegant
creasing DGLA could be readily accomplished approach began to manifest themselves. It apby supplementation with seed oils (such as peared that females and males required differborage) that are rich in gamma linolenic acid ent ratios of EPA to GLA, and that there was
(GLA). The increased levels of GLA would be significant diversity in hormonal response
rapidly elongated (by the elongase enzyme) to even within gender classes.14,23 In the late
DGLA, which is then the substrate to make 1980s, what provided a clue to this biological
strong anti-inflammatory eicosanoids. How- diversity was working with elite level swimever the DGLA is also a substrate for the delta 5 mers who ingested different ratios of EPA to
desaturase enzyme that would convert it to GLA to reduce the muscular inflammation due
AA. Since the same enzyme produces EPA, to rigorous training.14 It was noticed that a
that end product (EPA) would become a feed- rapid increase in their pro-inflammatory reback inhibitor of delta 5 desaturase. The ques- sponses occurred once they returned to dormi-

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ZONE DIET

29

tory living in the fall after living on their own

during the summer. This forced a constant
change in their ratio of EPA to GLA on almost
a weekly basis, whereas during the summer
months in which they were living on their
own, the ratio of EPA/GLA required to control
inflammation was relatively constant.
Revisiting the earlier literature, it become
clear the causal factor in changing the activity
of delta 5 desaturase was an increase in insulin
due to increased carbohydrate consumption
from consuming higher levels of grains and
starches. From animal studies33,34 and later
demonstrated in human studies,35 insulin was
shown to be a powerful stimulator of delta 5 desaturase activity, thus causing a rapid increase
in AA formation from DGLA. The increase in
AA undermined the delicate balance that had
been built up during the summer months in
the swimmers thereby explaining the significant increase in inflammation with a return to
high GL diet (Fig. 2).
Diet and inflammation
To ultimately control the inflammatory process, the development of a dietary approach
that maintained a therapeutic zone of insulin
was required to prevent an activation of the

delta 5-desaturase enzyme.14,23 Such a diet

would be an anti-inflammatory diet which
when coupled to the appropriate manipulation
of eicosanoids using fish oil would offer the
greatest potential for control of the inflammatory process. Just as the balance of eicosanoids
is controlled by the balance of omega-6 to
omega-3 fatty acids in the diet, the secretion of
insulin is influenced by the GL of the diet.
The Zone Diet was the first dietary program to initially put forward the concept of
the GL using a concept of carbohydrate food
blocks.14,36,37 Each carbohydrate food block
had a defined amount of carbohydrate and
was defined as favorable or unfavorable
defined by the GI of the carbohydrate. The
number of carbohydrate food blocks for a typical day would be a translation into a GL of approximately 5070 g.
The control of insulin by the diet depends
not only the GL of the diet, but also the ratio
of protein to carbohydrate at each meal. Although protein can stimulate insulin secretion,
it has a much larger impact on the primary
counter-regulatory hormone to insulin, which
is glucagon. In addition to controlling the secretion of insulin, glucagon is responsible for
the restoration of blood glucose levels from
stored glycogen in the liver. This has impor-

Dihomo Gamma Linoleic Acid (DGLA)

Delta 5 desaturase
Activated by insulin

Strong anti-inflammatory eicosanoids

Arachidonic Acid (AA)

Strong pro-inflammatory eicosanoids

FIG. 2.

Effect of insulin on amino acid production.

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tant consequences in the reduction of hunger

between meals.
Of course the question became what the right
balance of protein to carbohydrate might be.
Searching for an appropriate starting point,
published data on speculations of the neoPaleolithic diet approximately 10,00015,000
years ago prior to the advent of grain cultivation
was used.38 This was approximately a proteinto-carbohydrate ratio of three parts protein to
four parts carbohydrate. Since such a diet would
be richer in carbohydrates than protein, it could
not be called a high-protein diet. In addition, the
carbohydrates in such a neo-Paleolithic diet
came primarily from low-GL sources (primarily
vegetables and fruits). Furthermore there were
initial studies in humans that appeared to
support that protein-to-carbohydrate ratio in
providing an appropriate ratio of insulin to
glucagon.39
The final question was the amount of fat and
type of fat. The primary choice of added fat
should be primarily non-inflammatory monounsaturated fat coupled with high enough
levels of long-chain omega-3 fatty acids to reduce inflammatory responses induced by high
intake of omega-6 fatty acids, which would lead
to pro-inflammatory responses. The greater the
effort to reduce dietary omega-6 fatty acids, the
less EPA would be required to control chronic
inflammation. Finally, the total concentration of
all fats in the diet should bring the total caloric
load to approximately 30%. At this fat level, one
could maintain adequate caloric intake without
using excessive levels of protein or carbohydrate. In addition, this level of fat would also
deliver more than adequate levels of micronutrients and a broad range of phytochemicals, if
using low-GL carbohydrates since they are rich
in micronutrients with the least amount of associated carbohydrates. The final result was the
development of the first generation of the Zone
Diet in 1992, the same year that the USDA Food
Guide Pyramid was introduced.
The Zone Diet can be considered to be an
anti-inflammatory diet due to its ability to control the activity of enzyme delta 5 desaturase
by keeping insulin within a defined zone and
simultaneously supplying adequate levels of
EPA to provide a negative feedback inhibition
on the same enzyme. The end result would be

SEARS AND BELL

an improved balance of DGLA to AA, and

therefore increased production of strong antiinflammatory eicosanoids and a corresponding reduction of the strong pro-inflammatory
eicosanoids. The DGLA to AA ratio can be considerably enhanced by the general reduction
of all omega-6 fatty acids in the diet by replacing them with non-inflammatory monounsaturated fats.
At the time of the publication of The Zone in
1995, this anti-inflammatory dietary approach
was greeted with great skepticism by the nutritional community.14 But as we will show, the
published data has confirmed its efficacy in
the treatment of obesity, diabetes, and heart
disease.

ISOCALORIC STUDIES USING

LOW-GLYCEMIC LOAD DIETS
There have been numerous isocaloric studies that have compared high-GL diets (such as
the USDA Food Guide Pyramid and American
Heart Association diet) to the Zone concept. If
the fat intake is relatively constant between the
two isocaloric diets, then the only variables become (1) the GL of the diet, and (2) the ratio of
protein-to-carbohydrate in the diets. The standard diet usually chosen is the macronutrient
compositions of the USDA Food Guide Pyramid or American Heart Association. Both diets
can be characterized as a high glycemic-load
(greater than 200) diet with a protein-to-carbohydrate ratio of approximately 0.3. On the
other hand, a Zone Diet is characterized as a
low glycemic-load diet (less than 70 g) with a
protein-to-carbohydrate ratio between 0.5 and
1.0 with a mid-range of approximately 0.75,
which is similar to published data on neoPaleolithic diets.38 Although the Zone Diet has
a higher protein percentage of calories than
the USDA Food Guide Pyramid, it still contains more carbohydrate than protein. Thus it
should not be considered a high-protein diet,
although that mistake is commonly carried
though both the scientific and lay literature.
Most of the carbohydrates on the Zone Diet
come from low-GL fruits and non-starchy vegetables and selected grains, such as steel cut
oats and barley, as they are rich in soluble

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ZONE DIET

fiber. On the other hand, the USDAs Food

Guide Pyramid recommends that most of the
carbohydrates come from grains and starches,
both of which have high GIs and GLs.2,13 When
compared to the USDA Food Guide Pyramid
or the American Heart Association diet under
isocaloric conditions, the low-GL Zone Diet
has been shown to reduce hunger, promote
weight loss, and reduce risk factors associated
with chronic disease such as type 2 diabetes
and heart disease to a far greater extent.4050 In
addition, a positive relationship exists between
a high-GL diet and C-reactive protein, a marker
of inflammation associated with cardiovascular disease risk.22 Detailed below are the studies that support such a broad range of benefits
of the low-GL Zone Diet.
Changes in hormonal control
Twelve adolescent males were evaluated on
three separate occasions using a crossover
design protocol.40 Eucaloric test meals were
consumed at breakfast; the only difference between the meals was the GIs of the various
carbohydrates used, which were classified, as
low-, medium-, or high-GI. The macronutrient
composition of the low-GL Zone Diet had 40%
of the energy from low-GI carbohydrates, 30%
of the energy from protein, and 30% of the energy from fat. The other two diets had 64% of
the energy either from medium- and high-GI
carbohydrates, 16% of the energy from protein,
and 20% of the energy from fat (a regimen
based on the USDAs Food Guide Pyramid).
Selected blood hormone concentrations were
measured to explain differences in food intake
and degree of hunger.
Compared to the low-GL Zone meal, the
voluntary calorie intake five hours after the
test meals was 53% higher in the medium-GI
meal and 81% higher in the high-GL meal.40
Using a 10-point analog hunger scale, subjects
were consistently less hungry following consumption of the low-GL Zone meal, intermediate for the medium-GL meal, and most hungry
after the high-GL meal.
Serial measurements of hormonal changes
supported these findings. First, the measured
AUC for serum insulin levels was 52% higher
for the high-GL meal (p < 0.01) than the low-

31

GL Zone meal.40 This indicated that foods

with higher-GL caused a greater insulin response than those with low-GLs, despite being
eucaloric. Second, the mean plasma glucose
nadir was 72% lower after the high-GL meal
compared to the other two meals (p < 0.02).
The high-GL meal produced the greatest adverse effect on glycemia because it was digested and absorbed more quickly, thereby
causing a greater insulin surge that caused an
increase in post-prandial hypoglycemia.
Third, plasma glucagon levels only rose after
the low-GL Zone meal, and were suppressed
about 10% for the other two higher-GL meals
during the 5 h after the test meal (p < 0.01).40
Glucagon is primarily responsible for stimulating the release of stored glycogen from the
liver to maintain blood sugar concentrations,
thereby reducing hunger between meals.
This short-term study illustrated the effects
of different GLs and protein-to-carbohydrate
ratios on hunger, which were supported by
changes in post-prandial hormones.40 These
physiological changes may explain how appetite was better controlled.
Changes in energy expenditure
These authors speculated that a low-GL Zone
Diet would control hunger even in the face of
energy restriction, and that energy expenditure
would not decrease as much as usually occurs with energy restriction.41 In a randomized,
crossover design study, an eucaloric comparison was made between a high-GL diet (carbohydrate = 67%, protein = 15%, and fat = 27% of
total energy intake), and a low-GL Zone Diet
(carbohydrate = 43%, protein = 27%, and fat =
30% of total energy intake). Ten subjects were
studied for 9 days on two separate occasions.
For the first six days, the subjects received an
energy-restricted diet containing either a highGL diet or the low-GL Zone Diet. For days
seven and eight, the subjects consumed these
same diets ad libitum.
Mean post-prandial area under the glycemic
response curve was twice as large for the highGL diet (2.69 0.47 mmol/h/L) compared to
the low-GL Zone Diet (1.30 0.19 mmol/h/L;
p = 0.001).41 The mean area under the insulinemic curve was nearly 50% greater with the

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high-GL diet than with the low-GL Zone Diet

(p = 0.01). Resting energy expenditure declined
less with the low-GL Zone Diet during the
energy-restricted phase compared with the highGL diet (24.6%; p = 0.03 vs. 210.5%; p = 0.005).
Nitrogen balance was positive with the low-GL
Zone Diet, but was negative with the high-GL
diet (25.7 14.1 vs. 29.7 5.5 N/kg/d; p = 0.06).
After the reduced energy phase, ad libitum food
intake was 25% greater following the high-GL
diet than the low-GL Zone Diet (p = 0.009).
The results of this study helped explain
why using a high-GL diet for weight reduction may have poor long-term success.41 With
such a diet, hunger was more intense, and energy expenditure declined more during caloric
restriction compared to a low-GL Zone Diet. A
high-GL diet thus sets up individuals for failurethey will be constantly hungry and will
expend fewer calories at rest, so weight loss is
almost impossible to achieve. In addition, during the high-GL regimen, muscle tissue was
catabolized at a greater degree (i.e., negative
nitrogen balance) and fat was oxidized to a
lesser degree as an energy source. This may explain why the current guidelines for healthy
eating may be related to increase in weight of
the population. Instead, the low-GL Zone Diet
was shown to be better at controlling hunger,
increasing energy expenditure and fat oxidation, and maintaining lean body mass.
Changes in metabolic risk factors
The role of the GL of the diet on metabolic
risk factors is equally suggestive.42 In this
study, a comparison was made between a lowGL Zone Diet (macronutrient percentages of
energy: carbohydrate = 37%, protein = 31%,
and fat = 30%) and the Step 1, high-GL American Heart Association (AHA) diet (macronutrient percentages of energy: carbohydrate =
55%, protein = 15%, and fat = 30%). Twelve
overweight, but otherwise healthy subjects,
participated in a randomized, crossover design involving two experimental conditions.
The two diets were prepared and eaten in a
metabolic ward, and the subjects consumed
the diets ad libitum for 6 days.42 While consuming the AHA diet, the subjects consumed

SEARS AND BELL

2,785 277 kcal/day (11,695 1,163 kJ/day);

the plasma triglycerides rose 28% and the
high-density lipoprotein (HDL)-cholesterol
decreased 10%. The risk of coronary heart disease (CHD) was theoretically increased by
these changes in blood lipids. First, the triglyceride/HDL-cholesterol ratio increased,
which has been shown to be associated with an
increased number of small, dense low-density
lipoprotein (LDL)-cholesterol particles.51 These
small particles are more atherogenic than
larger, less dense particles. Second, the ratio
of total cholesterol/HDL-cholesterol increased
even though total cholesterol concentrations
did not increase significantly. The change in
this ratio also increases the risk for CHD.
In contrast, when the same subjects consumed the low-GL Zone Diet ad libitum, they
spontaneously ate 25% fewer calories compared to when they ate the high-GL diet.42 This
spontaneous reduction in energy intake42 was
similar to that observed in other studies.40,41
Following the ad libitum low-GL Zone Diet,
plasma triglycerides decreased 35%.42 Plasma
insulin measured in a fasting state or over the
daytime in response to a 75-g glucose challenge was decreased on the low-GL Zone Diet;
no decrease occurred with the high-GL diet.
This may be indicative of increased insulin
sensitivity with the low-GL Zone Diet. In addition, a significant reduction in weight and decreases in waist and hip circumference were
observed with the low-GL Zone Diet, but none
was observed with the high-GL diet.
During the next phase of the study, the subjects again followed the high-GL diet, but this
time, ate the same number of calories they ate
while following the ad libitum low-GL Zone
Diet.42 Under these eucaloric conditions, there
was a trend in decline in the HDL-cholesterol,
which significantly increased the total cholesterol to HDL-cholesterol ratio (p < 0.0001) on
the high-GL American Heart Association diet.
There was also a significant increase in hunger
(p < 0.0002) and decrease in satiety (p < 0.007)
for these subjects on the high-GL diet.
This study showed that the low-GL Zone
Diet promoted satiety and reduced hunger better than a high-GL diet, which was similar to
the USDAs Food Guide Pyramid or the Amer-

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ZONE DIET

ican Heart Association.2,42 The low-GL Zone

Diet contributed to weight loss and a decrease
in the amount of visceral fat as determined by
measurements of waist circumference. These
changes occurred within six days. In addition,
CHD risk was reduced and plasma insulin
concentrations decreased. These metabolic,
hormonal, and anthropometric changes may
be beneficial for reducing the development of
type 2 diabetes and CHD. Based on this study,
healthy, overweight individuals can derive
benefit from a low-GL Zone Diet.
Changes in weight
The previously described studies supporting the metabolic benefits and weight loss of a
low-GL Zone Diet were short-terma couple
of hours to a few days. The next longer studies
showed that a low-GL Zone Diet promoted
weight loss.44,45
Weight loss was compared over 4 months in
107 obese children who consumed either a
low-GL diet or a standard, high-GL, weightreducing diet.44 The standard diet had a
macronutrient composition of >55% of the energy coming from carbohydrate, 1520% of
the energy from protein, and 2530% of the energy from fat. The low-GL Zone Diet had a
macronutrient composition of 4550% of the
energy from low-GL carbohydrates, 2025% of
the energy from protein, and 3035% of the
energy from fat. Both diets were energyrestricted to provide 250500 kcal less than
needed to maintain weight.
Both body weight and BMI decreased significantly (p < 0.001) more in the low-GL Zone Diet
group than in the standard diet group.44 The
change in body weight was 22.03 kg [95% confidence interval 23.19 to 20.88] in the low-GL
Zone Diet group and +1.31 kg [95% confidence
interval 20.11 to +2.72] in the standard diet
group. The BMI change was 21.53 kg/m2 [95%
confidence interval 21.94 to 21.12] in the lowGL Zone diet group compared to 20.06 kg/m2
[95% confidence interval 20.56 to +0.44] in the
high-GL group. Significantly more subjects in
the low-GL Zone Diet group experienced at
least 3 kg/m2 decrease in BMI than in the standard, high-GL diet group (17% vs. 2%) (p < 0.03).

33

In the same study design, 14 adolescents

(aged 1321 years) completed a 12-month
weight reduction study. Those in the low-GL
group lost significantly more weight and BMI
units than the low-fat group (21.3 0.7 vs.
0.7 0.5; p = 0.02). Most of the weight loss was
from the loss of body fat.
These studies illustrated that a low-GL Zone
Diet is effective at promoting weight loss in
children.44,45 Others have shown this to be true
in adults,41,42,46,47 thereby adding more support
that an energy restricted low-GL Zone Diet
may be a viable substitute the reduction of excess body weight than the energy-restricted,
high-GL diet that is currently recommended.
Changes in body composition, cardiovascular
risk factors, and glycemic control
Twenty-four overweight women were randomly assigned to one of two isoenergetic
diets containing about 1,600 kcal/day and 50 g
of fat.46,47 The diets differed only in protein and
carbohydrate content. One diet had the macronutrient percentages of the Zone Diet (40% of
the energy as carbohydrate, and 30% of the energy as protein and fat). This was termed the
Protein group. The other diet complied with
the guidelines of the USDAs Food Guide
Pyramid: 60% of the energy as carbohydrate,
16% protein, and 26% fat. This was referred to
as the Carbohydrate group.
During the 10-week study, weight loss was
similar between the two groups after 10 weeks
(6.96 1.36 kg in the Carbohydrate group versus 7.53 1.44 kg in the Protein group (i.e.,
Zone group).46,47 However, significantly more
fat was lost and lean tissue was spared in the
Protein group (p < 0.05).
Both groups experienced reductions in total
cholesterol (10%), but only those in the Protein
group (i.e., Zone group) had a reduction in
serum triglycerides (221%) and the ratio of
triglycerides/HDL-cholesterol (223%).46,47 Subjects in the Carbohydrate group exhibited
greater increases in two-hour post-prandial
insulin levels (384 27 pmol/L in the Carbohydrate group versus 251 21 pmol/L in the
Protein (p < 0.05). Similarly, these subjects had
significantly higher blood glucose levels at

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34

the same period (3.77 0.14 mmol/L in the

Carbohydrate group versus 4.34 0.15
mmol/L in the Protein group; p < 0.05). These
changes may explain why the subjects in the
Protein (i.e., Zone group) group were more
satisfied with their diet than those in the Carbohydrate group.
In another study, 57 subjects followed an
energy-restricted diet with either the unique
macronutrient composition of the Zone Diet or
one based on the USDAs Food Guide Pyramid
for 12 weeks, followed by a 4-week energy balance period.48 During the energy-restricted
phase, weight loss and fat mass loss were similar between the two groups. At the beginning
and end of the study, a 3-h meal tolerance test
was performed and serial measurements of
glycemic control were made. Subjects following the Zone Diet had a significantly lower
glycemic response (plasma glucose curve); insulin concentrations did not differ between the
two diets (p < 0.03). Dietary composition had
no effect on blood lipids except for a significant decrease in serum triacylglycerol concentrations (p < 0.0001) that was seen with the
Zone Diet. At week 12, the triglyceride levels
decreased by 29% in the Zone Diet and increased by 12% in the diet with high GL diet.
Although no differences were observed in
the rate of weight loss in this study between
the two isocaloric diets, the Zone Diet produced improvements in the glycemic response
and in serum triacylglycerols levels.48 In addition, the higher intake of protein had no deleterious effects on bone turnover. One criticism of
the Zone diet is that the higher protein content
will cause calcium to be leeched out of the
bones. This study,48 coupled with the others
using the macronutrient composition of the
Zone Diet,4047 support the safety and benefits
of such a regimen relative to bone composition.
Changes in dietary thermogenesis
and nitrogen balance
Acute energy-cost of meal-induced thermogenesis was compared after consumption
of a diet with the Zone Diet composition compared to the usual care diet based on the macronutrient composition of the USDAs Food Guide

SEARS AND BELL

Pyramid under isocaloric conditions.43 Ten

healthy, normal weight females participated in
this prospective, cross-over study design. For
each arm of the study, a different diet was consumed over a 24-h period. The composition of
the usual care diet was 60% of the energy from
carbohydrate, 17% of the energy from protein,
and 26% of the energy from fat. The Zone Diet
had a macronutrient composition of 40% of the
energy from carbohydrate, and 30% of the energy each from protein and fat.
On the morning following the consumption
of the test diet, the non-protein respiratory quotient (RQ) was measured after a 10-h fast and at
2.5 h after each meal that day.43 Post-meal thermogenesis (calculated as the difference between post-meal resting energy expenditure
[REE] and fasting REE) was twofold higher on
the diet with the unique macronutrient composition compared to the one based on the
USDAs Food Guide Pyramid (p < 0.05) under
eucaloric conditions. Post-prandial REE was
8 kcal/h higher for the Zone Diet after breakfast
and lunch; after dinner it was 14 kcal/h higher
than the other diet. Over the course of a day,
this accounted for 90-kcal more energy used in
the Zone Diet. During the course of a year, this
theoretically could account for an extra expenditure of 33,000-calories (roughly 4.3 kg).
Nitrogen balance (assessed from 24-h urinary urea nitrogen) was greater for the diet
with the Zone Diet compared to the other
(+7.6 0.9 versus 20.04 0.5 g N/day; p <
0.05).43 In addition, glomerular filtration rate
did not differ between the two diets. This is
important because another criticism of the
Zone Diet is that the higher percentage of energy from dietary protein will impair renal
function. In this study, no adverse change in
kidney damage was observed.
This study also demonstrated the benefits of
the proposed macronutrient composition on
thermogenesis and nitrogen balance over what
is currently recommended.43 Increased diet
thermogenesis, coupled with a sustained increase in REE for as long as 45 h after a meal,
may contribute to the reported weight loss
success observed with the Zone Diet using the
same approximate macronutrient percentages
used in other studies.41,42,4447 In addition, lean

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ZONE DIET

tissue was better preserved, and no damage

occurred to renal function from the higher protein intake.
Changes in insulin resistance
Markovic et al. conducted one of the earliest
studies on the Zone Diet in treating insulin resistance.49 This was a single arm study using
an energy-restricted Zone diet under metabolic ward conditions. Although there was no
control group, it was demonstrated that insulin resistance could be corrected in as soon
as four days. This is important since very little
weight loss had occurred in this time period,
indicating that insulin resistance was addressed by rapid hormonal changes as opposed to generalized weight loss.
An elegant cross-over study confirmed
the point.50 This randomized study compared
the Zone Diet to an isocaloric diet using the
macronutrient composition of the USDA
Food Guide Pyramid for a 5-week period before switching patients.2 The caloric content
of the diets was set so that no weight loss occurred, thus overcoming the confounding impact of weight loss on insulin resistance. It
was found that, after five wks, the glycosylated hemoglobin (a marker of long-term
glycemic control) was significantly lower in
the Zone Diet group than in the USDA Food
Guide Pyramid group.

EFFECT OF FISH OIL ON

THE REDUCTION OF
CARDIOVASCULAR MORTALITY
The primary reason the Zone Diet was developed was to treat cardiovascular disease.14 The
above studies indicated that the macronutrient
recommendations of the Zone diet were superior to those of the USDA Food Guide Pyramid
in terms of hunger control, hormonal control,
changes in lipoprotein levels, fat loss, and reduction of inflammation. While all of these
changes should be beneficial to the reduction
of heart disease, they remain only suggestive.
On the other hand, the data impact of fish oil
on heart disease is incredibly robust. This is

35

probably due to the inhibitory effects of EPA on

the production of pro-inflammatory eicosanoids
as described above. This is why fish oil is such
a significant component of the Zone Diet.23
The GISSI study was a secondary prevention trial with more than 11,000 individuals in
four distinct arms taken on a daily basis for
4 years.52 One arm consisted of a placebo, the
second arm consisted of 300 mg of vitamin E,
the third arm consisted of a fish oil concentrate
containing 0.9 grams of long-chain omega-3
fatty acids, and the final arm consisted of the
combination of vitamin E and fish oil concentrate. After 3.5 years, only the fish oil concentrate arms had any significant reduction in
cardiovascular mortality. Sudden cardiovascular death decreased by 45% compared to the
control group, overall cardiovascular mortality decreased by 20%, and all-cause mortality
decreased by 10%. More importantly, the mortality curves between the fish oil concentrate
arms and the placebo began to diverge after
the first four months of the study.
A more detailed analysis of the anti-inflammatory impact of fish oil came from a surgical
study on the removal of vascular tissue containing atherosclerotic lesions.53 In this randomized study, subjects were given either
fish oil or safflower oil prior to their surgery.
The atherosclerotic lesions were then analyzed. Compared to the group getting the
same level of safflower oil (rich in omega-6
fatty acids), the lesions in the subjects taking
the fish oil had a thicker fibrous cap, a significant change in the omega-3 fatty composition
of the plaque, and lower levels of macrophages in the plaques. All of these changes
were consistent with decreased inflammation
within the plaque and took place in a relatively short period of time (mean 45 days).
The effects of excess omega-6 fatty acids on
cardiovascular mortality was also explored
in the Lyon Diet Heart study, which like
the GISSI study was a secondary prevention
trial.54 The control group was following the
American Heart Association diet, which is
based upon the USDA Food Guide Pyramid,
and the other group was instructed to eat more
fish, vegetables, and fruits, and there was a rigorous exclusion of much of the omega-6 fat in

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SEARS AND BELL

the diet. The reduction alone in omega-6 fatty

acid intake would significantly reduce the production of pro-inflammatory eicosanoids, however this was further accelerated by the lower
GL of the diet. At the end of 4 years, there was a
70% decrease in both the number of fatal and
non-fatal heart attacks. This is vastly superior to
any reported drug intervention study.
Finally, in a recent more detailed dietary
analysis of the GISSI data,52 it was found that
the more low GL carbohydrates that were
eaten, the more fish consumed, and the more
non-inflammatory monounsaturated fats that
were consumed, the greater the decrease in the
all-cause mortality with those having the diets
more closely related to the Zone Diet having a
reduction of nearly 50% in all-cause mortality.55 There was no one particular food group,
simply a cumulative effect of lowering the dietary GL. Couple this low GL diet rich in monounsaturated fat with supplemental fish oil,
and you have the Zone Diet.

APPLICATIONS: EASE OF INTEGRATION

OF THE ZONE DIET
Adoption of a low-GL diet such as the Zone
Diet means that several changes need to be
made to the USDAs Food Guide Pyramid diet
as shown in Table 2. The practical guidelines
for following the proposed diet are listed
below:

1. Increased consumption of low-GL fruits

and non-starchy vegetables
2. Reduced intake of high-GL carbohydrates,
with high-carbohydrate densities such as
starches (e.g., potatoes, pasta, and rice) and
grains. The only exception would be the
moderate use of selected whole-grain products, such as steel-cut oatmeal and barley,
which are rich in soluble fiber.
3. Consumption of moderate amounts of
legumes, due to their high-carbohydrate
density.
4. Adequate levels (2030 g) of low-fat protein, such as lean meat, fish, poultry, a
low-fat dairy products, or protein-rich vegetarian source (e.g., soy imitation meat
products) at each meal.
5. Having most of the total fat intake from
nuts or oils that are rich in monounsaturated fats (e.g., olive oil, almonds).
6. Eating three meals and two snacks every
day, trying to let no more than five hours
elapse between them.
7. Trying to maintain the same protein-tocarbohydrate ratio at each meal or snack.
8. Restricting the GL of a single meal to no
more than 25 g.
9. Taking a fish oil supplement containing at
least one gram of long-chain omega-3 fatty
acids per day.
Many diets are available to the public. Recently, 160 overweight adults followed one of

TABLE 2. DAILY MEAL PLAN FOR THE PROPOSED, LOW-GLYCEMIC LOAD ZONE DIET WITH A
MACRONUTRIENT PERCENTAGE OF 40% OF THE ENERGY FROM CARBOHYDRATE AND 30% OF THE
ENERGY EACH FROM PROTEIN AND FATa
Food category
Bread, cereal, rice, and pasta
Whole grains (e.g., steel-cut
oatmeal, barley)
Vegetables
Fruits
Lean meat, skinless poultry, fish,
occasional legumes, and low-fat
dairy (e.g., milk, yogurt, cheese)
Fats and oils
Foods with added sugar
aData

from Sears.14,23

Number of servings per day

Use sparingly (12 servings of condimentsize portions)
12 servings
710 servings of non-starchy type
35 servings of low-GI selections
(e.g., cherries, berries, pears, oranges,
and grapefruit)
Enough to obtain at least:
75 g of protein for women and
100 g of protein for men
12 tablespoons of oils rich in
monounsaturated fatty acids
Use very sparingly

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37

four popular diets for 12 months: Atkins diet

(high-protein, high-fat), Weight Watchers (lowfat, energy restricted), Ornish diet (very low
fat), and the Zone Diet (M.L. Dansinger et al.,
2004, personal communication). Weight loss
was the same amount all of the groups during
the study; subjects lost 2.13.1% of their initial
body weight. The Zone and Weight Watchers
diets had the best compliance (65% retention)
compared to the Atkins diet (52%) and the Ornish diet (50%). In a shorter study (6 weeks), no
differences were observed between an Atkinslike and a Zone-like diet in weight loss, loss of
body fat, or waist-to-hip ratio.56

CONCLUSION
The Zone Diet offers many advantages over
the diets that are currently recommended in
terms of safety, compliance, and clinically relevant results. More importantly, it can have a
significant effect on inflammation that is a primary factor in the development and mortality
of heart disease. As more criticism is directed
toward the recommendations of the USDAs
Food Guide Pyramid, low-GL, anti-inflammatory diets such as the Zone Diet may be a fruitful direction to explore. The published data
supports such optimism.

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Address reprint requests to:

Barry Sears, Ph.D.
Zone Labs
222 Rosewood Dr.
Danvers, MA 01923

E-mail: [email protected]