Review Article Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease1�3 Richard J Johnson, Mark S Segal, Yuri Sautin, Takahiko Nakagawa, Daniel I Feig, Duk-Hee Kang, Michael S Gersch, Steven Benner, and Laura G Sánchez-Lozada ABSTRACT Currently, we are experiencing an epidemic of cardiorenal disease characterized by increasing rates of obesity, hypertension, the met- abolic syndrome, type 2 diabetes, and kidney disease. Whereas ex- cessive caloric intake and physical inactivity are likely important factors driving the obesity epidemic, it is important to consider additional mechanisms. We revisit an old hypothesis that sugar, particularly excessive fructose intake, has a critical role in the epi- demic of cardiorenal disease. We also present evidence that the unique ability of fructose to induce an increase in uric acid may be a major mechanism by which fructose can cause cardiorenal disease. Finally, we suggest that high intakes of fructose in African Ameri- cans may explain their greater predisposition to develop cardiorenal disease, and we provide a list of testable predictions to evaluate this hypothesis. Am J Clin Nutr 2007;86:899 –906. KEY WORDS Fructose, uric acid, sugar, arteriosclerosis, en- dothelial dysfunction, hypertension, obesity, chronic kidney dis- ease, metabolic syndrome INTRODUCTION Despite our best efforts, the epidemic of cardiorenal disease continues to increase at an alarming rate. Obesity affects one- third of adults and one-sixth of children in the United States and continues to increase; although dietary interventions are often initially successful, they often fail over time because of attrition (1). Likewise, hypertension affects nearly one-third of the pop- ulation, but despite the presence of effective antihypertensive agents, nearly two-thirds of these patients remain either un- treated or are treated ineffectively (2). Furthermore, even if the hypertension is controlled, these subjects continue to have in- creased cardiovascular mortality (3). Diabetes, a complication of obesity, now affects 7% of our population, with approximately one-third doomed to develop various complications such as ret- inopathy or nephropathy (4). Kidney disease also continues to increase at a deplorable rate, a consequence of the increasing frequency of hypertension and diabetes (5). Today, nearly 20 million Americans have stage 1 kidney disease or greater (de- fined as the presence of microalbuminuria or a glomerular fil- tration rate �90 mL�min�1�1.73 m�2; 6), and, although treat- ments such as angiotensin-converting enzyme inhibitors are beneficial, they act primarily to delay the progression to renal failure as opposed to halting the process (7). It is our opinion that the potential mechanisms underlying the epidemic should be carefully reappraised. On the basis of both the experimental studies performed in our laboratorie ...

1. Review Article
Potential role of sugar (fructose) in the epidemic of
hypertension,
obesity and the metabolic syndrome, diabetes, kidney disease,
and
cardiovascular disease1�3
Richard J Johnson, Mark S Segal, Yuri Sautin, Takahiko
Nakagawa, Daniel I Feig, Duk-Hee Kang, Michael S Gersch,
Steven Benner, and Laura G Sánchez-Lozada
ABSTRACT
Currently, we are experiencing an epidemic of cardiorenal
disease
characterized by increasing rates of obesity, hypertension, the
met-
abolic syndrome, type 2 diabetes, and kidney disease. Whereas
ex-
cessive caloric intake and physical inactivity are likely
important
factors driving the obesity epidemic, it is important to consider
additional mechanisms. We revisit an old hypothesis that sugar,
particularly excessive fructose intake, has a critical role in the
epi-
demic of cardiorenal disease. We also present evidence that the
unique ability of fructose to induce an increase in uric acid may
be a
major mechanism by which fructose can cause cardiorenal
disease.
Finally, we suggest that high intakes of fructose in African
Ameri-

2. cans may explain their greater predisposition to develop
cardiorenal
disease, and we provide a list of testable predictions to evaluate
this
hypothesis. Am J Clin Nutr 2007;86:899 –906.
KEY WORDS Fructose, uric acid, sugar, arteriosclerosis, en-
dothelial dysfunction, hypertension, obesity, chronic kidney dis-
ease, metabolic syndrome
INTRODUCTION
Despite our best efforts, the epidemic of cardiorenal disease
continues to increase at an alarming rate. Obesity affects one-
third of adults and one-sixth of children in the United States
and
continues to increase; although dietary interventions are often
initially successful, they often fail over time because of attrition
(1). Likewise, hypertension affects nearly one-third of the pop-
ulation, but despite the presence of effective antihypertensive
agents, nearly two-thirds of these patients remain either un-
treated or are treated ineffectively (2). Furthermore, even if the
hypertension is controlled, these subjects continue to have in-
creased cardiovascular mortality (3). Diabetes, a complication
of
obesity, now affects 7% of our population, with approximately
one-third doomed to develop various complications such as ret-
inopathy or nephropathy (4). Kidney disease also continues to
increase at a deplorable rate, a consequence of the increasing
frequency of hypertension and diabetes (5). Today, nearly 20
million Americans have stage 1 kidney disease or greater (de-
fined as the presence of microalbuminuria or a glomerular fil-
tration rate �90 mL�min�1�1.73 m�2; 6), and, although
treat-
ments such as angiotensin-converting enzyme inhibitors are
beneficial, they act primarily to delay the progression to renal

3. failure as opposed to halting the process (7).
It is our opinion that the potential mechanisms underlying the
epidemic should be carefully reappraised. On the basis of both
the experimental studies performed in our laboratories and an
extensive review of the literature, we revisit an old hypothesis
that a simple dietary substance may have a significant role in
driving the epidemic. Interestingly, reappraising the role of
sugar
and its influence in the development of cardiorenal disease may
lead to a new understanding of why certain populations, such as
African Americans, Native Americans, Maori, and Australian
Aborigines, are at greater risk of developing the disease.
Similar
to the relation between high intakes of salt or protein and the
risk
of developing kidney disease or to the relation between a high-
fat
diet and the atherosclerotic phenotype, we propose that sugars
containing fructose may play a major role in the development of
hypertension, obesity, and the metabolic syndrome and in the
subsequent development of kidney disease. Although physical
inactivity and overeating are major contributors to the obesity
epidemic, we present evidence that fructose may be the “caries”
at the epidemic’s root.
THE EPIDEMIC OF CARDIORENAL DISEASE
If the goal is to understand the causes of the epidemic, it is
important to first review the literature to understand the timing
and origins of the epidemic of cardiorenal disease. This type of
epidemiologic analysis may provide insights into the potential
etiologies that can then be tested in the experimental setting.
After the introduction of the inflatable cuff for blood pressure
measurement by Riva Rocci in the late 1800s, population-based

4. studies were performed throughout the world (reviewed in 8). A
1 From the Division of Nephrology and Department of
Medicine, Univer-
sity of Florida, Gainesville, FL (RJJ, MSS, YS, TN, and MSG);
the Division
of Pediatric Nephrology, Texas Children’s Hospital, Baylor
College of Med-
icine, Houston, TX (DIF); the Division of Nephrology, Ewha
Woman’s
University College of Medicine, Seoul, Korea (D-HK); the
Foundation for
Applied Molecular Evolution, Gainesville, FL (SB); and the
Instituto Na-
cional de Cardiologia Ignacio Chavez, Mexico City, Mexico
(LGS-L).
2 Supported by NIH grants DK-52121, HL-68607, and HL-
79352 (to RJJ)
and by a grant from the Korea Health 21 R&D Project, Ministry
of Health &
Welfare, Republic of Korea (A050626; to D-HK).
3 Address reprint requests to RJ Johnson, CG-98, 1600 Archer
Road,
Gainesville, FL 32610. E-mail: [email protected]
Received November 16, 2006.
Accepted for publication March 5, 2007.
899Am J Clin Nutr 2007;86:899 –906. Printed in USA. © 2007
American Society for Nutrition
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study performed between 1907 and 1919 in �140 000 healthy
adults applying for life insurance in the New York region sug-
gested that a blood pressure of 140 (systolic)/90 (diastolic) mm
Hg was abnormal because it reflected only 5-6% of the popula-
tion in the United States (9); however, by nature, these early
studies may not have been representative of the general popula-
tion because they usually did not include subjects of lower so-
cioeconomic status who could not afford insurance or patients
who had been previously diagnosed with a disease.
Nevertheless,
on the basis of these early studies, a blood pressure of 140/90
mm
Hg was adopted as the definition of hypertension.
There has been a remarkable increase in the prevalence of
hypertension in the US population since the early 1900s. In a

8. study performed in 1939 of �11 000 residents in the Chicago
area, only 11-13% of the adult population had blood pressures
in
the hypertensive range (10); this increased to 25% in 1975 (11),
to 28% in 1990 (12), and to 31% (61 million people) in 2004
(13).
Similar observations were noted in other countries. Hyperten-
sion was initially rare in all parts of the world except in Europe,
particularly in England, France, Germany, and the United States
(14 –16). In studies conducted as late as 1940, hypertension ap-
pears to have been almost nonexistent in non-Western peoples,
including studies performed in Native Americans, Australian
Aborigines, Maori, Alaskan Eskimos, Asians, and African
blacks (reviewed in 8). However, with the introduction of a
Western culture and diet, there has been a significant change.
The
prevalence of hypertension has been increasing throughout the
world, and the greatest relative increase has been observed in
groups with less socioeconomic support (8).
Not surprisingly, a rise in hypertension is paralleled by in-
creasing rates of obesity and diabetes. In a study of Civil War
veterans, obesity [defined as a body mass index (BMI; in
kg/m2)
�30] was observed in only 3.4% of 50- to 59-y-old male
veterans
in 1890, but this percentage rose slightly to 5.9% by 1900 (17).
Obesity rates continued to increase during the early 1900s,
reach-
ing 14.5% in 1976 –1980, 22.5% in 1988 –1994, and 30.4% in
1999 –2002 (4, 18). Similarly, Osler (19) estimated a
prevalence
of 2–3 cases of diabetes per 100 000 persons in the population
in
1893; however, today, type 2 diabetes affects �7% of our pop-

9. ulation and is estimated to double in prevalence by 2020. The
increases in the rates of obesity and diabetes are being observed
throughout the world (20). As with hypertension, these condi-
tions are greatest among the less privileged in societies such as
African Americans, Native Americans, and Hispanics in the
United States; the Maori in New Zealand; and Aborigines in
Australia (20).
There has also been a remarkable increase in chronic kidney
disease (4, 21). The incidence of end-stage renal disease in the
United States has increased 4-fold between 1980 and 2002 (21),
and similar increases are being observed throughout the world.
Most of the increase is due to diabetes and hypertension. The
incidence of end-stage renal disease in the United States has
increased 4-fold between 1980 and 2002 (21), and similar in-
creases are being observed throughout the world. Most of the
increase is due to diabetes and hypertension.
The increase in hypertension and diabetes translates into in-
creased rates of stroke, heart failure, and myocardial infarction.
Indeed, there has also been a remarkable increase in cardiovas-
cular disease throughout the world. Coronary artery disease was
once considered rare and was observed primarily in Europe and
in the United States (22). By 1929, Platt (23) noted that
coronary
disease had increased in frequency such that it was commonly
observed by the family practitioner; by 1940, cardiology was
initiated as a discipline in the United States. By 1950, there
were
only 500 cardiologists in the United States, and, by 1960, the
World Health Organization pronounced a world epidemic of
cardiovascular disease. Today, there are �25 000 cardiologists
in the United States performing �1 million coronary
angiograms
yearly, and �720 000 cardiovascular surgeries are performed

10. an-
nually (4). Cardiovascular disease is currently the major cause
of
death in the United States, accounting for 37% of all deaths, and
is
considered a contributing factor in an additional 21% of the
popu-
lation (4). Similar increases in coronary artery disease and
cardio-
vascular mortality have also been observed in other countries
(20).
Some have argued that there is no cardiovascular epidemic,
because the absolute number of cardiovascular deaths in the
United States and the calculated rates per population are cur-
rently decreasing (4). It has also been stated that the increase in
hypertension simply reflects the increase in the aging
population,
because the average life span has increased from 47 y in 1900 to
77 y today (24). Furthermore, the increasing longevity of the
population has been used as an argument that the increase in
obesity may not be a disadvantage. However, these arguments
are lacking. First, the observed decline in cardiovascular mor-
tality rates is probably not due to a decrease in cardiovascular
disease, but rather to the fact that we have developed better
ways
to control cardiovascular disease after it has developed. Today,
we have antihypertensive agents, statins, antiplatelet drugs, and
a host of surgical and nonsurgical treatments for those with cor-
onary artery disease. Whereas it is true that an aging population
will likely mean higher rates of hypertension, we are now ob-
serving hypertension in adolescents that cannot be explained by
an aging population (13). Furthermore, in the 1939 study (10),
only 12–13% of 50- to 55-y-old men had hypertension (and only
1.6% had systolic blood pressures �140 mm Hg); today, age-
matched men have a hypertension frequency of 31%. Finally,

11. the
comment that obesity is an advantage because people are living
longer negates the fact that, in the general population, longevity
is greater in persons with a normal BMI than in those with a
high
BMI (25). It is more likely that increased longevity relates to
better hygiene, a reduction in malnutrition, the introduction of
antibiotics, and the increasing affluence of the world
population.
THE PARALLEL EPIDEMIC OF SUGAR
CONSUMPTION
Whereas today the intake of foods containing table sugar (su-
crose) occurs with almost every meal, the introduction of sugar
into the diet is relatively recent. Before the introduction of
sugar,
the primary sweetener had been honey, but because it was rela-
tively rare and not mass produced, the majority of people (espe-
cially the poorer classes) had no sweeteners at all in their
normal
diet (26).
Sugar derived from sugar cane was first developed in New
Guinea and in the Indian subcontinent and was a rare and
expen-
sive commodity that was introduced into Europe via Venice,
Italy, and other trading ports during the Middle Ages. During
this
time, only royalty or the very wealthy could afford this luxury.
However, by the late 1400s, Spain and Portugal began growing
sugar cane in the Canary Islands, in Madeira, and in Silo Tome;
this led to such wealth that King Emmanuel I of Portugal, “the
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Fortunate” (1469 –1521), sent life-sized sugar effigies of the
Cardinals and the Pope to the Vatican in 1513 as a gift (27).
The discovery of the New World provided a mechanism for
expanding sugar production. Christopher Columbus brought
sugar
cane to Santo Domingo on the island of Hispaniola (which is
now
Haiti and the Dominican Republic) on his second voyage in
1493;
shortly thereafter, sugar plantations were established in the
Carib-

15. bean islands, in the Guiana coasts, in Brazil, and eventually in
the
southern United States. Although initially an attempt was made
to
use Native Americans to work the plantations, a Catholic priest,
Bartholomew de las Casas, requested King Ferdinand of Spain
for
the protection of the local Taino Indians because of the large
num-
bers who had been killed or who were dying from smallpox or
other
diseases. So, in 1505, the first ship of African slaves departed
for
America to work the plantations. The next three and a half
centuries
witnessed the infamous “Triangle Trade,” in which ships would
sail
to Africa, loaded with manufactured goods such as brass,
copper,
lead, salt, and gunpowder, which would be used to purchase
slaves
who were then shipped across the famed “Middle Passage” to
the
sugar plantations in the Caribbean and southern states. It is
estimated
that between 10 and 20 million Africans were brought to
America
during this period.
Whereas initially Portugal and Spain were the major importers
of sugar, the capture of the Spanish settlement of Kingston,
Jamaica, by the English in 1655 resulted in much of the sugar
being exported to England. Sugar was such a desirable commod-
ity that England began to hoard the sugar for its own people.
Whereas in 1660, England exported 67% of its sugar to the rest
of Europe, by 1753, this dropped to 5.5% (28). The increase in

16. sugar production resulted in its increased availability to the
pub-
lic. Before the introduction of sugar, the primary diet was car-
bohydrate based, but it was primarily starch, consisting of a diet
rich in barley, wheat, oats, and rye. Sugar had been used
primarily
as a costly medicinal. However, with the increased availability
of
sugar, it could also be used to sweeten chocolates, teas, and
cakes.
The average per capita sugar intake in England was 4 lb (1.8 kg)
in 1700 and 18 lb (8.1 kg) in 1800, and it increased even more
after the prime minister, William Gladstone, removed the sugar
tax in 1874, which led to a mean consumption of 100 lb (45 kg)
in 1950 (29; Figure 1).
The blockade of sugar importation to Europe by the British
navy after 1700 caused a shortage of sugar to these countries.
As
a consequence, techniques were developed to extract sugar from
beets, and by the beginning of the 18th century, a thriving sugar
beet industry was developing in Germany, France, and Austria.
The combined production of sugar from sugar cane and beets
led
to a marked increase in world sugar production, from 250 000
tons in 1800 to 8 million tons in 1900 (33).
Sugar consumption continued to increase in the 1900s, with an
overall doubling in the United States and the United Kingdom
between 1900 and 1967 (34). By 1993, �110 million tons of
sugar were produced worldwide (33). Whereas sugar intake con-
tinues to be marked in the industrialized nations, it is in the
developing countries that the greatest increase in the rates of
sugar consumption has been observed (35 ). By the early 1970s,
an additional sweetener, high-fructose corn syrup (HFCS), was

17. introduced in the United States, which had certain advantages
over table sugar with relation to shelf life and cost. This sweet-
ener, the composition of which is similar to that of sucrose, is
used extensively to sweeten soft drinks, fruit punches, pastries,
and processed foods. The combination of table sugar and HFCS
has resulted in an additional 30% increase in overall sweetener
intake over the past 40 y, mostly in soft drinks. Currently, con-
sumption of these sweeteners is almost 150 lb (67.6 kg) per
person per year (36), which has resulted in the ingestion of
�500
kcal/d (37; Figure 1).
ARE THESE EPIDEMICS RELATED?
Keys (38) is credited with the discovery of an association of
Western diets with the development of coronary artery disease.
Keys focused on the relative increase in fat intake with a
decrease
in total carbohydrate intake, and this general finding (“nutrition
transition”) has been confirmed in numerous studies, which has
led to the widespread recognition of the importance of fat intake
in the development of heart disease. However, Yudkin (39)
showed in the early 1960s that the Western diets high in fat are
also high in sugar, and he proposed that sugar intake may also
play an underlying role in the cardiovascular epidemic. In addi-
tion, recent history in the United States has shown that,
although
a low-fat intake has been promoted, rates of obesity have con-
tinued to increase as sugar consumption has continued. In addi-
tion, recent studies showing that a low-carbohydrate, high-fat
diet has no adverse cardiovascular effects (40, 41) suggest that
it
is time to revisit the causes of the cardiorenal disease epidemic.
In 2002, Havel’s group (37) made the case that the fructose
content of sugar may be the critical component associated with
the risks of obesity and heart disease. Sucrose is a disaccharide

18. consisting of 50% fructose and 50% glucose, and HFCS is also a
mixture of free fructose and glucose of approximately the same
proportion (55:45).
There are some striking epidemiologic associations between
sugar intake and the epidemic of cardiorenal disease. For exam-
ple, obesity was initially seen primarily in the wealthy, who
would have been the only ones able to afford sugar. Also, the
first
documentation of hypertension, diabetes, and obesity occurred
in the very countries (England, France, and Germany) where
sugar first became available to the public. The rise in sugar
intake
in the United Kingdom and the United States (Figure 1) also
correlates with the rise in obesity rates observed in these coun-
tries. Furthermore, the later introduction of sugar to developing
countries also correlates with the later rise in their rates of
obesity
and heart disease. A series of epidemiologic studies linked the
FIGURE 1. Sugar intake per capita in the United Kingdom from
1700 to
1978 (30, 31; E) and in the United States from 1975 to 2000
(32; �) is
compared with obesity rates in the United States in non-
Hispanic white men
aged 60 – 69 y (17; F). Values for 1880-1910 are based on
studies conducted
in male Civil War veterans aged 50 –59 y (18).
SUGAR AND THE CARDIORENAL DISEASE EPIDEMIC 901
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ingestion of soft drinks to obesity, hypertension, and diabetes
(42, 43) and the consumption of fruit juice and fruit punch to
obesity in children (44, 45). Although these epidemiologic as-
sociations suggest a potential causal role, are there any direct
experimental data to show that sucrose or fructose can induce
obesity or hypertension?
SUGAR (FRUCTOSE) STUDIES IN HUMANS AND
EXPERIMENTAL ANIMAL MODELS
Clinical studies have confirmed that sucrose (and particularly
fructose) can induce weight gain and features of the metabolic
syndrome. For example, serum triacylglycerols increased in
young men receiving a diet supplemented with 200 g sucrose/d,
whereas concentrations did not increase when starch was the
primary carbohydrate (46). Hyperinsulinemia developed in one-

22. third of these subjects (30). In another study, the administration
of sucrose supplements resulted in weight gain, a significant
rise
in serum triacylglycerols, and a rise in systolic blood pressure
(47). An increase in blood pressure was also observed in healthy
adults fed a diet of 33% sucrose for 6 wk but not when diets of
5%
or 18% sucrose were fed (48). Others have also reported that
diets
enriched in either sucrose (49) or fructose (50) cause impaired
glucose tolerance and insulin resistance. Notably, most of these
diets provided fructose in the range of 400 – 800 kcal/d, which
is
within the upper range of what is currently being ingested in the
United States.
Rodents also develop features of the metabolic syndrome after
ingesting sucrose. As in humans, it was shown that the active
ingredient is fructose rather than glucose: feeding fructose to
rats
resulted in the metabolic syndrome, whereas equivalent amounts
of glucose or starch did not induce these features (51). In
addition
to the metabolic syndrome, the administration of fructose re-
sulted in the development of renal hypertrophy, afferent arterio-
lar thickening, glomerular hypertension, and cortical vasocon-
striction (52). Furthermore, feeding fructose to rats with chronic
renal disease (rats that have had five-sixths of their renal mass
removed) resulted in an increased progression of the disease, as
evidenced by worsening proteinuria, renal function, and glomer-
ulosclerosis (53). Worsening of renal function was not observed
in rat pairs fed dextrose (53).
It has been argued that the fructose studies in rodents should
not be compared with human studies because the doses of fruc-
tose administered to rodents are not physiologic, inasmuch as

23. they usually account for 60-70% of the diet. However, we re-
cently found that lower doses of fructose (10% given in the
water,
resulting in one-half of the caloric intake, compared with the
classic 60% fructose diet) can also induce hypertension and
renal
microvascular changes, although they are less severe (52).
MECHANISMS FOR FRUCTOSE-INDUCED
METABOLIC SYNDROME
Fructose may cause obesity via several different mechanisms.
First, Havel’s group (54) conducted a clinical study that found
that fructose may not cause the level of satiety equivalent to
that
of a glucose-based meal. Specifically, the differences in the ef-
fect of fructose and glucose consumption (consumed as bever-
ages with 3 meals) on ad libitum food intake and hunger rating
were observed on the day after the exposure to the sweetened
beverages. The mechanism was related to the inability of
fructose
to acutely stimulate insulin and leptin and to inhibit ghrelin, all
factors that are known to affect the satiety center in the central
nervous system. Yudkin (34) also argued that the sweetness of
fructose (or sucrose) often makes food more palatable, and, in-
deed, the food industry has capitalized on this by frequently
adding HFCS or sugar to normally nonsweetened foods (such as
crackers) to enhance the taste. This may stimulate more food
intake. Furthermore, mice fed fructose-sweetened water gain
more weight than do mice given the same calories as starch,
which suggests that fructose may also slow the basal metabolic
rate (55 ).
One unique aspect of fructose is that it is the only sugar that
raises uric acid concentrations, and this can be shown in both

24. humans (56) and rodents (57). Fructose enters hepatocytes and
other cells (including tubular cells, adipocytes, and intestinal
epithelial cells), where it is completely metabolized by fructoki-
nase with the consumption of ATP; unlike in glucose metabo-
lism, there is no negative regulatory mechanism to prevent the
depletion of ATP. As a consequence, lactic acid and uric acid
are generated in the process, and uric acid concentrations may
rise by 1– 4 mg/dL after the ingestion of a large fructose-based
meal (58).
Although the rise in uric acid concentrations has historically
been viewed as simply a potential risk factor for inducing gout,
recent studies suggest that this may be a key mechanism to
explain how fructose causes cardiovascular disease. In addition,
it also provides a mechanism to explain why rodents are rela-
tively resistant to the effects of fructose (see below).
FRUCTOSE-INDUCED HYPERURICEMIA AS A
MECHANISM FOR CARDIORENAL DISEASE
Nakagawa et al (51) recently showed in experimental animals
that lowering uric acid concentrations could largely prevent fea-
tures of the metabolic syndrome induced by fructose, including
weight gain, hypertriacylglycerolemia, hyperinsulinemia and in-
sulin resistance, and hypertension. The protective effect of low-
ering uric acid concentrations on the development of the meta-
bolic syndrome was shown regardless of whether the uric acid
concentrations were lowered by using a xanthine oxidase inhib-
itor or a uricosuric agent (51).
These studies were surprising, because most authorities had
considered uric acid to be either biologically inert or an
important
antioxidant in the plasma (59). However, uric acid was found to
have numerous deleterious biologic functions. For example, uric
acid stimulates both vascular smooth muscle cell proliferation

25. and the release of chemotactic and inflammatory substances
(60 – 62), induces monocyte chemotaxis (63), inhibits endothe-
lial cell proliferation and migration (64, 65), and causes
oxidative
stress in adipocytes, which results in the impaired secretion of
adiponectin (66).
In animals, the effect of elevated uric acid concentrations is
even more pronounced. For example, mildly hyperuricemic rats
develop hypertension because of the inhibition of nitric oxide
synthase in the macula densa, the stimulation of intrarenal
renin,
and a reduction in endothelial nitric oxide bioavailability (67).
Over
time, hyperuricemic rats develop renal arteriosclerosis that then
causes the animals to develop a salt-sensitive form of
hypertension
(62). Hyperuricemic rats also develop slowly progressive renal
dis-
ease with renal vasoconstriction and glomerular hypertension
(68).
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An increase in uric acid in animals with preexistent renal
disease
accelerates the progression of the disease (69).
Whereas human diseases such as obesity, renal disease, and
cardiovascular diseases likely have complex and multifactorial
origins, recent studies have suggested that uric acid is an inde-
pendent risk factor for these diseases. Uric acid has now been
found to be an independent predictor of hypertension in 15 of
16
published studies, including a recent report by the Framingham
Heart Study group (70 – 85). Uric acid is also an independent
predictor of obesity (86), hyperinsulinemia (87), and renal dis-
ease (88). Furthermore, uric acid concentrations are elevated in
the vast majority (89%) of adolescents with new-onset hyper-
tension, and in pilot studies, the lowering of uric acid
concentra-
tions was found to reduce blood pressure in these subjects (89,
90). A recent prospective, controlled trial also reported that the
lowering of uric acid concentrations in patients with hyperuri-
cemia and renal disease resulted in significantly slower renal
progression and a significant (13 mm Hg) fall in systolic blood
pressure that was not observed in the controls (91). Whereas
more clinical studies are clearly needed, these data suggest that

29. uric acid may contribute to the cardiorenal disease epidemic.
The mechanism by which uric acid causes these effects may
involve a reduction in the concentrations of endothelial nitric
oxide. Uric acid potently reduces the concentrations of endothe-
lial nitric oxide in vitro and in vivo in experimental animals
(64,
65). Hyperuricemia in humans is also strongly associated with
endothelial dysfunction (92, 93), and lowering uric acid concen-
trations has consistently been shown to improve endothelial
function after several weeks (94 –98). In turn, a reduction in
endothelial nitric oxide predisposes animals to develop features
of the metabolic syndrome. For example, genetically modified
mice that lack endothelial nitric oxide synthase develop many
features of metabolic syndrome, including hypertension, hyper-
triacylglycerolemia, and insulin resistance (99).
Several potential mechanisms may explain how an impaired
production of endothelial nitric oxide results in features of the
metabolic syndrome. For example, a reduction in nitric oxide
results in systemic and intrarenal vasoconstriction, renal micro-
vascular disease, and systemic hypertension (100). Endothelial
nitric oxide is also critical in mediating the increase in blood
flow
to the skeletal muscle in response to insulin, and blocking nitric
oxide can result in higher blood insulin concentrations and pe-
ripheral insulin resistance (101). In turn, insulin stimulates the
secretion of hepatic triacylglycerol (102).
It should be noted that obesity itself can also induce insulin
resistance, in part by the intracellular accumulation of triacyl-
glycerols (102). Once renal arteriosclerosis develops, hyperten-
sion also becomes salt sensitive and renal dependent (103). Fi-
nally, the progressive loss of renal function and mass will result
in intrarenal hemodynamic changes that favor a continued de-
cline in renal function (104). Hence, fructose- and uric acid–

30. associated mechanisms are likely to be of more importance in
the
initial development of the metabolic syndrome phenotype and
may become less important once obesity, hypertension, and
renal
disease become established.
WHY ARE AFRICAN AMERICANS SUSCEPTIBLE TO
CARDIOVASCULAR DISEASE?
It is well known that African Americans have higher rates of
obesity, hypertension, diabetes, kidney disease, and heart
disease
(105). This increased rate of cardiorenal disease contrasts with
a
near absence of hypertension and obesity in studies performed
in
the early 20th century in blacks living in Africa (106, 107). It is
interesting to speculate that African Americans may also have
been exposed quite early to sugar. Early workers cut and
bundled
the sugar cane in the fields, pressed the cane in the local mills
to
get the sugary extract, and boiled this extract in the sugar
houses
to generate the sugar crystals and leftover molasses. Molasses
(which is sucrose) was a staple in the early African American
diet, and one wonders whether it may have played a role in the
increased frequency of hypertension that was noted in early ep-
idemiologic studies performed in the Caribbean and in
Louisiana
(108, 109). Recent studies also have documented that the sugar
intake of African Americans is greater than that of whites (110,
111). Similar high sugar intakes were noted in studies of Aus-
tralian Aborigines and Samoans living in New Zealand (112,

31. 113). Furthermore, it is known that African Americans have
higher concentrations of uric acid (114); in the African
American
Study of Hypertension and Kidney Disease, the average uric
acid
concentration was 8.3 mg/dL (115).
Other explanations are also possible, including the preferential
survival during the early years of slavery of subjects with
higher
blood pressures, salt sensitivity, obesity and insulin resistance,
and better wound healing (116). Indeed, African Americans with
hypertension and renal disease have been found to have a higher
frequency of a polymorphism for transforming growth factor-�
(TGF-�) and elevated serum TGF-� concentrations (117).
TGF-� is a cytokine important in wound healing and was re-
cently shown to have a role in blood pressure (118). An increase
in TGF-� could also explain the rapid progression of microvas-
cular injury and renal disease characteristic of African Ameri-
cans (119) and, by inducing microvascular disease, could also
have a role in the induction of salt sensitivity (103).
A congenital mechanism has also been proposed. African
Americans have a higher frequency of low-birth-weight infants,
which has been linked to a low nephron number (120). In turn, a
low nephron number is associated with the later development of
hypertension, diabetes, and obesity (121). Interestingly, low-
birth-weight infants are known to develop early hyperuricemia
and endothelial dysfunction (122). Indeed, evidence that uric
acid may have a role in this condition is mounting (123).
Finally, an environmental mechanism also seems likely. Af-
rican Americans may be under more societal stress owing to
lower socioeconomic conditions (124). They also have diets
higher in sodium and lower in potassium (125).

32. CAVEATS
A key difficulty in proving that sugars play a participatory role
in the epidemic of cardiorenal disease is separating the effect of
fat intake and the effect of sugar intake. That is, survival for
thousands of years was based on our ability to store triacylglyc-
erol for survival during times when food was scarce. Since the
industrial revolution, food has been plentiful, and obesity has
increased because of the innate nature to store triacylglycerols
in
the face of excessive caloric intake. However, whereas an in-
creased intake of calories as fat can cause obesity and obesity
can
lead to insulin resistance, it is our hypothesis that only sugars
can
directly lead to insulin resistance. In addition, for the past 20 y,
there has been a push to lower fat intake, and the result of these
SUGAR AND THE CARDIORENAL DISEASE EPIDEMIC 903
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programs has been a marked increase in the prevalence of obe-
sity. Interestingly, during this period, the level of fructose
intake
increased considerably.
Another difficulty in showing causation in human studies of
the effect of fructose on the incidence of cardiorenal disease,
independent of obesity, is that obesity and fructose intake track
together. Thus, whereas animal studies have shown a causal
effect of fructose on cardiorenal markers, independent of
obesity,
causation cannot be shown in human studies.
CONCLUSION
In conclusion, we propose that sugar intake, and particularly
that of fructose, may have an important participatory role in the
current cardiorenal disease epidemic and may also explain why
certain subgroups, such as African Americans, are particularly
prone to disease. This pathway may well be mediated, in part,
by
the unique ability of fructose to raise uric acid. This may also
explain why rodents are relatively resistant to fructose, because
these animals have lower uric acid concentrations owing to the
presence of an enzyme (uricase) that degrades uric acid to allan-
toin. Indeed, when uricase is inhibited in the rat, fructose will
cause a 5-fold greater increase in uric acid concentrations (57).

36. The observation that uric acid may play a key role in the
process suggests that other mechanisms that raise uric acid con-
centrations may also play a role in the epidemic. In this regard,
17th and 18th century England is also famous for the enormous
importation of fortified wines such as port and Madeira rich in
sugar and lead (126). Lead can also cause hyperuricemia and
hypertension. We have been able to block lead-induced hyper-
tension by lowering uric acid concentrations (126). This would
suggest that a low level of lead ingestion may act as an
additional
synergistic factor, particularly during the early part of the epi-
demic. Uric acid concentrations have increased within the gen-
eral population in parallel with the epidemic of cardiorenal dis-
ease (8, 127).
If the hypothesis is correct that fructose has a role in the
epidemic of cardiovascular disease, then a number of
predictions
should arise from future studies. First, fructose intake will be a
risk factor for hypertension, insulin resistance,
hypertriacylglyc-
erolemia, obesity, type 2 diabetes, preeclampsia, chronic kidney
disease, stroke, cardiovascular disease, and mortality. Second,
reducing uric acid in patients with uric acid concentrations �6.0
mg/dL will improve endothelial dysfunction, decrease systemic
vascular resistance, lower blood pressure, lower triacylglycerol
concentrations, improve body weight, lower the risk of the pro-
gression of renal disease, and reduce cardiovascular disease
risk.
Third, low-fructose diets coupled with mild purine restriction
will improve weight and reduce cardiovascular disease risk.
Fourth, fructokinase will be identified as a key enzyme
mediating
the cardiorenal disease syndrome; genetic polymorphisms will
be associated with cardiovascular disease risk, and blocking the
enzyme will provide a novel way to prevent cardiorenal disease.

37. Clearly, much more work needs to be done to prove or disprove
this hypothesis.
The authors’ responsibilities were as follows—RJJ, MSS, and
LGS-L:
primary preparation of the manuscript; and YS, TN, DIF, D-HK,
MSG, and
SB: generation of ideas incorporated into this manuscript and
the final ap-
proval of the manuscript. RJJ is a consultant for Nephromics
Inc. None of the
other authors had a conflict of interest.
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Commentary
Consumption of high-fructose corn syrup in beverages may play
a
role in the epidemic of obesity1,2
George A Bray, Samara Joy Nielsen, and Barry M Popkin
ABSTRACT
Obesity is a major epidemic, but its causes are still unclear. In
this
article, we investigate the relation between the intake of high-
fructose corn syrup (HFCS) and the development of obesity. We
analyzed food consumption patterns by using US Department of
Agriculture food consumption tables from 1967 to 2000. The
con-
sumption of HFCS increased � 1000% between 1970 and 1990,
far
exceeding the changes in intake of any other food or food
group.
HFCS now represents � 40% of caloric sweeteners added to
foods
and beverages and is the sole caloric sweetener in soft drinks in
the
United States. Our most conservative estimate of the
consumption of
HFCS indicates a daily average of 132 kcal for all Americans
aged
� 2 y, and the top 20% of consumers of caloric sweeteners
ingest

67. 316 kcal from HFCS/d. The increased use of HFCS in the
United States
mirrors the rapid increase in obesity. The digestion, absorption,
and
metabolism of fructose differ from those of glucose. Hepatic
metabo-
lism of fructose favors de novo lipogenesis. In addition, unlike
glucose,
fructose does not stimulate insulin secretion or enhance leptin
produc-
tion. Because insulin and leptin act as key afferent signals in
the regu-
lation of food intake and body weight, this suggests that dietary
fructose
may contribute to increased energy intake and weight gain.
Further-
more, calorically sweetened beverages may enhance caloric
overcon-
sumption. Thus, the increase in consumption of HFCS has a
temporal
relation to the epidemic of obesity, and the overconsumption of
HFCS
in calorically sweetened beverages may play a role in the
epidemic of
obesity. Am J Clin Nutr 2004;79:537– 43.
KEY WORDS Epidemiology, food intake, obesity, artificial
sweeteners, fructose
INTRODUCTION
As obesity has escalated to epidemic proportions around the
world, many causes, including dietary components, have been
suggested. Excessive caloric intake has been related to high-fat
foods, increased portion sizes, and diets high both in simple
sugars such as sucrose and in high-fructose corn syrup (HFCS)

68. as
a source of fructose (1–3). In this article, we discuss the
evidence
that a marked increase in the use of HFCS, and therefore in total
fructose consumption, preceded the obesity epidemic and may
be
an important contributor to this epidemic in the United States.
To provide a common frame of reference for the terms used in
this paper, the following definitions should be understood.
Sugar
is any free monosaccharide or disaccharide present in a food.
Sugars includes at least one sugar; composite sugars refers to
the
aggregate of all forms of sugars in a food and is thus
distinguish-
able from specific types of sugar, such as fructose, glucose, or
sucrose. Added sugar is sugar added to a food and includes
sweeteners such as sucrose, HFCS, honey, molasses, and other
syrups. Naturally occurring sugar is sugar occurring in food and
not added in processing, preparation, or at the table. Total
sugars
represents the total amount of sugars present in a food and in-
cludes both naturally occurring and added sugars. Free fructose
is fructose that exists in food as the monosaccharide. Fructose
refers to both the free and bound forms of fructose (4).
Added sweeteners are important components of our diet, rep-
resenting 318 kcal of dietary intake for the average American
aged � 2 y, or 16% of all caloric intake as measured by a na-
tionally representative survey in 1994 –1996 (5). Sweet corn-
based syrups were developed during the past 3 decades and now
represent close to one-half of the caloric sweeteners consumed
by
Americans (6, 7). HFCS made by enzymatic isomerization of

69. glucose to fructose was introduced as HFCS-42 (42% fructose)
and HFCS-55 (55% fructose) in 1967 and 1977, respectively,
and
opened a new frontier for the sweetener and soft drink
industries.
Using a glucose isomerase, the starch in corn can be efficiently
converted to glucose and then to various amounts of fructose.
The
hydrolysis of sucrose produces a 50:50 molar mixture of
fructose
and glucose. The development of these inexpensive, sweet corn-
based syrups made it profitable to replace sucrose (sugar) and
simple sugars with HFCS in our diet, and they now represent
40%
of all added caloric sweeteners (8). Fructose is sweeter than
sucrose. In comparative studies of sweetness, in which the
sweet-
ness of sucrose was set at 100, fructose had a sweetness of 173
and glucose had a sweetness of 74 (9). If the values noted above
are applied, HFCS-42 would be 1.16 times as sweet as sucrose,
and HFCS-55 would be 1.28 times as sweet as sucrose. This
contrasts with the estimates reported by Hanover and White
(10).
In their study, the sweetness of sucrose was set at 100 as in
reference 8. Fructose, however, had a sweetness of only 117,
whereas a 50:50 mixture of fructose and sucrose had a
sweetness
of 128. It is difficult to see why fructose and sucrose combined
would be sweeter than either one alone and as sweet as HFCS-
55.
On the basis of data in Agriculture Handbook no. 8 from the US
Department of Agriculture (USDA) (11), a cola beverage in
1963
1 From the Pennington Biomedical Research Center, Louisiana
State Uni-

70. versity, Baton Rouge, LA (GAB), and the Department of
Nutrition, Univer-
sity of North Carolina, Chapel Hill (SJN and BMP).
2 Reprints not available. Address correspondence to GA Bray,
Pennington
Biomedical Research Center, 6400 Perkins Road, Baton Rouge,
LA 70808.
E-mail: [email protected]
Received October 3, 2003.
Accepted for publication December 15, 2003.
537Am J Clin Nutr 2004;79:537– 43. Printed in USA. © 2004
American Society for Clinical Nutrition
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had 39 kcal/100 g, whereas a cola beverage in 2003 had 41 kcal/
100 g. Because the number of calories per 100 g has not
changed
substantially over the past 40 y, current beverages are probably
sweeter, depending on the temperature at which they are served.
HFCS has become a favorite substitute for sucrose in carbon-
ated beverages, baked goods, canned fruits, jams and jellies,
and
dairy products (10). The major user of HFCS in the world is the
United States; however, HFCS is now manufactured and used in
many countries throughout the world (7). In the United States,
HFCS is the major source of caloric sweeteners in soft drinks
and
many other sweetened beverages and is also included in numer-
ous other foods; therefore, HFCS constitutes a major source of
dietary fructose. Few data are available on foods containing
HFCS in countries other than the United States (7).
THE BIOLOGY
Absorption of fructose
The digestive and absorptive processes for glucose and fruc-
tose are different. When disaccharides such as sucrose or
maltose
enter the intestine, they are cleaved by disaccharidases. A
sodium-
glucose cotransporter absorbs the glucose that is formed from
cleav-
age of sucrose. Fructose, in contrast, is absorbed further down
in the
duodenum and jejunum by a non-sodium-dependent process.

74. After
absorption, glucose and fructose enter the portal circulation and
either are transported to the liver, where the fructose can be
taken up
and converted to glucose, or pass into the general circulation.
The
addition of small, catalytic amounts of fructose to orally
ingested
glucose increases hepatic glycogen synthesis in human subjects
and
reduces glycemic responses in subjects with type 2 diabetes
mellitus
(12), which suggests the importance of fructose in modulating
me-
tabolism in the liver. However, when large amounts of fructose
are
ingested, they provide a relatively unregulated source of carbon
precursors for hepatic lipogenesis.
Fructose and insulin release
Along with 2 peptides, glucose-dependent insulinotropic
polypeptide and glucagon-like peptide-1 released from the gas-
trointestinal tract, circulating glucose increases insulin release
from the pancreas (13, 14). Fructose does not stimulate insulin
secretion in vitro, probably because the � cells of the pancreas
lack the fructose transporter Glut-5 (15, 16). Thus, when
fructose
is given in vivo as part of a mixed meal, the increase in glucose
and insulin is much smaller than when a similar amount of glu-
cose is given. However, fructose produces a much larger
increase
in lactate and a small (1.7%) increase in diet-induced thermo-
genesis (17), which again suggests that glucose and fructose
have
different metabolic effects.

75. Insulin and leptin
Insulin release can modulate food intake by at least 2 mecha-
nisms. First, Schwartz et al (18) have argued that insulin con-
centrations in the central nervous system have a direct
inhibitory
effect on food intake. In addition, insulin may modify food
intake
by its effect on leptin secretion, which is mainly regulated by
insulin-induced changes in glucose metabolism in fat cells (19,
20). Insulin increases leptin release (21) with a time delay of
several hours. Thus, a low insulin concentration after ingestion
of
fructose would be associated with lower average leptin concen-
trations than would be seen after ingestion of glucose. Because
leptin inhibits food intake, the lower leptin concentrations
induced
by fructose would tend to enhance food intake. This is most
dramat-
ically illustrated in humans who lack leptin (22, 23). Persons
lacking
leptin (homozygotes) are massively obese (22), and
heterozygotes
with low but detectable serum leptin concentrations have
increased
adiposity (23), which indicates that low leptin concentrations
are
associated with increased hunger and gains in body fat.
Adminis-
tration of leptin to persons who lack it produces a dramatic
decrease
in food intake, as expected. Leptin also increases energy
expendi-
ture, and during reduced calorie intake, leptin attenuates the de-

76. creases in thyroid hormones and 24-h energy expenditure (24).
To
the extent that fructose increases in the diet, one might expect
less
insulin secretion and thus less leptin release and a reduction in
the
inhibitory effect of leptin on food intake, ie, an increase in food
intake. This was found in the preliminary studies reported by
Teff et
al (25). Consumption of high-fructose meals reduced 24-h
plasma
insulin and leptin concentrations and increased postprandial
fasting
triacylglycerol concentrations in women but did not suppress
circu-
lating ghrelin concentrations.
Fructose and metabolism
The metabolism of fructose differs from that of glucose in
several other ways as well (3). Glucose enters cells by a
transport
mechanism (Glut-4) that is insulin dependent in most tissues.
Insulin activates the insulin receptor, which in turn increases
the
density of glucose transporters on the cell surface and thus
facilitates
the entry of glucose. Once inside the cell, glucose is
phosphorylated
by glucokinase to become glucose-6-phosphate, from which the
intracellular metabolism of glucose begins. Intracellular
enzymes
can tightly control conversion of glucose-6-phosphate to the
glyc-
erol backbone of triacylglycerols through modulation by
phospho-

77. fructokinase. In contrast with glucose, fructose enters cells via
a
Glut-5 transporter that does not depend on insulin. This
transporter
is absent from pancreatic � cells and the brain, which indicates
limited entry of fructose into these tissues. Glucose provides
“sati-
ety” signals to the brain that fructose cannot provide because it
is not
transported into the brain. Once inside the cell, fructose is
phosphor-
ylated to form fructose-1-phosphate (26). In this configuration,
fruc-
tose is readily cleaved by aldolase to form trioses that are the
back-
bone for phospholipid and triacyglycerol synthesis. Fructose
also
provides carbon atoms for synthesis of long-chain fatty acids,
al-
though in humans, the quantity of these carbon atoms is small.
Thus,
fructose facilitates the biochemical formation of
triacylglycerols
more efficiently than does glucose (3). For example, when a
diet
containing 17% fructose was provided to healthy men and
women,
the men, but not the women, showed a highly significant
increase of
32% in plasma triacylglycerol concentrations (27).
Overconsumption of sweetened beverages
One model for producing obesity in rodents is to provide sweet-
ened (sucrose, maltose, etc) beverages for them to drink (28). In
this

78. setting, the desire for the calorically sweetened solution reduces
the
intake of solid food, but not by enough to prevent a positive
caloric
balance and the slow development of obesity. Adding the same
amount of sucrose or maltose as of a solid in the diet does not
produce the same response. Thus, in experimental animals,
sweet-
ened beverages appear to enhance caloric consumption.
Fructose and soft drinks
A similar argument about the role of overconsumption of
calorically sweetened beverages may apply to humans (29 –32).
538 BRAY ET AL
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Mattes (29) reported that when humans ingest energy-containing
beverages, energy compensation is less precise than when solid
foods are ingested. In another study in humans, DiMeglio and
Mattes (30) found that when 15 healthy men and women were
given a carbohydrate load of 1880 kJ/d (450 kcal/d) as a calori-
cally sweetened soda for 4 wk, they gained significantly more
weight than when the same carbohydrate load was given in a
solid
form as jelly beans. Additional support for our hypothesis that
calorically sweetened beverages may contribute to the epidemic
of obesity comes from a longitudinal study in adolescents. Lud-
wig et al (31) showed that in adolescents participating in the
Planet Health project, the quantity of sugar-sweetened
beverages
ingested predicted initial body mass index (BMI; in kg/m2) and
gain in BMI during the follow-up period. Raben et al (32) de-
signed a randomized, double-blind study to compare the effect
of
calorically sweetened beverages with that of diet drinks on
weight gain in moderately overweight men and women. This
European study found that drinking calorically sweetened bev-
erages resulted in greater weight gain over the 10-wk study than
did drinking diet drinks. Compared with the subjects who con-
sumed diet drinks, those who consumed calorically sweetened
beverages did not compensate for this consumption by reducing
the intake of other beverages and foods and thus gained weight.
The beverages in this study were sweetened with sucrose,
whereas in the United States almost all calorically sweetened
beverages are sweetened with HFCS. Thus, we need a second
randomized controlled study that compares sucrose- and HFCS-

82. sweetened beverages. This could establish whether the form of
the caloric sweetener played a role in the weight gain observed
in
the study by Raben et al (32).
The results of the studies by Raben et al (32) and Ludwig et al
(31) suggest that the rapid increase in the intake of calorically
sweetened soft drinks could be a contributing factor to the epi-
demic of weight gain. Between 1970, when HFCS was intro-
duced into the marketplace, and 2000, the per capita
consumption
of HFCS in the United States increased from 0.292 kg ·
person�1
· y�1 (0.6 lb · person�1 · y�1) to 33.4 kg · person�1 · y�1
(73.5 lb
· person�1 · y�1), an increase of � 100-fold (8) (Table 1). The
total consumption of fructose increased nearly 30%. The con-
sumption of free fructose showed a greater increase, which re-
flected the increasing use of HFCS (Figure 1). During the same
interval, the consumption of sucrose decreased nearly 50%, and
TABLE 1
Availability of high-fructose corn syrup (HFCS) in the US
caloric sweetener supply1
Year HFCS Total caloric sweeteners
HFCS as percentage of total
caloric sweeteners
Percentage of HFCS
from HFCS-42
Percentage of HFCS from
HFCS-55

83. g � person�1 � d�1 g � person�1 � d�1 % % %
1966 0.0 165.9 0.0 — —
1970 0.8 175.1 0.4 100.0 0.0
1975 7.1 168.8 4.2 100.0 0.0
1980 27.3 176.0 15.5 71.2 28.8
1985 64.7 184.4 35.1 34.3 65.7
1990 71.0 195.7 36.3 41.0 59.0
1995 82.3 211.7 38.9 39.9 60.1
2000 91.6 218.0 42.0 38.8 61.2
1 Data from reference 8. HFCS-42 and HFCS-55, HFCS
containing 42% and 55% fructose, respectively.
FIGURE 1. Estimated intakes of total fructose (F), free fructose
(Œ), and high-fructose corn syrup (HFCS, �) in relation to
trends in the prevalence of
overweight (■) and obesity (x) in the United States. Data from
references 7 and 35.
HIGH-FRUCTOSE CORN SYRUP AND OBESITY 539
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the intakes of sucrose and HFCS are now nearly identical. Al-
though this shift has clearly led to a major increase in free-
fructose consumption, it is unclear how much of the increase in
consumption of calorically sweetened soft drinks is a result of
the
shift to beverages in which one-half of the fructose is free
rather
than bound with glucose as in sucrose. A recent review
described
many facets of this issue (3).
HFCS USE AND INTAKE
Availability of HFCS in the food supply
In 1970 HFCS represented � 1% of all caloric sweeteners
available for consumption in the United States, but the HFCS
portion of the caloric sweetener market jumped rapidly in the
1980s and by 2000 represented 42.0% of all caloric sweeteners
(Table 1) (8). HFCS-42 was initially the only HFCS component,
but by the early 1980s, HFCS-55 had become the major source
and constituted 61.2% of all HFCS in 2000. These data are
based
on per capita food disappearance data. In the absence of direct
measures of HFCS intake, these data provide the best indirect
measure of the HFCS available for consumption in the United

87. States. The data are useful for studying trends but probably
over-
estimate intake patterns. Although it is useful to understand that
HFCS intake represents more than two-fifths of the total intake
of
caloric sweeteners in the United States, it is also important to
recognize that the proportion of HFCS in some foods is much
higher than that in other foods.
Foods containing HFCS
In the United States, HFCS is found in almost all foods con-
taining caloric sweeteners. These include most soft drinks and
fruit drinks, candied fruits and canned fruits, dairy desserts and
flavored yogurts, most baked goods, many cereals, and jellies.
Over 60% of the calories in apple juice, which is used as the
base
for many of the fruit drinks, come from fructose, and thus apple
juice is another source of fructose in the diet. Lists of HFCS-
containing foods can be obtained from organizations concerned
with HFCS-related allergies (33). It is clear that almost all
caloric
sweeteners used by manufacturers of soft drinks and fruit drinks
are HFCS (4, 34). In fact, about two-thirds of all HFCS
consumed
in the United States are in beverages. Aside from beverages,
there
is no definitive literature on the proportion of caloric
sweeteners
that is HFCS in other processed foods. HFCS is found in most
processed foods; however, the exact compositions are not avail-
able from either the manufacturer or any publicly available
food-
composition table.
Trends in obesity and HFCS availability

88. There are important similarities between the trend in HFCS
availability and the trends in the prevalence of obesity in the
United States (Figure 1). Using age-standardized, nationally
rep-
resentative measures of obesity at 5 time points from 1960 to
1999
(35) and data on the availability of HFCS collected annually
over
this same period, we graphed both patterns. The data on obesity
are
from the National Center for Health Statistics for the following
periods: 1960 –1962 (National Health Examination Survey I),
1971–1975 [National Health and Nutrition Examination Survey
(NHANES)], 1976 –1980 (NHANES II), 1988 –1994 (NHANES
III), and 1999 (NHANES 1999 –2000) (35). The HFCS data are
those from Table 1. The prevalence of overweight (BMI of 25–
29.9)
and the prevalence of obesity (BMI � 30) were fit with fourth-
order
polynomial curves so that the limited number of data points
could be
fitted into a curve to capture the US trends. We also included
esti-
mates of free-fructose intake and total fructose intake. Total
fructose
is the sum of free fructose and fructose that is part of the
disaccharide
sucrose. Free fructose is the monosaccharide in HFCS and is
also
obtained in small amounts from other sources. Free-fructose
intake
closely follows the intake of HFCS. Total fructose intake
increased
nearly 30% between 1970 and 2000.

89. Estimated HFCS consumption
The intake of caloric sweeteners in the United States has in-
creased rapidly, and nationally representative data from 1994 to
1998 from the USDA allow us to estimate an intake of 318
kcal/d
for the average US resident aged � 2 y. This value is one-sixth
of the intake of all calories and close to one-third of the intake
of
all carbohydrates and represents a significant increase over the
past
2 decades (Table 2). As the intake of caloric sweeteners
increased,
so did the fructose load, which increased from 158.5 to 228 kcal
·
person�1 · d�1 between 1977–1978 (36) and 1994 –1998 (38,
39).
Furthermore, as shown in Table 2, the major increase in the
intake of caloric sweeteners from 1977 to 1998 came from the
intake of soft drinks and fruit drinks, and these intake values
were
105 and 31 kcal · person�1 · d�1, respectively, of the total
added
sugar intake of 318 kcal · person�1 · d�1 in 1994 –1998.
More-
over, more than one-half of the increased caloric sweetener in-
take during this time period came from the intake of these bev-
erages. The intakes of these 2 types of beverages and of desserts
total about two-thirds of all caloric sweetener intake in the
United
States today (Table 2).
We have no way to directly measure total HFCS use. However,
one Food and Drug Administration study used very conservative

90. methods to estimate HFCS use for the nationally representative
dietary intake sample from 1977 to 1978 from the USDA (35).
Using measures of the proportion of HFCS in each food, Glins-
mann et al (40) created food category–wide estimates of the
proportion of caloric sweeteners that is HFCS. We applied those
same proportions to a set of food groups to estimate the use of
caloric sweeteners not only during 1977–1978 but also during
later periods. Using our conversion technique applied to the
initial 1977–1978 Nationwide Food Consumption Survey data,
we obtained results that were only 4 kcal higher than the esti-
mates of Glinsmann et al (39). This approach is based on HFCS
composition in the early 1980s. With the use of the USDA value
of 4.2 g HFCS/tsp (0.84 g/mL), the availability of HFCS in the
food supply in the early 1980s was only one-half of the current
availability on a gram per capita basis (as shown in Table 1).
Thus, we feel confident that we can use this approach to provide
a conservative lower limit of HFCS intake.
In Table 2, the 2 columns at the right contain our estimates of
HFCS intake and total fructose intake. On the basis of the trend
in intakes, our estimate of HFCS intake for the most recent
period
of measurement from 1994 –1998 is 132 kcal · person�1 · d�1
(37). This represents a shift between 1977–1978 and 1994 –
1998
from 4.5% of total calories to 6.7% of total calories, or from
10.1% of carbohydrates to 13.1% of carbohydrates (41). The
estimate of total fructose intake, which was obtained from the
intakes of sucrose and HFCS, would be somewhat higher if
we knew the fructose content of the fruit drinks.
540 BRAY ET AL
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Distribution of HFCS intake matters!
We also explored the distribution of HFCS consumption by
examining quintiles of caloric sweetener intake among Ameri-
cans aged � 2 y (Table 3). Most of the increase in caloric
sweetener intake from the middle quintile to the upper quintile
came from increases in the intake of calorically sweetened bev-
erages, particularly soft drinks. Consumers in the top quintile,
which represents 20% of all Americans, consume � 11% of
their
calories from HFCS. Again, remember that this is a very conser-
vative estimate. This same group obtains almost one-half of its
carbohydrates from caloric sweeteners and one-fifth of its car-

94. bohydrates from HFCS.
DISCUSSION
Genetic factors play an important role in the development of
obesity (42). However, the rapidity with which the current epi-
demic of obesity has descended on the United States (35) and
TABLE 2
Trends in intakes of added sugar (sucrose) and high-fructose
corn syrup (HFCS) by Americans aged � 2 y1
Soft drinks Fruit drinks Desserts
Total added
sugar
Estimated HFCS
intake2
Estimated total fructose
intake3
Intake (kcal � person�1 � d�1)
1977–1978 52 18 54 235 80 158.5
1989–1991 744 19 474 242 95 170
1994–1998 1054,5 314,5 604,5 3184,5 132 228
Percentage of total energy (%)
1977–1978 2.9 1.0 3.0 13.1 4.5 8.8
1989–1991 4.14 1.1 2.64 13.5 5.3 9.4
1994–1998 5.34,5 1.64,5 3.04,5 16.04,5 6.7 11.5
Percentage of total carbohydrates (%)
1977–1978 6.5 2.3 6.8 29.5 10.1 19.8
1989–1991 8.54 2.2 5.44 27.8 10.9 19.5

95. 1994–1998 10.44,5 3.14,5 5.94,5 31.54,5 13.1 22.8
1 Data from references 36 –39.
2 Coefficients derived from Glinsmann et al (40) were used to
estimate HFCS intake.
3 Estimated as 50% of sucrose � fructose in HFCS.
4 Significantly different from 1977–1978, P � 0.01 (t test).
5 Significantly different from 1989 –1991, P � 0.01 (t test).
TABLE 3
Distribution of consumption of added caloric sweeteners and
high-fructose corn syrup (HFCS) by quintile (Q) of added sugar
intake in persons aged � 2 y
(1994 –1996, 1998)1
Q1 (n � 3907) Q2 (n � 4259) Q3 (n � 4228) Q4 (n � 3645) Q5
(n � 2988) Total (n � 19 027) P for trend
Added caloric sweeteners
Intake (kcal � person�1 � d�1)
Soft drinks 6 31 69 129 290 105 0.022
Fruit drinks 4 14 26 43 69 31 0.003
Total 69 169 263 388 703 318 0.001
Percentage of total energy in kcal (%)
Soft drinks 0.4 1.9 3.7 6.0 10.2 5.3 0.004
Fruit drinks 0.3 0.8 1.4 2.0 2.4 1.6 0.0001
Total 4.9 10.2 14.0 18.1 24.7 16.0 0.0004
Percentage of carbohydrates (%)
Soft drinks 0.9 3.8 7.3 11.6 18.8 10.4 0.003
Fruit drinks 0.6 1.7 2.8 3.9 4.5 3.1 0.0004
Total 10.5 20.8 27.9 35.0 45.6 31.4 0.0002
HFCS

96. Intake (kcal � person�1 � d�1)
Soft drinks 4 22 49 91 205 74 0.022
Fruit drinks 3 10 18 30 49 22 0.004
Total 21 58 103 166 316 132 0.012
Percentage of total energy in kcal (%)
Soft drinks 0.3 1.3 2.6 4.2 7.2 3.7 0.005
Fruit drinks 0.2 0.6 1.0 1.4 1.7 1.1 �0.0001
Total 1.5 3.5 5.5 7.7 11.1 6.7 0.0007
Percentage of carbohydrates (%)
Soft drinks 0.6 2.7 5.2 8.2 13.3 7.3 0.003
Fruit drinks 0.4 1.2 1.9 2.7 3.2 2.2 0.0002
Total 3.2 7.2 10.9 14.9 20.5 13.1 0.0002
1 Data from references 38 and 39 (weighted to be nationally
representative).
HIGH-FRUCTOSE CORN SYRUP AND OBESITY 541
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many other countries (43) makes environmental factors the more
likely explanation. From a public health perspective, the key
question is whether there are modifiable environmental agents
that could have triggered this epidemic and that might be
altered.
Several environmental agents, including reduced levels of phys-
ical activity (44), a decrease in smoking, increased portion size
(2), eating outside the home and at fast-food restaurants, and
changes in the types of food that are ingested (45), have been
suggested. In this article, we propose that the introduction of
HFCS and the increased intakes of soft drinks and other sweet-
ened beverages have led to increases in total caloric and
fructose
consumption that are important contributors to the current epi-
demic of obesity.
In this article, we address an important potential hypothesis by
which HFCS may have an environmental link with the epidemic
of obesity. When total calorie intake is fixed, ie, if a person eats
the same amount of fructose, glucose, or sucrose in a metaboli-
cally controlled setting, the response should be the same, and
this
was shown by McDevitt et al (46). This situation is not one in
which differences in taste and portion size are allowed to
operate.
However, many biological factors that we noted in this article
suggest that calorically sweetened beverages are associated with

100. overconsumption when the sweetener is in a liquid form (29 –
32).
The collective data suggest that overconsumption of beverages
sweetened with HFCS and containing � 50% free fructose and
the increased intake of total fructose may play a role in the
epidemic of obesity. Whether HFCS used in solid food produces
the same overconsumption as it does in beverages is unknown,
but we suspect that if the HFCS was entirely in the solid form,
it
would not pose the same problem (30). Total fructose, both free
fructose and fructose combined in sucrose, in both beverages
and
solid food may be viewed as a precursor to fat because of the
ease
with which the carbon skeleton of fructose can form the back-
bone for triacylglycerols and be used for the synthesis of long-
chain fatty acids (25). Additional clinical trials are clearly
needed
to buttress the conclusions of Raben et al (32) that beverages
containing sugar caused more weight gain over 10 wk than did
diet beverages.
There is a distinct likelihood that the increased consumption of
HFCS in beverages may be linked to the increase in obesity.
One
US study showed that beverages sweetened with HFCS are
linked with increased energy intake and weight gain (31). Fur-
thermore, we showed that the increase in the use of HFCS was
concurrent with the increase in obesity rates in the United
States.
HFCS was introduced into the food supply just before 1970 and
increased rapidly to constitute � 40% of the sweeteners used by
2000 (8). The increase in HFCS consumption just preceded the
rapid increase in the prevalence of obesity that occurred
between
the National Center for Health Statistics survey in 1976 –1980

101. and the next survey in 1988 –1994 (35) (Figure 1).
HFCS is used in soft drinks, and HFCS and apple juice, which
has 65% fructose, are used as the principal sweeteners for fruit
drinks. The increasing consumption of calorically sweetened
soft
drinks has been associated with a decrease in the intake of milk
(5, 8, 47, 48). This relation adds another mechanism by which
HFCS consumption in beverages may be related to the epidemic
of obesity. Per capita calcium intake decreased from 890 to
860 mg/d between 1970 and 1981 but has increased slowly since
then (8). This was a mean 3% decrease that probably reflected a
much larger decrease in calcium intake at the upper ends of the
skewed distribution for intake. In US teenagers, total calcium
intake decreased by � 50 mg/d (� 10%) between 1977 and 1996
(49). A convincing set of epidemiologic and clinical studies
suggests that dairy products may have a favorable effect on
body
weight and insulin resistance in both children and adults (50 –
52).
During the interval from 1970 to 1990, the intake of whole milk
decreased 58%. However, the intake of cheese, which is high in
fat, increased and partially offset the decrease in calcium intake
from milk (8). Because milk is a major source of dietary
calcium
for most humans, this decrease in milk intake may play an im-
portant role in the decrease in calcium in the diet.
One possible public health option is to address the sweet taste
preference of humans by reducing HFCS and, if sweetness is
needed, relying on artificial sweeteners to make up any differ-
ence in sweetness. It is becoming increasingly clear that soft
drink consumption may be an important contributor to the epi-
demic of obesity, in part through the larger portion sizes of
these

102. beverages and through the increased intake of fructose from
HFCS and sucrose (53). If HFCS acts as an agent in the disease,
then reducing exposure to this agent may help to reduce the
epidemic (54).
Some will question our measures of HFCS intake and avail-
ability. Our very conservative estimate of HFCS use and the
Food
and Drug Administration data showed high HFCS intakes for a
large segment of the US population (39).
In conclusion, we believe that an argument can now be made
that the use of HFCS in beverages should be reduced and that
HFCS should be replaced with alternative noncaloric sweeten-
ers. Sweetness is a preferred taste as well as an acquired one
that
may be enhanced by exposure to sweet foods. The hypothesis
that
providing sodas and juice drinks in which caloric sweeteners are
partially or completely replaced with noncaloric sweeteners will
help reduce the prevalence of obesity is worth testing. If the
intake of calorically sweetened beverages is contributing to the
current epidemic, then reducing the availability of these bever-
ages by removing soda machines from schools would be a strat-
egy worth considering, as would reducing the portion sizes of
sodas that are commercially available (55).
We thank Dan Blanchette for programming assistance, Tom
Swasey for
graphics support, and Frances Dancy for support in
administrative matters.
We also thank Linda Adair for thoughtful comments on an early
version of
this article.
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