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REVIEW
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Hypothesis: fructose-induced hyperuricemia
as a causal mechanism for the epidemic of the
metabolic syndrome
Takahiko Nakagawa*, Katherine R Tuttle, Robert A Short and Richard J Johnson
INTRODUCTION
Obesity is epidemic. Prevalence has quad-
rupled in the past 25 years; 16% of children
and 30% of adults in the US are now affected.
1
Many obese people suffer from the ‘metabolic
syndrome’, which is characterized by insulin
resistance, hypertriglyceridemia and hyper-
tension.
2
Progression of the obesity epidemic
has coincided with increased frequency of type
diabetes, and now affects more than 17 million
individuals in the US.
A simple explanation for the obesity epidemic
is that individuals ingest more calories than they
consume. One contributory factor is ready access
to foods high in fat and sugar. ‘Fast foods’ such
as soft drinks, burgers, pizza, chips and pastries
comprise nearly 20% of total energy intake
for the average American.
3
Epidemiological
studies implicate the introduction of ‘Western
diets’ high in fatty meats and refined sugars in
the epidemics of obesity, diabetes and hyper-
tension currently occurring in Africa, Asia, South
America, Australia/New Zealand and Oceania.
4,5
Not surprisingly, up to 45% of females and
30% of males are dieting at any given time.
6
Unfortunately, most studies show that, regard-
less of whether a low-fat or low-carbohydrate
diet is followed, and despite often impressive
weight loss in the first few months of a diet, long-
term weight-reduction goals are seldom achieved
because of poor adherence to the diet and high
attrition rates.
7
It is important to consider mechanisms of,
and strategies for preventing and treating, the
obesity epidemic. We propose that certain foods,
particularly fructose-based sweeteners, cause the
metabolic syndrome by increasing serum uric
acid levels.
FRUCTOSE AND THE OBESITY EPIDEMIC
Fructose is a simple sugar present in honey and
fruit. It constitutes 50% of table sugar (sucrose;
a disaccharide consisting of one glucose and
one fructose molecule) and accounts for 55%
of the sugar content of high-fructose corn syrup
The increasing incidence of obesity and the metabolic syndrome over the
past two decades has coincided with a marked increase in total fructose
intake. Fructose—unlike other sugars—causes serum uric acid levels to rise
rapidly. We recently reported that uric acid reduces levels of endothelial
nitric oxide (NO), a key mediator of insulin action. NO increases blood
flow to skeletal muscle and enhances glucose uptake. Animals deficient
in endothelial NO develop insulin resistance and other features of the
metabolic syndrome. As such, we propose that the epidemic of the
metabolic syndrome is due in part to fructose-induced hyperuricemia that
reduces endothelial NO levels and induces insulin resistance. Consistent
with this hypothesis is the observation that changes in mean uric acid
levels correlate with the increasing prevalence of metabolic syndrome in
the US and developing countries. In addition, we observed that a serum
uric acid level above 5.5 mg/dl independently predicted the development
of hyperinsulinemia at both 6 and 12 months in nondiabetic patients with
first-time myocardial infarction. Fructose-induced hyperuricemia results
in endothelial dysfunction and insulin resistance, and might be a novel
causal mechanism of the metabolic syndrome. Studies in humans should
be performed to address whether lowering uric acid levels will help to
prevent this condition.
KEYWORDS essential hypertension, insulin resistance, metabolic syndrome,
obesity, uric acid
T Nakagawa is Research Assistant Professor in the Division of Nephrology,
Hypertension, and Transplantation at the University of Florida, Gainesville,
FL, KR Tuttle is the Medical and Scientific Director at The Heart Institute
and Providence Medical Research Center, Spokane, Washington, DC,
RA Short is a faculty member at Washington State University, Spokane,
Washington, DC, and RJ Johnson is the J Robert Cade Professor of
Nephrology and the Chief of the Division of Nephrology, Hypertension
and Transplantation at the University of Florida, Gainesville, FL, USA.
Correspondence
*Division of Nephrology, Hypertension and Transplantation, PO Box 100224, University of Florida,
Gainesville, FL 32610, USA
nakagt@medicine.ufl.edu
Received 2 July 2005 Accepted 11 August 2005
www.nature.com/clinicalpractice
doi:10.1038/ncpneph0019
SUMMARY
80 NATURE CLINICAL PRACTICE NEPHROLOGY DECEMBER 2005 VOL 1 NO 2
REVIEW CRITERIA
We searched PubMed in June 2005 for articles published between 1983 and 2005,
containing the terms “uric acid”, “fructose”, “obesity”, “diabetes”, “hypertension”,
“metabolic syndrome”, “insulin resistance”, “hypertriglyceridemia”, “nitric oxide”
and “endothelial dysfunction”.
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(HFCS). HFCS was introduced in the US in
1967 as a more stable and less expensive alterna-
tive to table sugar. It is currently used in many
foods, particularly soft drinks, baked goods,
candies/sweets, jams/preserves, yogurts, and
sweetened and packaged products. While yearly
per capita sucrose intake decreased from 44 to
30 kg between 1966 and 2001, HFCS consump-
tion increased from 0 to 29 kg.
8,9
So, in the US,
there has been an approximately 30% increase in
total fructose intake, contributing to a 25–30%
increase in total sweetener consumption, over
the past 35 years.
10
Over the past 25 years, the increased fructose
intake correlates with the acceleration of the
obesity epidemic.
10
Ingestion of soft drinks,
which are high in HFCS, is associated with an
increased risk of obesity in adolescents
11
and
of type 2 diabetes in young and middle-aged
women.
12
Similarly, excessive consumption
of fruit juice, which is also high in fructose, is
associated with obesity in children.
13
Feeding
fructose to rats causes rapid development of the
metabolic syndrome, including obesity, hyper-
tension, insulin resistance, hypertriglyceridemia
and hyperinsulinemia.
14,15
There are several reasons why fructose, as
opposed to other sugars, might cause obesity.
14
Fructose is phosphorylated in the liver by fructo-
kinase. Further metabolism generates glycerol-3-
phosphate, which is crucial in the synthesis of
triglycerides. Fructose administration marked ly
enhances triglyceride synthesis,
15,16
which
increases intramyocellular triglyceride content in
the skeletal muscle, causing insulin resistance.
17
Evidence indicates that fructose does not suppress
appetite to the same degree as glucose. Glucose
ingestion causes transient elevation of serum
glucose and insulin. The latter then stimulates
leptin release, signaling the brain to stop eating.
Ingestion of fructose decreases postprandial
glucose levels. Subsequently lower insulin and
leptin levels result, thereby predisposing the
individual to continue to eat.
16
FRUCTOSE-INDUCED HYPERURICEMIA
AND THE METABOLIC SYNDROME
We have identified another mechanism by which
fructose might cause the metabolic syndrome.
We propose that development of the metabolic
syndrome is related to the unique ability of fruc-
tose to increase serum uric acid levels. Oral or
intravenous ingestion of fructose results in a rapid
(30–60 min) increase in serum uric acid in humans,
which might be sustained;
18–21
glucose and other
simple sugars do not have the same effect. The effect
of fructose intake on serum uric acid is greatest in
patients with gout and their children.
18–20
ATP acts as a phosphate donor during phos-
phorylation of fructose by fructokinase in hepato-
cytes (Figure 1). ADP is generated, and is further
metabolized to various purine substrates.
14
The rapid depletion of phosphate during these
re actions stimulates AMP deaminase. The combi-
nation of increased substrate (via oral ingestion
of fructose) and enzyme (AMP deaminase)
upregulates urate production.
22
High levels of uric acid could lead to endo thelial
dysfunction and reduced bioavailability of endo-
thelial nitric oxide (NO). Soluble uric acid potently
reduces NO levels in cultured human and bovine
endothelial cells.
23,24
Decreased levels of plasma
nitrites (NO breakdown products) in hyper-
uricemic rats can be restored if uric acid concentra-
tion is lowered with allopurinol.
23
Vasorelaxation
of arterial rings in response to acetylcholine,
a process that is mediated by NO, is blocked by
uric acid (T Nakagawa et al., un published data).
In humans, serum uric acid concentration varies
inversely with plasma NO during the day; urate
levels peak in the morning when plasma NO is
low.
25
Lowering uric acid levels using allo purinol
also improves endo thelial function in patients with
heart failure, diabetes and hypercholesterolemia,
and in heavy smokers.
26–30
Decreased endothelial NO in turn results in
development of insulin resistance and obesity. A
contributory mechanism to this phenomenon is
inhibition of insulin-dependent NO production,
which is crucial for the enhancement of blood
flow that allows glucose delivery to the skeletal
Fructokinase
Uric acid
AMP deaminase
Fructose
Fructose-1-
phosphate
ATP
ADP AMP
IMP
ATP consumption Pi
Figure 1 Fructose-induced production of uric acid in the hepatocyte.
GLOSSARY
TYPE 2 DIABETES
Referred to as maturity-
onset diabetes; it is not
usually dependent on insulin
injections and control is
achieved through changes
in lifestyle
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muscle and adipose tissues.
31
Mice deficient in
endothelial NO synthase develop features of the
metabolic syndrome including hypertension,
insulin resistance and hyper triglyceridemia.
32
In studies in which NO synthesis was blocked in
rats in vivo with l-NAME (N-nitro-l-arginine
methyl ester), rates of insulin-dependent
glucose uptake into skeletal muscle and adipose
tissue were significantly decreased and insulin
resistance developed.
33
We therefore propose that rapid ingestion of
fructose causes a transient increase in serum uric
acid that limits endothelial NO bioavailability.
By this theory, uric acid-induced NO inhibition
would occur while concomitant intake of glucose
stimulated insulin secretion. The consequence
would be inhibition of insulin-mediated NO
release, and slowing of rates of glucose delivery
to skeletal muscle (Figure 2). The physiological
response would be to increase insulin levels to over-
come the acquired insulin resistance, leading to
hyperinsulinemia. As less glucose would be deliv-
ered to skeletal muscle than is normal for the level
of insulin, it is possible that signaling in the central
nervous system could sustain ingestion.
SUPPORTING EVIDENCE
Several lines of evidence support our hypoth-
esis (Box 1). Fructose-fed rats develop hyper-
uricemia, endothelial dysfunction, insulin
resistance and the metabolic syndrome.
14
If
fructose-induced hyperuricemia is prevented by
administration of allopurinol, the develop ment
of obesity, hyper insulinemia, hyper tension and
hyper triglyceridemia is significantly attenuated
(T Nakagawa et al., unpublished data). Two older
studies showed that rats made hyper uricemic using
different uricase inhibitors develop hypertension,
hyperglycemia and hyper triglyceridemia.
34,35
These data are consistent with recent work
demonstrating a strong causal relationship
between experimentally induced hyperuricemia
and hypertension.
36
Further support for our hypothesis is the fact
that elevated serum uric acid independently
predicts development of the metabolic syndrome;
for example, increased serum levels of uric acid
independently predict development of obesity,
37
insulin resistance
38
and hypertension.
36,39
In a
secondary analysis, we examined whether serum
uric acid might predict the development of hyper-
insulinemia in 60 nondiabetic adults admitted
with first-time myocardial infarction (45 males
and 15 females; mean age 57 ± 9 years, range
39–80 years). Fasting serum uric acid, plasma
insulin and a series of cardiovascular risk factors
were measured in the first month following
myo cardial infarction, and 6 and 12 months later.
The power of serum uric acid to predict hyper-
insulinemia (defined as a plasma insulin concen-
tration >12 μ U/ml) at 6 and 12 months was
determined using a multiple logistic regression
model that controlled for gender, age >60 years,
Fructose-containing foods
Endothelial dysfunction; Nitric oxide
Hyperuricemia Hypertriglyceridemia
Hypertension Insulin resistance
Figure 2 Proposed pathway of fructose-induced metabolic syndrome.
Box 1 Evidence supporting involvement of uric
acid in development of insulin resistance.
■ Uric acid predicts, and is an integral
component of, the metabolic syndrome.
36–41
■ Serum uric acid levels are elevated in
secondary insulin-resistance syndromes (e.g. gout,
transplantation, pre-eclampsia and diuretic use).
42–45
■ Elevated serum uric acid levels correlate
with increased frequency of obesity and insulin
resistance in the US, in developing countries, and
in studies of immigrant populations.
47–57
■ Experimental hyperuricemia induces diabetes
and hypertension in animals.
34,35
■ Fructose-induced hyperuricemia in rats
leads to hypertension, insulin resistance, obesity
and hypertriglyceridemia; these conditions are
ameliorated by decreasing uric acid levels. (REFS
14,16 and T Nakagawa et al., unpublished data.)
■ Fructose ingestion increases serum uric acid
levels
18–21
and correlates with progression of the
obesity epidemic.
10–13
■ Uric acid-induced endothelial dysfunction
with impaired NO production might mediate
development of insulin resistance and hypertension.
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calculated (mdrd formula) glomerular filtration
rate <60 ml/min, insulin levels at baseline and at
6 months, and baseline BMI ≥27 kg/m
2
.
At baseline, 28 of 60 patients (47%) had serum
uric acid levels ≥5.5 mg/dl (mean 6.6 ± 0.8 mg/ dl)
and 32 patients had serum uric acid levels
<5.5 mg/dl (mean 4.9 ± 0.5 mg/dl). Patients with
higher (≥5.5 mg/dl) serum uric acid levels at base-
line were more likely to develop hyperinsulinemia
at 6 months (odds ratio 5.47, 90% CI 1.6–17.7,
n = 60, P = 0.01) and 12 months (odds ratio 3.4,
90% CI 1.1–10.4, n = 53, P = 0.04) (Figure 3).
Hyperuricemia and endothelial dysfunction are
common in subjects with the metabolic syndrome;
hyperuricemia is an integral component of
the metabolic syndrome in both children and
adults.
40,41
Elevated uric acid concentrations are
also evident in other insulin-resistant conditions,
such as gout,
42
pre-eclampsia
43
and transplanta-
tion,
44
and during low-dose diuretic treatment.
45
Altered bioavailability of endothelial NO is also
common in subjects with the metabolic syndrome,
hypertension and/or vascular disease.
46
Epidemiological studies have established a link
between the increasing prevalence of the meta-
bolic syndrome and an elevated population mean
serum uric acid concentration. Notwithstanding
different methods of determining uric acid levels,
there has been a general increase in population
mean uric acid in the US—levels have risen in
men from <3.5 mg/dl in the 1920s,
47
to approxi-
mately 5.0 mg/dl in the 1950s,
48
to 5.5 mg/dl in
the 1960s,
49
and to 6.0–6.5 mg/dl in the 1970s.
50,51
Similar changes over time have been reported in
Germany.
52
The escalation of serum uric acid
levels during the twentieth century correlates not
only with the frequency of diabetes and obesity,
but also with a progressive increase in hyper-
tension. In the 1930s, 10–11% of the US popula-
tion were affected by hypertension.
53
Today, the
incidence of hypertension has tripled to 30%.
A study in Rochester, MN, detected a twofold
increase in the incidence of gout between 1977 and
1995.
54
The onset and increasing impact of gout in
indigenous populations, such as the Maori of New
Zealand, also parallels the increased frequency of
diabetes, hypertension and obesity that accom-
panied their adoption of the Western diet.
55
Developing countries such as the Seychelles
currently have high frequencies of hyperuricemia
that correlate closely with para meters of the
metabolic syndrome, particularly hyper-
trigylceridemia and hypertension.
56
Similarly,
studies of immigrants have linked dietary changes
with elevated serum uric acid concentrations,
increased frequency of hypertension, and higher
fasting plasma glucose levels.
57
Ingestion of alcohol (especially beer and hard
drinks) and foods rich in purines (such as fatty red
meats [beef, pork and lamb], shellfish, lobster, dark
fish and organ meats) also increases levels of serum
uric acid. Increased consumption of these types of
food correlates with an increased risk of gout,
58
and with the global epidemic of hyper tension,
diabetes, obesity and cardio vascular disease.
59
It is
likely that the increase in fatty meat consumption
had a role in increasing rates of obesity during the
early twenti eth century; however, it is unlikely to
have been the pre dominant mechanism behind
the rise in obesity during the past 20 years. The
average per capita intake of red meat decreased by
a little more than 10% between 1980 and 2001,
8
and so does not correlate with the marked increase
in obesity observed during this time.
Once frank diabetes develops, serum uric acid
levels fall. This action is a function of glyco-
suria stimulating renal urate excretion. So,
serum concentrations of uric acid are elevated
in insulin resistance but not necessarily in
diabetes.
60
Interestingly, in studies of type 2
diabetes, persistent hyperuricemia has been asso-
ciated with progression of renal disease, whereas
hypouricemia correlates with poor metabolic
control, hyper filtration and decreased risk of
Baseline serum uric acid level
Measurement occasion (months)
Number of patients with insuln >12 μU/ml (%)
≤5.5 mg/dl
>5.5 mg/dl
6 12
P = 0.01
50
-
40
-
30
-
20
-
10
-
0
-
P = 0.04
Figure 3 Uric acid predicts hyperinsulinemia in
first-time myocardial infarction patients.
GLOSSARY
MDRD FORMULA
Used to calculate
glomerular filtration rate;
developed as a result of the
Modification of Diet in Renal
Disease study conducted by
Levey et al. in 1999
ODDS RATIO
Ratio of odds of an event in
intervention group to odds
in control group; when <1
for an undesirable outcome,
the intervention reduced
the risk
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renal-disease progression.
61
One might posit
that this phenomenon is the result of the fact that
experimental hyperuricemia promotes glomerular
hypertension and renal vaso constriction,
62
both of
which can induce and accelerate renal injury.
63
We propose that hyperuricemia has a role in
inducing insulin resistance that could become
less important once insulin resistance and
obesity are established. It is well documented
that obesity itself causes insulin resistance,
either as an effect of increased triglycerides in
adipocyte and muscle cells,
18
or because associ-
ated hyperglycemia and/or advanced glycation
endproducts impair endothelial cell-dependent
release of NO.
64,65
Hyperuricemia might there-
fore be more important in the development
phase of insulin resistance than in maintenance
of prediabetic and diabetic states.
The renin–angiotensin system has a key role
in mediating the endothelial and vascular effects
associated with experimental hyperuricemia
66
and fructose-induced endothelial dysfunction,
67
and in rats in which NO synthesis is chronically
inhibited.
68
Preservation of endothelial function
by angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers in response
to hyperuricemia or other mechanisms might
explain why these agents have been found to
reduce the incidence of type 2 diabetes.
69
COUNTERING ARGUMENTS
There are countering issues to the above proposi-
tions to consider. First, fructose has been consid-
ered safe for consumption by diabetics as it does
not elevate glucose levels to the extent of glucose
itself;
70
however, if fructose causes insulin resist-
ance, its benefit as a nonglucose carbohydrate
source might be nullified. Second, several studies
indicate that uric acid is elevated in the meta-
bolic syndrome because insulin enhances uric
acid reabsorption.
71
This evidence does not,
however, negate the possibility that uric acid
might also cause hyperinsulinemia. Third, there
are certain populations, particularly in Oceania,
whose serum uric acid levels are elevated without
concomitant obesity, hypertension or cardio-
vascular disease.
72
It is possible that these indi-
viduals have the advantage of mechanisms that
confer protection; for example, the raw cocoa
ingested by the Kuna Indians of Panama contains
flavonoids that enhance NO release from
endothelial cells.
73
Finally, one study found that
infusion of uric acid into human volunteers did
not impair brachial artery reactivity, a reflection
of endothelial function.
74
Our more recent
studies, however, indicate that the mechanism
of urate-induced endo thelial dysfunction could
be a consequence of a urate oxidant-based
reaction, rather than a direct effect of uric acid
(A Angerhofer et al., unpublished data). As such,
direct infusion studies might not reproduce the
physiological mechanism by which uric acid
exerts its effect.
CONCLUSIONS
It was over 100 years ago that Osler prescribed
diets low in fructose as a means to prevent gout.
He wrote in his 1893 text
75
that “The sugar
should be reduced to a minimum. The sweeter
fruits should not be taken”. This brilliant insight
gels with our proposition that foods that elevate
serum uric acid levels induce transient endothelial
dys function, which in turn causes insulin resist-
ance and hypertension to develop. The primary
dietary inductive factors are foods containing
fructose or table sugar, and fatty meats that
contain high concentrations of purines. We have
outlined a mechanistic pathway that at least
partially explains why low-carbohydrate diets
such as the Atkins diet, and more classic eating
plans, are successful to some degree. Adherence
to most diets can decrease uric acid levels in
concert with weight loss.
76
Importantly, once
a person becomes obese and diabetic, insulin
resistance will be driven primarily by the obesity
itself, as a consequence of elevated intramuscular
tri glyceride levels.
18
Clinical studies of either low-
fructose diets and/or lowering uric acid levels with
allopurinol as a means of preventing or treating
the early metabolic syndrome, should be consid-
ered. Such a trial is urgent given the magnitude of
the metabolic syndrome epidemic.
KEY POINTS
■ Increased ingestion of fructose in processed
foodstuffs has correlated with development of the
obesity epidemic
■ Hypothesis: fructose-mediated elevation of
serum uric acid levels has a role in development of
the metabolic syndrome
■ By the proposed hypothesis, transient
hyperuricemia would exert its effect by limiting
bioavailability of endothelial nitric oxide, leading to
insulin resistance and hypertension
■ Low-fructose diets or allopurinol-mediated
lowering of serum uric acid levels might prevent or
successfully treat early stage metabolic syndrome
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Acknowledgments
This study was supported
by NIH grants DK-52121,
HL-68607, a George
O’Brien Center grant (DK-
P50-DK064233) and a pilot
grant from the Juvenile
Diabetes Foundation. We
thank Amy Buhler for help in
obtaining some of the older
references, and Edward
R Block, Daniel I Feig,
Olena Glushakova, Jaime
Herrera-Acosta, Hanbo Hu,
Xiaosen Ouyang and Sergey
Zharikov for assistance with
experimental studies.
Competing interests
The authors declared
competing interests; go to
the article online for details.
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