The evidence against fructose seems to be just overwhelming ...

Nat Clin Pract Nephrol. 2005 Dec;1(2):80-6.

Hypothesis: fructose-induced hyperuricemia as a causal mechanism for
the epidemic of the metabolic syndrome.

Nakagawa T, Tuttle KR, Short RA, Johnson RJ.
Division of Nephrology, Hypertension, and Transplantation, University
of Florida, Gainesville, FL 32610, USA. nakagt[at]medicine.ufl.edu

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.
PMID: 16932373

Am J Physiol Renal Physiol. 2006 Mar;290(3):F625-31. Epub 2005 Oct 18.

A causal role for uric acid in fructose-induced metabolic syndrome.

Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O,
Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ.
Division of Nephrology, Hypertension, and Transplantation, PO Box
100224, University of Florida, Gainesville, FL 32610, USA.
nakagt[at]medicine.ufl.edu

The worldwide epidemic of metabolic syndrome correlates with an
elevation in serum uric acid as well as a marked increase in total
fructose intake (in the form of table sugar and high-fructose corn
syrup). Fructose raises uric acid, and the latter inhibits nitric
oxide bioavailability. Because insulin requires nitric oxide to
stimulate glucose uptake, we hypothesized that fructose-induced
hyperuricemia may have a pathogenic role in metabolic syndrome. Four
sets of experiments were performed. First, pair-feeding studies showed
that fructose, and not dextrose, induced features (hyperinsulinemia,
hypertriglyceridemia, and hyperuricemia) of metabolic syndrome.
Second, in rats receiving a high-fructose diet, the lowering of uric
acid with either allopurinol (a xanthine oxidase inhibitor) or
benzbromarone (a uricosuric agent) was able to prevent or reverse
features of metabolic syndrome. In particular, the administration of
allopurinol prophylactically prevented fructose-induced
hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic
hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7
vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05)
at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake
of control diet in rats. Finally, uric acid dose dependently inhibited
endothelial function as manifested by a reduced vasodilatory response
of aortic artery rings to acetylcholine. These data provide the first
evidence that uric acid may be a cause of metabolic syndrome, possibly
due to its ability to inhibit endothelial function. Fructose may have
a major role in the epidemic of metabolic syndrome and obesity due to
its ability to raise uric acid.
PMID: 16234313

Am J Med. 2007 May;120(5):442-7.

Prevalence of the metabolic syndrome in individuals with
hyperuricemia.

Choi HK, Ford ES.
Rheumatology Division, Arthritis Research Centre of Canada, Department
of Medicine, Vancouver General Hospital, University of British
Columbia, Vancouver, Canada. hchoi[at]partners.org

PURPOSE: The link between hyperuricemia and insulin resistance has
been noted, but the prevalence of the metabolic syndrome by recent
definitions among individuals with hyperuricemia remains unclear. Our
objective was to determine the prevalence of the metabolic syndrome
according to serum uric acid levels in a nationally representative
sample of US adults. METHODS: By using data from 8669 participants
aged 20 years and more in The Third National Health and Nutrition
Examination Survey (1988-1994), we determined the prevalence of the
metabolic syndrome at different serum uric acid levels. We used both
the revised and original National Cholesterol Education Program Adult
Treatment Panel (NCEP/ATP) III criteria to define the metabolic
syndrome. RESULTS: The prevalences of the metabolic syndrome according
to the revised NCEP/ATP III criteria were 18.9% (95% confidence
interval [CI], 16.8-21.0) for uric acid levels less than 6 mg/dL,
36.0% (95% CI, 32.5-39.6) for uric acid levels from 6 to 6.9 mg/dL,
40.8% (95% CI, 35.3-46.4) for uric acid levels from 7 to 7.9 mg/dL,
59.7% (95% CI, 53.0-66.4) for uric acid levels from 8 to 8.9 mg/dL,
62.0% (95% CI, 53.0-66.4) for uric acid levels from 9 to 9.9 mg/dL,
and 70.7% for uric acid levels of 10 mg/dL or greater. The increasing
trends persisted in subgroups stratified by sex, age group, alcohol
intake, body mass index, hypertension, and diabetes. For example,
among individuals with normal body mass index (<25 kg/m2), the
prevalence increased from 5.9% (95% CI, 4.8-7.0), for a uric acid
level of less than 6 mg/dL, to 59.0%, (95% CI, 20.1-97.9) for a uric
acid level of 10 mg/dL or greater. With the original NCEP/ATP
criteria, the corresponding prevalences were slightly lower.
CONCLUSIONS: These findings from a nationally representative sample of
US adults indicate that the prevalence of the metabolic syndrome
increases substantially with increasing levels of serum uric acid.
Physicians should recognize the metabolic syndrome as a frequent
comorbidity of hyperuricemia and treat it to prevent serious
complications.
PMID: 17466656

Am J Clin Nutr. 2007 Oct;86(4):899-906.

Potential role of sugar (fructose) in the epidemic of hypertension,
obesity and the metabolic syndrome, diabetes, kidney disease, and
cardiovascular disease.

Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch
MS, Benner S, Sánchez-Lozada LG.
Division of Nephrology and Department of Medicine, University of
Florida, Gainesville, FL, USA. johnsrj[at]medicine.ufl.edu

Currently, we are experiencing an epidemic of cardiorenal disease
characterized by increasing rates of obesity, hypertension, the
metabolic syndrome, type 2 diabetes, and kidney disease. Whereas
excessive 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
epidemic 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 Americans
may explain their greater predisposition to develop cardiorenal
disease, and we provide a list of testable predictions to evaluate
this hypothesis.
PMID: 17921363

J Am Soc Nephrol. 2007 Oct;18(10):2724-31. Epub 2007 Sep 12.

Thiazide diuretics exacerbate fructose-induced metabolic syndrome.

Reungjui S, Roncal CA, Mu W, Srinivas TR, Sirivongs D, Johnson RJ,
Nakagawa T.
Division of Nephrology, Hypertension and Transplantation, University
of Florida, Gainesville, Florida, USA.

Fructose is a commonly used sweetener associated with diets that
increase the prevalence of metabolic syndrome. Thiazide diuretics are
frequently used in these patients for treatment of hypertension, but
they also exacerbate metabolic syndrome. Rats on high-fructose diets
that are given thiazides exhibit potassium depletion and
hyperuricemia. Potassium supplementation improves their insulin
resistance and hypertension, whereas allopurinol reduces serum levels
of uric acid and ameliorates hypertension, hypertriglyceridemia,
hyperglycemia, and insulin resistance. Both potassium supplementation
and treatment with allopurinol also increase urinary nitric oxide
excretion. We suggest that potassium depletion and hyperuricemia in
rats exacerbates endothelial dysfunction and lowers the
bioavailability of nitric oxide, which blocks insulin activity and
causes insulin resistance during thiazide usage. Addition of potassium
supplements and allopurinol with thiazides might be helpful in the
management of metabolic syndrome.
PMID: 17855639