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

Abstract

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.

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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Figure 1: Fructose-induced production of uric acid in the hepatocyte.
Figure 2: Proposed pathway of fructose-induced metabolic syndrome.
Figure 3: Uric acid predicts hyperinsulinemia in first-time myocardial infarction patients.

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Acknowledgements

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.

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Correspondence to Takahiko Nakagawa.

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Dr Johnson and Dr Nakagawa have submitted a patent application on lowering uric acid as a means for preventing or treating the metabolic syndrome. Dr Johnson is also a consultant for TAP Pharmaceuticals.

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Nakagawa, T., Tuttle, K., Short, R. et al. Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Rev Nephrol 1, 80–86 (2005). https://doi.org/10.1038/ncpneph0019

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