Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Clinical Practice Nephrology volume 1, pages 80–86 (2005)Cite this article

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

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Hedley AA et al. (2004) Prevalence of overweight and obesity among children, adolescents, and adults, 1999–2002. JAMA 2: 2847–2850

    Article  Google Scholar 

  2. Weiss R et al. (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350: 2362–2374

    Article  CAS  Google Scholar 

  3. Block G (2004) Foods contributing to energy intake in the U.S.: data from NHANES III and NHANES 1999–2000: J Food Comp Analysis 17: 439–447

    Article  Google Scholar 

  4. Johnson RJ et al. (2005) Uric acid, evolution, and primitive cultures. Sem Nephrol 25: 3–8

    Article  CAS  Google Scholar 

  5. Yusuf S et al. (2001) Global burden of cardiovascular diseases. Part I: General considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 104: 2746–2753

    Article  CAS  Google Scholar 

  6. Serdula MK et al. (1999) Prevalence of attempting weight loss and strategies for controlling weight. JAMA 282: 1353–1358

    Article  CAS  Google Scholar 

  7. Foster GD et al. (2003) A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 348: 2082–2089

    Article  CAS  Google Scholar 

  8. United States Department of Agriculture Economic Research Service report. [http://www.ers.usda.gov/data/foodconsumption/spreadsheets/sweets.xls]

  9. US Census Bureau (2003) Health and Nutrition. No. 214 Per Capita Consumption of Major Food Commodities: 1980 to 2001. In: Statistical Abstract of the United States: 2003, 143. Washington DC: US Census Bureau

  10. Bray GA et al. (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79: 537–543

    Article  CAS  Google Scholar 

  11. Ludwig DS et al. (2001) Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 357: 505–508

    Article  CAS  Google Scholar 

  12. Schulze MB et al. (2004) Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA 292: 927–934

    Article  CAS  Google Scholar 

  13. Dennison BA et al. (1997) Excess fruit juice consumption by preschool-aged children is associated with short stature and obesity. Pediatr 99: 15–22

    CAS  Google Scholar 

  14. Hallfrisch J (1990) Metabolic effects of dietary fructose. FASEB J 4: 2652–2660

    Article  CAS  Google Scholar 

  15. Lingelbach LB and McDonald RB (2000) Description of the long-term lipogenic effects of dietary carbohydrates in male Fischer 344 rats. J Nutr 130: 3077–3084

    Article  CAS  Google Scholar 

  16. Teff KL et al. (2004) Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89: 2963–2972

    Article  CAS  Google Scholar 

  17. Zammit VA et al. (2001) Insulin stimulation of hepatic triacylglycerol secretion and the etiology of insulin resistance. J Nutr 131: 2074–2077

    Article  CAS  Google Scholar 

  18. Perheentupa J and Raivio K (1967) Fructose induced hyperuricemia. Lancet 2: 528–535

    Article  CAS  Google Scholar 

  19. Emmerson BT (1974) Effect of oral fructose on urate production. Ann Rheum Dis 33: 276–280

    Article  CAS  Google Scholar 

  20. Stirpe F et al. (1970) Fructose-induced hyperuricemia. Lancet 2: 1310–1311

    Article  CAS  Google Scholar 

  21. Fox IH and Kelley WN (1972) Studies on the mechanism of fructose-induced hyperuricemia in man. Metabolism 21: 713–721

    Article  CAS  Google Scholar 

  22. Smith CM et al. (1977) Fructose-induced adenine nucleotide catabolism in isolated rat hepatocyte. Can J Biochem 55: 1237–1240

    Article  CAS  Google Scholar 

  23. Khosla UM et al. (2005) Hyperuricemia reversibly inhibits endothelial dysfunction in rats. Kidney Int 67: 1739–1742

    Article  Google Scholar 

  24. Kang DH et al. (2003) Uric acid induced C-reactive protein (CRP) expression via upregulation of angiotensin type 1 receptors (AT1) in vascular endothelial cells and smooth muscle cells [abstract #136]. J Am Soc Nephrol 14

  25. Kanabrocki EL et al. (2000) Circadian relationship of serum uric acid and nitric oxide. JAMA 283: 2240–2241

    Article  CAS  Google Scholar 

  26. Butler R et al. (2000) Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35: 746–751

    Article  CAS  Google Scholar 

  27. Doehner W et al. (2002) Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 105: 2619–2624

    Article  CAS  Google Scholar 

  28. Farquharson CA et al. (2002) Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 106: 221–226

    Article  CAS  Google Scholar 

  29. Cardillo C et al. (1997) Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 30: 57–63

    Article  CAS  Google Scholar 

  30. Guthikonda S et al. (2003) Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation 107: 416–421

    Article  CAS  Google Scholar 

  31. Scherrer U et al. (1994) Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 94: 2511–2515

    Article  CAS  Google Scholar 

  32. Cook S et al. (2003) Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice. Swiss Med Wkly 133: 360–363

    PubMed  Google Scholar 

  33. Roy D et al. (1998) Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. Am J Physiol 274: E692–E699

    CAS  PubMed  Google Scholar 

  34. Wexler BC and Greenberg BP (1977) Effect of increased serum urate levels on virgin rats with no arteriosclerosis versus breeder rats with preexistent arteriosclerosis. Metabolism 26: 1309–1320

    Article  CAS  Google Scholar 

  35. Wexler BC (1982) Allantoxanamide-induced myocardial necrosis in Sprague-Dawley vs. Spontaneously Hypertensive Rats. Proc Soc Exp Biol Med 170: 476–485

    Article  CAS  Google Scholar 

  36. Johnson RJ et al. (2005) The resurrection of uric acid as a causal factor in hypertension. Hypertension 45: 18–20

    Article  CAS  Google Scholar 

  37. Masuo K et al. (2003) Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 42: 474–480

    Article  CAS  Google Scholar 

  38. Nakanishi N et al. (2003) Serum uric acid and risk for development of hypertension and impaired fasting glucose or Type 2 diabetes in Japanese male office workers. Eur J Epidemiol 18: 523–530

    Article  CAS  Google Scholar 

  39. Sundström J et al. (2005) Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 45: 28–33

    Article  Google Scholar 

  40. Vuorinen-Markkola H and Yki-Järvinen H (1994) Hyperuricemia and insulin resistance. J Clin Endo Metab 78: 25–29

    CAS  Google Scholar 

  41. Costa A et al. (2002) Uric acid concentration in subjects at risk of type 2 diabetes mellitus: Relationship to components of the metabolic syndrome. Metabolism 51: 372–375

    Article  CAS  Google Scholar 

  42. Berkowitz D (1966) Gout, hyperlipidemia, and diabetes interrelationships. JAMA 197: 117–120

    Article  Google Scholar 

  43. Thadhani R et al. (2004) Insulin resistance and alterations in angiogenesis. Additive insults that may lead to preeclampsia. Hypertension 43: 988–992

    Article  CAS  Google Scholar 

  44. Pascual E (1994) Hyperuricemia and gout. Curr Opin Rheumatol 6: 454–458

    Article  CAS  Google Scholar 

  45. Lindholm LH et al. (2003) Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid profile in a North of Sweden Efficacy Evaluation (ALPIN study). J Hypertens 21: 1563–1574

    Article  CAS  Google Scholar 

  46. Deedwania PC (2003) Mechanisms of endothelial dysfunction in the metabolic syndrome. Curr Diab Rep 3: 289–292

    Article  Google Scholar 

  47. Fishberg AM (1924) The interpretation of increased blood uric acid in hypertension. Arch Int Med 34: 503–507

    Article  CAS  Google Scholar 

  48. Hall AP et al. (1967) Epidemiology of gout and hyperuricemia. Am J Med 42: 27–37

    Article  CAS  Google Scholar 

  49. Mikkelsen WM et al. (1965) The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia. Tecumseh, Michigan. 1959–1960. Am J Med 39: 242–251

    Article  CAS  Google Scholar 

  50. Glynn RJ et al. (1983) Trends in serum uric acid levels. 1961–1980. Arthritis Rheum 26: 87–93

    Article  CAS  Google Scholar 

  51. Freedman DS et al. (1995) Relation of serum uric acid to mortality and ischemic heart disease. Am J Epidemiol 141: 637–644

    Article  CAS  Google Scholar 

  52. Gresser U et al. (1990) Uric acid levels in Southern Germany in 1989. A comparison with studies from 1962, 1971, and 1984. Klin Wochenschr 68: 1222–1228

    Article  CAS  Google Scholar 

  53. Robinson SC and Brucer M (1939) Range of normal blood pressure. A statistical and clinical study of 11,383 persons. Arch Int Med 64: 409–444

    Article  Google Scholar 

  54. Arromedee E et al. (2002) Epidemiology of gout: Is the incidence rising? J Rheumatol 29: 2403–2406

    Google Scholar 

  55. Lennane GAQ et al. (1960) Gout in the Maori. Ann Rheum Dis 19: 120–125

    Article  CAS  Google Scholar 

  56. Conen D et al. (2004) Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country. BMC Public Health 4: 1–9

    Article  Google Scholar 

  57. Kagan A et al. (1974) Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii, and California. Demographic, physical, dietary and biochemical characteristics. J Chron Dis 27: 345–364

    Article  CAS  Google Scholar 

  58. Choi HK et al. (2004) Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 350: 1093–1103

    Article  CAS  Google Scholar 

  59. Johnson RJ and Rideout BA (2004) Uric acid and diet: insights into the epidemic of cardiovascular disease. N Engl J Med 350: 1071–1073

    Article  CAS  Google Scholar 

  60. Tuomilehto J et al. (1988) Plasma uric acid level and its association with diabetes mellitus and some biological parameters in a biracial population of Fiji. Am J Epidemiol 127: 321–336

    Article  CAS  Google Scholar 

  61. Bo S et al. (2001) Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest 31: 318–321

    Article  CAS  Google Scholar 

  62. Sánchez-Lozada LG et al. (2005) Mild hyperuricemia induces severe cortical vasoconstriction and perpetuates glomerular hypertension in normal rats and in experimental chronic renal failure. Kidney Int 67: 237–234

    Article  Google Scholar 

  63. Kang DH et al. (2002) A role for uric acid in renal progression. J Am Soc Nephrol 13: 2888–2897

    Article  CAS  Google Scholar 

  64. Beckman JA et al. (2002) Inhibition of protein kinase C β prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res 90: 107–111

    Article  CAS  Google Scholar 

  65. Hogan M et al. (1992) Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. J Clin Invest 90: 1110–1115

    Article  CAS  Google Scholar 

  66. Mazzali M et al. (2001) Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 38: 1101–1106

    Article  CAS  Google Scholar 

  67. Shinozaki K et al. (2004) Evidence for a causal role of the renin angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 43: 255–262

    Article  CAS  Google Scholar 

  68. Pollock DM et al. (1993) Angiotensin blockade reverses hypertension during long-term nitric oxide blockade. Hypertension 21: 660–666

    Article  CAS  Google Scholar 

  69. Yusuf S et al. (2001) HOPE Study Investigators. Ramipril and the development of diabetes. JAMA 286: 1882–1885

    Article  CAS  Google Scholar 

  70. Osei K et al. (1987) Metabolic effects of fructose as a natural sweetener in the physiological meals of ambulatory obese patients with type 2 diabetes. Am J Med 83: 249–255

    Article  CAS  Google Scholar 

  71. Galvan AQ et al. (1995) Effect of insulin on uric acid excretion in humans. Am J Physiol 268: E1–E5

    Google Scholar 

  72. Prior IAM et al. (1966) Hyperuricemia, gout and diabetic abnormality in Polynesian people. Lancet 1: 333–338

    Article  CAS  Google Scholar 

  73. Fisher ND et al. (2003) Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens 21: 2281–2286

    Article  CAS  Google Scholar 

  74. Waring WS et al. (2004) Hyperuricaemia does not impair cardiovascular function in healthy adults. Heart 90: 155–159

    Article  CAS  Google Scholar 

  75. Osler W (1893) Gout. In: The Principles and Practice of Medicine, edn 2, 287–295. New York: Appleton

    Google Scholar 

  76. Dessein PH et al. (2000) Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout; a pilot study. Ann Rheum Dis 59: 539–543

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Research Assistant Professor in the Division of Nephrology, Hypertension, and Transplantation at the University of Florida, Gainesville, FL

    Takahiko Nakagawa

  2. the Medical and Scientific Director at The Heart Institute and Providence Medical Research Center, Spokane, Washington, DC

    Katherine R Tuttle

  3. a faculty member at Washington State University, Spokane, Washington, DC

    Robert A Short

  4. 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

    Richard J Johnson

Authors
  1. Takahiko Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine R Tuttle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert A Short
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard J Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahiko Nakagawa.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0019

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing