Fructose and Uric Acid: Is There a Role in Endothelial Function?

  • Guanghong Jia
  • Annayya R. Aroor
  • Adam T. Whaley-Connell
  • James R. SowersEmail author
Hypertension and Metabolic Syndrome (JR Sowers and AT Whaley-Connell, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Hypertension and Metabolic Syndrome


Population level data support that consumption of fructose and fructose-based sweeteners has dramatically increased and suggest that high dietary intake of fructose is an important factor in the development of the cardiorenal metabolic syndrome (CRS). The CRS is a constellation of cardiac, kidney and metabolic disorders including insulin resistance, obesity, metabolic dyslipidemia, high blood pressure, and evidence of early cardiac and kidney disease. The consequences of fructose metabolism may result in intracellular ATP depletion, increased uric acid production, oxidative stress, inflammation, and increased lipogenesis, which are associated with endothelial dysfunction. Endothelial dysfunction is an early manifestation of vascular disease and a driver for the development of CRS. A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies.


Cardiorenal metabolic syndrome Nitric oxide Lipogenesis Insulin resistance Hypertension Oxidative stress Inflammation Estrogen 



The authors would like to thank Brenda Hunter for her editorial assistance. This research was supported by National Institutes of Health grants HL-73101 and HL-107910 to J.R.S. and AG-040638 to A.W.-C. and the Veterans Affairs Merit System 0018 (J.R.S.) and CDA-2 (A.W.-C.).

Compliance with Ethics Guidelines

Conflict of Interest Guanghong Jia, Annayya R. Aroor, Adam T. Whaley-Connell, and James R. Sowers declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Sheludiakova A, Rooney K, Boakes RA. Metabolic and behavioural effects of sucrose and fructose/glucose drinks in the rat. Eur J Nutr. 2012;51:445–54.PubMedGoogle Scholar
  2. 2.
    Lecoultre V, Egli L, Theytaz F, et al. Fructose-induced hyperuricemia is associated with a decreased renal uric acid excretion in humans. Diabetes Care. 2013;36:e149–50.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Lakhan SE, Kirchgessner A. The emerging role of dietary fructose in obesity and cognitive decline. Nutr J. 2013;12:114.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Cozma AI, Sievenpiper JL, de Souza RJ, et al. Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials. Diabetes Care. 2012;35:1611–20.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Kretowicz M, Johnson RJ, Ishimoto T, et al. The impact of fructose on renal function and blood pressure. Int J Nephrol. 2011;2011:315879.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Jindal A, Garcia-Touza M, Jindal N, et al. Diabetic kidney disease and the cardiorenal syndrome: old disease, new perspectives. Endocrinol Metab Clin N Am. 2013;42:789–808.Google Scholar
  7. 7.
    Tappy L, Lê KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev. 2010;90:23–46.PubMedGoogle Scholar
  8. 8.
    Rajwani A, Cubbon RM, Wheatcroft SB. Cell-specific insulin resistance: implications for atherosclerosis. Diabetes Metab Res Rev. 2012;28:627–34.PubMedGoogle Scholar
  9. 9.
    Collino M. High dietary fructose intake: sweet or bitter life? World J Diabetes. 2011;2:77–81.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Samuel VT. Fructose induced lipogenesis: from sugar to fat to insulin resistance. Trends Endocrinol Metab. 2011;22:60–5.PubMedGoogle Scholar
  11. 11.
    Fushinobu S, Nishimasu H, Hattori D, et al. Structural basis for the bifunctionality of fructose -1,6-bisphosphate aldolase/phosphatase. Nature. 2011;478:538–41.PubMedGoogle Scholar
  12. 12.
    Johnson RJ, Sanchez-Lozada LG, Nakagawa T. The effect of fructose on renal biology and disease. J Am Soc Nephrol. 2010;21:2036–9.PubMedGoogle Scholar
  13. 13.
    Debosch BJ, Chen Z, Finck BN, et al. Glucose transporter-8 (GLUT8) mediates glucose intolerance and dyslipidemia in high-fructose diet-fed male mice. Mol Endocrinol. 2013;27:1887–96.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Masterjohn C, Park Y, Lee J, et al. Dietary fructose feeding increases adipose methylglyoxal accumulation in rats in association with low expression and activity of glyoxalase-2. Nutrients. 2013;5:3311–28.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Khitan Z, Kim DH. Fructose: a key factor in the development of metabolic syndrome and hypertension. J Nutr Metab. 2013;2013:682673.PubMedPubMedCentralGoogle Scholar
  16. 16.••
    Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–15. This study showed the major discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity, and provides new insights into pathogenesis and therapies for this important disease.PubMedPubMedCentralGoogle Scholar
  17. 17.•
    Sowers JR, Whaley-Connell A, Hayden MR. The role of overweight and obesity in the cardiorenal syndrome. Cardiorenal Med. 2011;1:5–12. This study revealed the potential mechanisms by which obesity and other metabolic abnormalities interact to promote heart and progressive kidney disease.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Dhar I, Dhar A, Wu L, Desai KM. Increased methylglyoxal formation with upregulation of Renin Angiotensin system in fructose fed sprague dawley rats. PLoS One. 2013;8:e74212.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Feinman RD, Fine EJ. Fructose in perspective. Nutr Metab (Lond). 2013;10:45.Google Scholar
  20. 20.
    Stanhope KL, Havel PJ. Fructose consumption: recent results and their potential implications. Ann N Y Acad Sci. 2010;1190:15–24.PubMedPubMedCentralGoogle Scholar
  21. 21.••
    Chaudhary K, Malhotra K, Sowers J, Aroor A. Uric acid - key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med. 2013;3:208–20. This study also found that elevated serum levels of uric acid appear to contribute to impaired nitric oxide production/endothelial dysfunction, increased vascular stiffness, inappropriate activation of the renin-angiotensin-aldosterone system, enhanced oxidative stress, and maladaptive immune and inflammatory responses.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Sowers JR. Diabetes mellitus and vascular disease. Hypertension. 2013;61:943–7.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Aroor AR, McKarns S, Demarco VG, et al. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism. 2013;62:1543–52.PubMedGoogle Scholar
  24. 24.
    So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;120:1791–9.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rev. 2013;15:175–81.Google Scholar
  26. 26.
    Jindal A, Brietzke S, Sowers JR. Obesity and the cardiorenal metabolic syndrome: therapeutic modalities and their efficacy in improving cardiovascular and renal risk factors. Cardiorenal Med. 2012;2:314–27.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Sluijs I, Beulens JW, van der Daphne AL, et al. Plasma uric acid is associated with increased risk of type 2 diabetes independent of diet and metabolic risk factors. J Nutr. 2013;143:80–5.PubMedGoogle Scholar
  28. 28.
    Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev. 2009;30:96–116.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Santos RD. Elevated uric acid, the metabolic syndrome and cardiovascular disease: cause, consequence, or just a not so innocent bystander? Endocrine. 2012;41:350–2.PubMedGoogle Scholar
  30. 30.
    Zapolski T, Waciński P, Kondracki B, et al. Uric acid as a link between renal dysfunction and both pro-inflammatory and prothrombotic state in patients with metabolic syndrome and coronary artery disease. Kardiol Pol. 2011;69:319–26.PubMedGoogle Scholar
  31. 31.
    Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011;60:1258–69.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Riegersperger M, Covic A, Goldsmith D. Allopurinol, uric acid, and oxidative stress in cardiorenal disease. Int Urol Nephrol. 2011;43:441–9.PubMedGoogle Scholar
  33. 33.
    Gul R, Demarco VG, Sowers JR, et al. Regulation of overnutrition-induced cardiac inflammatory mechanisms. Cardiorenal Med. 2012;2:225–33.PubMedPubMedCentralGoogle Scholar
  34. 34.••
    Muniyappa R, Sowers JR. Endothelial insulin and IGF-1 receptors: when yes means NO. Diabetes. 2012;61:2225–7. This report also revealed that interventions aimed at downregulating IGF-1R expression may augment endothelial insulin sensitivity in the pathological states.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Zhang Y, Sowers JR, Ren J. Pathophysiological insights into cardiovascular health in metabolic syndrome. Exp Diabetes Res. 2012;2012:320534.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Liu J, Shen W, Zhao B, et al. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: hope from natural mitochondrial nutrients. Adv Drug Deliv Rev. 2009;61:1343–52.PubMedGoogle Scholar
  37. 37.•
    Muniyappa R, Sowers JR. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord. 2013;14:5–12. This study revealed the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- atherogenic and anti-atherogenic actions of insulin.PubMedPubMedCentralGoogle Scholar
  38. 38.
    van Bussel BC, Schouten F, Henry RM, et al. Endothelial dysfunction and low-grade inflammation are associated with greater arterial stiffness over a 6-year period. Hypertension. 2011;58:588–95.PubMedGoogle Scholar
  39. 39.
    Ait-Oufella H, Salomon BL, Potteaux S, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006;12:178–80.PubMedGoogle Scholar
  40. 40.
    He S, Li M, Ma X, et al. CD4 + CD25 + Foxp3+ regulatory T cells protect the proinflammatory activation of human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 2010;30:2621–30.PubMedGoogle Scholar
  41. 41.
    Garcia-Vargas L, Addison SS, Nistala R, et al. Gestational diabetes and the offspring: implications in the development of the cardiorenal metabolic syndrome in offspring. Cardiorenal Med. 2012;2:134–42.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Kim JA, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102:401–14.PubMedPubMedCentralGoogle Scholar
  43. 43.•
    Kim JA, Jang HJ, Martinez-Lemus LA, Sowers JR. Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. Am J Physiol Endocrinol Metab. 2012;302:E201–8. This report showed that Ang II-mediated impairment of vascular actions of insulin may help explain the role of Ang II as a link between insulin resistance and hypertension.PubMedGoogle Scholar
  44. 44.
    Bender SB, McGraw AP, Jaffe IZ, Sowers JR. Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease? Diabetes. 2013;62:313–9.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr. 2012;23:222–31.PubMedPubMedCentralGoogle Scholar
  46. 46.•
    Tran LT, Yuen VG, McNeill JH. The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem. 2009;332:145–59. This study addressed the role of sympathetic nervous system overactivation, increased production of vasoconstrictors, such as endothelin-1 and angiotensin II, and prostanoids in the development of hypertension in fructose-fed rats.PubMedGoogle Scholar
  47. 47.•
    Manrique C, DeMarco VG, Aroor AR, et al. Obesity and insulin resistance induce early development of diastolic dysfunction in young female mice fed a Western diet. Endocrinology. 2013;154:3632–42. This report also revealed that higher aldosterone levels, in concert with insulin resistance, may promote myocardial stiffness and diastolic dysfunction in response to overnutrition in females.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Galipeau D, Verma S, McNeill JH. Female rats are protected against fructose-induced changes in metabolism and blood pressure. Am J Physiol Heart Circ Physiol. 2002;283:H2478–84.PubMedGoogle Scholar
  49. 49.
    Song D, Arikawa E, Galipeau D, et al. Androgens are necessary for the development of fructose-induced hypertension. Hypertension. 2004;43:667–72.PubMedGoogle Scholar
  50. 50.
    Martins-Maciel ER, Campos LB, Salgueiro-Pagadigorria CL, et al. Raloxifene affects fatty acid oxidation in livers from ovariectomized rats by acting as a pro-oxidant agent. Toxicol Lett. 2013;217:82–9.PubMedGoogle Scholar
  51. 51.
    Manrique C, Lastra G, Habibi J, et al. Loss of estrogen receptor α signaling leads to insulin resistance and obesity in young and adult female mice. Cardiorenal Med. 2012;2:200–10.PubMedPubMedCentralGoogle Scholar
  52. 52.
    O'Lone R, Knorr K, Jaffe IZ, et al. Estrogen receptors alpha and beta mediate distinct pathways of vascular gene expression, including genes involved in mitochondrial electron transport and generation of reactive oxygen species. Mol Endocrinol. 2007;21:1281–96.PubMedGoogle Scholar
  53. 53.
    Masood DE, Roach EC, Beauregard KG, Khalil RA. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab. 2010;11:693–714.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Miller VM, Duckles SP. Vascular actions of estrogens: functional implications. Pharmacol Rev. 2008;60:210–41.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lee SA, Kim EY, Jeon WK, et al. The inhibitory effect of raloxifene on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells is mediated through a ROS/p38 MAPK/CREB pathway to the up-regulation of heme oxygenase-1 independent of estrogen receptor. Biochimie. 2011;93:168–74.PubMedGoogle Scholar
  56. 56.
    Jaubert AM, Mehebik-Mojaat N, Lacasa D, et al. Nongenomic estrogen effects on nitric oxide synthase activity in rat adipocytes. Endocrinology. 2007;148:2444–52.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Guanghong Jia
    • 1
    • 3
    • 5
  • Annayya R. Aroor
    • 1
    • 3
    • 5
  • Adam T. Whaley-Connell
    • 1
    • 2
    • 3
    • 5
  • James R. Sowers
    • 1
    • 3
    • 4
    • 5
    Email author
  1. 1.Division of Endocrinology and Metabolism, Department of MedicineUniversity of Missouri School of MedicineColumbiaUSA
  2. 2.Division of Nephrology and Hypertension, Department of MedicineUniversity of Missouri School of MedicineColumbiaUSA
  3. 3.Research Service Harry S Truman Memorial Veterans Hospital, Research ServiceColumbiaUSA
  4. 4.Department of Medical Pharmacology and PhysiologyUniversity of Missouri School of MedicineColumbiaUSA
  5. 5.Diabetes and Cardiovascular CenterUniversity of Missouri School of MedicineColumbiaUSA

Personalised recommendations