Epidemiology and population health

Temporal relationship between hyperuricemia and obesity, and its association with future risk of type 2 diabetes




Although hyperuricemia and obesity are significantly correlated, their temporal relationship and whether this relationship is associated with future risk of diabetes are largely unknown. This study examined temporal relationship between hyperuricemia and obesity, and its association with future risk of type 2 diabetes.


This study examined two longitudinal cohorts totally including 17,044 subjects from China with an average of 6.0 years follow-up. Measurements of body mass index (BMI), waist circumference (WC), percentage of body fat and fasting serum uric acid were obtained at two time points. Cross-lagged panel and mediation analysis were used to examine the temporal relationship between hyperuricemia and obesity, and the association of this temporal relationship with follow-up diabetes.


In combined data of the two cohorts, the cross-lagged path coefficient (β1 = 0.121; 95% confidence interval (CI): 0.108–0.135) from baseline uric acid to the follow-up BMI was significantly greater than the path coefficient (β2 = 0.055, 95% CI: 0.038–0.072) from baseline BMI to the follow-up uric acid (P = 8.14e−10 for the difference between β1 and β2) with adjustment for covariates. The separate cross-lagged path models of uric acid with WC and percentage of body fat showed temporal patterns similar to that noted for uric acid with BMI. Further, the path coefficient (β1) from baseline uric acid to follow-up BMI in the group with diabetes was significantly greater than without diabetes (P = 0.003 for the difference of β1s in the two groups). BMI partially mediated the association of uric acid with risk of diabetes, and the percentage of mediated-association was estimated at 20.3% (95% CI: 15.7–24.8%). Results of these analyses in the combined data were consistent with those in the two cohorts, respectively.


These findings indicated that increased uric acid levels probably associated with obesity and type 2 diabetes, and more definite research is needed to define any role for uric acid in relation to these diseases.

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  1. 1.

    Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med. 2010;123:957–61.

  2. 2.

    Haslam DW, James WP. Obesity. Lancet. 2005;366:1197–209.

  3. 3.

    Tanaka K, Ogata S, Tanaka H, Omura K, Honda C, Hayakawa K. The relationship between body mass index and uric acid: a study on Japanese adult twins. Environ Health Prev Med. 2015;20:347–53.

  4. 4.

    Wang H, Wang L, Xie R, Dai W, Gao C, Shen P, et al. Association of serum uric acid with body mass index: a cross-sectional study from Jiangsu Province, China. Iran J Public Health. 2014;43:1503–9.

  5. 5.

    Oyama C, Takahashi T, Oyamada M, Oyamada T, Ohno T, Miyashita M, et al. Serum uric acid as an obesity-related indicator in early adolescence. Tohoku J Exp Med. 2006;209:257–62.

  6. 6.

    Johnson RJ, Lanaspa MA, Gaucher EA. Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Semin Nephrol. 2011;31:394–9.

  7. 7.

    de Oliveira EP, Burini RC. High plasma uric acid concentration: causes and consequences. Diabetol Metab Syndr. 2012;4:12.

  8. 8.

    Li C, Hsieh MC, Chang SJ. Metabolic syndrome, diabetes, and hyperuricemia. Curr Opin Rheumatol. 2013;25:210–6.

  9. 9.

    Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension. 2003;42:474–80.

  10. 10.

    Ishizaka N, Ishizaka Y, Toda A, Tani M, Koike K, Yamakado M, et al. Changes in waist circumference and body mass index in relation to changes in serum uric acid in Japanese individuals. J Rheumatol. 2010;37:410–6.

  11. 11.

    Chen W, Li S, Fernandez C, Sun D, Lai CC, Zhang T, et al. Temporal relationship between elevated blood pressure and arterial stiffening among middle-aged black and white adults: the Bogalusa Heart Study. Am J Epidemiol. 2016;183:599–608.

  12. 12.

    Zhang T, Zhang H, Li Y, Sun D, Li S, Fernandez C, et al. Temporal relationship between childhood body mass index and insulin and its impact on adult hypertension: the Bogalusa Heart Study. Hypertension. 2016;68:818–23.

  13. 13.

    Han T, Cheng Y, Tian S, Wang L, Liang X, Duan W, et al. Changes in triglycerides and high-density lipoprotein cholesterol may precede peripheral insulin resistance, with 2-h insulin partially mediating this unidirectional relationship: a prospective cohort study. Cardiovasc Diabetol. 2016;15:154.

  14. 14.

    Cameron AJ, Boyko EJ, Sicree RA, Zimmet PZ, Söderberg S, Alberti KG, et al. Central obesity as a precursor to the metabolic syndrome in the AusDiab study and Mauritius. Obesity. 2008;16:2707–16.

  15. 15.

    Pan A, Teng GG, Yuan JM, Koh WP. Bidirectional association between diabetes and gout: the Singapore Chinese Health Study. Sci Rep. 2016;6:25766.

  16. 16.

    Norvik JV, Storhaug HM, Ytrehus K, Jenssen TG, Zykova SN, Eriksen BO, et al. Overweight modifies the longitudinal association between uric acid and some components of the metabolic syndrome: the Tromsø Study. BMC Cardiovasc Disord. 2016;16:85.

  17. 17.

    Ferrara LA, Wang H, Umans JG, Franceschini N, Jolly S, Lee ET, et al. Serum uric acid does not predict incident metabolic syndrome in a population with high prevalence of obesity. Nutr Metab Cardiovasc Dis. 2014;24:1360–4.

  18. 18.

    Chien KL, Chen MF, Hsu HC, Chang WT, Su TC, Lee YT, et al. Plasma uric acid and the risk of type 2 diabetes in a Chinese community. Clin Chem. 2008;54:310–6.

  19. 19.

    Na L, Wu X, Feng R, Li J, Han T, Lin L, et al. The Harbin Cohort Study on diet, nutrition and chronic non-communicable diseases: study design and baseline characteristics. PLoS ONE. 2015;10:e0122598.

  20. 20.

    Jöreskog, KG, Sörbom, D. LISREL 8: Structural equation modeling with the SIMPLIS command language. Chicago, IL, US: Scientific Software International; Hillsdale, NJ, US: Lawrence Erlbaum Associates, Inc.; 1993.

  21. 21.

    Joreskog KG, Sörbom D. LISREL 8: user’s reference guide. Chicago: Scientific Software International, Inc.; 1996.

  22. 22.

    Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. mediation: R package for causal mediation analysis. J Stat Softw 2014;59:1–38.

  23. 23.

    Keenan T, Blaha MJ, Nasir K, Silverman MG, Tota-Maharaj R, Carvalho JA, et al. Relation of uric acid to serum levels of high-sensitivity C-reactive protein, triglycerides, and high-density lipoprotein cholesterol and to hepatic steatosis. Am J Cardiol. 2012;110:1787–92.

  24. 24.

    Shafiu M, Johnson RJ, Turner ST, Langaee T, Gong Y, Chapman AB, et al. Urate transporter gene SLC22A12 polymorphisms associated with obesity and metabolic syndrome in Caucasians with hypertension. Kidney Blood Press Res. 2012;35:477–82.

  25. 25.

    Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem. 2012;287:40732–44.

  26. 26.

    Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, Li N, Roncal-Jimenez CA, Ishimoto T, et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS ONE. 2012;7:e47948.

  27. 27.

    Lanaspa MA, Cicerchi C, Garcia G, Li N, Roncal-Jimenez CA, Rivard CJ, et al. Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS ONE. 2012;7:e48801.

  28. 28.

    Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–15.

  29. 29.

    Stirpe F, Della CE, Bonetti E, Abbondanza A, Abbati A, De Stefano F. Fructose-induced hyperuricaemia. Lancet. 1970;2:1310–1.

  30. 30.

    Akinyanju PA, Qureshi RU, Salter AJ, Yudkin J. Effect of an “atherogenic” diet containing starch or sucrose on the blood lipids of young men. Nature. 1968;218:975–7.

  31. 31.

    Raben A, Vasilaras TH, Møller AC, Astrup A. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk of supplementation in overweight subjects. Am J Clin Nutr. 2002;76:721–9.

  32. 32.

    Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Ren Physiol. 2006;290:F625–631.

  33. 33.

    Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci USA. 2009;106:17787–92.

  34. 34.

    Sánchez-Lozada LG, Lanaspa MA, Cristóbal-García M, García-Arroyo F, Soto V, Cruz-Robles D, et al. Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp Nephrol. 2012;121:e71–78.

  35. 35.

    Lyngdoh T, Marques-Vidal P, Paccaud F, Preisig M, Waeber G, Bochud M, et al. Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS ONE. 2011;6:e19901.

  36. 36.

    Quiñones GA, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995;268:E1–5.

  37. 37.

    Schwartz IF, Grupper A, Chernichovski T, Grupper A, Hillel O, Engel A, et al. Hyperuricemia attenuates aortic nitric oxide generation, through inhibition of arginine transport, in rats. J Vasc Res. 2011;48:252–60.

  38. 38.

    Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol. 2008;295:C1183–1190.

  39. 39.

    Roncal-Jimenez CA, Lanaspa MA, Rivard CJ, Nakagawa T, Sanchez-Lozada LG, Jalal D, et al. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism. 2011;60:1259–70.

  40. 40.

    Duffy WB, Senekjian HO, Knight TF, Weinman EJ. Management of asymptomatic hyperuricemia. JAMA. 1981;246:2215–6.

  41. 41.

    Miller TQ. Statistical methods for describing temporal order in longitudinal research. J Clin Epidemiol. 1997;50:1155–68.

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We are indebted to the participants of HDNNCDS and MPHS for their continued cooperation and participation. This work was supported by funds from the National Natural Science Foundation of China (81472981), the Wu Liande Grant of Harbin Medical University (WLD-QN1406) and by the Postdoctoral Science Foundation of China (2013T60393).

Author information

Author notes

  1. These authors contributed equally: Lixin Na, Ying Li, Changhao Sun.


  1. National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People’s Republic of China

    • Tianshu Han
    • , Xing Meng
    • , Ruiqi Shan
    • , Tianqi Zi
    • , Yingmei Li
    • , Hao Ma
    • , Yanhe Zhao
    • , Dan Shi
    • , Rongge Qu
    • , Xiaoyu Guo
    • , Lei Liu
    • , Lixin Na
    • , Ying Li
    •  & Changhao Sun


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The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Lixin Na or Ying Li or Changhao Sun.

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