Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online October 31, 2007
Diabetes Care 31:361-362, 2008
DOI: 10.2337/dc07-1276
© 2008 by the American Diabetes Association
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-1276v1
31/2/361    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dehghan, A.
Right arrow Articles by Witteman, J. C.M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dehghan, A.
Right arrow Articles by Witteman, J. C.M.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Cardiovascular and Metabolic Risk
Original Research

High Serum Uric Acid as a Novel Risk Factor for Type 2 Diabetes

Abbas Dehghan, MD, DSC1, Mandy van Hoek, MD2, Eric J.G. Sijbrands, MD, PHD2, Albert Hofman, MD, PHD1 and Jacqueline C.M. Witteman, PHD1

1 Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
2 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands

Address correspondence and reprint requests to Dr. J.C.M. Witteman, PhD, Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, Netherlands. E-mail: j.witteman{at}erasmusmc.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
OBJECTIVE—To investigate the association between serum uric acid level and risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS—The population for analysis consisted of 4,536 subjects free from diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes.

RESULTS—The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96–1.76) for the second, 1.63 (1.21–2.19) for the third, and 2.83 (2.13–3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78–1.49), 1.12 (0.81–1.53), and 1.68 (1.22–2.30), respectively.

CONCLUSIONS—The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Serum uric acid is positively associated with serum glucose in healthy subjects.(1,2) However, this association is not consistent between healthy and diabetic individuals (3–5), as a low serum level of uric acid is reported in the hyperglycemic state (6). Since most individuals experience a phase of impaired glucose tolerance before progression to diabetes, it is not clear whether raised serum uric acid predicts the risk of type 2 diabetes (4,5). We investigated the association between serum uric acid and risk of diabetes in the Rotterdam Study, a large population-based, prospective cohort study among subjects aged 55 years and older.


   RESEARCH DESIGN AND METHODS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
The Rotterdam Study has been described in detail elsewhere (7). Written informed consent was obtained from all participants, and the Medical Ethics Committee of Erasmus Medical Center approved the study. At baseline, serum uric acid was measured (8,9) and prevalent diabetes cases were excluded (10). Incident cases of diabetes were diagnosed during follow-up based on the guidelines of the American Diabetes Association (11) and World Health Organizatioin (12) using the information from general practitioners, pharmacies’ databases, and fasting blood samples that were taken during follow-up examinations (10). The association was assessed by Cox regression analysis. The population-attributable risk and 95% CIs were calculated with use of the Interactive Risk Assessment Program (IRAP) (13).


   RESULTS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Serum uric acid was ranged from 107 to 756 µmol/l with a mean ± SD of 323.7 ± 82.2 µmol/l. Age BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol were significantly correlated with serum uric acid. The correlation coefficient ranged from 0.03 for diastolic blood pressure to 0.35 for waist circumference. Except for HDL cholesterol, the correlations were positive.

During a mean follow-up of 10.1 years, 462 of 4,536 participants developed diabetes (incidence rate 10.1 per 1,000 person-years). The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96–1.76) for the second, 1.63 (1.21–2.19) for the third, and 2.83 (2.13–3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. In a multivariate-adjusted model (Table 1), the HRs (95% CIs) decreased to 1.08 (0.78–1.49), 1.12 (0.81–1.53), and 1.68 (1.22–2.30), respectively. The population-attributable risk of high serum uric acid for diabetes was 0.24 (95% CI 0.17–0.30) for the fourth quartile, 0.09 (0.3–0.15) for the third quartile, and 0.04 (–0.01 to 0.10) for the second quartile.


View this table:
[in this window]
[in a new window]

  		Table 1— HR (95% CI) for diabetes according to level of serum uric acid

 

   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
We showed that the subjects with higher levels of serum uric acid are more at risk of developing type 2 diabetes. We also found that one-quarter of diabetes cases can be attributed to a high serum uric acid level.

Our finding is in agreement with previous studies. At least two studies in 1980s reported on the association of serum uric acid with the risk of diabetes (14,15); however, the association was not adjusted for any potential confounder. Lately, it has been shown in middle-aged Japanese men (4) that serum uric acid level is significantly associated with the risk of diabetes. However, another study in middle-aged Japanese men in Osaka showed that the association was not significant after adjustment for BMI, alcohol consumption, smoking, physical activity, fasting blood glucose, and parental history of diabetes. The absence of an independent effect in this study could be explained by the fact that the study population only consisted of men. We observed in our study that, although not significantly, the association was weaker in men than in women (data not shown).

Recognition of high serum uric acid as a risk factor for diabetes has been a matter of debate for a few decades, since hyperuricemia has been presumed to be a consequence of insulin resistance rather than its precursor. However, recent findings suggest that uric acid could be related to the development of diabetes. Serum uric acid has been shown to be associated with oxidative stress (16) and production of tumor necrosis factor-{alpha} (16), which are both related to the development of diabetes. In addition, a recent study in rats showed that fructose-induced hyperuricemia plays a pathogenic role in the metabolic syndrome (17). These findings support high serum uric acid as a precursor of type 2 diabetes.

Currently, gout and renal disorders are the only consequences considered for hyperuricemia. Recent studies have introduced serum uric acid as a potential risk factor for hypertension (18), stroke (8), and cardiovascular diseases (19). Our findings suggest that type 2 diabetes is another consequence of hyperuricemia. The importance of this finding is even clearer when considering that lowering serum uric acid in subjects in the highest quartile may decrease the incidence of diabetes by 24%, if the relationship is causal. Hence, the public health impact of high serum uric acid may be larger than currently thought. Even so, uric acid is neither a target for treatment in asymptomatic hyperuricemia nor a risk marker in clinical practice (20), but methods for assessment of serum uric acid are widely available and inexpensive. Moreover, xanthine oxidase inhibitors, which are currently used to decrease serum uric acid, are safe and inexpensive.

In conclusion, our findings, together with those from previous literature, indicate that lowering uric acid may be a novel treatment target for preventing diabetes and justify a prospective clinical trial on the possible benefits of the measurement and lowering of serum uric acid on multiple chronic disease end points.


   Acknowledgments
 
The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam. A.D. is supported by a scholarship from Hormozgan University of Medical Science, Bandar Abbas, Iran.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 31 October 2007. DOI: 10.2337/dc07-1276.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication July 6, 2007. Accepted for publication October 23, 2007.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Modan M, Halkin H, Karasik A, Lusky A: Elevated serum uric acid: a facet of hyperinsulinaemia. Diabetologia 30: 713–718, 1987[Medline]
  2. Facchini F, Chen YD, Hollenbeck CB, Reaven GM: Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 266: 3008–3011, 1991[Abstract]
  3. Wun YT, Chan CSY, Lui CS: Hyperuricaemia in type 2 diabetes mellitus. Diabetes Nutr Metab 12: 286–291, 1999[Medline]
  4. Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K, Tatara K: Serum uric acid and risk for development of hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers. Eur J Epidemiol 18: 523–530, 2003[Medline]
  5. Taniguchi Y, Hayashi T, Tsumura K, Endo G, Fujii S, Okada K: Serum uric acid and the risk for hypertension and type 2 diabetes in Japanese men: the Osaka Health Survey. J Hypertens 19: 1209–1215, 2001[Medline]
  6. Nan H, Dong Y, Gao W, Tuomilehto J, Qiao Q: Diabetes associated with a low serum uric acid level in a general Chinese population. Diabetes Res Clin Pract 2006
  7. Hofman A, Grobbee DE, de Jong PT, van den Ouweland FA: Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 7: 403–422, 1991[Medline]
  8. Bos MJ, Koudstaal PJ, Hofman A, Witteman JCM, Breteler MMB: Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam Study. Stroke 37: 1503–1507, 2006[Abstract/Free Full Text]
  9. Trivedi R, Rebar L, Berta E, Stong L: New enzymatic method for serum uric acid at 500 nm. Clin Chem 24: 1908–1911, 1978[Abstract/Free Full Text]
  10. Dehghan A, Kardys I, de Maat MP, Uitterlinden AG, Sijbrands EJ, Bootsma AH, Stijnen T, Hofman A, Schram MT, Witteman JC: Genetic variation, C-reactive protein levels, and incidence of diabetes. Diabetes 56: 872–878, 2007[Medline]
  11. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20: 1183–1197, 1997[Medline]
  12. World Health Organization: Diabetes Mellitus Fact Sheet 138. Geneva, World Heath Org., 2002
  13. Gail DM: Interactive Risk Assessment Program. 2.2 ed., 2002
  14. Brand FN, McGee DL, Kannel WB, Stokes J III, Castelli WP: Hyperuricemia as a risk factor of coronary heart disease: the Framingham study. Am J Epidemiol 121: 11–18, 1985[Abstract/Free Full Text]
  15. Herman JB, Goldbourt U: Uric acid and diabetes: observations in a population study. Lancet 2: 240–243, 1982[Medline]
  16. Butler R, Morris AD, Belch JJ, Hill A, Struthers AD: Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35: 746–751, 2000[Abstract/Free Full Text]
  17. 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: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290: F625–F631, 2006[Abstract/Free Full Text]
  18. Johnson RJ, Feig DI, Herrera-Acosta J, Kang DH: Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 45: 18–20, 2005[Free Full Text]
  19. Baker JF, Krishnan E, Chen L, Schumacher HR: Serum uric acid and cardiovascular disease: recent developments, and where do they leave us? Am J Med 118: 816–826, 2005[Medline]
  20. Duffy WB, Senekjian HO, Knight TF, Weinman EJ: Management of asymptomatic hyperuricemia. JAMA 246: 2215–2216, 1981[Abstract]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 NEJMHome page
D. I. Feig, D.-H. Kang, and R. J. Johnson
Uric Acid and Cardiovascular Risk
N. Engl. J. Med., October 23, 2008; 359(17): 1811 - 1821.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
C.-Y. Dai, W.-L. Chuang, C.-K. Ho, T.-T. Ou, J.-F. Huang, M.-Y. Hsieh, and M.-L. Yu
High Serum Uric Acid as a Novel Risk Factor for Type 2 Diabetes: Response to Dehghan et al.
Diabetes Care, September 1, 2008; 31(9): e67 - e67.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
G. Lippi, G. Targher, M. Montagnana, G. L. Salvagno, and G. C. Guidi
High Serum Uric Acid as a Novel Risk Factor for Type 2 Diabetes: Response to Dehghan et al.
Diabetes Care, September 1, 2008; 31(9): e68 - e68.
[Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
M. T. Le, M. Shafiu, W. Mu, and R. J. Johnson
SLC2A9--a fructose transporter identified as a novel uric acid transporter
Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2746 - 2749.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
H. Mangge, S. Pilz, S. Haj-Yahya, and G. Almer
Uric Acid Indicates a High Cardiovascular Risk Profile but Is Not Closely Associated With Insulin Resistance in Obese Adolescents
Diabetes Care, April 1, 2008; 31(4): e21 - e21.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-1276v1
31/2/361    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dehghan, A.
Right arrow Articles by Witteman, J. C.M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dehghan, A.
Right arrow Articles by Witteman, J. C.M.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum