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Diabetes Care 29:709-711, 2006
DOI: 10.2337/diacare.29.03.06.dc05-1465
© 2006 by the American Diabetes Association
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Epidemiology/Health Services/Psychosocial Research
Brief Report

Serum Uric Acid as a Harbinger of Metabolic Outcome in Subjects With Impaired Glucose Tolerance

The Finnish Diabetes Prevention Study

Leo Niskanen, MD, PHD1, David E. Laaksonen, MD, PHD, MPH1, Jaana Lindström, MS, PHD2, Johan G. Eriksson, MD, PHD2, Sirkka Keinänen-Kiukaanniemi, MD, PHD3, Pirjo Ilanne-Parikka, MD4, Sirkka Aunola, PHD5, Helena Hämäläinen, MD, PHD6, Jaakko Tuomilehto, MD, PHD2,7, Matti Uusitupa, MD, PHD8 for the Finnish Diabetes Prevention Study Group

1 Department of Medicine, Kuopio University Hospital, Kuopio, Finland
2 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
3 Department of Public Health Science and General Practice, Unit of General Practice, Oulu University Hospital, Oulu, Finland
4 Finnish Diabetes Association and Tampere University Hospital Research Unit, Tampere, Finland
5 Laboratory for Population Research, Department of Health and Functional Capacity, National Public Health Institute, Turku, Finland
6 Research Department, Social Insurance Institution, Turku, Finland
7 Department of Public Health, University of Helsinki, Helsinki, Finland
8 Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland

Address correspondence and reprint requests to Leo Niskanen, MD, Department of Medicine, Kuopio University Hospital, Bld nro 5, FIN-70210, Kuopio, Finland. E-mail: leo.niskanen{at}kuh.fi

Abbreviations: LTPA, leisure-time physical activity


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Serum uric acid is the major product of purine metabolism (1). In cross-sectional studies, uric acid correlates with components of the metabolic syndrome: hypertension, obesity, low HDL cholesterol, hypertriglyceridemia, hyperinsulinemia, and insulin resistance (2–4). Although determination of uric acid is widely available and inexpensive, it has been overlooked as a marker of disturbed glucose metabolism. We studied its role in predicting changes in glucose tolerance and insulin levels and in the development of type 2 diabetes in the Finnish Diabetes Prevention Study.


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
The design of the Finnish Diabetes Prevention Study has been previously described in detail (5). Briefly, 40- to 65-year-old overweight or obese individuals with impaired glucose tolerance were eligible. Impaired glucose tolerance was defined as a 2-h plasma glucose at 7.8–11.0 mmol/l after oral glucose (75 g) with a fasting glucose <7.8 mmol/l (6). The protocol was approved by the ethics committee of the National Public Health Institute (Helsinki, Finland). All participants gave written informed consent.

In all, 522 individuals from five study centers were randomly assigned to the intervention (n = 265) or control (n = 257) groups. Serum uric acid concentrations were measured at baseline and at least once during the follow-up in 475 of the 522 participants, and these 475 are included in the present study. The original trial ended after an average follow-up of 3.2 years. In this study, follow-up was extended to 4.1 years (range 1–6). In all, 103 of the 475 participants for whom repeated measurements of uric acid were carried out developed diabetes during the 4.1-year follow-up.

Details on the intervention and assessments of leisure-time physical activity (LTPA) and nutrient intakes as well as the changes in dietary factors and body weight have been previously reported (7,8). Uric acid was determined photometrically by the hydroxylamine method (9). Diabetes was defined by the 1985 World Health Organization criteria as fasting plasma glucose concentrations ≥7.8 or 2-h concentrations ≥11.1 mmol/l (6). A general linear model was used to assess the association of clinical, biochemical, LTPA, and dietary variables at baseline according to baseline uric acid categorized into thirds. The changes in variables denote baseline levels subtracted from the average follow-up levels. A general linear model was also used to assess the association of uric acid and its changes with changes in plasma glucose and insulin concentrations after adjustment for covariates. The association of baseline uric acid concentrations and its changes during the follow-up with the risk of type 2 diabetes was assessed with Cox proportional hazards models. Statistical significance was P < 0.05. Analyses were performed with SPSS 11.0 for Windows (Chicago, IL).


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
At baseline, women had lower uric acid than men (327 ± 74 vs. 393 ± 76 µmol/l, P < 0.001). BMI and plasma glucose and insulin concentrations increased across uric acid tertiles (Table 1). The increase in body weight and waist circumference across uric acid tertiles was partly influenced by sex but remained highly significant when adjusted for sex (not shown).


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  		Table 1— Baseline characteristics of the Finnish Diabetes Prevention Study participants according to tertiles of baseline serum uric acid and its changes

 
Concentrations of uric acid decreased by 4.7 µmol/l in the control group and by 7.7 µmol/l in the intervention group (P = 0.44, ANCOVA model with adjustment for sex, age, and baseline uric levels). Female sex (P = 0.001), lower BMI (P = 0.008), and a decrease in BMI (P < 0.001) were each independently associated with a decrease in uric acid in a model where the change of uric acid was a continuous dependent variable and sex, age, randomization group, baseline uric acid, BMI and its changes, energy-adjusted dietary fiber intake and its changes, and moderate-to-vigorous LTPA and its changes were used as explanatory variables. Baseline energy-adjusted fiber intake (P = 0.090) and its changes (P = 0.089) also tended to predict the changes in uric acid in this model.

Baseline uric acid levels (Table 1) were associated with the increase in fasting and 2-h plasma glucose concentrations during the follow-up but not after including baseline BMI and its changes in the model (not shown). Baseline uric acid levels were associated with the changes in insulin levels after adjustment for changes in uric acid during follow-up (Table 1) and for 2-h insulin, even in a model including age, sex, group, blood pressure medication, and baseline creatinine, systolic blood pressure, triglycerides, BMI, levels of daily energy intake, intakes of poly-, monounsaturated, and saturated fat and fiber, and LTPA and their changes during the follow-up (model 2) (P = 0.001). The changes in uric acid levels were associated with changes in fasting and 2-h glucose and insulin concentrations during the follow-up after adjustment for baseline uric acid (Table 1). These associations persisted in model 2, described above for fasting and 2-h glucose (P = 0.040 and 0.011) but not for insulin.

Individuals with changes in uric acid levels in the upper third were nearly twice as likely to develop diabetes during the follow-up (Table 1). Baseline uric acid predicted diabetes (P = 0.037) even after adjustment for variables in model 2, but after extensive adjustment, the changes in uric acid concentrations were not associated with incident diabetes (P = 0.30).

We checked whether the associations with metabolic outcome were modified by sex, intervention, BMI at baseline, or weight loss during the trial. Uric acid and its changes seemed to be more strongly associated with metabolic outcome in women, the control group, and individuals with a BMI above the median, but the interactions were not significant (P = 0.11–0.81).


   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
In this lifestyle intervention study in high-risk middle-aged subjects with impaired glucose tolerance, baseline uric acid and its changes predicted a twofold increase in the likelihood of developing type 2 diabetes. Furthermore, uric acid and its changes during follow-up were related to corresponding changes in fasting and postload glucose and insulin levels. Although hyperuricemia and hyperinsulinemia are closely linked, the mechanisms behind this association remain obscure. The most conceivable hypothesis is that this occurs at the renal level: renal tubular function is influenced by hyperinsulinemia, and urinary uric acid clearance decreases with decreasing insulin-mediated glucose disposal. Thus, decreased uric acid excretion leads to hyperuricemia (3). Hyperuricemia has been an independent risk factor for progression to hyperinsulinemia and thereby preceded hyperinsulinemia in the 11-year follow-up of nondiabetic participants of Atherosclerosis Risk in Communities Study (10). However, hyperglycemia may lead to increased urinary excretion of uric acid (11), which could partly explain the nonsignificant difference in the decrease of uric acid between intervention and control groups.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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 August 5, 2005. Accepted for publication December 8, 2005.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Becker BF: Towards the physiological function of uric acid. Free Radic Biol Med 14:615–631, 1993[Medline]
  2. Modan A, Halkin H, Karasik A, Lusky A: Elevated serum uric acid: a facet of hyperinsulinaemia. Diabetologia 30:713–718, 1987[Medline]
  3. 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]
  4. Vuorinen-Markkola H, Yki-Järvinen H: Hyperuricemia and insulin resistance. J Clin Endocrinol Metab 78:25–29, 1994[Abstract]
  5. Eriksson J, Lindström J, Valle T, Aunola S, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Lauhkonen M, Lehto P, Lehtonen A, Louheranta A, Mannelin M, Martikkala V, Rastas M, Sundvall J, Turpeinen A, Viljanen T, Uusitupa M, Tuomilehto J: Prevention of type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland: study design and 1-year interim report on the feasibility of the lifestyle intervention program. Diabetologia 42:793–801, 1999[Medline]
  6. World Health Organization: Diabetes Mellitus: Report of a WHO Study Group. Geneva, World Health Org., 1985 (Tech. Rep. Ser., no 727)
  7. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, the Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350, 2001[Abstract/Free Full Text]
  8. Lindström J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, Uusitupa M, Tuomilehto J, the Finnish Diabetes Prevention Study Group: The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 26:3230–3236, 2003[Abstract/Free Full Text]
  9. Musser AW, Ortigoza C: Automated determination of uric acid by the hydroxylamine method. Tech Bull Reg Med Tech 36:21–25, 1966
  10. Carnethon MR, Fortmann SP, Palaniappan L, Duncan BB, Schmidt MI, Chambless LE: Risk factors for progression to incident hyperinsulinemia: the Atherosclerosis Risk in Communities Study, 1987–1998. Am J Epidemiol158:1058–1067, 2003
  11. Herman B, Goldbourt U: Uric acid and diabetes: observations in a population study. Lancet 2:240–243, 1982[Medline]

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