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

RESEARCH DESIGN AND METHODS

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

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).

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

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.