Background
Hyperuricemia or elevated serum uric acid levels have been considered not only an independent risk factor for cardiovascular diseases but this also plays a role in the development of metabolic diseases [
1‐
4]. Previous studies reported that the serum uric acid level is associated with the individual components of metabolic syndrome such as obesity, dyslipidemia and hypertension [
5,
6]. As for the association between the serum uric acid levels and obesity, a number of epidemiological and clinical studies have demonstrated a positive correlation between the serum uric acid levels and obesity [
5,
7].
The visceral fat component and the subcutaneous fat component may have differential metabolic risks [
8]. The visceral fat component is metabolically active and it regulates numerous adipocytokines and other vasoactive substances, which may be associated with an increased cardiometabolic risk [
9‐
11]. As for the association between the serum uric acid levels and the regional abdominal adipose tissue distribution, previous studies showed that the serum uric acid level was related with visceral fat accumulation as measured using computed tomography (CT) or bioelectrical impedance analysis in general populations [
12‐
14].
Diabetes mellitus (DM) is associated with the cardiovascular complications of metabolic syndrome and obesity is more prevalent in people with DM compared in people without DM [
15]. Furthermore, the distribution of abdominal adipose tissue was significantly altered in people with type 2 DM; the visceral fat component was greater and the subcutaneous fat component was less in the subjects with type 2 DM than that in the healthy control subjects [
16]. The association between the regional distribution of abdominal adipose tissue and the serum uric acid levels in people with type 2 DM is not well established. We hypothesized that the visceral fat component would be more associated with the serum uric acid levels, as compared to that of the subcutaneous fat component, in people with type 2 DM. The aim of our study is to determine the relationships between the regional abdominal adipose tissue distribution and the serum uric acid levels in people with type 2 diabetes mellitus. Examining the influence of the regional abdominal adipose tissue distribution on serum uric acid levels may help to define it as a risk factor for the cardiometabolic complications with type 2 DM.
Discussion
In the present study, we demonstrated that the visceral fat area were positively associated with the serum uric acid levels and predictive for the hyperuricemia in subjects with type 2 DM, but the subcutaneous fat area was not significantly associated with the serum uric acid levels. In our knowledge, this is a first report for the association between the regional abdominal adipose tissue distribution and the serum uric acid levels in subjects with type 2 DM, in which the distribution of the abdominal adipose tissue was significantly altered as compared to that of the subjects with normal glucose tolerance. The amount of visceral fat area was greater and the amount of subcutaneous fat area was less in people with type 2 DM than that in the people with normal glucose tolerance [
16].
Some previous studies that focused on general populations reported that the serum uric acid levels were positively correlated with both the visceral fat area and the subcutaneous fat area; particularly, the serum uric acid levels were more closely correlated with the visceral fat [
12‐
14]. Matsuura et al. reported that the serum uric acid levels were higher in both the subcutaneous obesity group and the visceral obesity group of male obese subjects than that in the non-obese control group [
12]. They also showed that urinary uric acid excretion was higher in the visceral obesity group than that in the subcutaneous obesity group, which suggested that visceral fat accumulation may be associated with overproduction of uric acid. Hikita et al reported that the serum uric acid levels were related with both the visceral fat area and the subcutaneous fat area in 508 Japanese man industrial workers, which support the results of previous study [
14]. In our study, only the visceral fat area was associated with the serum uric acid levels and subcutaneous fat area was not associated with the serum uric acid levels, which is some different from the previous studies. This discrepancy may be due to the differences of the study designs or the populations of the studies. In our study, only subjects with type 2 DM were recruited while the previous study was a community-based study. The amount of visceral fat area was greater and the amount of subcutaneous fat area was less in people with type 2 DM than that in the people with normal glucose tolerance [
16]. Furthermore, visceral fat area, but not subcutaneous fat area, is associated with a decrease in peripheral insulin sensitivity in type 2 DM [
21], which may decrease the urinary excretion of uric acid and this may causes hyperuricemia especially in the subjects with type 2 DM [
22,
23].
Some studies have suggested the mechanisms that link visceral fat accumulation and an elevated serum uric acid level. The visceral fat component has been regarded as the more pathologic adipose tissue compartment as compared with the subcutaneous fat component, and the visceral fat component more strongly associated with the cardiometabolic risk, as compared to that of subcutaneous adiposity [
8,
9]. The visceral fat component is metabolically active and it regulates numerous adipocytokines such as leptin and adiponectin, which have been associated with insulin resistance [
24,
25]. Insulin resistance or hyperinsulinemia increases the reabsorption of sodium and uric acid on the renal tubules, thereby decreasing the urinary excretion of uric acid and this causes hyperuricemia [
22,
23]. In our study, the insulin resistance (log HOMA-IR) was significantly correlated with the serum uric acid levels, which supports the results of previous studies [
22,
23].
Another mechanism that visceral fat accumulation is associated with the overproduction of uric acid has been suggested by several investigators. Increased visceral fat accumulation provides excessive free fatty acid in the portal vein, which accelerates the overproduction of very low-density lipoprotein and this causes hypertriglyceridemia. This also accelerates the de novo purine synthesis by NADPH produced in the pentose phosphate pathway which increases the uric acid production [
26,
27]. In our study, the visceral fat area was more closely correlated with the serum triglyceride levels (
r = 0.244,
p < 0.001
) than the subcutaneous fat area (
r = 0.094,
p = 0.012) (data not shown). The serum triglyceride levels were positively associated with the serum uric acid levels after adjustment for age, sex, systolic blood pressure, diastolic blood pressure, BMI, serum creatinine, hemoglobin, serum albumin, serum HDL, serum triglyceride, urinary albumin excretion and hemoglobin A1c (β-coefficient = 0.109,
p = 0.003) (data not shown), and this all supports the relationships between uric acid production and triglyceride synthesis.
Previous studies demonstrated that the reduced GFR was correlated with hyperuricemia [
28]. In our study, eGFR was negatively related with serum uric acid levels and the association was stronger between eGFR and serum uric acid levels (r = -0.378, p < 0.001) than the association between visceral fat area and serum uric acid levels (r = 0.230, p < 0.001) (Table
2). To determine whether the visceral fat area was associated with serum uric acid levels independent of the reduced renal function, we analyzed the association between visceral fat area and serum uric acid levels in patients with normal renal function (eGFR > 6o ml/min/1.73 m
2). The number of patients with eGFR > 6o ml/min/1.73 m
2 was 629 (90%) in our study. In patients with eGFR > 6o ml/min/1.73 m
2, the association between visceral fat area and serum uric acid levels was stronger (r = 0.290, p < 0.001) than the association between eGFR and serum uric acid levels (r = - 0.269, p < 0.001) (data not shown). Furthermore, in the multivariate logistic regression analyses, visceral fat area was independently associated with serum uric acid levels (Table
4). These findings suggest that the visceral fat area was associated with serum uric acid levels independent of the reduced renal function.
In our study, hyperuricemia is more prevalent in males than in females, which was consistent with previous studies [
19]. This finding may be due that estrogen promotes more efficient renal clearance of uric acid [
29]. It would be interesting to analyze the associations between hyperuricemia and the regional abdominal adipose tissue distribution separately in males and females. However, in our study, the sample size of subjects with hyperuricemia in females (n = 18) was relatively small to generate the significant results by statistical analysis. Therefore, we analyzed the association of visceral fat area tertiles for hyperuricemia in both genders in logistic regression model including gender as independent variables (Table
4). The incidence of hyperuricemia was statistically significant increases in the group with high visceral fat area after adjustment of clinical variables including gender. A larger study may elucidate the associations separately in males and females.
Our study has several limitations. First, our study was the cross-sectional study; therefore, it is difficult to infer causality between visceral fat accumulation and the serum uric acid levels. Second, this study was a single center study; thus, it is uncertain whether our results are generalizable to other ethnic groups with type 2 DM. Third, we did not examined urinary uric acid levels in our study. Therefore, we could not analyze the association between uric acid metabolism or the type of hyperuricemia and the regional distribution of abdominal adipose tissue. Fourth, smoking habit or adipokines such as leptin may influence the distribution of regional abdominal adiposity and insulin resistance [
30,
31]. Unfortunately, the clinical information in our study did not include the smoking history or adipokines. It would be interesting to analyze the associations between smoking habit or adipokines levels and abdominal adiposity and serum uric acid levels.
Despite the above limitations, the present study is the first to investigate the differential association between the abdominal fat compartment and the serum uric acid levels in people with type 2 DM and who have a different regional abdominal adipose tissue distribution compared to that of people with normal glucose tolerance.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
THK, SSL, JHY, SRK, SJY, HCS, YSK, EJC contributes in execution, analysis, manuscript drafting and critical discussion. YKK contributes in study design, execution, analysis, manuscript drafting and critical discussion. All authors read and approved the final manuscript.