The link between insulin resistance parameters and serum uric acid is mediated by adiposity

Highlights

• To evaluated the role of different adiposity factors on the association between serum uric acid, inflammation and glucose/insulin homeostasis.

• We accomplished this aim by applying in large and representative sample size of the US adults.

• We shed light on the complex link of SUA with inflammation and glucose/insulin homeostasis.

Abstract

Background and aims

Conflicting results suggest a link between serum uric acid (SUA), inflammation and glucose/insulin homeostasis; however, the role of adiposity in this relationship is not clear. Therefore, we evaluated the role of different adiposity factors, including central body mass index (BMI), peripheral waist circumference (WC), and visceral adiposity [visceral adipose tissue (apVAT)], on the association between SUA, inflammation and glucose/insulin homeostasis among US adults.

Methods

Data were extracted from the 2005–2010 US National Health and Nutrition Examination Surveys. Overall, 16,502 participants were included in the analysis (mean age = 47.1 years, 48.2% men). Analysis of co-variance and “conceptus causal mediation” models were applied, while accounting for survey design.

Results

Corrected models showed that subjects with higher SUA levels have a less favorable profile of inflammation and glucose/insulin homeostasis parameters (all p < 0.001). We found that all our potential mediators (BMI, WC and apVAT) had an impact (to various extents) on the link between variables, including serum C-reactive protein (CRP), apolipoprotein-B (apoB), insulin resistance markers, 2-h blood glucose (2hG) and triglyceride, and fasting blood glucose (FBG) (TyG) index (all p < .001), while none of the potential mediators (BMI, apVAT, WC) had an impact on the link between FBG and glycated hemoglobin with SUA (all p > 0.05). We have found that all of our mediators partially mediated the link between inflammation and glucose/insulin homeostasis parameters and SUA. Of note, apVAT fully mediated the association between SUA and 2hG.

Conclusions

By applying advanced statistical techniques, we shed light on the complex link of SUA with inflammation and glucose/insulin homeostasis and quantify the role of adiposity factors in that link.

Introduction

Numerous studies have established that C-reactive protein (CRP), as a marker of low-grade inflammation, can predict coronary artery disease (CAD) in apparently healthy individuals [1,2].

Recent experimental, clinical, and epidemiological studies have shown that hyperuricemia may cause endothelial dysfunction and pathologic vascular remodeling, and hence play a role in the pathogenesis of cardiovascular diseases, stroke, chronic heart failure, type 2 diabetes mellitus (T2DM) and insulin resistance [[3], [4], [5], [6], [7], [8], [9]]. Serum uric acid (SUA) induces CRP mRNA expression in human vascular endothelial and smooth muscle cells [3]. A significant positive crude correlation between CRP and SUA was also found in a German population-based study [10]. A positive and significant association between SUA levels and inflammatory biomarkers, including CRP, tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6), was reported among older persons [11].

Research showed that diabetes was associated with low SUA levels [[12], [13], [14]]. A prospective study among 10,000 men reported that SUA levels were higher in pre-diabetics than in non-diabetics [15]. In contrast, a series of cohort studies and subsequent meta-analysis assessed the association of SUA levels with the incidence of impaired fasting glucose (IFG) and T2DM, suggesting that hyperuricemia is an early important indicator of impaired glucose control [[16], [17], [18]]. Moreover, recent prospective studies with representative samples indicate hyperuricemia as a predictor for the development of insulin resistance and T2DM [18,19].

Obese individuals have lower uric acid (UA) renal excretion, and may also have increased production of uric acid [20]. However, we still do not know the role of adiposity in the link between SUA and glucose/insulin homeostasis and inflammation. Mediation analysis could clarify the role of adiposity, if any, in the relation between SUA and inflammation or glucose/insulin homeostasis [21]. From a statistical standpoint, mediation analysis can be used to explore and quantify the extent to which the relationship between an exposure and an outcome of interest, occurs through the effect of a third variable. The traditional approach to mediation analysis tends to produce a bias when there is a confounding uncontrolled mediator outcome or an interaction between exposure and mediator [21,22]. Using the counterfactual framework in causal mediation analysis, unbiased valid estimates of direct and indirect effects can be obtained [21,22]. Moreover, simple regression analysis is frequently used to evaluate the association between SUA and disease risk, but it may be characterized by a limited capacity to identify putative biological mechanisms which could possibly explain the association between SUA and risk of high inflammation and impaired glucose/insulin control [11].

The present analysis aims to specifically investigate the link between SUA with CRP and glucose/insulin homeostasis and identify adiposity factors that may mediate these associations. These factors include markers of adiposity [waist circumference (WC), body mass index (BMI), visceral adipose tissue (apVAT)], in a representative population of US adults by using National Health and Nutrition Examination Survey (NHANES) database. We hypothesized that a higher SUA would be associated with less favorable concentrations of inflammatory and glucose/insulin homeostasis biomarkers among adults and that these associations would be partly or fully mediated by adiposity markers.