Elevated serum uric acid is a facilitating mechanism for insulin resistance mediated accumulation of visceral adipose tissue

Abstract

BACKGROUND: Serum uric acid (SUA) has a relationship with cardiometabolic conditions such as insulin resistance (IR) and visceral adipose tissue (VAT) accumulation. Here, we aimed to clarify the nature of this relationship and the underlying causality mechanism. METHODS: We conducted a population-based cross-sectional study comprising 8,504 subjects joining both NHANES 2003-2004 and 2011-2012 cycles and ENSANUT Medio Camino 2016. We performed mixed effects linear regression models using HOMA2-IR, adipoIR, and METS-VF as indicators of IR and VAT accumulation. Furthermore, we performed mediation analyses to assess a potential causal mechanism and ROC curves to establish cut-off points for identification of IR and visceral obesity using SUA. Finally, with an additional dataset comprised of 226 subjects with both euglycemic hyperinsulinemic clamp (EHC) and dual X-ray absorptiometry (DXA) measurements for IR and VAT accumulation, we performed a network of confirmatory mediation analyses. RESULTS:We found that SUA has a mediating role inside the bidirectional relationship between IR and visceral obesity, and it is part of an underlying causality mechanism which includes adiponectin. The proportion of the mechanism mediated by SUA is greater when stated that IR (in either peripheral or adipose tissue) leads to VAT accumulation (14.90%[13.20%-17.00%] and 15.54%[13.61% - 18.00%] to 4.88%[3.06%-7.00%] and 8.13%[5.91% - 10.00%]) instead of the opposite direction. This result was confirmed by mediation analyses using gold-standard measurements. CONCLUSIONS:Elevated SUA acts as mediator inside the bidirectional relationship between IR andVAT accumulation. Its role appears to be larger when considering adipose tissue IR as the promoter for VAT accumulation.

Changes in levels of testosterone, insulin sensitivity and metabolic profiles during GnRH therapy: Reciprocity between insulin sensitivity and pituitary responsiveness to GnRH in teenage and young male patients with congenital hypogonadotropic hypogonadism

“…It is widely believed that plasma levels of serum uric acid are negatively correlated with e-GFR and insulin sensitivity. 26,27 Herein, we provided more reliable evidence that the improved insulin sensitivity during GnRH therapy was at least partially attributable to the increased testosterone-related muscle mass, which acts as the primary source of purine and thereby leads to an upregulation of serum uric acid. Moreover, there is consistent evidence of the involvement of impaired insulin sensitivity in the development of renal dysfunction.…”

Purine metabolites and complex diseases: role of genes and nutrients

“…Moreover, reactive oxygen species (ROS) generated during the formation of urate or from activation of NAD phosphate oxidase by urate also diminish insulin signaling [49]. Several studies have shown that increased HOMA-IR predicts hyperuricemia independent of dyslipidemia, hypertension, and/or obesity [53]. Moreover, slightly elevated serum urate concentrations may be beneficial by preserving the activity of superoxide dismutase 3, and AKT3/phosphoinositide 3 signaling regulates de novo and salvage purine nucleotide synthesis by regulating the production of phosphoribosyl diphosphate from glucose [53][54][55].…”

“…Several studies have shown that increased HOMA-IR predicts hyperuricemia independent of dyslipidemia, hypertension, and/or obesity [53]. Moreover, slightly elevated serum urate concentrations may be beneficial by preserving the activity of superoxide dismutase 3, and AKT3/phosphoinositide 3 signaling regulates de novo and salvage purine nucleotide synthesis by regulating the production of phosphoribosyl diphosphate from glucose [53][54][55]. Adenosine, a purine metabolite, is also known to regulate insulin-mediated glucose uptake and the decline of inosine monophosphate (IMP) dehydrogenase in diabetes was restored by insulin treatment, in animal studies [56 & ].…”