Abstract
High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to IR and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to IR that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage.
Highlights
Uric acid (UA) is the end-product of purine metabolism, with both anti-oxidant and pro-oxidant properties; it has been demonstrated to have a key role in the redox process related to oxidative stress [1] that is involved in vascular damage and metabolic alterations [2,3,4]
The metabolic and hemodynamic effects of insulin are mediated by the activation of PI3K/Akt axis that induces a phosphorylation cascade leading to glycogen synthesis and glucose uptake and, above all, endothelial nitric oxide synthase (eNOS) activation that increases nitric oxide (NO) production promoting in turn vasodilation and improving endothelial function
Given the inhibitory effect of uric acid (UA) on Akt/eNOS signaling pathway, we hypothesized that UA could exert a direct action on insulin signaling at membrane level
Summary
Uric acid (UA) is the end-product of purine metabolism, with both anti-oxidant and pro-oxidant properties; it has been demonstrated to have a key role in the redox process related to oxidative stress [1] that is involved in vascular damage and metabolic alterations [2,3,4]. Recent pieces of evidence suggest that UA alone or in association with endothelial dysfunction plays a causative role in the appearance of incident diabetes [13, 15,16,17]. This association may be justified by the pro-oxidant and pro-inflammatory actions of UA that affect both glucose homeostasis and insulin sensitivity, promoting clinically evident diabetes [18,19,20]. We demonstrated that UA levels are associated with an impairment of glucose tolerance status during an oral glucose tolerance test in hypertensive subjects [21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
