Deleterious Effects Of Hyperuricemia On Pancreatic β-cells And The Molecular Mechanism

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of high concentration of uric acid on β-cell viability and function, then we explored the potential molecular mechanism. First of all, we identified urate transporters-URAT1 and GLUT9 in human, rat and mouse’s islets. Then we did experiments in vivo and in vitro. In vivo, uric acid solution(250 mg/kg) or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. In vitro, uric acid treatment increased apoptosis and downregulated Bcl-2 expression in INS-1 or Min6 cells. Meanwhile, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. Further investigation indicated that uric acid suppressed levels of MafA. Treatment of β-cells with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase(iNOS) expression and excessive nitric oxide(NO) production.These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Collectively, our data suggest that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.