Jia Lu, Xing Jing, Ding Ying, Shen Yachen, Shi Xuhui, Ren Wei, Wan Meng, Guo Jianjin, Zheng Shujing, Liu Yun, Liang Xiubin, Su Dongming
Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province, China.
PLoS One. 2013 Oct 25;8(10):e78284. doi: 10.1371/journal.pone.0078284. eCollection 2013.
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 uric acid on β-cell viability and function. Uric acid solution 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. Treatment of β-cells in vitro 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. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. 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. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.
越来越多的临床证据表明，高尿酸血症与2型糖尿病风险增加有关。然而，尿酸水平升高是否会直接损伤胰腺β细胞仍不清楚。在本研究中，我们检测了尿酸对β细胞活力和功能的影响。每天给小鼠腹腔注射尿酸溶液或生理盐水，持续4周。与对照小鼠相比，尿酸处理的小鼠在葡萄糖刺激后表现出明显受损的葡萄糖耐量和较低的胰岛素水平。然而，两组之间的胰岛素敏感性没有显著差异。与对照小鼠的胰岛相比，尿酸处理小鼠的胰岛明显更小，胰岛素含量更低。用尿酸体外处理β细胞通过IκBα磷酸化激活NF-κB信号通路，导致诱导型一氧化氮合酶（iNOS）表达上调和过量一氧化氮（NO）生成。尿酸处理还增加了Min6细胞的凋亡并下调了Bcl-2表达。此外，在尿酸处理的小鼠胰岛中观察到葡萄糖刺激下胰岛素分泌减少。尿酸转运体抑制剂苯溴马隆、NOS抑制剂L-NMMA和NF-κB抑制剂Bay 11-7082减轻了尿酸对胰腺β细胞的这些有害影响。进一步研究表明，尿酸通过增强MafA蛋白的降解来抑制其水平。总体而言，我们的数据表明，尿酸水平升高通过NF-κB-iNOS-NO信号轴导致β细胞损伤。
