Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease
Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease
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DOI：
10.1172/jci86181
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Poitout, Vincent
中科院分区：
文献类型：
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作者：
Koppe, Laetitia;Nyam, Elsa;Poitout, Vincent
葡萄糖稳态紊乱在慢性肾脏病（CKD）中很常见，并与死亡率增加有关，但这种疾病中胰岛素分泌受损的机制仍不清楚。在这里，我们测试的假设，有缺陷的胰岛素分泌OM是由尿素对胰腺β细胞的直接影响。在5/6肾切除诱导CKD的小鼠模型（CKD小鼠）中，我们观察到体内和分离的胰岛中葡萄糖刺激的胰岛素分泌缺陷。同样，在用疾病相关浓度的尿素培养的正常小鼠和人胰岛中，以及在用尿素口服治疗3周的正常小鼠胰岛中，胰岛素分泌受损。在CKD小鼠胰岛以及尿素暴露的正常胰岛中，我们观察到氧化应激和蛋白质O-GlcNAc化的增加。在CKD患者的胰腺切片中也观察到蛋白O-GlcNAc化。CKD小鼠和尿素暴露的胰岛中胰岛素分泌受损与葡萄糖利用和磷酸果糖激酶1（PFK-1）活性降低相关，这可以通过抑制O-GlcNAc酰化来逆转。在两种小鼠模型中，O-GlcNAc化的抑制也恢复了胰岛素分泌。这些结果表明，与CKD相关的胰岛素分泌缺陷是由于循环中尿素水平升高而引起的，尿素水平升高会增加胰岛蛋白O-GlcNAc酰化并损害糖酵解。
Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in OM is caused by a direct effect of urea on pancreatic beta cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea exposed normal islets, we observed an increase in oxidative stress and protein O-GIcNAcylation. Protein O-GIcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea -exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GIcNAcylation. Inhibition of O-GIcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GIcNAcylation and impair glycolysis.