Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia
Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia
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DOI：
10.1073/pnas.152346899
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发表时间：
2002-08-06
影响因子：
11.1
通讯作者：
Hanover, JA
中科院分区：
文献类型：
--
作者：
McClain, DA;Lubas, WA;Hanover, JA
胰岛素抵抗和β细胞毒性是2型糖尿病的主要特征。一个主要的假说认为这些异常是由于通过UDP-己糖胺生物合成途径的营养物质过度流动导致的“葡萄糖毒性”。“己糖胺途径的产物如何介导这些作用尚不清楚。在这里，我们表明，转基因过表达的酶，使用UDP-葡萄糖胺酸修饰蛋白质与O-葡萄糖胺酸产生2型糖尿病表型。即使是肌肉和脂肪中O-GlcNAc转移酶同种型的适度过度表达，也会导致胰岛素抵抗和高瘦素血症。这些数据支持O-连接GlcNAc转移酶参与与胰岛素抵抗和瘦素产生相关的己糖胺依赖性信号传导途径的提议。
Insulin resistance and beta cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormalities result from excessive flux of nutrients through the UDP-hexosamine biosynthetic pathway leading to "glucose toxicity." How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpression of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia. These data support the proposal that O-linked GlcNAc transferase participates in a hexosamine-dependent signaling pathway that is linked to insulin resistance and leptin production.