聚糖依赖性信号改变会诱发胰岛素抵抗和高瘦素血症。
Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia.
作者信息
McClain Donald A, Lubas William A, Cooksey Robert C, Hazel Mark, Parker Glendon J, Love Dona C, Hanover John A
机构信息
Department of Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT 84112, USA.
出版信息
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10695-9. doi: 10.1073/pnas.152346899. Epub 2002 Jul 22.
Abstract
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.
摘要
胰岛素抵抗和β细胞毒性是2型糖尿病的关键特征。一个主要假说是，这些异常是由于营养物质通过UDP-己糖胺生物合成途径过度流动导致“葡萄糖毒性”所致。己糖胺途径的产物如何介导这些效应尚不清楚。在此，我们表明，使用UDP-GlcNAc以O-GlcNAc修饰蛋白质的一种酶的转基因过表达会产生2型糖尿病表型。即使在肌肉和脂肪中适度过表达O-GlcNAc转移酶的一种同工型，也会导致胰岛素抵抗和高瘦素血症。这些数据支持这样的提议，即O-连接的GlcNAc转移酶参与了与胰岛素抵抗和瘦素产生相关的己糖胺依赖性信号通路。
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