Macauley Matthew S, Shan Xiaoyang, Yuzwa Scott A, Gloster Tracey M, Vocadlo David J
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Chem Biol. 2010 Sep 24;17(9):949-58. doi: 10.1016/j.chembiol.2010.07.005.
The O-GlcNAc modification is proposed to be a nutrient sensor with studies suggesting that global increases in O-GlcNAc levels cause insulin resistance and impaired glucohomeostasis. We address this hypothesis by using a potent and selective inhibitor of O-GlcNAcase, known as NButGT, in a series of in vivo studies. Treatment of rats and mice with NButGT, for various time regimens and doses, dramatically increases O-GlcNAc levels throughout all tissues but does not perturb insulin sensitivity or alter glucohomeostasis. NButGT also does not affect the severity or onset of insulin resistance induced by a high-fat diet. These results suggest that pharmacological increases in global O-GlcNAc levels do not cause insulin resistance nor do they appear to disrupt glucohomeostasis. Therefore, the protective benefits of elevated O-GlcNAc levels may be achieved without deleteriously affecting glucohomeostasis.
O-GlcNAc修饰被认为是一种营养传感器，研究表明O-GlcNAc水平的整体升高会导致胰岛素抵抗和葡萄糖稳态受损。我们通过在一系列体内研究中使用一种强效且选择性的O-葡萄糖苷酶抑制剂NButGT来验证这一假设。用NButGT对大鼠和小鼠进行不同时间方案和剂量的处理，会显著提高所有组织中的O-GlcNAc水平，但不会干扰胰岛素敏感性或改变葡萄糖稳态。NButGT也不会影响高脂饮食诱导的胰岛素抵抗的严重程度或发病时间。这些结果表明，药理学上提高整体O-GlcNAc水平不会导致胰岛素抵抗，也似乎不会破坏葡萄糖稳态。因此，在不有害影响葡萄糖稳态的情况下，可能实现升高O-GlcNAc水平的保护益处。
