Tissue-specific role of glycogen synthase kinase 3β in glucose homeostasis and insulin action
Tissue-specific role of glycogen synthase kinase 3β in glucose homeostasis and insulin action
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DOI：
10.1128/mcb.00763-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
Woodgett, James R.
中科院分区：
文献类型：
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作者：
Patel, Satish;Doble, Bradley W.;Woodgett, James R.
蛋白激酶糖原合成酶激酶3 （GSK-3）的失调与2型糖尿病的发展有关。GSK-3蛋白表达和激酶活性在糖尿病中升高，而选择性GSK-3抑制剂已显示出作为葡萄糖代谢和胰岛素敏感性调节剂的前景。哺乳动物中有两种GSK-3亚型：GSK-3 α和GSK-3 β。缺乏GSK-3 β的小鼠在胚胎发生后期因肝脏凋亡而死亡，而缺乏GSK-3 α的小鼠存活，并表现出改善的胰岛素敏感性和肝脏葡萄糖稳态。为了评估GSK-3 β在胰岛素功能中的潜在作用，我们采用了一种条件基因靶向方法，即在胰岛素敏感组织中产生GSK-3 β表达的小鼠。肝脏特异性GSK-3 β敲除小鼠是存活的，具有葡萄糖和胰岛素耐受性，并表现出“正常”的代谢特征和胰岛素信号。骨骼肌中缺乏GSK-3 β表达的小鼠也可以存活，但与肝脏缺失的小鼠相比，小鼠表现出更好的葡萄糖耐量，这与胰岛素刺激的糖原合成酶调节和糖原沉积增强相结合。这些数据表明，GSK-3 α和GSK-3 β不仅在成人中有不同的作用，而且与这些亚型相关的组织特异性表型也不同。
Dysregulation of the protein kinase glycogen synthase kinase 3 (GSK-3) has been implicated in the development of type 2 diabetes mellitus. GSK-3 protein expression and kinase activity are elevated in diabetes, while selective GSK-3 inhibitors have shown promise as modulators of glucose metabolism and insulin sensitivity. There are two GSK-3 isoforms in mammals, GSK-3 alpha and GSK-3 beta. Mice engineered to lack GSK-3 beta die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3 alpha are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3 beta in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3 beta was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3 beta knockout mice are viable and glucose and insulin tolerant and display "normal" metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3 beta in skeletal muscle are also viable but, in contrast to the liver-deleted animals, display improved glucose tolerance that is coupled with enhanced insulin-stimulated glycogen synthase regulation and glycogen deposition. These data indicate that there are not only distinct roles for GSK-3 alpha and GSK-3 beta within the adult but also tissue-specific phenotypes associated with each of these isoforms.