Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
PLoS One. 2011 Jan 6;6(1):e15845. doi: 10.1371/journal.pone.0015845.
Over-activity and elevated expression of glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology of insulin resistance and Type 2 diabetes. Administration of specific GSK-3 inhibitors to diabetic or obese rodent models improves glycaemic control and insulin sensitivity. However, due to the indiscriminatory nature of these inhibitors, the relative contribution of the two isoforms of GSK-3 (GSK-3α and GSK-3β) is not known. Recently, we demonstrated that an out-bred strain of mice (ICR) lacking expression of GSK-3α in all tissues displayed improved insulin sensitivity and enhanced hepatic glucose metabolism. We also found that muscle (but not liver) inactivation of GSK-3β conferred insulin and glucose sensitization in an in-bred strain of mice (C57BL/6).
METHODOLOGY/PRINCIPAL FINDINGS: Here, we have employed tissue-specific deletion of GSK-3α, to examine the relative contribution of two insulin-sensitive tissues, muscle and liver, towards the insulin sensitization phenotype originally observed in the global GSK-3α KO animals. We found that mice in which GSK-3α has been inactivated in either skeletal-muscle or liver displayed no differences in glucose tolerance or insulin sensitivity compared to wild type littermates. Given the strain differences in our original analyses, we examined the insulin and glucose sensitivity of global GSK-3α KO animals bred onto a C57BL/6 background. These animals also revealed no significant differences in glucose metabolism/insulin sensitivity compared to their wild type littermates. Furthermore, deletion of hepatic GSK-3α on the out-bred, ICR background failed to reproduce the insulin sensitivity manifested by the global deletion of this isoform.
CONCLUSIONS/SIGNIFICANCE: From these data we conclude that the improved insulin sensitivity and hepatic glucose homeostasis phenotype observed upon global inactivation of GSK-3α is strain-specific. We surmise that the insulin-sensitization observed in the out-bred strain of mice lacking GSK-3α is mediated by indirect means that do not require intrinsic function of GSK-3α in skeletal muscle and liver tissues.
糖原合酶激酶-3（GSK-3）的过度活跃和表达升高与胰岛素抵抗和 2 型糖尿病的病因有关。在糖尿病或肥胖啮齿动物模型中给予特定的 GSK-3 抑制剂可改善血糖控制和胰岛素敏感性。然而，由于这些抑制剂的无差别性质，两种 GSK-3 同工型（GSK-3α 和 GSK-3β）的相对贡献尚不清楚。最近，我们证明，一种组织中缺乏 GSK-3α 表达的远交系小鼠（ICR）表现出改善的胰岛素敏感性和增强的肝葡萄糖代谢。我们还发现，肌肉（但不是肝脏）中 GSK-3β 的失活赋予了近交系小鼠（C57BL/6）的胰岛素和葡萄糖敏感性。
方法/主要发现：在这里，我们利用组织特异性的 GSK-3α 缺失，来研究两种胰岛素敏感组织（肌肉和肝脏）对最初在全局 GSK-3α KO 动物中观察到的胰岛素敏化表型的相对贡献。我们发现，与野生型同窝仔相比，在骨骼肌或肝脏中 GSK-3α 失活的小鼠在葡萄糖耐量或胰岛素敏感性方面没有差异。鉴于我们最初分析中的品系差异，我们研究了在 C57BL/6 背景下繁殖的全局 GSK-3α KO 动物的胰岛素和葡萄糖敏感性。与野生型同窝仔相比，这些动物的葡萄糖代谢/胰岛素敏感性也没有显著差异。此外，在远交系，ICR 背景下删除肝 GSK-3α 未能再现该同工型全局缺失所表现出的胰岛素敏感性。
结论/意义：从这些数据中，我们得出结论，在 GSK-3α 全局失活时观察到的改善的胰岛素敏感性和肝葡萄糖稳态表型是品系特异性的。我们推测，在缺乏 GSK-3α 的远交系小鼠中观察到的胰岛素敏感性是通过不需要 GSK-3α 在骨骼肌和肝脏组织中的固有功能的间接方式介导的。
