Henriksen Erik J, Teachey Mary K
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
Metabolism. 2007 Jul;56(7):931-8. doi: 10.1016/j.metabol.2007.03.002.
Overactivity of glycogen synthase kinase 3 (GSK-3) is associated with insulin resistance of skeletal muscle glucose transport in prediabetic and type 2 diabetic rodent models. However, limited information is available concerning the potential molecular mechanisms underlying the role GSK-3 plays in the etiology of insulin resistance in the male Zucker Diabetic Fatty (ZDF) rat, a model of type 2 diabetes mellitus. Therefore, we assessed the functionality of proximal and distal insulin signaling elements in isolated type I (slow-twitch oxidative) soleus muscles of ZDF rats after in vitro exposure to a selective GSK-3 inhibitor (1 micromol/L CT98014, K(i) <10 nmol/L for GSK-3alpha and GSK-3beta). Moreover, Ser307 phosphorylation of insulin receptor substrate 1 (IRS-1), which has been implicated in the development of insulin resistance, was also determined in the absence or presence of this GSK-3 inhibitor. Maximally insulin-stimulated (5 mU/mL) GSK-3beta serine phosphorylation was significantly less (35%, P < .05) in soleus muscle of ZDF rats compared with insulin-sensitive lean Zucker rats, indicating GSK-3 overactivity. In the absence of insulin, no effects of GSK-3 inhibition were detected. GSK-3 inhibition led to significant enhancement (28%) of insulin-stimulated glucose transport activity that was associated with significant up-regulation of tyrosine phosphorylation of IR (52%) and IRS-1 (50%), and with enhanced Akt Ser473 phosphorylation (48%) and GSK-3beta Ser9 phosphorylation (36%). Moreover, the selective GSK-3 inhibitor induced a significant reduction in the phosphorylation of IRS-1 Ser307 (26%) and c-jun N-terminal kinases 1 and 2 (31%), a mediator of IRS-1 Ser307 phosphorylation. These results indicate that selective inhibition of GSK-3 activity in type I skeletal muscle from overtly diabetic ZDF rats enhances IRS-1-dependent insulin signaling, possibly by a decrease in c-jun N-terminal kinase activation and a diminution of the deleterious effects of IRS-1 Ser307 phosphorylation.
在糖尿病前期和2型糖尿病啮齿动物模型中，糖原合酶激酶3（GSK-3）活性过高与骨骼肌葡萄糖转运的胰岛素抵抗相关。然而，关于GSK-3在2型糖尿病模型雄性Zucker糖尿病脂肪（ZDF）大鼠胰岛素抵抗病因中所起作用的潜在分子机制，目前可用信息有限。因此，我们在体外暴露于选择性GSK-3抑制剂（1微摩尔/升CT98014，对GSK-3α和GSK-3β的K(i)<10纳摩尔/升）后，评估了ZDF大鼠分离的I型（慢肌氧化型）比目鱼肌中近端和远端胰岛素信号元件的功能。此外，还在有或无这种GSK-3抑制剂的情况下，测定了与胰岛素抵抗发展有关的胰岛素受体底物1（IRS-1）的Ser307磷酸化。与胰岛素敏感的瘦型Zucker大鼠相比，ZDF大鼠比目鱼肌中最大胰岛素刺激（5毫单位/毫升）的GSK-3β丝氨酸磷酸化显著减少（35%，P<.05），表明GSK-3活性过高。在无胰岛素的情况下，未检测到GSK-3抑制的作用。GSK-3抑制导致胰岛素刺激的葡萄糖转运活性显著增强（28%），这与IR（52%）和IRS-1（50%）酪氨酸磷酸化的显著上调、Akt Ser473磷酸化增强（48%）和GSK-3β Ser9磷酸化增强（36%）相关。此外，选择性GSK-3抑制剂使IRS-1 Ser307磷酸化（26%）以及IRS-1 Ser307磷酸化的介质c-jun氨基末端激酶1和2（31%）的磷酸化显著降低。这些结果表明，对明显糖尿病的ZDF大鼠I型骨骼肌中GSK-3活性的选择性抑制可增强IRS-1依赖性胰岛素信号传导，这可能是通过降低c-jun氨基末端激酶的激活以及减少IRS-1 Ser307磷酸化的有害作用来实现的。
