Song X M, Kawano Y, Krook A, Ryder J W, Efendic S, Roth R A, Wallberg-Henriksson H, Zierath J R
Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.
Diabetes. 1999 Mar;48(3):664-70. doi: 10.2337/diabetes.48.3.664.
To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.
为了确定胰岛素信号转导途径至葡萄糖转运的缺陷是否以肌肉纤维类型特异性的方式发生，我们在来自Wistar或糖尿病GK大鼠的氧化型（比目鱼肌）和糖酵解型（趾长伸肌[EDL]）骨骼肌中评估了受体后胰岛素信号事件。与Wistar大鼠相比，GK大鼠比目鱼肌中胰岛素刺激的（120 nmol/l）最大葡萄糖转运显著降低。在GK大鼠的EDL肌肉中，胰岛素刺激的最大葡萄糖转运正常，而与Wistar大鼠相比，次最大反应降低。接下来，我们用根皮苷治疗糖尿病GK大鼠4周，以确定血糖恢复是否会导致胰岛素信号转导改善。根皮苷治疗GK大鼠导致比目鱼肌和EDL肌肉中胰岛素刺激的葡萄糖转运完全恢复。与Wistar大鼠相比，GK大鼠比目鱼肌中次最大和最大胰岛素刺激的胰岛素受体底物（IRS）-1酪氨酸磷酸化以及与IRS-1相关的磷脂酰肌醇（PI）3激酶活性显著降低，但根皮苷治疗后仅次最大胰岛素刺激的PI 3激酶恢复。在EDL肌肉中，GK大鼠和Wistar大鼠之间胰岛素刺激的IRS-1酪氨酸磷酸化和与IRS-1相关的PI-3激酶没有改变。GK大鼠比目鱼肌中最大胰岛素刺激的Akt（蛋白激酶B）激酶活性降低，血糖正常化后恢复（Krook等人，《糖尿病》46:2100 - 2114，1997）。在此，我们表明，在GK大鼠的EDL肌肉中，最大胰岛素刺激的Akt激酶活性也受损，根皮苷治疗后恢复到Wistar大鼠水平。总之，糖尿病GK大鼠骨骼肌中IRS-1和PI 3激酶的功能缺陷是纤维类型特异性的，在氧化型而非糖酵解型肌肉中观察到改变。此外，无论肌肉纤维类型如何，PI 3激酶的下游步骤（即Akt和葡萄糖转运）对血糖水平变化敏感。
