Division of Trauma and Critical Care, Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920, USA.
Shock. 2011 Jan;35(1):80-5. doi: 10.1097/SHK.0b013e3181e762da.
Burn injury is associated with a decline in glucose utilization and insulin sensitivity due to alterations in postreceptor insulin signaling pathways. We have reported that blockade of the renin-angiotensin system with losartan, an angiotensin II type 1 (AT1) receptor blocker, improves whole body insulin sensitivity and glucose metabolism after burn injury. This study examines whether losartan improves insulin signaling pathways and insulin-stimulated glucose transport in skeletal muscle in burn-injured rats. Rats were injured by a 30% full-skin-thickness scalding burn and treated with losartan or placebo for 3 days after burn. Insulin signaling pathways were investigated in rectus abdominus muscle taken before and 90 s after intraportal insulin injection (10 U·kg). Insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase and plasma membrane-associated GLUT4 transporter were substantially increased with losartan treatment in burn-injured animals (59% above sham). Serine phosphorylated AKT/PKB was decreased with burn injury, and this decrease was attenuated with losartan treatment. In a separate group of rats, the effect of insulin on 2-deoxyglucose transport was significantly impaired in burned as compared with sham soleus muscles, in vitro; however, treatment of burned rats with losartan completely abolished the reduction of insulin-stimulated 2-deoxyglucose transport. These findings demonstrate a cross talk between the AT1 and insulin receptor that negatively modulates insulin receptor signaling and suggest a potential role of renin-angiotensin system blockade as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle and improving whole-body glucose homeostasis in burn injury.
烧伤可导致受体后胰岛素信号通路改变，从而引起葡萄糖利用和胰岛素敏感性下降。我们曾报道，血管紧张素 II 型 1（AT1）受体阻滞剂氯沙坦阻断肾素-血管紧张素系统可改善烧伤后全身胰岛素敏感性和葡萄糖代谢。本研究旨在探讨氯沙坦是否可改善烧伤大鼠骨骼肌胰岛素信号通路和胰岛素刺激的葡萄糖转运。采用 30%全皮肤厚度烫伤建立大鼠烧伤模型，伤后 3 天分别给予氯沙坦或安慰剂治疗。于门静脉内注射胰岛素（10 U·kg）前及 90 s 时取大鼠腹直肌，检测胰岛素信号通路。结果显示，与假手术组相比，氯沙坦治疗可显著增加烧伤大鼠胰岛素受体底物 1 相关的磷酸化 3-激酶和质膜相关葡萄糖转运体 4 的胰岛素刺激活性（增加 59%）。与假手术组相比，烧伤大鼠 AKT/PKB 丝氨酸磷酸化减少，而氯沙坦治疗可减弱这种减少。在另一组大鼠中，与假手术组比，烧伤大鼠比目鱼肌体外对胰岛素的 2-脱氧葡萄糖转运明显受损，而氯沙坦治疗可完全消除胰岛素刺激的 2-脱氧葡萄糖转运的减少。这些发现表明 AT1 和胰岛素受体之间存在串扰，负调节胰岛素受体信号，提示肾素-血管紧张素系统阻断可能作为一种增强骨骼肌胰岛素敏感性和改善烧伤后全身葡萄糖稳态的治疗策略。
