Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects
Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects
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DOI：
10.2337/diabetes.54.6.1692
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发表时间：
2005-06-01
期刊：
影响因子：
7.7
通讯作者：
Wallberg-Henriksson, H
中科院分区：
文献类型：
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作者：
Karlsson, HKR;Zierath, JR;Wallberg-Henriksson, H
AS160是一种新发现的蛋白激酶Akt底物，它连接胰岛素信号和GLUT4运输。在这项研究中，我们测定了胰岛素在人骨骼肌AS160上的表达和体内作用。此外，我们还比较了10例轻中度肥胖2型糖尿病患者和9例健康受试者生理性高胰岛素血症对AS160磷酸化的影响。胰岛素输注增加了几种与磷酸化Akt底物抗体反应的蛋白质的磷酸化。我们重点研究了AS160，因为这种Akt底物与葡萄糖运输有关。用AS160特异性抗体进行免疫印迹分析，确定一个160 kDa的磷酸化蛋白为AS160。生理性高胰岛素血症使对照组受试者骨骼肌中AS160磷酸化水平增加2.9倍(P<；0.001)。在2型糖尿病患者中，胰岛素刺激的AS160磷酸化降低了39%(P<；0.05)。AS160蛋白在2型糖尿病患者和对照组中的表达相似。AS160磷酸化受损与Akt信号异常有关；与对照组相比，2型糖尿病患者胰岛素对Akt Ser(473)磷酸化的作用没有明显降低，而Thr(308)磷酸化受损51%(P<；0.05)。总而言之，生理性高胰岛素血症增加了人骨骼肌中AS160的磷酸化。此外，胰岛素在AS 160上的作用缺陷可能会损害2型糖尿病患者的GLUT4追踪。
AS160 is a newly described substrate for the protein kinase Akt that links insulin signaling and GLUT4 trafficking. In this study, we determined the expression of and in vivo insulin action on AS160 in human skeletal muscle. In addition, we compared the effect of physiological hyperinsulinemia on AS160 phosphorylation in 10 lean-to-moderately obese type 2 diabetic and 9 healthy subjects. Insulin infusion increased the phosphorylation of several proteins reacting with a phospho-Akt substrate antibody. We focused on AS160, as this Akt substrate has been linked to glucose transport. A 160-kDa phosphorylated protein was identified as AS160 by immunoblot analysis with an AS160-specific antibody. Physiological hyperinsulinemia increased AS160 phosphorylation 2.9-fold in skeletal muscle of control subjects (P < 0.001). Insulin-stimulated AS160 phosphorylation was reduced 39% (P < 0.05) in type 2 diabetic patients. AS160 protein expression was similar in type 2 diabetic and control subjects. Impaired AS160 phosphorylation was related to aberrant Akt signaling; insulin action on Akt Ser(473) phosphorylation was not significantly reduced in type 2 diabetic compared with control subjects, whereas Thr(308) phosphorylation was impaired 51% (P < 0.05). In conclusion, physiological hyperinsulinemia increases AS160 phosphorylation in human skeletal muscle. Moreover, defects in insulin action on AS 160 may impair GLUT4 tracking in type 2 diabetes.