Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle

被引:61
作者
Oku, A
Nawano, M
Ueta, K
Fujita, T
Umebayashi, I
Arakawa, K
Kano-Ishihara, T
Saito, A
Anai, M
Funaki, M
Kikuchi, M
Oka, Y
Asano, T
机构
[1] Univ Tokyo, Fac Med, Dept Internal Med 3, Bunkyo Ku, Tokyo 1138655, Japan
[2] Tanabe Seiyaku Co Ltd, Discovery Res Lab, Toda, Saitama 3358505, Japan
[3] Asahi Life Fdn, Inst Adult Dis, Tokyo 116, Japan
[4] Yamaguchi Univ, Fac Med, Dept Internal Med 3, Ube, Yamaguchi 755, Japan
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2001年 / 280卷 / 05期
关键词
Akt/protein kinase B; insulin resistance; streptozotocin; T-1095;
D O I
10.1152/ajpendo.2001.280.5.E816
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
To determine the molecular mechanism underlying hyperglycemia-induced insulin resistance in skeletal muscles, postreceptor insulin-signaling events were assessed in skeletal muscles of neonatally streptozotocin-treated diabetic rats. In isolated soleus muscle of the diabetic rats, insulin-stimulated 2-deoxyglucose uptake, glucose oxidation, and lactate release were all significantly decreased compared with normal rats. Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. The amelioration of hyperglycemia by T-1095, a Na+-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle.
引用
收藏
页码:E816 / E824
页数:9
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