Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle. Oku, Akira, Masao Nawano, Kiichiro Ueta, Takuya Fujita, Itsuro Umebayashi, Kenji Arakawa, Tomomi Kano-Ishihara, Akira Saito, Motonobu Anai, Makoto Funaki, Masayoshi Kikuchi, Yoshitomo Oka, and Tomoichiro Asano. 1Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Saitama 335«hyphen»8505; 2Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113«hyphen»8655; 3Institute for Adult Disease, Asahi Life Foundation, Tokyo 116; and 4Third Department of Internal Medicine, Faculty of Medicine, University of Yamaguchi, Yamaguchi 755, Japan
APStracts 8:0027E, 2001.
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. 

Received 18 September 2000; accepted in final form 30 January 2001
APS Manuscript Number E434-0.
Article publication pending Am J Physiol Endocrinol Metab
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 27 February 2001