Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats

被引:90
作者
Henriksen, EJ
Kinnick, TR
Teachey, MK
O'Keefe, MP
Ring, D
Johnson, KW
Harrison, SD
机构
[1] Univ Arizona, Coll Med, Dept Physiol, Muscle Metab Lab, Tucson, AZ 85721 USA
[2] Chiron Corp, Emeryville, CA 94608 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2003年 / 284卷 / 05期
关键词
glycogen synthase kinase-3; type; 2; diabetes; glucose transport; epitrochlearis; soleus; cell surface glucose transporter-4; lithium;
D O I
10.1152/ajpendo.00346.2002
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity ( 49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 x 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated ( 26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.
引用
收藏
页码:E892 / E900
页数:9
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