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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 284; no. 5; pp. E892 - E900
• Main Authors: Henriksen, Erik J, Kinnick, Tyson R, Teachey, Mary K, O'Keefe, Matthew P, Ring, David, Johnson, Kirk W, Harrison, Stephen D
• Format: Journal Article
• Language: English
• Published: United States 01.05.2003
• Subjects: Administration, Oral; Animals; Biological Transport - drug effects; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Membrane - metabolism; Diabetes Mellitus - metabolism; Enzyme Inhibitors - pharmacology; Glucose - metabolism; Glucose Transporter Type 4; Glycogen Synthase - metabolism; Glycogen Synthase Kinase 3 - metabolism; Insulin Resistance; Lithium - pharmacology; Male; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Muscle, Skeletal - metabolism; Obesity; Rats; Rats, Zucker
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00346.2002

1  Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721; and 2  Chiron Corporation, Emeryville, California 94608 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 × 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. glycogen synthase kinase-3; type 2 diabetes; glucose transport; epitrochlearis; soleus; cell surface glucose transporter-4; lithium