title: Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats.
abstract: 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.
authors.affiliation: Muscle Metabolism Laboratory, Department of Physiology, Ina E. Gittings Building #93, University of Arizona College of Medicine, Tucson, AZ 85721, USA. ejhenrik@u.arizona.edu
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Henriksen
authors.forename: Tyson R
authors.initials: TR
authors.lastname: Kinnick
authors.forename: Mary K
authors.initials: MK
authors.lastname: Teachey
authors.forename: Matthew P
authors.initials: MP
authors.lastname: O'Keefe
authors.forename: David
authors.initials: D
authors.lastname: Ring
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Harrison
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007333:Insulin Resistance; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D008094:Lithium; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3; D005947:Glucose