title: Roles of insulin signalling and p38 MAPK in the activation by lithium of glucose transport in insulin-resistant rat skeletal muscle.
abstract: We have demonstrated previously in insulin-sensitive skeletal muscle that lithium, an alkali metal and non-selective inhibitor of glycogen synthase kinase-3 (GSK-3), activates glucose transport by engaging the stress-activated p38 mitogen-activated protein kinase (p38 MAPK). However, it is presently unknown whether this same mechanism underlies lithium action on the glucose transport system in insulin-resistant skeletal muscle. We therefore assessed the effects of lithium on basal and insulin-stimulated glucose transport, glycogen synthesis, insulin signalling (insulin receptor (IR), Akt, and GSK-3), and p38 MAPK in soleus muscle from female obese Zucker rats. Lithium (10 mM LiCl) increased basal glucose transport by 49% (p < 0.05) and net glycogen synthesis by 2.4-fold (p < 0.05). In the absence of insulin, lithium did not induce IR tyrosine phosphorylation, but did enhance (p < 0.05) Akt ser(473) phosphorylation (40%) and GSK-3beta ser(9) phosphorylation (88%). Lithium potentiated (p < 0.05) the stimulatory effects of insulin on glucose transport (74%), glycogen synthesis (2.4-fold), Akt ser(473) phosphorylation (39%), and GSK-3beta ser(9) phosphorylation (36%), and elicited robust increases (p < 0.05) in p38 MAPK phosphorylation both in the absence (100%) or presence (88%) of insulin. The selective p38 MAPK inhibitor A304000 (10 muM) completely blocked basal activation of glucose transport by lithium, and significantly reduced (42%, p < 0.05) the lithium-induced enhancement of insulin-stimulated glucose transport in insulin-resistant muscle. These results indicate that lithium enhances both basal and insulin-stimulated glucose transport and glycogen synthesis in insulin-resistant skeletal muscle of female obese Zucker rats, and that these lithium-dependent effects are associated with enhanced Akt and GSK-3beta serine phosphorylation. As in insulin-sensitive muscle, the lithium-induced activation of glucose transport in insulin-resistant skeletal muscle is dependent on the engagement of p38 MAPK.
authors.affiliation: Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721, USA.
authors.forename: Antoni R
authors.initials: AR
authors.lastname: Macko
authors.forename: Alan N
authors.initials: AN
authors.lastname: Beneze
authors.forename: Mary K
authors.initials: MK
authors.lastname: Teachey
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Henriksen
mesh_terms: D000818:Animals; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007328:Insulin; D006003:Glycogen; D008094:Lithium; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose