Roles of insulin signalling and p38 MAPK in the activation by lithium of glucose transport in insulin-resistant rat skeletal muscle

Antoni R. Macko, Alan N. Beneze, Mary K. Teachey, Erik J. Henriksen

Research output: Contribution to journalArticle

17 Scopus citations

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 ser473 phosphorylation (40%) and GSK-3ss ser9 phosphorylation (88%). Lithium potentiated (p < 0.05) the stimulatory effects of insulin on glucose transport (74%), glycogen synthesis (2.4-fold), Akt ser473 phosphorylation (39%), and GSK-3ss ser9 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 μM) 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-3ss 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.

Original languageEnglish (US)
Pages (from-to)331-339
Number of pages9
JournalArchives of Physiology and Biochemistry
Volume114
Issue number5
DOIs
StatePublished - Dec 2008

Keywords

  • A304000
  • Akt
  • Glycogen synthase kinase-3
  • Obese Zucker rat

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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