Essential role of p38 MAPK for activation of skeletal muscle glucose transport by lithium

Nicholas B. Harrell, Mary K. Teachey, Nancy J. Gifford, Erik J. Henriksen

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Lithium increases glucose transport and glycogen synthesis in insulin-sensitive cell lines and rat skeletal muscle, and has been used as a non-selective inhibitor of glycogen synthase kinase-3 (GSK-3). However, the molecular mechanisms underlying lithium action on glucose transport in mammalian skeletal muscle are unknown. Therefore, we examined the effects of lithium on glucose transport activity, glycogen synthesis, insulin signaling elements (insulin receptor (IR), Akt, and GSK-3), and the stress-activated p38 mitogen-activated protein kinase (p38 MAPK) in the absence or presence of insulin in isolated soleus muscle from lean Zucker rats. Lithium (10mM LiCl) enhanced basal glucose transport by 62% (p0.05) and augmented net glycogen synthesis by 112% (p0.05). Whereas lithium did not affect basal IR tyrosine phosphorylation or Akt ser473 phosphorylation, it did enhance (41%, p0.05) basal GSK-3 ser9 phosphorylation. Lithium further enhanced (p0.05) the stimulatory effects of insulin on glucose transport (43%), glycogen synthesis (44%), and GSK-3 ser9 phosphorylation (13%). Lithium increased (p0.05) p38 MAPK phosphorylation both in the absence (37%) and presence (41%) of insulin. Importantly, selective inhibition of p38 MAPK (using 10M A304000) completely prevented the basal activation of glucose transport by lithium, and also significantly reduced (52%, p0.05) the lithium-induced enhancement of insulin-stimulated glucose transport. Theses results demonstrate that lithium enhances basal and insulin-stimulated glucose transport activity and glycogen synthesis in insulin-sensitive rat skeletal muscle, and that these effects are associated with a significant enhancement of GSK-3 phosphorylation. Importantly, we have documented an essential role of p38 MAPK phosphorylation in the action lithium on the glucose transport system in isolated mammalian skeletal muscle.

Original languageEnglish (US)
Pages (from-to)221-227
Number of pages7
JournalArchives of Physiology and Biochemistry
Issue number4-5
StatePublished - Oct 2007


  • A304000
  • Glycogen synthase kinase-3
  • Insulin signaling

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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