Involvement of the protein kinase Akt2 in insulin-stimulated Rac1 activation leading to glucose uptake in mouse skeletal muscle

PLoS One. 2019 Feb 8;14(2):e0212219. doi: 10.1371/journal.pone.0212219. eCollection 2019.


Translocation of the glucose transporter GLUT4 to the sarcolemma accounts for glucose uptake in skeletal muscle following insulin administration. The protein kinase Akt2 and the small GTPase Rac1 have been implicated as essential regulators of insulin-stimulated GLUT4 translocation. Several lines of evidence suggest that Rac1 is modulated downstream of Akt2, and indeed the guanine nucleotide exchange factor FLJ00068 has been identified as an activator of Rac1. On the other hand, the mechanisms whereby Akt2 and Rac1 are regulated in parallel downstream of phosphoinositide 3-kinase are also proposed. Herein, we aimed to provide additional evidence that support a critical role for Akt2 in insulin regulation of Rac1 in mouse skeletal muscle. Knockdown of Akt2 by RNA interference abolished Rac1 activation following intravenous administration of insulin or ectopic expression of a constitutively activated phosphoinositide 3-kinase mutant. The activation of another small GTPase RalA and GLUT4 translocation to the sarcolemma following insulin administration or ectopic expression of a constitutively activated form of phosphoinositide 3-kinase, but not Rac1, were also diminished by downregulation of Akt2 expression. Collectively, these results strongly support the notion that Rac1 acts downstream of Akt2 leading to the activation of RalA and GLUT4 translocation to the sarcolemma in skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Insulin / pharmacology*
  • Male
  • Mice
  • Muscle, Skeletal / metabolism*
  • Mutation
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / biosynthesis*
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA Interference
  • Sarcolemma / enzymology*
  • Sarcolemma / genetics
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism


  • Glucose Transporter Type 4
  • Insulin
  • Neuropeptides
  • Rac1 protein, mouse
  • Slc2a4 protein, mouse
  • Phosphatidylinositol 3-Kinases
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Rala protein, mouse
  • rac1 GTP-Binding Protein
  • ral GTP-Binding Proteins
  • Glucose

Grant support

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant number, 17K15093; URL, to NT and a grant from the Naito Foundation (no grant number; URL, to TS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.