Abstract
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.
Highlights
The glucose transporter GLUT4 is responsible for insulin-dependent glucose uptake in skeletal muscle and adipose tissue [1,2,3]
We aim to provide additional in vivo evidence for the involvement of Akt2 in Rac1 activation in skeletal muscle insulin signaling by using a mouse model
We took advantage of this significant methodological improvement to obtain evidence supporting a critical role of Akt2 in insulin-dependent activation of Rac1 and subsequent signaling events
Summary
The glucose transporter GLUT4 is responsible for insulin-dependent glucose uptake in skeletal muscle and adipose tissue [1,2,3]. GLUT4 is stored in specific intracellular compartments termed GLUT4 storage vesicles in unstimulated cells, and vesicles containing GLUT4 molecules are transported toward the plasma membrane in response to insulin stimulation. GLUT4 is redistributed to the plasma membrane through fusion of GLUT4-containing vesicles with the plasma membrane, and permits blood glucose to be incorporated into the cell across the plasma membrane. Various signaling pathways for the induction of the plasma membrane translocation of GLUT4 are activated downstream of the insulin receptor.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
