Abstract

Insulin is a hormone that regulates the blood glucose level by stimulating various physiological responses in its target tissues. In skeletal muscle and adipose tissue, insulin promotes membrane trafficking of the glucose transporter GLUT4 from GLUT4 storage vesicles to the plasma membrane, thereby facilitating the uptake of glucose from the circulation. Detailed mechanisms underlying insulin-dependent intracellular signal transduction for glucose uptake remain largely unknown. In this article, I give an overview on the recently identified signaling network involving Rab, Ras, and Rho family small guanosine triphosphatases (GTPases) that regulates glucose uptake in insulin-responsive tissues. In particular, the regulatory mechanisms for these small GTPases and the cross-talk between protein kinase and small GTPase cascades are highlighted.

Highlights

  • Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan; External Editor: Jeremy Simpson

  • Insulin is an anabolic hormone that acts on various target tissues, including the liver, skeletal muscle, and fat tissue, regulating the blood glucose level [1,2,3,4]

  • Sci. 2014, 15 insulin promotes the uptake of circulating glucose into its target tissues, such as skeletal muscle and fat tissue, and thereby reduces the blood glucose level

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Summary

Mechanisms for Rac1 Activation in Response to Insulin Stimulation

The involvement of PI3K in the activation of Rac following insulin stimulation has been demonstrated by studies using specific inhibitors [47,50]. GLUT4 translocation induced by constitutively activated Akt was totally down-regulated when Rac was knocked down in cultured myoblasts and mouse gastrocnemius muscle [60]. These observations suggest a crucial role for Akt in insulin-stimulated Rac activation. FLJ00068 is a feasible candidate for the regulator of Rac in skeletal muscle insulin signaling In support of this idea, constitutively activated FLJ00068-dependent GLUT4 translocation to the sarcolemma was observed in wild-type, but not muscle-specific rac knockout, mouse skeletal muscle [64]. FLJ00068 may not be phosphorylated by active Akt directly because the consensus sequence for Akt substrates is not found in FLJ00068

Signaling Pathways Downstream of Rac1 for the Induction of Glucose Uptake
Role of Rac1 in Glucose Uptake Stimulated by Muscle Contraction
11. Conclusions
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