One of the hallmarks of postprandial glucose homeostasis is the ability of insulin to promote glucose uptake into skeletal muscles. Insulin achieves this feat by enhancing the recruitment of glucose transporter 4 (GLUT4) from an intracellular compartment to the plasma membrane of muscles in order to create a net increase in surface GLUT4, which results in elevated glucose uptake. From a molecular perspective, this insulin-regulated GLUT4 traffic action requires the independent activation of Akt and Rac-1 in muscle cells because perturbation of either molecule results in an impaired response. Although Rac-1 has been validated as key component of insulin response, its downstream signalling capacity contributing to GLUT4 translocation remains unexplored.
Studies on Rac-1 have shown that it is responsible for the formation of cortical remodelled actin that facilitates GLUT4 translocation following insulin stimulation. However, the downstream Rac-dependent molecules governing this actin remodelling are undetermined. Here we identified Arp2/3 and cofilin as the Rac-dependent regulators of insulin-induced actin remodelling in muscle cells. While Arp2/3 acts to initiate a burst of actin polymerization, cofilin balances out the actin dynamics through its severing/depolymerizing activity. Inhibition of either molecule’s function leads to defective GLUT4 translocation mediated by insulin in muscle cells, suggesting the requirement of actin dynamics to facilitate GLUT4 traffic to the plasma membrane.
Furthermore, given the importance of Rac-1 in insulin-mediate GLUT4 traffic, its application potential to reverse insulin resistance has never been explored. We discovered that providing muscle cells with additional Rac-1 activity produces an insulin-independent gain in surface GLUT4 with magnitude comparable to that normally elicited by insulin. This phenotype is accomplished because of the concomitant cross-activation of Akt pathway when supplying the cells with active Rac-1. Interestingly, this response can bypass signalling defects imposed by cellular insulin resistance conditions, leading to restoration of GLUT4 translocation in muscle cells.
Overall, these results not only reinforce the functional impact of Rac-1 on GLUT4 traffic but also identify additional molecules governed by Rac-1 contributing to the integrity of this insulin-mediated response in muscle cells.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/65651 |
| Date | 18 July 2014 |
| Creators | Chiu, Ting Tim |
| Contributors | Klip, Amira |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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