Solving how insulin regulates glucose transport into skeletal muscle and adipose tissue remains a fundamental challenge in biology and a significant issue in medicine. A central feature of this process is the coordinated accumulation of the glucose transporter GLUT4 into the plasma membrane. New signaling and cytoskeletal mechanisms of insulin-stimulated GLUT4 exocytosis are of emerging interest, particularly those at or just beneath the plasma membrane. This review examines signals that functionally engage GLUT4 exocytosis, considers cytoskeletal regulation of the stimulated GLUT4 itinerary, and appraises the involvement of plasma membrane parameters in GLUT4 control. We also explore how these newly-defined signaling, cytoskeletal and membrane mechanisms could be of therapeutic interest in the treatment and/or prevention of GLUT4 dysregulation in disease.
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