![]() Insulin signaling greatly stimulates the rate of exocytosis, leading to recruitment of up to 50% of the transporter to the cell surface where it facilitates glucose uptake. Glut4 cycles between the plasma membrane and cytoplasmic storage sites, with most of the transporter residing intracellularly in the absence of insulin signaling because the basal rate of endocytosis exceeds the basal rate of exocytosis. Insulin-stimulated uptake of glucose by fat and muscle and the maintenance of glucose homeostasis are primarily mediated by the Glut4 glucose transporter ( Bryant et al., 2002). The fusion block caused by RNA interference-mediated PLD1 deficiency is rescued by exogenous provision of a lipid that promotes fusion pore formation and expansion, suggesting that the step regulated by PA is late in the process of vesicle fusion. Diminished PA production does not substantially hinder trafficking of the vesicles or their docking at the plasma membrane, but it does impede fusion-mediated extracellular exposure of the transporter. Increasing PLD1 activity facilitates glucose uptake, whereas decreasing PLD1 activity is inhibitory. PLD1 is found on Glut4-containing vesicles, is activated by insulin signaling, and traffics with Glut4 to exocytic sites. We show here that phospholipase D (PLD) production of the lipid phosphatidic acid (PA) is a key event in the fusion process. This process requires the trafficking of Glut4-containing vesicles toward the cell periphery, docking at exocytic sites, and plasma membrane fusion. Insulin stimulates glucose uptake in fat and muscle by mobilizing Glut4 glucose transporters from intracellular membrane storage sites to the plasma membrane.
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