Abstract
Glucose uptake is stimulated by insulin via stimulation of glucose transporter 4 (GLUT4) translocation to the plasma membrane from intracellular compartments in adipose tissue and muscles. Insulin stimulation for prolonged periods depletes GLUT4 protein, particularly in highly insulin-responsive GLUT4 storage vesicles. This depletion mainly occurs via H2O2-mediated retromer inhibition. However, the post-receptor mechanism of insulin activation of oxidative stress remains unknown. Here, we show that phosphatidylcholine-specific phospholipase C (PC-PLC) plays an important role in insulin-mediated downregulation of GLUT4. In the study, 3T3-L1 adipocytes were exposed to a PC-PLC inhibitor, tricyclodecan-9-yl-xanthogenate (D609), for 30 min prior to the stimulation with 500 nM insulin for 4 h, weakening the depletion of GLUT4. D609 also prevents insulin-driven H2O2 generation in 3T3-L1 adipocytes. Exogenous PC-PLC and its product, phosphocholine (PCho), also caused GLUT4 depletion and promoted H2O2 generation in 3T3-L1 adipocytes. Furthermore, insulin-mediated the increase in the cellular membrane PC-PLC activity was observed in Amplex Red assays. These results suggested that PC-PLC plays an important role in insulin-mediated downregulation of GLUT4 and that PCho may serve as a signaling molecule.
Highlights
Glucose transporter 4 (GLUT4) is a primary glucose transporter in the muscle and adipose tissue that plays an important role in the regulation of blood glucose homeostasis
GW4869 inhibition of sphingomyelinase does not prevent insulin downregulation of GLUT4 (Fig. 1b); DG can be produced from phosphatidylinositol by phosphoinositidespecific phospholipase C (PI-PLC)
The mechanism of GLUT4 downregulation by chronic insulin stimulation was investigated, and the results provided evidence that phosphatidylcholine-specific phospholipase C (PC-PLC) is essential for the regulation of GLUT4 concentration
Summary
Glucose transporter 4 (GLUT4) is a primary glucose transporter in the muscle and adipose tissue that plays an important role in the regulation of blood glucose homeostasis. It is inserted into the budding GLUT4 storage vesicles (GSVs) that are sequestered within cells [13]. The blood glucose increase after meals promotes insulin secretion, which induces GSVs to translocate to the plasma membrane by exocytosis. The GLUT4 inserted in the plasma membrane transports glucose into the cells [4, 9, 11]. The balance of GLUT4 translocation, exocytosis, and endocytosis is important for glucose homeostasis [10].
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