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Insulin‐stimulated PAK1 activation is required for glucose uptake in skeletal muscle cells (797.1)

Skeletal muscle accounts for ~80% of postprandial glucose clearance, crucial for maintaining euglycemia and insulin sensitivity. Insulin‐stimulated glucose uptake entails recruitment of glucose transporters (GLUT4) to the plasma membrane (PM) in a process that requires cortical F‐actin remodeling; this process is dysregulated in Type 2 Diabetes. Recent studies have implicated PAK1 as a required element in GLUT4 recruitment in mouse skeletal muscle in vivo, although its underlying mechanism of action and requirement in glucose uptake remains undetermined. Toward this, we have employed the PAK1 inhibitor, IPA3, in studies using L6‐GLUT4‐myc muscle cells, the premiere skeletal muscle cell line for glucose uptake analyses. Confocal microscopy showed IPA3 to fully ablate insulin‐stimulated GLUT4 translocation to the PM, corroborating the observation of ablated insulin‐stimulated GLUT4 accumulation in the PM of skeletal muscle from PAK1‐/‐ knockout mice. IPA3‐treatment also abolished insulin‐stimulated glucose uptake into skeletal myotubes. Mechanistically, live‐cell imaging of myoblasts expressing the F‐actin biosensor LifeAct‐GFP treated with IPA3 showed blunting of the normal insulin‐induced cortical actin remodeling. This blunting was underpinned by a loss of normal insulin‐stimulated Cofilin dephosphorylation in IPA3‐treated myoblasts, suggesting a new model: insulin activates PAK1 to signal downstream to Cofilin to trigger actin severing, providing substrate for F‐actin remodeling, which facilitates GLUT4 vesicle translocation toward the PM where GLUT4 promotes glucose uptake into the skeletal muscle cell.