Skeletal muscle insulin resistance is a major contributor to type 2 diabetes and is linked to the consumption of saturated fats. In healthy muscle cells, insulin induces translocation of glucose transporter type 4 (GLUT4) to the cell surface, where it can facilitate glucose uptake. However, excess levels of saturated fats, such as palmitate (PA), inhibit this translocation of GLUT4 and thus induce insulin resistance. Mechanistically, however, it is not clear how saturated fats impair GLUT4 translocation. In this study (Tokarz et al., 2023), Amira Klip and colleagues address this question by inducing insulin resistance in skeletal muscle myoblasts and myotubes with PA. Previous studies have suggested that Akt signalling, which acts downstream of insulin, is important for GLUT4 translocation. However, the authors find that suppression of GLUT4 translocation by PA occurs without disrupting Akt signalling. Instead, PA causes dispersal of perinuclear stores of GLUT4 along with syntaxin-6 (STX6)-positive subcompartments, suggesting that there is altered GLUT4 intracellular sorting, and in turn an altered response to insulin . Compounding these effects, PA also perturbs Rac1-dependent actin remodelling, resulting in increased cortical stiffness, possibly impairing vesicle fusion with the membrane. Together, these findings suggest that PA inhibits GLUT4 translocation by perturbing physical sorting of GLUT4 through intracellular compartments, providing valuable insights into mechanisms of insulin resistance and thus insulin-sensitizing strategies.
