In normal myocytes, insulin treatment activates glucose uptake to the muscle by promoting the cell surface delivery of cytoplasmic storage vesicles that contain the glucose transporter GLUT4.
Like other examples of regulated membrane dynamics, this process involves the local rearrangement of the cortical actin cytoskeleton. Tong et al. have applied sophisticated microscopic imaging to follow the intracellular events that mediate this physiologically important response.
They show here that GLUT4 is inserted into the myotube plasma membrane at regions of membrane ruffling, where cytoskeletal remodeling takes place. Perturbing the cytoskeleton with specific drugs not only blocks the formation of the membrane ruffles, but also prevents the delivery of GLUT4 to the cell surface.
The authors also provide tantalizing clues that these membrane-cytoskeletal interactions go awry in diabetes. In cultured myotubes, the high insulin and glucose levels that prevail with advancing insulin resistance are sufficient to block the formation of membrane ruffles and the fusion of GLUT4-containing vesicles with the cell surface.
The reason for this diminished response is not understood, but if it reflects events in vivo, it could provide a novel explanation for the loss of glucose homeostasis by muscle and thus help explain the progression of insulin resistance to diabetes.
Journal of Clinical Investigation