Which signaling pathways are involved in translocating GLUT4 to the cell surface in response to insulin and in response to exercise?

• A. JAK-STAT for insulin; mTOR for exercise.
• B. PI3K-AKT for insulin; AMPK for exercise to translocate GLUT4.
• C. MAPK for insulin; PLC for exercise.
• D. AMPK for insulin; PI3K-AKT for exercise.

Answer: (B)

Glucose uptake in muscle relies on moving GLUT4 transporters from internal vesicles to the cell surface, and the triggers for this translocation are different depending on the stimulus.

Insulin activates a signaling cascade starting with its receptor, leading to IRS and PI3K activation, which then activates AKT. Activated AKT phosphorylates targets like AS160, removing the brake on GLUT4 vesicles and promoting their movement to and fusion with the plasma membrane. This is how insulin rapidly increases glucose uptake after a meal.

During exercise, contracting muscle increases the cellular energy demand, raising the AMP/ATP ratio and activating AMPK. AMPK also promotes GLUT4 translocation—again through pathways that relieve vesicle retention—so glucose can enter muscle cells to fuel contraction even when insulin is not driving the process.

The best pairing reflects these distinct routes: insulin uses the PI3K-AKT pathway, while exercise uses AMPK to drive GLUT4 to the surface. Other pathways (like JAK-STAT, mTOR, MAPK, or PLC) aren’t the primary routes for GLUT4 translocation in response to insulin or exercise, so they don’t fit this specific mechanism.