Practice question

Facilitative GLUT transporters use alternating access without ion coupling. GLUT4 encoded by SLC2A4 is insulin-responsive isoform in skeletal, cardiac muscle and adipose, handling major postprandial glucose disposal. In basal fasting state most GLUT4 sequestered in storage vesicles containing IRAP, sortilin, LRP1 and VAMP2 retained by TUG tether and AS160 GAP keeping Rabs GDP-bound. Insulin triggers receptor tyrosine autophosphorylation, IRS recruitment, PI3K activation producing PIP3 recruiting Akt2 which phosphorylates AS160 relieving Rab8A, Rab10, Rab14 inhibition, mobilizing vesicles along actin tracks to plasma membrane increasing surface density twentyfold within minutes. Once inserted, GLUT4 works as uniporter moving D-glucose down gradient without Na+ coupling or ATP, stereospecific, saturable Km near 5 mM close to plasma glucose, inhibited by cytochalasin B. Entry followed by hexokinase II phosphorylation trapping glucose for glycogen synthesis. Insulin resistance in type 2 diabetes impairs translocation despite preserved total protein due to defective Akt signaling and lipid-induced serine phosphorylation. Recruitment also involves myosin motors and actin remodeling that facilitate vesicle movement toward cortex.