INTRO: The classic model of hexose transport in intestinal epithelium assumes carrier-mediated apical uptake of luminal glucose occurs via sodium glucose transporter-1 (SGLT-1), and the facilitated transporter, glucose transporter-2 (GLUT-2), is located only at the basolateral membrane. Recent studies challenge this model suggesting GLUT-2 is trafficked to the apical membrane in response to glucose.
HYPOTHESIS: GLUT-2 is trafficked to the apical membrane by SGLT-1 signaling via membrane-bound protein kinase C.
Methods: Carrier-mediated uptake was measured in 300-350g Lewis rats using 1cm segments of duodenum, jejunum, and ileum everted over a rod immersed in 1mM, 20mM, and 50mM glucose solutions for 1 min. 14C-D-glucose was the marker for carrier-mediated glucose uptake; 3H-L-glucose corrected for adherent fluid and passive diffusion. Counts were obtained by liquid scintillation, and carrier-mediated glucose uptake was calculated for 3 groups (n=6 each): group1-control, group2-treated with SGLT-1 antagonist, phlorizin (0.2mM), and group3-treated with GLUT-2 inhibitor, phloretin (1mM) which inhibits membrane-bound protein kinase C.
Results: The control group had an incremental, saturable increase in uptake with increasing glucose concentrations, consistent with Michaelis-Menten kinetics (Fig 1). Specific inhibition of SGLT-1 with phlorizin caused near-complete inhibition of carrier-mediated uptake compared to controls in all three segments (Fig 1, p<0.003). Treatment with GLUT-2 inhibitor, phloretin, also decreased carrier-mediated uptake compared to controls in all three segments but not as profound as phlorizin (Fig 1, p<0.003).
SUMMARY: Inhibition of SGLT-1 inhibits most apical carrier-mediated glucose uptake. Inhibition of GLUT-2 alone also decreases apical uptake.
Conclusion: Although SGLT-1 accounts for most apical carrier-mediated glucose uptake, GLUT-2 is also involved in hexose absorption at the apical membrane of enterocytes; this activity appears to be mediated by SGLT-1 through protein kinase C. [Supported by NIH-R01 DK39331-MGS]