The diffusive component of intestinal glucose absorption is mediated by the glucose-induced recruitment of GLUT2 to the brush-border membrane

Abstract

We have investigated the mechanism responsible for the diffusive component of intestinal glucose absorption, the major route by which glucose is absorbed. In perfused rat jejunum in vivo, absorption was strongly inhibited by phloretin, an inhibitor of GLUT2. The GLUT2 level at the brush-border membrane increased some 2-fold when the luminal glucose concentration was changed from 0 to 100 mM. The phloretin-sensitive or diffusive component of absorption appeared superficially linear and consistent with simple diffusion, but was in fact carrier-mediated and co-operative (n=1.6, [G(1/2)]=56 mM; where [G(1/2)] is the glucose concentration at half V(max)) because of the glucose-induced activation and recruitment of GLUT2 to the brush-border membrane. Diffusive transport by paracellular flow was negligible. The phloretin-insensitive, SGLT1-mediated, component of glucose absorption showed simple saturation kinetics with [G(1/2)]=27 mM: the activation of protein kinase C (PKC) betaII, the isoenzyme of PKC that most probably controls GLUT2 trafficking [Helliwell, Richardson, Affleck and Kellett (2000) Biochem. J. 350, 149-154], also showed simple saturation kinetics, with [G(1/2)]=21 mM. We conclude that the principal route for glucose absorption is by GLUT2-mediated facilitated diffusion across the brush-border membrane, which is up to 3-fold greater than that by SGLT1; the magnitude of the diffusive component at any given glucose concentration correlates with the SGLT1-dependent activation of PKC betaII. The implications of these findings for the assimilation of sugars immediately after a meal are discussed.

Live imaging of GLUT2 glucose-dependent trafficking and its inhibition in polarized epithelial cysts

“…Phloretin was subsequently found to block sugar uptake in intestinal tissue [51], drawing significant interest to its application in the treatment of diabetes. Phloretin was shown to specifically inhibit GLUT2 and to a lesser extent SGLT1 [22,52]. Here, we show that phloretin inhibits the transport of GLUT2 between the apical and basal membranes in both directions.…”

“…In rat intestine, at least, there are two components of apical GLUT2, differing in their trafficking speed and PKC dependence. One millimolar of phloretin was necessary to inhibit absorption by both components at 75 mM glucose, while maintaining specificity [52,53]. Here, we present IC 50 values for inhibition of GLUT2 translocation by phloretin that suggest that the ability to inhibit PKC activity underlies its inhibition of GLUT2 translocation.…”

Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes

“…A jejunal perfusion protocol in rats29 was modified for use in mice in which 1 ml of saline or saline containing 25% glucose or 25% 2-deoxyglucose (a non-metabolisable non-sweet osmotic control)19 was perfused in single-pass mode over 15 min. Blood glucose levels were monitored at 5 min intervals starting 10 min prior to perfusion using a glucometer (Medisense Precision QID) to confirm that the blood glucose concentration did not rise during glucose perfusion.…”

Effect of High Sugar Intake on Glucose Transporter and Weight Regulating Hormones in Mice and Humans

“…SGLT1, is a low-capacity, high-affinity transporter and the only transporter capable of moving glucose against a concentration gradient. While SGLT1 is saturated already at millimolar glucose levels, facilitated diffusion via GLUT2 seems to be the principal route for glucose and fructose absorption [15]. GLUT2 is the glucose transporter with the lowest affinity/specificity and the highest capacity for glucose (15).…”