Response to Comment on: Gorboulev et al. Na⁺-d-glucose Cotransporter SGLT1 Is Pivotal for Intestinal Glucose Absorption and Glucose-Dependent Incretin Secretion. Diabetes 2012;61:187–196

In response to the commentary of Professor Kellett (1), we would like to clarify the following points. The data reported in our article (2) confirm the observation that SGLT1-mediated D-glucose uptake in the presence of a high D-glucose concentration in the small intestinal lumen mediates translocation of GLUT2 to the luminal membrane of the enterocytes; however, they contradict the hypothesis that GLUT2 is the major pathway of D-glucose absorption when glucose is plentiful (3–6). Comparing SGLT1-mediated and GLUT2-mediated glucose uptake into isolated brush-border membrane (BBM) vesicles, we present evidence that SGLT1 transports about 90% of D-glucose into the enterocytes in the presence of high luminal glucose whereas only about 10% is transported by GLUT2. The fraction transported by GLUT2 is probably overestimated since we measured GLUT2-mediated uptake into BBM vesicles in the presence of an initial 100 mmol/L (out > in) D-glucose gradient, whereas the glucose concentrations in the gut average between 0.4 and 24 mmol/L under normal conditions including postfeeding (7). The minor role of GLUT2 for the D-glucose uptake into the enterocytes is also indicated by the previous observation that D-glucose reabsorption after a high glucose load was not changed in GLUT2 knockout mice (8). To the best of our knowledge, an attempt to compare SGLT1-mediated and GLUT2-mediated D-glucose uptake across the BBM has only been performed once (3). In that study, Kellett and Helliwell measured glucose-dependent removal of D-glucose from perfused rat small intestines in the presence and absence of 0.2–1 mmol/L phloretin (see Fig. 2 in ref. 3). Glucose removal in the presence of phloretin, a hydrophobic GLUT2 inhibitor, was measured about 30 min after the addition of phloretin. Using this experimental setup, it cannot be excluded that phloretin also inhibits GLUT2 at the basolateral membrane since phloretin diffuses passively across plasma membranes. In later reviews, Kellett and coworkers always presented this initial experiment (Fig. 2 in ref. 4, Fig. 1 in refs. 5 and 6). In the quoted publication of Gouyon et al. (9), upregulation of GLUT2 in the BBM has been confirmed but neither GLUT2- nor SGLT1-mediated glucose uptake has been measured.

Whereas Kellett and Helliwell reported that the concentration of SGLT1 protein in BBMs of rat jejunum was not changed after perfusion with 100 mmol/L D-glucose (Fig. 3 in ref. 3), we observed that SGLT1 in small intestinal BBMs of mice was increased after gavage with D-glucose leading to an upregulation of SGLT1-mediated glucose uptake across the BBM. In the quoted article by Habold et al. (10), it is described that SGLT1 protein in total plasma membranes of rat small intestine was not changed when the animals were starved for 1–6 days, and no upregulation of SGLT1 was observed after refeeding. This difference to our results may be due to incomplete separation of BBMs and intracellular membranes.

Taking together the data reported in our article indicate that GLUT2 plays a minor role for D-glucose uptake across the BBM of the small intestine after high glucose load. Additional measurements in which GLUT2-mediated and SGLT1-mediated glucose uptake into BBM vesicles is directly compared are required to decide whether our observation is restricted to mice and/or to the employed experimental conditions.