The facilitated component of intestinal glucose absorption

Abstract

Over the last decade, a debate has developed about the mechanism of the passive or 'diffusive' component of intestinal glucose absorption and, indeed, whether it even exists. Pappenheimer and colleagues have proposed that paracellular solvent drag contributes a passive component, which, at high concentrations of sugars similar to those in the jejunal lumen immediately after a meal, is severalfold greater than the active component mediated by the Na+-glucose cotransporter SGLT1. On the other hand, Ferraris & Diamond maintain that the kinetics of glucose absorption can be explained solely in terms of SGLT1 and that a passive or paracellular component plays little, if any, part. Recently, we have provided new evidence that the passive component of glucose absorption exists, but is in fact facilitated since it is mediated by the rapid, glucose-dependent activation and recruitment of the facilitative glucose transporter GLUT2 to the brush-border membrane; regulation involves a protein kinase C (PKC)-dependent pathway activated by glucose transport through SGLT1 and also involves mitogen-activated protein kinase (MAP kinase) signalling pathways. This topical review seeks to highlight the significant points of the debate, to show how our proposals on GLUT2 impact on different aspects of the debate and to look at the regulatory events that are likely to be involved in the short-term regulation of sugar absorption during the assimilation of a meal.

Figure 1. Excision of jejunum results in rapid loss of GLUT2 from the brush-border membrane

Three pairs of normal jejuna were each perfused with 5 mm fructose in vivo for 30 min and then for different times in vitro; pair 1 was not perfused further (0 min in vitro), pair 2 was perfused for 25 min in vitro and pair 3 was perfused for 60 min in vitro. Three pairs were perfused in the absence of PMA (no PMA, left-hand side) and three pairs in the presence of PMA (with PMA, right-hand side). After perfusion, trafficking was stopped by flushing with ice-cold perfusate, and brush-border membrane vesicles were prepared and blotted for GLUT2. As soon as jejunum from normal rats is excised, PKC is inactivated because of the loss of influence of endogenous hormones, and about 75 % of the GLUT2 is lost from the membrane within minutes. If, however, PKC remains active because the jejunum is perfused with PMA, then GLUT2 is not lost. All types of in vitro preparations from normal, untreated jejunum suffer loss of GLUT2 from the brush-border membrane and the passive component is not readily detectable; see text. Reproduced with permission from Helliwell et al. (2000a), Biochemical Journal 350, 149-154. © The Biochemical Society.

Figure 2. Brush-border membrane glucose absorption in rat jejunum in vivo comprises an active and a passive component

Total glucose absorption by rat jejunum in vivo (▪) comprises a phloretin-sensitive, GLUT2-mediated component (•) and a phloretin-insensitive, SGLT1-mediated component (▴). The value of [G_1/2] for the passive component was determined to be 56 ± 14 mm by fitting the data by non-linear regression analysis to a Hill-type equation: v = (V_max[G]^h)/(K+[G]^h), where V_max is the maximal rate of transport, [G_1/2] is the glucose concentration at half V_max, K =[G_1/2]^h and h is the Hill coefficient. Data for the active component were fitted to a simple Michaelis-Menten equation to give a K_m of 27 ± 7 mm. The corresponding theoretical lines for the passive and active components are shown together with the line for the total rate given by their sum. Reproduced with permission from Kellett & Helliwell (2000), Biochemical Journal 350, 155-162. © The Biochemical Society.

Figure 3. A working model for the regulation of the facilitated component of glucose absorption by glucose during the assimilation of sugars after a meal

This cartoon of our current working model shows the absorptive epithelial cell before (A) and after (B) a meal. Before a meal, the glucose concentration in the lumen is very low, being less than that in the blood. The level and intrinsic activity of GLUT2 are low, indicated by the pale yellow ellipse for GLUT2; absorption of glucose against its concentration gradient occurs through SGLT1. After a meal, high local concentrations of glucose are present at the microvilli from the hydrolysis of dissacharides, for example, by the action of isomaltase (IM) on maltose. Transport of glucose through SGLT1 results in activation of PKC βII and activation and recruitment of GLUT2 to the brush-border membrane, indicated by the bright yellow circle for GLUT2. The rate of absorption through GLUT2 is then severalfold greater than that through SGLT1. Transport of glucose through SGLT1 also results in contraction of the peri-junctional actomyosin ring (just below the tight junction), causing subtle rounding of the surface of the absorptive cell. Both processes may be mediated by a glucose-induced increase in intracellular Ca²⁺ concentrations. For further explanation see text.