Intestinal hexose absorption: transcellular or paracellular fluxes

The currently accepted model of intestinal hexose transport (Fig. 1) has entry across the brush-border membrane (BBM) mediated by the sodium-dependent glucose-galactose transporter (SGLT1) and by the facilitated fructose transporter GLUT5. Exit of all three hexoses across the basolateral membrane (BLM) into the blood stream is mediated by another facilitated transporter, GLUT2. The absorption of hexoses by the small intestine in mammalian omnivores is a very efficient process which has a safety factor to ensure that hexoses do not spill over into the colon. The arrival of sugars in the lower bowel can produce diarrhoea resulting from an osmotically induced back-flux of water into the lumen or as the consequence of the increased nutrients driving a bacterial overgrowth. One mechanism designed to avoid this situation is the ability of the small intestine to increase its absorptive capacity for hexoses when their dietary load increases. If alterations in dietary carbohydrate are sustained for three or more days, expression of the transport proteins responsible for hexose absorption are altered in parallel (Ferraris, 2001). In addition, there is recent evidence to indicate that some transporter activity is regulated within the time course of a single meal (Cheeseman, 1997). However, these transcellular pathways for the intestinal absorption of hexoses have been calculated to have a limited capacity and appear to provide a rather low safety margin for the complete absorption of dietary carbohydrate (Lam et al. 2002). Madara & Pappenheimer (1987) proposed that additional transepithelial fluxes could be accounted for by paracellular solute movement carried by solvent drag, i.e. diffusion. This proposal generated a debate over the actual substrate concentrations achieved in the intestinal lumen during a carbohydrate rich meal, with a suggested range from 50 to 250 mm. However, this did little to settle the actual issue of whether the major proportion of hexoses cross the enterocytes mediated by transporter proteins or whether passage between the cells is nutritionally significant. It is clear that, when glucose transport is measured in vivo over a wide range of luminal concentrations, uptake has both a saturable, carrier-mediated component and an almost linear component which could represent diffusion. Several questions remain to be clarified with regard to this model. For example, it is important to determine how lactate affects spontaneous firing in different types of neurons, and how this is correlated with changes in intracellular ATP and KATP channel activity. Combining the cytosolic and submembrane measurements of ATP pioneered by Ainscow et al. (2002) with perforated patch recordings in the same cell within a brain slice will be the next step towards tackling such questions. Recently, a new model for hexose absorption has been proposed which could explain the majority of these experimental observations and which would indicate that hexose movement is almost exclusively transcellular. In this issue of The Journal of Physiology, Helliwell & Kellett (2002) provide compelling evidence that the majority of glucose absorption is carrier mediated. However, entry into the epithelium involves not only SGLT1 but also GLUT2, the low affinity facilitated hexose transporter previously believed to be only expressed in the BLM. Apparently, the expression of GLUT2 in the apical membrane is highly regulated through the activation of PKC βII when SGLT1 transports glucose. GLUT2 in the BBM would provide a high capacity, low affinity pathway for the entry of glucose, galactose and fructose into the epithelium, i.e. the so-called diffusional pathway. Thus, at the early stages of a meal, when the luminal concentrations of hexoses are high, entry would be rapid and obviate any need for non-specific paracellular fluxes. Helliwell & Kellett (2002) argue that this additional pathway has been frequently overlooked because of the sensitivity of apical GLUT2 expression to tissue stress such as luminal distention or poor oxygenation. Many classical techniques used in the past to investigate hexose absorption have employed high luminal perfusion rates, which cause distention, or involve significant handling of the tissue to gain access to the luminal surface. Such conditions induce the internalisation of apical GLUT2, down-regulating this entry pathway. Additional support for this new model comes from two sets of independent observations. The increased presence of GLUT2 has been detected in the rat jejunal BBM using immunohistochemistry (Au et al. 2002) in response to luminal glucose and/or vascular glucagon-like peptide 2. Also, the majority of glucose absorption in the dog small intestine has been shown to be carrier mediated and can be blocked by transport inhibitors (Pencek et al. 2002). Thus, as summarised in Fig. 2, it appears there are at least three paths of entry for hexoses into the intestinal epithelium, SGLT1, GLUT5 and GLUT2. Both SGLT1 and GLUT2 are highly regulated by the insertion or removal of transporter protein from the BBM in response to the presence of hexoses in the lumen. While I have retained a paracellular route, evidence would suggest that this may account for only 1–2 % of the total hexose fluxes during a meal. Also, the previously determined safety factors for hexose absorption need to be reassessed given that the total carrier-mediated capacity appears to have been significantly underestimated. These new ideas regarding the routes and regulation of hexose absorption will provide a fertile new area of investigation on how hexose transport proteins are targeted and trafficked to and from the intestinal BBM. The signalling pathways for these events also need to be defined in more detail and may provide useful loci for modulating absorption rates under a variety of conditions.

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