Intestinal incretin responses to increased GLUT2 expression – Chacun à son goût
Article first published online: 14 JUN 2012
© 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society
The Journal of Physiology
Volume 590, Issue 12, pages 2825–2826, June 2012
How to Cite
Naftalin, R. J. (2012), Intestinal incretin responses to increased GLUT2 expression – Chacun à son goût. The Journal of Physiology, 590: 2825–2826. doi: 10.1113/jphysiol.2012.233445
- Issue published online: 14 JUN 2012
- Article first published online: 14 JUN 2012
Innovative experimental methodologies leading to important and convincing new findings are rare and welcome events, particularly in the fields of in vitro and in vivo gastrointestinal (GI) physiology. In this issue of The Journal of Physiology, Mace et al. (2012) have achieved this feat by ingeniously adapting the venerable technique of single-pass luminal perfusion of isolated rat small intestine. In their preparation the serosal side of the tissue is immersed in liquid paraffin, so the relatively undiluted gut incretin peptides, gluco-insulinotropic peptide (GLP), glucagon-like peptide (GLP-1) and peptide tyrosine-tyrosine (PYY), present in trans-tissue transported fluid droplets are easily collected and serially analysed. Thus, a new, simple and potentially profitable way of investigating intestinal incretin responses to luminal and splanchnic neural stimulation has been uncovered.
Adaptive changes in gut absorption are complex and fraught with ambiguities that often give rise to dispute. Currently there are two salient issues: does the low-affinity glucose transporter, GLUT2, have a regulatory role in glucose absorption across the apical membrane of small intestinal enterocytes and does GLUT2 have a role in stimulating incretin release from enterocytes and/or enterochromaffin cells? This second question has been unequivocally answered by this current paper by Mace et al., at least in their rat model. Figure 1A and B show that phloridzin, an inhibitor of the Na+-dependent glucose transporter (SGLT1) inhibited GLP-1 release by 50%. A similar effect is produced by depleting the luminal solution of Na+ (Fig. 1D). In the presence of phloridzin, the remaining GLP-1 release is almost entirely inhibited by cytochalasin B or phloretin (Fig. 1A and B), which are potent inhibitors of GLUT2. Notably, they do not inhibit GLUT5, the fructose transporter, which is also present in the apical membrane. Thus, it appears that GLUT5 is not a necessary agent for incretin release. This leaves GLUT2 as the main alternative sugar, or sweetener-dependent intermediary of GLP-1 release (Fig. 1C). However, as a cautionary note, a recent study in healthy human subjects showed no alteration in plasma GLP-1 secretion or glucose absorption following intra-duodenal infusion of 4 mm sucralose together with very high glucose concentrations (Ma et al. 2010). Although the luminal glucose concentration used (280 mm) may obscure any possible synergism with sucralose, this study suggests that in humans at least, intestinal incretin secretion may be unrelated to GLUT2-mediated events at the brush border.
There are currently two favoured positions regarding up-regulation of glucose transport across small intestinal apical membranes following acute exposure to high glucose or glucose combined with sweeteners: regulation occurs secondary to increased SGLT1 expression, but not that of GLUT2, which is absent from the brush border at baseline (Shirazi-Beechey et al. 2011); the other view is that regulation occurs by two independent signals, one from SGLT1 and one from sweet taste receptors, which in combination increase the abundance of GLUT2 in the brush border (Mace et al. 2007; Gorboulev et al. 2012). The signal from SGLT1 is triggered by apical membrane depolarization leading to raised Ca2+ influx into the enterocytes and enterochromaffin cells (Mace et al. 2007; Gorboulev et al. 2012). In agreement with the current paper and a previous paper (Mace et al. 2007, 2012), Ait-Omar et al. (2011) showed that GLUT2 is up-regulated in this way and in fact is a major sensor of sweet taste within the brush borders of enterocytes and enterochromaffin cells from either obese Ob−/− mice or morbidly obese human subjects. They observed that 3-O-methyl glucose flux across enterocyte apical membranes was increased in the Ob−/− mice in vivo, and was sensitive to inhibition by cytochalasin B. Thus, although it appears that GLUT2 probably does have a role to play in glucose absorption, in contrast to the model espoused by Shirazi-Beechey, it remains an open question whether the up-regulation of intestinal brush border GLUT2 expression observed in obese mice and humans applies also to normal sized humans or other species. No matter what, there is little dissent about the later stages of the incretin release mechanism. Release is triggered by closure of tolbutamide-sensitive KATP channels (Fig. 1E) which subsequently raises cytosolic Ca2.
Another possible mechanism for the regulation of glucose uptake that has received little recent attention is that high luminal glucose concentrations lead to a raised submucosal osmolarity with enhanced paracellular solute flows of sugars, salt and water (Debnam & Levin, 1975). Osmotic pressure is a powerful force and stretch of the basal-lateral membranes due to widening and stretching of the lateral intercellular spaces could be a powerful independent stimulant to both incretin release and insertion of transporters into the brush border.
So this current paper by Mace et al. unlocks new ways of obtaining answers to intriguing, but until now elusive, questions, such as whether the incretin response is specific to particular luminal stimuli, from sugars, amino acids or lipids. Are the responses the same in all species? Do metabolic diseases affect the responses? We look forward expectantly to the answers.
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