Does apical membrane GLUT2 have a role in intestinal glucose uptake? [v1; ref status: indexed, http://f1000r.es/4w6]

F1000Research 2014, 3:304 Last updated: 28 MAR 2022 REVIEW Does apical membrane GLUT2 have a role in intestinal glucose uptake? [version 1; peer review: 1 approved, 2 approved with reservations] Richard J. Naftalin Department of Physiology and BHF Centre of Research Excellence, King's College London, School of Medicine, London, SE1 9HN, UK v1 First published: 12 Dec 2014, 3:304 https://doi.org/10.12688/f1000research.5934.1 Latest published: 12 Dec 2014, 3:304 https://doi.org/10.12688/f1000research.5934.1 Abstract It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations. Open Peer Review Approval Status version 1 12 Dec 2014 1 2 3 view view view 1. George Kellett, University of York, York, UK 2. Hannelore Daniel, Technical University of Munich, Munich, Germany 3. Edith Brot-Laroche, Université Pierre et Marie Curie, Paris, France Any reports and responses or comments on the article can be found at the end of the article. Page 1 of 36 F1000Research 2014, 3:304 Last updated: 28 MAR 2022 Corresponding author: Richard J. Naftalin () Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2014 Naftalin RJ. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). How to cite this article: Naftalin RJ. Does apical membrane GLUT2 have a role in intestinal glucose uptake? [version 1; peer review: 1 approved, 2 approved with reservations] F1000Research 2014, 3:304 https://doi.org/10.12688/f1000research.5934.1 First published: 12 Dec 2014, 3:304 https://doi.org/10.12688/f1000research.5934.1 Page 2 of 36 F1000Research 2014, 3:304 Last updated: 28 MAR 2022 Introduction Intestinal glucose absorption has been studied for more than a century and still remains controversial. During the last fifty years the main research thrust has been to identify and characterize the individual transport components within the intestinal epithelium. This progressively reductivist approach has been very successful: we have a comprehensive knowledge of the nature of the driving forces generating sugar absorption; the specificity range of the sugar transporters involved; their sites of activity within the enterocytes and of how the individual transport processes function at a molecular level1–3. Less clear is how the intestine functions as a working ensemble to absorb glucose over the wide range of luminal concentrations occurring within the small intestine and how this process is controlled, both in the short and long-term. These uncertainties arise from the multiplicity and complexity of interactive processes and lack of a comprehensive model permitting an integrated view of intestinal glucose uptake. The early opinion on intestinal glucose transport was that stereospecific electrogenic active transcellular transport process coexisted with a variable non-specific paracellular diffusive flux4–8. Intestinal glucose absorption entails specific sodium-dependent hexose interactions with jejunal and ileal enterocyte glucose transporters in the apical and sodium-independent passive downhill transport via basal-lateral membranes and transit by solvent drag via nonselective paracellular pathways, generated by electro-osmotic flow of Na+ and water7,9,10, or by paracellular passive diffusion down the glucose concentration gradient existing between the intestinal lumen and lamina propria11,12. This diffusive route permits nonspecific transport of L-glucose, D-rhamnose, or mannitol, as well as D-glucose at rates that are correlated with net fluid transport13. The general consensus was that at around a luminal glucose ≈ 25 mM the active and passive components are about equal and above this passive absorption becomes dominant (Figure 1). This dual transport model explained why the apparent affinity of total net glucose uptake is much less, Km > 62.3±3.2 mM than the Km obtained for electrogenic glucose transport (Km = 17.9±0.4 mM); and why phloridzin, a blocker of Na-coupled glucose transport via SGLT1 at the luminal surface, affects mainly electrogenic transport, but not transport via the paracellular route4. Parsons and colleagues14,15 were amongst the first to postulate parallel active and passive absorptive processes in the luminal surface intestinal membrane. Kellett and colleagues1,16,17 later proposed that when luminal glucose is raised above 15 mM, that the non-saturable absorptive component, instead of being via the paracellular route is due to influx via a low affinity glucose transporter, GLUT2, whose presence is regulated within jejunal and ileal enterocytes apical membranes. The salient experimental evidence supporting this view is that the “non-saturable” component of glucose absorption is inhibited by either high phloretin (0.75–1 mM), or high cytochalasin B (0.2 mM) concentrations, both of which inhibit GLUT2 and neith (...truncated)