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Does apical membrane GLUT2 have a role in intestinal glucose uptake?

Naftalin RJ - F1000Res (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and BHF Centre of Research Excellence, King's College London, School of Medicine, London, SE1 9HN, UK.

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.

No MeSH data available.


Related in: MedlinePlus

These diagrams show snapshots of the simulated glucose flows from intestinal lumen loaded with 50 mM in 150 mM NaCl to capillaries perfusing the submucosal spaces, whose afferent arterial concentration contains 150 mM NaCl and 5 mM D glucose.The tissue in panelA has low apical GLUT2 and GLUT5 activity and low capillary permeability and perfusion rates (clearance). In panelB the tissue apical membrane GLUT2 activity is increased by 4-fold above that in panelA, capillary perfusion is unchanged. In panelC, the apical GLUT2 activity is the same as in panelA, but capillary clearance is increased by 10-fold. In panelD, the apical GLUT2 is raised, as in panelB and the capillary clearance raised, as in panelC.The rates of glucose uptake are normalized relative to the rate of SGLT1 glucose uptake (panelA). Altering either GLUT2, or capillary clearance have negligible effects on glucose inflow via SGLT1. However, after raising the apical GLUT2 activity, the steady state glucose concentration within the cytosol decreases from 68 to 52 mM (c.f. PanelsA andC). On raising capillary clearance, the steady state of cytosolic glucose concentration also decreases (c.f. PanelA versus PanelC and PanelB versus PanelD).Raising capillary glucose clearance increases the rate of glucose inflow from the interstitial to capillary fluid by fourteen fold (c.f. PanelA andC). These changes are accompanied by decreased interstitial fluid glucose from 52 to 40 mM and reductions in the mean capillary glucose from 23 to 18 mM. Reduced interstitial glucose concentrations reverse the direction of the glucose gradient across the paracellular pathway from -2 to + 10 mM. Thus raising the capillary clearance of glucose, reverses the direction of paracellular glucose flow from (-0.38) to (+2.46) and increases the net glucose inflow across the luminal surface from (0.22 to 3.23).Although raising apical membrane GLUT2 activity by fourfold reduces net glucose influx across the apical border from 0.63 to 0.15, it also indirectly leads to an increase in paracellular glucose flux and thereby causes a slight increase in net glucose flux across the luminal border.When capillary clearance is raised, either by enhanced perfusion rates, or increased endothelial permeability, increasing apical membrane GLUT2 enhances apical membrane glucose reflux from -0.14 to -0.31. This has no significant effect on glucose flow from the interstitial to capillary fluid. (c.f. panelC andD).
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f1: These diagrams show snapshots of the simulated glucose flows from intestinal lumen loaded with 50 mM in 150 mM NaCl to capillaries perfusing the submucosal spaces, whose afferent arterial concentration contains 150 mM NaCl and 5 mM D glucose.The tissue in panelA has low apical GLUT2 and GLUT5 activity and low capillary permeability and perfusion rates (clearance). In panelB the tissue apical membrane GLUT2 activity is increased by 4-fold above that in panelA, capillary perfusion is unchanged. In panelC, the apical GLUT2 activity is the same as in panelA, but capillary clearance is increased by 10-fold. In panelD, the apical GLUT2 is raised, as in panelB and the capillary clearance raised, as in panelC.The rates of glucose uptake are normalized relative to the rate of SGLT1 glucose uptake (panelA). Altering either GLUT2, or capillary clearance have negligible effects on glucose inflow via SGLT1. However, after raising the apical GLUT2 activity, the steady state glucose concentration within the cytosol decreases from 68 to 52 mM (c.f. PanelsA andC). On raising capillary clearance, the steady state of cytosolic glucose concentration also decreases (c.f. PanelA versus PanelC and PanelB versus PanelD).Raising capillary glucose clearance increases the rate of glucose inflow from the interstitial to capillary fluid by fourteen fold (c.f. PanelA andC). These changes are accompanied by decreased interstitial fluid glucose from 52 to 40 mM and reductions in the mean capillary glucose from 23 to 18 mM. Reduced interstitial glucose concentrations reverse the direction of the glucose gradient across the paracellular pathway from -2 to + 10 mM. Thus raising the capillary clearance of glucose, reverses the direction of paracellular glucose flow from (-0.38) to (+2.46) and increases the net glucose inflow across the luminal surface from (0.22 to 3.23).Although raising apical membrane GLUT2 activity by fourfold reduces net glucose influx across the apical border from 0.63 to 0.15, it also indirectly leads to an increase in paracellular glucose flux and thereby causes a slight increase in net glucose flux across the luminal border.When capillary clearance is raised, either by enhanced perfusion rates, or increased endothelial permeability, increasing apical membrane GLUT2 enhances apical membrane glucose reflux from -0.14 to -0.31. This has no significant effect on glucose flow from the interstitial to capillary fluid. (c.f. panelC andD).

Mentions: 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 non-selective 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 non-specific 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).


Does apical membrane GLUT2 have a role in intestinal glucose uptake?

Naftalin RJ - F1000Res (2014)

These diagrams show snapshots of the simulated glucose flows from intestinal lumen loaded with 50 mM in 150 mM NaCl to capillaries perfusing the submucosal spaces, whose afferent arterial concentration contains 150 mM NaCl and 5 mM D glucose.The tissue in panelA has low apical GLUT2 and GLUT5 activity and low capillary permeability and perfusion rates (clearance). In panelB the tissue apical membrane GLUT2 activity is increased by 4-fold above that in panelA, capillary perfusion is unchanged. In panelC, the apical GLUT2 activity is the same as in panelA, but capillary clearance is increased by 10-fold. In panelD, the apical GLUT2 is raised, as in panelB and the capillary clearance raised, as in panelC.The rates of glucose uptake are normalized relative to the rate of SGLT1 glucose uptake (panelA). Altering either GLUT2, or capillary clearance have negligible effects on glucose inflow via SGLT1. However, after raising the apical GLUT2 activity, the steady state glucose concentration within the cytosol decreases from 68 to 52 mM (c.f. PanelsA andC). On raising capillary clearance, the steady state of cytosolic glucose concentration also decreases (c.f. PanelA versus PanelC and PanelB versus PanelD).Raising capillary glucose clearance increases the rate of glucose inflow from the interstitial to capillary fluid by fourteen fold (c.f. PanelA andC). These changes are accompanied by decreased interstitial fluid glucose from 52 to 40 mM and reductions in the mean capillary glucose from 23 to 18 mM. Reduced interstitial glucose concentrations reverse the direction of the glucose gradient across the paracellular pathway from -2 to + 10 mM. Thus raising the capillary clearance of glucose, reverses the direction of paracellular glucose flow from (-0.38) to (+2.46) and increases the net glucose inflow across the luminal surface from (0.22 to 3.23).Although raising apical membrane GLUT2 activity by fourfold reduces net glucose influx across the apical border from 0.63 to 0.15, it also indirectly leads to an increase in paracellular glucose flux and thereby causes a slight increase in net glucose flux across the luminal border.When capillary clearance is raised, either by enhanced perfusion rates, or increased endothelial permeability, increasing apical membrane GLUT2 enhances apical membrane glucose reflux from -0.14 to -0.31. This has no significant effect on glucose flow from the interstitial to capillary fluid. (c.f. panelC andD).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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f1: These diagrams show snapshots of the simulated glucose flows from intestinal lumen loaded with 50 mM in 150 mM NaCl to capillaries perfusing the submucosal spaces, whose afferent arterial concentration contains 150 mM NaCl and 5 mM D glucose.The tissue in panelA has low apical GLUT2 and GLUT5 activity and low capillary permeability and perfusion rates (clearance). In panelB the tissue apical membrane GLUT2 activity is increased by 4-fold above that in panelA, capillary perfusion is unchanged. In panelC, the apical GLUT2 activity is the same as in panelA, but capillary clearance is increased by 10-fold. In panelD, the apical GLUT2 is raised, as in panelB and the capillary clearance raised, as in panelC.The rates of glucose uptake are normalized relative to the rate of SGLT1 glucose uptake (panelA). Altering either GLUT2, or capillary clearance have negligible effects on glucose inflow via SGLT1. However, after raising the apical GLUT2 activity, the steady state glucose concentration within the cytosol decreases from 68 to 52 mM (c.f. PanelsA andC). On raising capillary clearance, the steady state of cytosolic glucose concentration also decreases (c.f. PanelA versus PanelC and PanelB versus PanelD).Raising capillary glucose clearance increases the rate of glucose inflow from the interstitial to capillary fluid by fourteen fold (c.f. PanelA andC). These changes are accompanied by decreased interstitial fluid glucose from 52 to 40 mM and reductions in the mean capillary glucose from 23 to 18 mM. Reduced interstitial glucose concentrations reverse the direction of the glucose gradient across the paracellular pathway from -2 to + 10 mM. Thus raising the capillary clearance of glucose, reverses the direction of paracellular glucose flow from (-0.38) to (+2.46) and increases the net glucose inflow across the luminal surface from (0.22 to 3.23).Although raising apical membrane GLUT2 activity by fourfold reduces net glucose influx across the apical border from 0.63 to 0.15, it also indirectly leads to an increase in paracellular glucose flux and thereby causes a slight increase in net glucose flux across the luminal border.When capillary clearance is raised, either by enhanced perfusion rates, or increased endothelial permeability, increasing apical membrane GLUT2 enhances apical membrane glucose reflux from -0.14 to -0.31. This has no significant effect on glucose flow from the interstitial to capillary fluid. (c.f. panelC andD).
Mentions: 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 non-selective 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 non-specific 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).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and BHF Centre of Research Excellence, King's College London, School of Medicine, London, SE1 9HN, UK.

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.

No MeSH data available.


Related in: MedlinePlus