Abstract
Background
Glucose absorption postprandially increases markedly to levels far greater than possible by the classic glucose transporter sodium–glucose cotransporter 1 (SGLT1).
Hypothesis
Luminal concentrations of glucose >50 mM lead to rapid, phenotypic, non-genomic adaptations by the enterocyte to recruit another transporter, glucose transporter 2 (GLUT2), to the apical membrane to increase glucose absorption.
Methods
Isolated segments of jejunum were perfused in vivo with glucose-containing solutions in anesthetized rats. Carrier-mediated glucose uptake was measured in 10 and 100 mM glucose solutions (n = 6 rats each) with and without selective inhibitors of SGLT1 and GLUT2.
Results
The mean rate of carrier-mediated glucose uptake increased in rats perfused with 100 mM versus 10 mM glucose to 13.9 ± 2.9 μmol from 2.1 ± 0.1 μmol, respectively (p < 0.0001). Using selective inhibitors, the relative contribution of GLUT2 to glucose absorption was 56% in the 100 mM concentration of glucose compared to the 10 mM concentration (27%; p < 0.01). Passive absorption accounted for 6% of total glucose absorption at 100 mM glucose.
Conclusion
A small amount of GLUT2 is active at the lesser luminal concentrations of glucose, but when exposed to concentrations of 100 mM, the enterocyte presumably changes its phenotype by recruiting GLUT2 apically to markedly augment glucose absorption.
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Acknowledgments
This work was supported in part by a grant from the National Institutes of Health-DK39337 (Dr. Sarr).
The authors wish to thank Deborah Frank for her expertise in preparing the manuscript for submission.
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Discussant
Dr. Stanley W. Ashley (Boston, MA): This was a terrific presentation of a well-designed and nicely conducted study examining what remains a relatively controversial hypothesis, i.e., that the GLUT2 transporter, traditionally believed to be primarily a basolateral membrane transporter, plays a role in apical glucose transport as well. Twenty years ago, this debate focused on the question of whether the apical sodium–glucose contransporter SGLT1 could explain all such transports or whether there was also some component of transport through the intercellular junctions with water, at least at high glucose concentrations. The hypothesis that GLUT2 also contributes to this is a relatively new one, and the authors have added significantly to the evidence supporting this and strengthened the argument that paracellular transport plays a minimal role. I have a couple of questions: (1) Phlorizin and phloretin seem equally effective in inhibiting transport at high glucose concentrations—does this mean that the inhibitors are less specific than we would hope or is there some interaction between the transporters? (2) Some investigators in this area have suggested that differences in species may explain some of the discrepancies between studies—do you think this is a rodent-only phenomenon or more generalizable? (3) Why have such a complex mechanism of acute adaptation? Would not it just be more simple to have the transporters there at all times rather than to insert them into the membrane only when glucose concentrations are high? Do the authors think this adaptation has any clinical significance?
Closing Discussant
Dr. Rizwan Chaudry: Thank you for the comments and excellent questions. In regard to your first question, phlorizin and phloretin at the concentrations used have been shown to be quite specific in their actions on transporters SGLT1 and GLUT2, respectively, as has been validated in several previous studies (Sarr et al. and Kellet et al.). Furthermore, in our current study, phlorizin and phloretin display significantly different effects on absorption at the 10 mM concentration of glucose, with phlorizin causing a much greater relative decrease in absorption as expected. The reason we see a similar effect on absorption (i.e., a significant decrease) with both inhibitors at the greater glucose concentration suggests that SGLT1 is necessary in GLUT2 translocation and may act as the rate-limiting step in the process; once translocated, however, GLUT2 accounted for the majority of the absorption (56%) at the greater concentration.
Although recent investigators have been studying intestinal glucose transport in vivo using a rat model, this phenomenon is not limited to this particular species. For example, a similar in vivo study was conducted in unanesthetized mongrel dogs in 1999 by Ashley et al. that showed paracellular transport to be minimal (2–5%) in its contribution to glucose absorption at supraphysiologic concentrations of glucose. Our experimental results for passive absorption at greater concentrations of glucose, although conducted in rats, paralleled what occurred in live dogs. Neither we nor to the best of our knowledge others have looked for this phenomenon in mice or other species.
Your third question, sir, is a bit more difficult to answer since we ourselves are trying to figure out the intricacies of this process. It may be that GLUT2 resides in the cytoplasm of the enterocyte and inserts to the apical membrane, or even the basolateral membrane, through an on-demand basis. As SGLT1, a high-affinity, low-capacity transporter becomes saturated, GLUT2, a low-affinity, high-capacity transporter, is rapidly available through activation of intracellular pathways involving a protein kinase C isoenzyme. The reason why GLUT2 just does not simply reside only at the apical membrane, and thus be readily available to transport glucose when luminal concentrations exceed 30 mM, could be because it may be needed in different amounts at the basolateral membrane as well, based on the amount of glucose needed to be absorbed systemically compared to the amount of glucose needed by the enterocyte itself for energy metabolism. Metabolic derangements such as hypo- or hyperglycemia may demand different amounts of GLUT2 to be readily available at certain locations of the cell Thus, a “pool” of GLUT2 deposits residing within the cytosol, being available on-demand for apical or basolateral glucose transport, makes sense.
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Chaudhry, R.M., Scow, J.S., Madhavan, S. et al. Acute Enterocyte Adaptation to Luminal Glucose: A Posttranslational Mechanism for Rapid Apical Recruitment of the Transporter GLUT2. J Gastrointest Surg 16, 312–319 (2012). https://doi.org/10.1007/s11605-011-1752-y
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DOI: https://doi.org/10.1007/s11605-011-1752-y