The Role of SGLT1 and GLUT2 in Intestinal Glucose Transport and Sensing

Pia V Röder,Bernard Thorens,Hannelore Daniel,Hermann Koepsell,Kerstin E Geillinger,Tamara S Zietek,Marià Alemany

doi:10.1371/journal.pone.0089977

Pia V Röder, Bernard Thorens + Show 5 more

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https://doi.org/10.1371/journal.pone.0089977

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Abstract

Intestinal glucose absorption is mediated by SGLT1 whereas GLUT2 is considered to provide basolateral exit. Recently, it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion. Moreover, SGLT1 and GLUT2 are suggested to play an important role in intestinal glucose sensing and incretin secretion. In mice that lack either SGLT1 or GLUT2 we re-assessed the role of these transporters in intestinal glucose uptake after radiotracer glucose gavage and performed Western blot analysis for transporter abundance in apical membrane fractions in a comparative approach. Moreover, we examined the contribution of these transporters to glucose-induced changes in plasma GIP, GLP-1 and insulin levels.In mice lacking SGLT1, tissue retention of tracer glucose was drastically reduced throughout the entire small intestine whereas GLUT2-deficient animals exhibited higher tracer contents in tissue samples than wild type animals. Deletion of SGLT1 resulted also in reduced blood glucose elevations and abolished GIP and GLP-1 secretion in response to glucose. In mice lacking GLUT2, glucose-induced insulin but not incretin secretion was impaired. Western blot analysis revealed unchanged protein levels of SGLT1 after glucose gavage. GLUT2 detected in apical membrane fractions mainly resulted from contamination with basolateral membranes but did not change in density after glucose administration.SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion. Our studies do not provide evidence for GLUT2 playing any role in either apical glucose influx or incretin secretion.

Highlights

The worldwide increase in obesity and diabetes mellitus type 2 [1] has brought new interest to the mechanisms by which dietary monosaccharides are absorbed in the intestine and to which extent these systems undergo diet-dependent regulation
Brush border membranes (BBM) were isolated from mucosal scrapings before and after intragastric glucose gavage
BBM were isolated from mucosal scrapings obtained from wild type as well as appropriate sglt1 and glut2 knockout mice before and after the glucose gavage followed by Western blot analysis and determination of protein densities

Summary

Introduction

The worldwide increase in obesity and diabetes mellitus type 2 [1] has brought new interest to the mechanisms by which dietary monosaccharides are absorbed in the intestine and to which extent these systems undergo diet-dependent regulation. Glucose derived either from hydrolysis of starch or from sucrose is taken up into the epithelial cell predominantly by the sodium-dependent glucose cotransporter SGLT1 [2,3,4]. Its pivotal role in glucose absorption is demonstrated by the inability of animals lacking SGLT1 to survive on glucose-containing diets. Sglt knockout mice maintained on a glucose2/galactose-free diet are viable, healthy and fertile they exhibit impaired intestinal glucose absorption [5]. Already in 1933, Wertheimer classified intestinal sugar transport as determined by two components – one inhibited by phlorizin (today known as the most potent SGLT1 inhibitor) and a phlorizin-insensitive part [7]. It was later demonstrated that the component inhibited by phlorizin was saturable and electrogenic in nature [8] and that it contributed to water absorption [9]

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