There are two classes of glucose transporters involved in glucose homeostasis in the body, the facilitated transporters or uniporters (GLUTs) and the active transporters or symporters (SGLTs). The ...

Biology of Human Sodium Glucose Transporters

Intestinal glucose absorption comprises two components. One is classical active absorption mediated by the Na+/glucose cotransporter. The other is a diffusive component, formerly attributed to paracellular flow. Recent evidence, however, indicates that the diffusive component is mediated by the transient insertion of glucose transporter type 2 (GLUT2) into the apical membrane. This apical GLUT2 pathway of intestinal sugar absorption is present in species from insect to human, providing a major route at high sugar concentrations. The pathway is regulated by rapid trafficking of GLUT2 to the apical membrane induced by glucose during assimilation of a meal. Apical GLUT2 is therefore a target for multiple short-term and long-term nutrient-sensing mechanisms. These include regulation by a newly recognized pathway of calcium absorption through the nonclassical neuroendocrine l-type channel Cav1.3 operating during digestion, activation of intestinal sweet taste receptors by natural sugars and artificial sweeteners, paracrine and endocrine hormones, especially insulin and GLP-2, and stress. Permanent apical GLUT2, resulting in increased sugar absorption, is a characteristic of experimental diabetes and of insulin-resistant states induced by fructose and fat. The nutritional consequences of apical and basolateral GLUT2 regulation are discussed in the context of Western diet, processed foods containing artificial sweeteners, obesity, and diabetes.

Sugar Absorption in the Intestine: The Role of GLUT2

We tested whether the dominant intestinal sugar transporter GLUT2 was inhibited by intestinal luminal compounds that are inefficiently absorbed and naturally present in foods. Because of their abundance in fruits and vegetables, flavonoids were selected as model compounds. Robust inhibition of glucose and fructose transport by GLUT2 expressed in Xenopus laevis oocytes was produced by the flavonols myricetin, fisetin, the widely consumed flavonoid quercetin, and its glucoside precursor isoquercitrin. IC50s for quercetin, myricetin, and isoquercitrin were ∼200- to 1000-fold less than glucose or fructose concentrations, and noncompetitive inhibition was observed. The two other major intestinal sugar transporters, GLUT5 and SGLT1, were unaffected by flavonoids. Sugar transport by GLUT2 overexpressed in pituitary cells and naturally present in Caco-2E intestinal cells was similarly inhibited by quercetin. GLUT2 was detected on the apical side of Caco-2E cells, indicating that GLUT2 was in the correct orientati...

Inhibition of the intestinal glucose transporter GLUT2 by flavonoids

We have investigated the mechanism responsible for the diffusive component of intestinal glucose absorption, the major route by which glucose is absorbed In perfused rat jejunum in vivo, absorption was strongly inhibited by phloretin, an inhibitor of GLUT2 The GLUT2 level at the brush-border membrane increased some 2-fold when the luminal glucose concentration was changed from 0 to 100 mM The phloretin-sensitive or diffusive component of absorption appeared superficially linear and consistent with simple diffusion, but was in fact carrier-mediated and co-operative (n=16, [G(1/2)]=56 mM; where [G(1/2)] is the glucose concentration at half V(max)) because of the glucose-induced activation and recruitment of GLUT2 to the brush-border membrane Diffusive transport by paracellular flow was negligible The phloretin-insensitive, SGLT1-mediated, component of glucose absorption showed simple saturation kinetics with [G(1/2)]=27 mM: the activation of protein kinase C (PKC) betaII, the isoenzyme of PKC that most probably controls GLUT2 trafficking [Helliwell, Richardson, Affleck and Kellett (2000) Biochem J 350, 149-154], also showed simple saturation kinetics, with [G(1/2)]=21 mM We conclude that the principal route for glucose absorption is by GLUT2-mediated facilitated diffusion across the brush-border membrane, which is up to 3-fold greater than that by SGLT1; the magnitude of the diffusive component at any given glucose concentration correlates with the SGLT1-dependent activation of PKC betaII The implications of these findings for the assimilation of sugars immediately after a meal are discussed

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The diffusive component of intestinal glucose absorption is mediated by the glucose-induced recruitment of GLUT2 to the brush-border membrane

Understanding the mechanisms that determine postprandial fluctuations in blood glucose concentration is central for effective glycemic control in the management of diabetes. Intestinal sugar absorption is one such mechanism, and studies on its increase in experimental diabetes led us to propose a new model of sugar absorption. In the apical GLUT2 model, the glucose transported by the Na(+)/glucose cotransporter SGLT1 promotes insertion of GLUT2 into the apical membrane within minutes, so that the mechanism operates during assimilation of a meal containing high-glycemic index carbohydrate to provide a facilitated component of absorption up to three times greater than by SGLT1. Here we review the evidence for the apical GLUT2 model and describe how apical GLUT2 is a target for multiple short-term nutrient-sensing mechanisms by dietary sugars, local and endocrine hormones, cellular energy status, stress, and diabetes. These mechanisms suggest that apical GLUT2 is a potential therapeutic target for novel dietary or pharmacological approaches to control intestinal sugar delivery and thereby improve glycemic control.

https://diabetes.diabetesjournals.org/content/diabetes/54/10/3056.full.pdf

Apical GLUT2: a major pathway of intestinal sugar absorption.

1. The kinetics of absorption of glucose, galactose and alpha-methyl glucoside have been measured in rat jejunum in vivo using a chemical method and a new electrical technique. 2. Sugar absorption estimated by chemical methods exhibited two components. One component was phlorrhizin-sensitive, saturable and generated electrical potential differences (electrogenic active component) while the other was phlorrhizin-insensitive, non-saturable and did not generate electrical potentials (diffusive component). 3. The diffusive component of the actively transported sugars was indentical to the absorption behaviour of sorbose, a hexose that is not actively transferred. 4. A method for correcting the data obtained from chemical absorption studies for the diffusive component was developed. The corrected, operational kinetic constants for ‘apparent Km’ obtained by this method were not significantly different to values obtained electrically. The identity between the values obtained by both methods supports the concept that they represent a measure of the same rate-limiting step in the absorption process. 5. The application and significance of the techniques is discussed in relation to the clinical assessment of intestinal sugar absorption.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1975.sp010885

An experimental method of identifying and quantifying the active transfer electrogenic component from the diffusive component during sugar absorption measured in vivo.

R J Levin

Papers

An experimental method of identifying and quantifying the active transfer electrogenic component from the diffusive component during sugar absorption measured in vivo.