Natural sugars and artificial sweeteners are sensed by receptors in taste buds. T2R bitter and T1R sweet taste receptors are coupled through G-proteins, α-gustducin and transducin, to activate phospholipase C β2 and increase intracellular calcium concentration. Intestinal brush cells or solitary chemosensory cells (SCCs) have a structure similar to lingual taste cells and strongly express α-gustducin. It has therefore been suggested over the last decade that brush cells may participate in sugar sensing by a mechanism analogous to that in taste buds. We provide here functional evidence for an intestinal sensing system based on lingual taste receptors. Western blotting and immunocytochemistry revealed that all T1R members are expressed in rat jejunum at strategic locations including Paneth cells, SCCs or the apical membrane of enterocytes; T1Rs are colocalized with each other and with α-gustducin, transducin or phospholipase C β2 to different extents. Intestinal glucose absorption consists of two components: one is classical active Na + -glucose cotransport, the other is the diffusive apical GLUT2 pathway. Artificial sweeteners increase glucose absorption in the order acesulfame potassium ∼ sucralose > saccharin, in parallel with their ability to increase intracellular calcium concentration. Stimulation occurs within minutes by an increase in apical GLUT2, which correlates with reciprocal regulation of T1R2, T1R3 and α-gustducin versus T1R1, transducin and phospholipase C β2. Our observation that artificial sweeteners are nutritionally active, because they can signal to a functional taste reception system to increase sugar absorption during a meal, has wide implications for nutrient sensing and nutrition in the treatment of obesity and diabetes.

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.

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=1.6, [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.

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. Diabetes 54:3056 -3062, 2005

The debate over the mechanism of the passive component of glucose absorption Following the initial proposal of Crane et al. (1961), the mechanism of Na + -glucose cotransport became firmly established over the next 25 years; for a review, see Stevens et al. (1984). One simple, but vital, point for the debate over the passive component is that there was and remains common agreement that Na + -glucose cotransport saturates at 30-50 mM glucose in vivo. Yet there were numerous reports that glucose absorption increases almost linearly from 50 mM to several hundred millimolar (see Fordtran & Inglefinger, 1968). It appeared that there must be other mechanisms for the absorption of glucose.Indeed, there was already much evidence, accruing alongside and even predating this intense period of work on Na + -glucose cotransport, that there is also a significant passive component of glucose absorption. Many papers referred to K m values for glucose absorption of 100 mM or more (see Parsons & Prichard, 1966); typical data are to be found in Holdsworth & Dawson (1964), showing that glucose and fructose absorption increased almost linearly up to a concentration of 280 mM. As early as 1956, Fullerton & Parsons reported that glucose absorption in vivo comprised two components: one was constant and not associated with water absorption (now identified with SGLT1); the other was variable and approximately proportional to water absorption up to 246 mM. Manome & Kuriaki (1961) used phloridzin to inhibit Na + -glucose cotransport and showed that glucose absorption in vivo comprised phloridzinsensitive and phloridzin-insensitive components. Using this approach, Debnam & Levin (1975) defined glucose absorption as the sum of an active component saturating around 30-50 mM glucose, and a phloridzin-insensitive component described as 'passive' or 'diffusive', since it was broadly linear and appeared non-saturable; the passive component equalled the active one at about 26 mM and continued to increase up to 128 mM glucose. Ilundain et al. (1979) and Lostao et al. (1991) reported that the passive component was some 3-5 times greater than the active component at high glucose concentrations. One significant point is that all studies showing clear evidence for a significant passive component are in vivo studies. That suggests (with hindsight -see below) that there is a significant difference between in vivo and in vitro preparations.Nineteen eighty-seven was a pivotal year for studies of intestinal glucose absorption. Pappenheimer & Reiss (1987) proposed the theory of paracellular solvent drag as an explanation for the passive component of glucose absorption, and Hediger et al. (1987) cloned the Na + -glucose cotransporter SGLT1. The molecular era of intestinal glucose absorption had arrived and produced a profound change in the intellectual climate of the field, which was to ensure that the molecular biology of SGLT1 Over the last decade, a debate has developed about the mechanism of the passive or 'diffusive' component of intestinal glucose absor...