Glucose is an important source of nutrients for mammals. It not only provides energy but also serves as a substrate for large molecules such as glycoproteins, proteoglycans, glycolipids and nucleic acids. Hence it plays a major role in maintaining cellular homeostasis and cellular metabolism (Shirazi-Beechey, 1995).
The uptake of glucose by cells is accomplished with the help of carrier proteins present in the plasma membrane. They bind with glucose and then transport it across the lipid bilayer. Two types of carrier proteins have been identified in mammalian cells;
the Na+-coupled glucose cotransporters (SGLT)
the facilitative glucose transporter (GLUT)
The function of these transporters is to transport monosaccharides namely glucose, galactose and fructose from the lumen of intestine to the blood (Ferraris, 2001).
The products of carbohydrate digestion, D_glucose and D-galactose are transported from the lumen across the brush border into the cells by SGLT1 and accumulate there. These products are then passed from these cells into the systemic circulation via GLUT 2 down the concentration gradient (Shirazi-Beechey, 1995).
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The study of transport measurements and ligand-binding experiments suggest that there are more than one type of SGLT proteins however so far only one type has been found; the SGLT1 (Ferraris, 2001).
SGLT1 is present in the brush border or apical membrane of the intestinal epithelial cells and is responsible for transport of glucose and galactose along with Na+ ions into the cytosol from lumen of the intestine. This movement occurs against the concentration gradient and electrochemical gradient. This gradient is maintained by virtue of an active transport of Na+ out of the cell at basolateral membrane which is done by Na+/K+ active transport (Shirazi-Beechey, 1995).
This transporter favours hexose sugars with equatorial hydroxyl at position C2. Hence a number of natural dietary carbohydrates such as D-glucose and D-galactose and nonmetabolized
sugars, 3-O-methyl-a,~-glucopyranosidaen d methyl-a,D-glucopyranoside can be transported. Being a cotransporter it needs coupling which is only done with Na+ ions and other ions such as K+ and Li+ do not carry out this transport (Shirazi-Beechey, 1995).
The SGLT1 consists of 664 amino acids in humans. The secondary structure reveals that it spans the plasma membrane 12 times.
The Effect of Diet
It has been identified that dietary carbohydrates can alter the levels of intestinal brush border membrane Na+/glucose cotransporter. Advances in the molecular biology techniques have led to an increase in the understanding of the molecular mechanisms which regulate the transport of sugars via SGLT1.
Initial evidence came from animal studies and it was shown that when there is an increase in the carbohydrate content of diets given to rats and mice, the rate of transport of D-glucose across the intestinal wall also increased 2-3 old and was reversible. On further exploration, it was shown that when mice consuming a carbohydrate free diet were subsequently switched to a high carbohydrate diet, Na+-dependent D-glucose almost doubled in 24 hours. Similarly, when mice on a high carbohydrate diet were switched to a carbohydrate free diet, it took 1-3 days before brush border glucose uptake decreased significantly from control values (Shirazi-Beechey, 1995). An infusion of glucose in the sheep intestinal lumen that does not normally express SGLT or mRNA showed a marked increase in SGLT1 activity and abundance. However, mRNA was not increased therefore suggesting that the dietary regulation of SGLT1 expression is probably modulated by some translational or posttranslational mechanism (Ferraris, 2001).
In humans also, SGLT1 may be affected by diet (Dyer, 1997). It has been shown by various studies that the glucose transport was greater in the brush border membrane vesicles of normal intestinal tissues in contrast to the vesicles obtained from the adjoining dysfunctional tissue with decreased exposure to intestinal nutrients. This decreased transfer of glucose was a result of decreased expression of SGLT1 and was independent of morphology of the villus.
Changes in the level of Na+ also have an effect on the glucose transport in intestinal cells as was shown by the studies demonstrating that a decreased sodium intake in the diet reduces the intestinal transport of glucose reaching a maximum within 2 days (Garriga et al, 2000). However, a higher dietary Na+ was shown to have no effect.
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The Crypt-illus Axis
Enterocytes along the crypt-villus axis respond differently due to variations in the state of differentiation along the crypt villus axis. Expression of SGLT1 protein and SGLT1 mRNA along the crypt villus-axis has been studied using immunocytochemical and in situ hybridization techniques. Results indicated that SGLT1 protein was expressed along the entire length of villus but the onset of glucose transport occured near the crypt-villus junction ((Shirazi-Beechey, 1995).
Hence, in SGLT1 model, the activity in villus cells cannot be controlled by diet (Figure1); the time course of change as shown in the figure 1 is due to migration and differentiation of cells
Figure:1 A model of SGLT1 regulation by diet (Source: Ferraris, 2001)
These facilitated glucose transporters are found in all mammalian cells. Different isoforms of GLUT are from GLUT1 to GLUT 7.
GLUT 1 -4 have a properly categorised tissue distribution and they have a role in the movement of glucose across the plasma membrane in and out of the cells along its chemical gradient (Kellett et al, 2008). GLUT 5 has been recognized as a fructose transporter and has a ubiquitous presence while GLUT6 is a pesudogene and hence is without a product. GLUT7 has been reported to have a role in transport of glucose in endoplasmic reticulum of enterocytes.
GLUT2 has been discussed here owing to its primary role in glucose transport.
It has been widely accepted that GLUT2 is involved in the basolateral transport of sugar (Kellett et al, 200o). It has been proposed that GLUT5 controls the traffic at the brush-border membrane while GLUT2 controls the traffic at the basolateral membrane of the rat intestine (Ferraris, 2001).
A recent study suggested that GLUT2 is also present at the brush border of normal cells in rat intestine and plays a role in glucose and fructose transport. However, it has not been possible to confirm its presence in vitro as GLUT2 is assumed to be rapidly lost from the brush border membrane soon after removal of jejunum from the animal (Ferraris, 2001). A study by Kellet et al (2008) suggested that apical GLUT2 might be present which play an important role in intestinal absorption of glucose and fructose. They have also suggested that this recruitment of GLUT2 to apical surface or brush border is in response to dietary glucose and contributes towards the diffuse component of intestinal glucose absorption. This GLUT2 has therefore become a potential target for agents that can be used for therapy of diabetes and obesity (Kwon et al, 2007).
One of such studies attempted to test whether the major sugar transporters such as SGLT1, GLUT2 and GLUT5 can be inhibited by the intestinal luminal contents naturally present in food such as flavonoids which were tested in this study (Kwon et al, 2007). The results indicated that an effective inhibition of glucose and fructose transport by GLUT2 was done by commonly consumed flavonoids such as flavonols, myricetin and fisetin. This was a non-competitive inhibition. However, no such effect was observed in case of other significant sugar transporters which are SGLT1 and GLUT5.Â Therefore these flavonoids can play a vital role in coping with problems such as obesity and diabetes.
In an effort to investigate the diurnal pattern of activity among the hexose transporters, a study was carried out on rats as they have nocturnal feeding habits (Corpe and Burant, 1996). The levels of mRNA and proteins were determined for three major transporters i.e. SGLT1, GLUT2 and GLUT5. It was shown that the levels of GLUT-5, GLUT-2, and SGLT-1 mRNA vary in a diurnal fashion, with increased mRNA for each of these transporters and occurred before the onset of peak feeding although the exact mechanisms behind this variation remain to be elucidated. GLUT5 protein also increased although out of phase in comparison to GLUT5 mRNA however no diurnal variation was observed in GLUT5 protein. A fructose rich diet was accompanied by elevation in levels of GLUT5 mRNA and protein whereas there was significant effect on diurnal pattern of GLUT2 and SGLT mRNA.
It is evident from the above discussion that the intestinal transport of glucose is mediated by two major glucose transporters namely SGLT1 and GLUT2. SGLT1 is primarily responsible for transport of glucose from the lumen into the cytosol through the brush border via a Na+ coupled transport mechanism. GLUT2 functions to transport this glucose into the systemic circulation at the basolateral cellular border through facilitated diffusion. However, recent evidence identified the presence of an apical GLUT2 which is thought to be recruited in response to dietary glucose. These transporters are thought to have varying expressions in response to changing glucose pattern in diet. A glucose rich diet increases the SGLT1 proteins in enterocytes and therefore increased transport of glucose. A low salt (Na+) diet decreases the intestinal transport of glucose. Similarly, more dietary glucose increases the expression of GLUT2. Food substances like falvonoids inhibit the GLUT2 associated transport of glucose and hence are potential therapeutic agents in obesity treatment. Moreover, SGLT1, GLUT2 and GLUT5 mRNA have been shown to exhibit a diurnal variation in rats.
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