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GLUT and SGLT: transport proteins and fructose malabsorption

GLUT and SGLT are transport proteins (carrier proteins) which are responsible for transporting certain substances through cell membranes. GLUT is an abbreviation for glucose-transporter, while SGLT is an abbreviation for „sodium-glucose linked transporter". The physiology as well as the exact functions and tasks of these transport proteins have not been fully examined yet. This means that it is not yet entirely clear by which mechanisms the different types of sugars are being absorbed into the body. There is heated debate amongst experts concerning this. Below is a summary of the current status, though only where relevant for fructose malabsorption.

Absorption of sugars from chyme (food mass)

A cell membrane is a barrier which is supposed to prevent the penetration of foreign substances into a cell. The body, however, needs to be able to absorb or emit certain substances into or from cells. Here there are different mechanisms in place in order to transport these substances through the cell membrane. In the case of transport proteins the active or passive substances can be channelled through the cell membranes of the cuticular layer (enterocytes). Several further factors might be required for this. The SGLT-1 transporter, for example, needs the sodium ion Na+. This sodium ion attaches itself to the transporter, which will then change its structure and only then can the glucose (together with the sodium) be transported through the cell membrane. The sodium can be described as the key which will unlock the door for the glucose.

Transport proteins are non-constant

These transport proteins are non-constant, which means that their production is dependent on need, time of day and age. If, for example, there is a lot of fructose in the chyme, then the SLC2A5 gene will be activated via a certain signal path in order to generate mRNA, which will then be translated into GLUT-5. Fructose can thus be absorbed. The body reacts to the supply of food by starting the corresponding absorption mechanisms. Thus GLUT are generated depending on the concentration of sugar in the chyme, amongst other things, and then transport the corresponding sugars into the cells of the small intestine, and then further into the blood. They are not embedded in the cell membrane, but are able to change their position (see example below).
Comment: mRNA is an abbreviation for Messenger-RNA. It is a copy of a certain gene segment created in the nucleus from which a protein can be produced via different processes.

GLUT-2 / SGLT-1

glut5-sglt-eng-webGLUT-2 is very effective at transporting glucose as well as mannose, galactose and fructose through the cell membrane. SGLT-1 transports glucose but not fructose. GLUT-2 is mainly present in liver cells, but also in many other organs such as for example the small intestine, where it is mainly responsible for the transport of glucose from the cells of the small intestine into the bloodstream. Glucose is however mainly absorbed from the intestine into the cells via SGLT-1. This process is dependent on sodium (Na+) which attaches to the SGLT-1 transporter in order to enable it to absorb glucose (and galactose) (4). If too much glucose is ingested with food then the GLUT-2 transporters can transfer to the cell membrane on the side of the small intestine or can also be newly generated on that side of the cell. Since it is possible for the GLUT-2 transporters to absorb fructose in addition, they can help to relieve the GLUT-5 transporters and thus also help to absorb fructose from the intestine.

GLUT-5 / GLUT-7

As outlined above, the quantity of GLUT-5 transporters also depends on the concentration of fructose in the chyme (3). GLUT-5 absorbs the fructose from the chyme and takes it to the small intestine cells. From here the fructose will reach the blood stream with the aid of the GLUT-2 transporters. The production of GLUT-5 is, however, not only dependent on the fructose in the chyme, but is also subjected to a circadian rhythm (2). In rats, for instance, the GLUT-5 is produced much more late in the day than early in the day. Thus the possibility arises that the time of day also may be of relevance to humans here. GLUT-7 is also capable of absorbing fructose from food (5), but it seems to only play a minor role in connection with the absorption of fructose.

What causes fructose malabsorption?

Now the important question remains: what mechanism is impaired in the case of fructose malabsorption? What is it that causes fructose malabsorption? Are the GLUT-5 transporters not functioning correctly? Are there not enough of these transporters around? Does the signal transmission not work and is therefore insufficient mRNA, and as a result insufficient transporters being produced? Or is the absorption of fructose impaired for another reason?
We don't know the answer (yet)! Anything is possible. It is also possible that there are various problems, the sum of which will result in the clinical picture of fructose malabsorption. Maybe there are two or three reasons, maybe even an undiscovered mechanism which could be to blame for the malabsorption of fructose. A lot of research still needs to be done in the near future.

Does sorbitol (E420) inhibit GLUT-5?

It has been mentioned again and again by different sources that sorbitol inhibits GLUT-5 and that it should thus be avoided by those affected by fructose malabsorption. Experience shows that sorbitol (and other sugar alcohols) do indeed have a negative influence on fructose malabsorption. Up to now there is a lack of scientific proof, especially in connection with the underlying mechanisms behind. These sugar alcohols should nonetheless be avoided.

Findings so far

Basics concerning the „glucose trick"

On the basis of the mechanism we have described above we know that glucose can help to absorb fructose:

  • On the one hand the GLUT-2 transporters will migrate to the lumen-side (apical) of the wall because of the high concentration of the glucose in the intestine, and since they transport fructose they are able to increase the absorption level of fructose from the intestine.
  • On the other hand glucose may have a positive effect on the production of GLUT-5 - similar to fructose ingestion being able to stimulate the production of GLUT-5. This in turn means that a complete avoidance of fructose would make the fructose malabsorption worsen, because the body has no more reason to produce GLUT-5.

Other findings

  • Sorbitol should be avoided because it is suspected of inhibiting the absorption of fructose by inhibiting the GLUT-5 transporter. It is not yet clear how this mechanism works, but experience shows that the connection exists.
  • Many patients are more successful in tolerating fructose in the afternoon. This may be connected to the circadian rhythm of the GLUT-5 expression.

Sources
[1] Castello A, Guma A, Sevilla L, Furriols M, Testar X, Palacin M, Zorzano A. Regulation of GLUT5 gene expression in rat intestinal mucosa: regional distribution, circadian rhythm, perinatal development and effect of diabetes. Biochem J 1995; 309 (Pt 1): 271-277 63
(2) Corpe, C.P., Burant, C.F., 1996. Hexose transporter expression in rat small intestine: effect of diet on diurnal variations. Am. J. Physiol. 271, G211–G216.
(3) Jiang, L., David, E.S., Espina, N., Ferraris, R.P., 2001. GLUT-5 expression in neonatal rats: crypt–villus location and age-dependent regulation. Am. J. Physiol. Gastrointest. Liver Physiol. 281 (3), G666–G674.
(4) Wright EM, Martin MG, Turk E. Intestinal absorption in health and disease--sugars. Best Pract Res Clin Gastroenterol 2003; 17: 943-956
(5) Li Q, Manolescu A, Ritzel M, Yao S, Slugoski M, Young JD, Chen XZ, Cheeseman CI. Cloning and functional characterization of the human GLUT7 isoform SLC2A7 from the small intestine. Am J Physiol Gastrointest Liver Physiol 2004; 287: G236-G242

Further literature:
• Drozdowski Laurie, Thomson Alan. Intestinal sugar transport. World J Gastroenterol 2006 March 21; 12(11):1657-1670
• Mueckler Mike, Thorens Bernard. The SLC2 (GLUT) family of membrane transporters. Molecular Aspects of Medicine 34 (2013) 121-138

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