Continued Glucose Transport Into Cells Lining the Lumen of the Small Intestine Requires a

Glucose/Sugar Transport in Bacteria

L. Guan , H.R. Kaback , in Encyclopedia of Biological Chemistry (Second Edition), 2013

SglT

SglT of V. parahaemolyticus, encoded by the sglS gene, consisting of 543 amino acid residues, has 14-transmembrane helices with extracellular N and C termini. The bacterial SglT catalyzes Na⁺-dependent sugar transport, with sugar preferences (galactose   >   glucose   >   fucose). The structural core is formed from two five-helix inverted repeats, helices II–IV and VII–XI. Different from the MFS, the co-substrate binding sites in the SglT are located in two connected pockets in the middle of the molecule ( Figure 2 ). Expression and function of SglT is not regulated by PTS. Human homologs of SglT are expressed primarily in the epithelia of the small intestine and the kidney where they play important roles in the physiology of these organs.

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CARBOHYDRATES | Digestion, Absorption, and Metabolism

D.H. Alpers , in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

Fructose Absorption

Fructose transport occurs by an Na⁺-independent, saturable system of lower capacity than that for glucose or galactose. The capacity for fructose absorption in humans is limited, although theoretical estimates of absorption capacity are relatively high. GLUT5 mediates all or most of fructose transport across the apical membrane of enterocytes. Human GLUT5 transports fructose alone, but the rat homolog recognizes both glucose and fructose. However, absorption of fructose in humans can be inhibited by the presence of glucose. Thus, it is possible that a second apical fructose transporter exists. Unlike the relatively wide tissue distribution in humans (Table 3), rat GLUT5 is expressed largely in the small bowel, kidney, and brain. Fructose is poorly metabolized in the enterocyte, and is transported from the cell by basolateral GLUT2, and in humans by basolateral GLUT5 as well. Expression of GLUT5 is increased in animals fed fructose. This adaptation accompanies the increase in sucrase-isomaltase found after fructose or sucrose feeding.

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Anatomy and physiology of blood-brain barrier

Smriti Gupta , ... Rajat Sandhir , in Brain Targeted Drug Delivery System, 2019

6.2 Hexose transport system

Hexose transport system is a family of transporters that allows movement of structural analogous of hexose across the BBB. Glucose, the sole energy source, is transferred through these transporters. These transporters apparently have high capacity of transferring drugs due to its significantly higher capacity of transferring glucose than other transporters ( Pardridge, 1983). These hexose transporters are classified under two categories: (1) Sodium-dependent transporter that is secondary active transport system. (2) Sodium-independent transporter or facilitated transporter which are molecularly classified into sodium-glucose transport proteins (SGLT)/SLC5 and GLUT/SLC2A families, respectively. It has been observed that GLUT1 gene is selectively expressed in the brain capillary endothelial cells, where 100% of the glucose transporter-binding sites at the BBB can be attributed to the GLUT1 isoform that functions to transport glucose independent of insulin (Pardridge et al., 1990). These transporters are membrane spanning glycoproteins containing 12 transmembrane domains and play a vital role in glucose uptake in brain (Carruthers et al., 2009). Hypoglycemic conditions inside the cells leads to up-regulation of GLUT1 transporters (Devaskar et al., 1991). Transport of sugar across the BBB and brain energy status can be controlled by the regulation of surface GLUT1 expression (Simpson et al., 2001). From the clinical perspective, GLUT1 is highly upregulated at BBB in patients with seizures and downregulated in Alzheimer's disease and diabetes (Barar et al., 2016a, b). We have also observed the decreased mRNA expression of these GLUTs (GLUT1 and GLUT3) in in vitro and in vivo models of sporadic Alzheimer's disease (Gupta et al., 2018). In addition, it has been observed that mutations in GLUT1 may lead to deficiencies in the transportation of glucose in the related disorders. Other than GLUT1, GLUT4 and neuron-specific GLUT3 transporter are expressed for regulated glucose uptake inside cell. These transporters have significance in the delivery of membrane-impermeable compounds and drugs that are structural analogues of sugar. It is proposed that glycosylation of peptides helps in stabilizing the peptides which assist their penetration through BBB (Negri et al., 1998).

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Volume 2

Ernest M. Wright , ... Donald D.F. Loo , in Physiology of the Gastrointestinal Tract (Sixth Edition), 2018

46.3.1 Physiological Importance of SGLT1 and GLUT2

While the basic model for glucose, galactose, and fructose transport across enterocytes (Fig. 46.3) is generally accepted, there are questions about the mechanism of glucose absorption at high concentrations in vivo. The basic observation is that absorption increases linearly with concentration up to 50–500   mM. George Kellett has championed the hypothesis that passive absorption is due to the insertion of GLUT2 into the brush border membrane (pathway #7 in Fig. 46.3). ²⁵ The hypothesis is controversial, especially since other investigators have not been able to detect GLUT2 in the brush border membrane.

OGTT tests in Glut2-null mice (Fig. 46.7) gave results indistinguishable from those in wild-type mice (Fig. 46.2) suggesting that GLUT2 does not play a significant role in glucose absorption. ⁷ Similar conclusions have emerged from studies on intestinal glucose absorption in patients with the Fanconi-Bickel syndrome. ²⁶ These patients have a massive glycosuria, but with a normal oral glucose tolerance ⁸ and the authors postulate the presence of other glucose transport pathways across the intestinal basolateral membrane.

Fig. 46.7. OGTT in Glut2-null mice. These OGTTs on Glut2-null mice were conducted before and after phlorizin pretreatment. Compare these results with the OGTTs on wild-type mice (Fig. 46.2).

(Redrawn from Stumpel F, et al. Normal kinetics of intestinal glucose absorption in the absence of GLUT2: evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum. Proc Natl Acad Sci U S A 2001;98(20):11330–5.)

OGTTs in Sglt1-null mice provide valuable information on the role of SGLT1 and GLUT2 in the intestinal glucose absorption in fully conscious animals. Fig. 46.8 shows such a test in Sglt1-null mice. It is clear that the absence of SGLT1 blunts, but does not eliminate, the rise in plasma glucose. ²⁹ Similar observations are reported in two other OGTTs on Sglt1-null mice. ^27,28 These results point to another mechanism of glucose absorption.

Fig. 46.8. OGTT in Sglt1-null mice. These experiments show the differences in plasma glucose following OGTTs in Sglt1-null and wild-type mice. Similar results were obtained in 60   min OGTTs performed by Powell et al. ^27,28

(Redrawn from Gorboulev V, et al. Na ⁺-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 2012;61(1):187–96.)

To address the question on the importance of SGLT1 and GLUT2 in vivo we have developed a method to follow glucose absorption in real time using PET and specific glucose tracers for SGLTs and GLUTs. Me-4FDG is specific for SGLTs and 2-FDG is specific for GLUTs. ³⁰ Our approach is to carry out microPET OGTTs in wild-type, Sglt1-null, and Glut2-null mice, and follow the distribution of tracers throughout the entire animal, conscious or anesthetized. Fig. 46.9 shows microPET studies with Me-4FDG and 2-FDG on anesthetized wild-type mice after being administered 2   g/kg of glucose containing 300   μCi of Me-4FDG (top) or 2-FDG (bottom) by oral gavage. The PET data were continuously acquired for 1   h, and this was followed with a CT scan.

Fig. 46.9. MicroPET analysis of OGTT in mice. 300   μCi Me-4FDG (top) or 2-FDG (bottom) were administered by oral gavage into the stomach of anesthetized wild-type mice, and continuous PET data were acquired over the following 60   min; a CT scan was performed at the end of the dynamic PET scan. Volumetric renderings of co-registered images at selected times after bolus administration for two representative experiments are shown. The PET images are displayed according to the NIH intensity scale for tracer activity, from red (highest) to green (intermediate) to purple (lowest). Stomach (st), intestine (in), and urinary bladder (bl) are indicated where visible.

(Monica Sala-Rabanal and Chiara Ghezzi (unpublished).)

The images at selected time intervals show that much of the Me-4FDG sugar remained in the stomach (40% after 1   h), and all the sugar that entered the small intestine was completely absorbed within 5   min. In the Sglt1-null mice similar amount of Me-4FDG remained in the stomach after 1   h, but absorption from the intestine was delayed (half-time 50   min) (not shown). Phlorizin also slowed the rate of intestinal absorption, but 90% of the glucose that entered the small intestine was absorbed by 1   h (not shown). Interestingly, the excretion of Me-4FDG into the urinary bladder increased from 0.3% to 18% in 1   h, and this partially accounts for the effect of phlorizin (1   mg/kg) on blood glucose levels in the OGTT (Fig. 46.2).

In the 2-FDG microPET experiment (Fig. 46.9, bottom) the amount of sugar remaining in the stomach after 1   h was comparable to that for Me-4FDG, but 2-FDG was still observed in the small intestine for up to 60   min. However, 75% of the sugar entering the intestine was absorbed by the end of the hour. In contrast to Me-4FDG, up to 20% of the absorbed 2-FDG appeared in the urinary bladder in 1   h, because 2-FDG is not a substrate for SGLTs in the proximal tubule. ³⁰ In the Glut2-null mice, 2-FDG absorption was not substantially lower than that in wild-type mice (not shown).

These OGTT microPET studies in mice suggest that: (1) the rate of gastric emptying in OGTTs impacts the appearance of glucose in blood; (2) SGLT1 plays an important role in the fast absorption of glucose that enters the small intestine; (3) in the absence of SGLT1 glucose is absorbed, albeit more slowly; and (4) oral doses of phlorizin are absorbed and can inhibit SGLT in the reabsorption of glucose from the glomerular filtrate. In addition, the absorption of 2-FDG is near completion in 1   h in both wild-type and Glut2-null mice. The overall conclusions are that SGLT1 is crucial for the fast absorption of an OGTT load of glucose, while GLUT2 is of lesser importance.

In addition to sugars, SGLT1 plays a major role in the absorption of water, 6–7   L per day. First, SGLT1 accounts for a large fraction of the osmotic water flow across the small intestine. We have found that the pathway for osmotic water flow follows that for Na⁺ and sugar transport across SGLT1, and that phlorizin blocks 60%–70% of the osmotic flow across the mouse small intestine. ³¹ Second, water transport is intimately coupled to Na⁺ glucose cotransport ^6,32 . Initially, we claimed that SGLT1 was a water pump, but an alternative explanation is that water flow is due to local osmosis generated by Na⁺/glucose cotransport. Irrespective of the precise molecular mechanism, we estimate that the SGLT1 accounts for ~   5   L of fluid absorption across the intestine each day. Overall, water interactions play a key role in the physiology of SGLT1 from the binding and transport of sodium and glucose to water transport.

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Sugar Absorption

Ernest M. Wright , ... Bruce A. Hirayama , in Physiology of the Gastrointestinal Tract (Fifth Edition), 2012

58.5.3 GLUT5

(1) The kinetics, specificity, and inhibition of fructose transport into brush border membrane vesicles and across the brush border membrane in intact tissues agree closely with those for fructose transport by GLUT5 in heterologous expression systems. (2) GLUT5 is expressed in the small intestine. (3) GLUT5 antibodies immunoreact with intestinal brush border membranes. (4). There is a good correlation between the level of GLUT5 mRNA and protein in the small intestine and the level of fructose transport in rodents as a function of development and diet. ⁸

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Gastrointestinal Digestion and Absorption

N.V. Bhagavan , Chung-Eun Ha , in Essentials of Medical Biochemistry (Second Edition), 2015

Intolerance of Other Carbohydrates

Intolerance to sucrose and α-limit dextrins may be due to deficiency of sucrase-α-dextrinase or to a defect in glucose–galactose transport. These disorders are rare autosomal recessive traits; clinical problems can be corrected by removing the offending sugars from the diet. Lactulose, a synthetic disaccharide consisting of galactose and fructose with a β(1→4) linkage, is hydrolyzed not in the small intestine but in the colon, and is converted to products similar to those derived from lactose fermentation. It has been used in the treatment of patients with liver disease. Normally, ammonia (NH₃) produced in the GI tract is converted in the liver to urea (Chapter 15); hence, in patients with severe liver disease, blood ammonia levels increase. Absorption of ammonia can be decreased by administration of lactulose, which acidifies the colonic constituents so that NH₃ is trapped as ${\text{NH}}_4^{+}$ ions (Chapter 8).

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Carbohydrate Digestion and Absorption

Eric Sibley , in Encyclopedia of Gastroenterology, 2004

Fructose Transport

The fructose monosaccharide is transported across the intestinal brush border membrane via a Na⁺-independent facilitated diffusion mechanism. GLUT5 is a 501-amino-acid transmembrane protein that transports fructose and glucose molecules. Fructose is transported from the enterocyte into the portal circulation via the basolateral membrane GLUT2 transporter. Fructose is not as well absorbed as is glucose. Consequently, ingestion of high levels of fructose in the diet can lead to carbohydrate intolerance. In children, drinking excessive amounts of juices high in fructose may result in nonspecific diarrhea and recurrent abdominal pain. In adults, fructose malabsorption has been associated with irritable bowel syndrome.

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DIGESTION AND ABSORPTION

Margaret E. Smith PhD DSc , Dion G. Morton MD DSc , in The Digestive System (Second Edition), 2010

Hexose transport

The uptake of glucose across the enterocyte plasma membrane involves the binding of glucose to the Na⁺/glucose cotransporter SGLT1, as described in Chapter 7. SGLT1 is present only in mature enterocytes in the upper regions of the villi. Galactose also binds to this carrier, but fructose does not. Glucose and galactose transport into the epithelial cell is via secondary active transport. The energy required is derived from the coupling of sugar transport to the transport of Na⁺ down the concentration and electrical gradients from the lumen into the cell. Both Na⁺ ions and the sugar are transported into the cell on the SGLT1 transporter. This represents a major route for the uptake of both the sugar and Na⁺ into the enterocyte. Thus the uptake of glucose is stimulated by the presence of Na⁺ in the intestinal chyme. The affinity of the carrier for glucose increases as the luminal Na⁺ concentration increases. The Km of SGLT1 in the presence of Na⁺ is less than 0.5   mM, but in its absence it is greater than 10   mM. The absorption of glucose is illustrated schematically in Figure 8.9. Each carrier molecule binds two Na⁺ ions and one glucose molecule. The glucose concentration in the cell may be higher than that in the lumen but the coupling of the transport of glucose with that of Na⁺, enables glucose to be transported into the cell against a concentration gradient.

Fructose does not bind to SGLT1 in the brush border. It is transported into the enterocyte, down its concentration gradient by GLUT5 (which does not transport glucose, Fig. 8.9). The separate pathways for glucose and fructose transport into the enterocyte can be inferred from the fact that normal fructose absorption is present in patients with inherited glucose-galactose malabsorption (see Box 8.1), and this provides the rationale for the treatment of this condition with fructose. GLUT5 is present only in mature enterocytes on the tips and sides of the villi in the jejunum.

Some glucose is utilized by the cell for its energy requirements. The transport of the remaining glucose, galactose and fructose across the basolateral membrane is accomplished by the GLUT2 transporter, which has a low-affinity for glucose (Km 23   mM). The presence of this low-affinity transporter allows the rate of glucose transport through the basolateral membrane to increase in proportion to the glucose concentration, which varies from 5   mM (the normal value) to 20   mM. GLUT1 is also present in enterocytes but its function is unclear. It is a high-affinity transporter that functions close to the Vmax even at normal blood concentrations. It may participate in the release of glucose at the basolateral border. However, in other tissues, such as the kidney tubules, where it is present in the basolateral membranes its function appears to be to provide the cells with a source of metabolic energy derived from the blood. Its function in the enterocyte may therefore be to provide glucose from the blood for metabolism during periods of fasting when it is not being absorbed from the intestinal lumen. The locations of the different transporters in the enterocyte are illustrated in Figure 8.9.

Malabsorption of carbohydrate is a feature of coeliac disease that involves damage to the mucosa of the proximal small intestine (see Case 8.1: 3).

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Nutrient Transport, Regulation of

Ronaldo P. Ferraris , in Encyclopedia of Gastroenterology, 2004

Macronutrients

Carbohydrates

The final products of carbohydrate digestion are glucose, galactose, and fructose. Glucose and galactose enter the intestinal cells across the brush border membrane via the sodium/glucose-dependent cotransporter 1 (SGLT1), whereas fructose is absorbed by the glucose transporter (GLUT5). In mammals with omnivorous diets, the number of SGLT1 and GLUT5 copies typically varies by two- to fourfold, and is correlated with dietary carbohydrate concentrations. In carnivores, the abundance of SGLT1 is low, and little regulation occurs. In most vertebrates, site density of SGLT1 and therefore glucose transport rate increase within 24 hours after increases in levels of dietary carbohydrate.

The proposed mechanism involves an increase in the number of brush border glucose transport systems in young cells located in the lower regions of intestinal villi. Intestinal glucose transport rate gradually increases as these cells migrate up the villus and replace cells that have a lower number of glucose transporters. The change in transport rate is complete when cells with more transporters have replaced all cells with few transporters.

The magnitude of diet-induced changes in site density of GLUT5 is typically greater than that of SGLT1, suggesting that average luminal fructose concentrations undergo wider fluctuations. The proposed mechanism underlying changes in intestinal fructose transport involves changes in the number of GLUT5 copies in all cells lining the villus. Although changes in the time course of glucose transport are dependent on transporter synthesis and cell migration rate, the time course of changes in fructose transport is dependent only on transporter synthesis. As a consequence, the time course of a diet-induced change in fructose transport is typically more rapid, in the range of 4–8 hours.

Changes in number of SGLT1 are brought about by increases in concentrations of many types of sugars, including galactose, fructose, mannose, xylose, glucose, and even some nonmetabolizable analogues of glucose. Because Na⁺ is also a substrate of SGLT1, increases in dietary Na⁺ concentration have been shown to increase glucose absorption. The signal to increase GLUT5 transporter number is only dietary fructose (or sucrose, which contains fructose) and is therefore quite specific.

Glucose, galactose, and fructose all share the basolateral sugar transporter GLUT2, which mediates the exit of sugars from the cytosol to the blood. Although there is no transepithelial glucose transport in the absence of SGLT1, there is glucose and fructose transport in GLUT2 −/− mice, indicating that an alternative basolateral pathway for sugars exists and that SGLT1 is the rate-limiting step in transepithelial glucose transport. Like GLUT5, site density of GLUT2 transporters also increases within a few hours following increases in dietary carbohydrate, but the mechanisms underlying dietary regulation are not known. Both luminal glucose and fructose can up-regulate GLUT2 mRNA and activity in all enterocytes located in the low to upper regions of the villus, and changes in transporter number have been shown to be dependent mainly on transporter synthesis and subsequent translocation to the basolateral membrane.

Proteins

Amino Acids

Transport of amino acids is accomplished by at least seven families of transporters, each family having several types or isoforms with overlapping specificities for different substrates. Many of these transporters are heterodimeric, such that a heavy-chain subunit is linked by disulfide bridges to a light-chain subunit. There are two known families of heavy subunits and at least five families of light subunits, and any light subunit can pair with any heavy subunit. The result is a large variety of amino acid transporters with overlapping specificities so that many types of amino acids can be transported by a single transporter, and thus a single type of amino acid can be transported by different transporters.

There are two typical ways of categorizing amino acid transporters, including by a transporter's dependence on the Na⁺ gradient and by its substrates. Imino and acidic amino acids each have a carrier family with subtypes dedicated to transport these substrates, but basic and neutral amino acids are thought to share several transport systems. The large number of amino acid transporters complicates any study related to their regulation.

Although sugar absorption rates typically vary in parallel with luminal concentration of carbohydrate digestion products, the absorption of amino acids does not always vary monotonically with dietary protein concentration. There are several explanations for this observation, and they involve the fact that all amino acids can yield energy and that some amino acids are required (essential) nutrients whereas others are toxic at high concentrations. At concentrations above minimum dietary requirements, absorption of essential amino acids increases with dietary protein, unless those amino acids are potentially toxic. Absorption of potentially toxic amino acids either does not increase or increases only modestly with dietary protein levels. Below minimum dietary requirements, absorption of essential amino acids typically increases, suggesting a regulatory mechanism that compensates for deficient dietary levels of a required nutrient. Intestinal absorption rates of nonessential amino acids that are usually not toxic are directly proportional with dietary protein levels. Because the molecular mechanisms of amino acid transporters have just been elucidated, the molecular mechanisms of their regulation are still being studied.

Peptides

Di- and tripeptides are absorbed from the intestinal lumen into the cell by the PEPT transporter family, which relies on the electrochemical gradient of hydrogen to supply the energy required for transport. Dietary free amino acids and dipeptides stimulate the transcription of the PEPT gene and increase PEPT mRNA as well as protein abundance, leading to enhanced peptide absorption rates. Increases in luminal dipeptide concentration have also been shown to increase PEPT mRNA stability. Hence, increases in dietary protein levels typically increase peptide transport across the brush border membrane. Regulation of peptide transport across the basolateral membrane, however, is not known.

Fatty Acids and Bile Acids

After digestion, dietary lipids that are sufficiently hydrophobic are likely to be incorporated into micelles and then passively absorbed by the intestinal cell. Passive transport is dependent on concentration gradients and hence cannot be regulated. However, fatty acids from pancreatic lipase digestion of triglycerides are thought to cross the brush border membrane by carriers that have not yet been extensively characterized at the molecular level. High-fat diets increase fatty acid transporter expression.

Bile acids, though not considered nutrients, are essential for fat digestion and absorption. Synthesis of bile acids is not sufficient to absorb the amount of fat consumed in a typical meal, hence bile acids need to be recycled. Bile acids are amphipathic molecules and require the Na⁺-dependent bile acid transporter (ASBT) for transport across the brush border membrane of enterocytes in the distal small intestine. ASBT expression and activity decrease when luminal bile acid concentrations decrease.

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The Biology of Nutrients

Supratim Choudhuri , Ronald F. Chanderbhan , in Nutraceuticals, 2016

Monosaccharide Transporters (SGLT and GLUT)

Glucose is a key fuel in tissues. It is obtained directly from the diet by digestion of ingested carbohydrates, and also by synthesis in the cell from other substrates through gluconeogenesis, which occurs primarily in the liver.

Glucose is transported by two structurally and functionally distinct types of transporters: Na⁺-glucose cotransporter (SGLT; gene SLC5A), which is a symporter, and Na⁺-independent glucose transporter (GLUT; gene SLC2A), which is a facilitative uniporter. The solute carrier (SLC) designation of the genes is given according to Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC) (Joost and Thorens, 2001).

SGLTs transport glucose and galactose through a secondary (2°) active transport mechanism (see Box 17.1). SGLT couples the transport of glucose and Na⁺ in the same direction (hence symporter). There are at least six SGLT transporters (SGLT1–6) identified to date, of which SGLT1–3 is well-characterized. SGLTs are expressed in all major tissues, but each member exhibits different substrate specificity, kinetics, and expression profiles. This facilitates tissue-specific adaptation of glucose uptake through differential regulation of these transporters. SGLT1 was the first member of this group to be cloned and characterized; it has 14 transmembrane domains (TMDs) and is strongly expressed in the small intestine, but it is expressed at lower levels in the kidney, liver, and lung. SGLT2 is predominantly expressed in the proximal convoluted tubules in the kidney. SGLT1 is a high-affinity but low-capacity glucose transporter that also transports galactose. In contrast, SGLT2 is a low-affinity but high-capacity glucose transporter and it does not transport galactose (Wright, 2001; Wright et al., 2011). SGLT2 transports the bulk of plasma glucose (low-affinity, high-capacity) from the glomerular filtrate into the cell, and any remaining glucose is recovered by SGLT1 (high-affinity, low-capacity).

Box 17.1

Primary and Secondary Active Transport, Facilitative Transport, Symporter, Antiporter, Uniporter

In primary active transport, ATP directly provides the energy needed to move a molecule against its concentration gradient, that is, from low to high concentration (uphill movement). The Na⁺/K⁺ pump is an example of a primary active transport system that maintains a gradient of approximately 140   mM Na⁺ outside of the cell and 5   mM Na⁺ inside the cell. In secondary active transport, the energy from ATP is not directly utilized. Instead, the electrochemical gradient of an ion, already established through primary active transport, is utilized to move a molecule across the membrane, usually against its concentration gradient. The ion that is moved down its electrochemical gradient is referred to as the driving ion (usually Na⁺ or H⁺), and the downhill movement of the driving ion is coupled with the uphill movement of the molecule. In other words, the energy-expending diffusion of the driving ion powers the energy-absorbing uphill movement of the driven molecule. Secondary active transport can be of two types—cotransport (or symport) and exchange (or antiport); thus, a transporter can be a cotransporter (symporter) or exchanger (antiporter). In cotransport (symport), Na⁺ or H⁺ and the transported molecule are transported in the same direction across the plasma membrane, whereas in exchange (antiport), Na⁺ or H⁺ and the transported molecule are transported in the opposite direction. In contrast to active transport, there is facilitative (facilitated) or passive transport. In facilitative transport, transporters passively transport substrates down the concentration gradient, that is, from high to low concentration, and do not require energy from ATP. Because the transport process is driven by concentration gradient, it is unidirectional; hence, the facilitative transporter is a uniporter.

GLUT2 is the major glucose transporter across the basolateral membrane. Concerted action of SGLT and GLUT thus prevents glucose loss in the urine (Wood and Trayhurn, 2003; Wright et al., 2011). Figure 17.1 shows the Na⁺-glucose cotransport. The regulation of SGLT1 has a significant translational or posttranslational component because infusion of d-glucose in the intestine increases SGLT1 mRNA by approximately 2-fold and the transporter mass and activity increase 60- to 90-fold. SGLT1 mRNA expression in rat intestine shows circadian rhythm, which is seven-fold higher in the morning (10:00–11:00 am) than in the afternoon (4:00–5:00 pm) (Rhoads et al., 1998). SGLT3 is not a transporter in some species. In humans, SGLT3 is a glucosensor expressed in the enteric nervous system ("brain of the gut") and muscles, and it colocalizes with the acetylcholine (ACh) receptor. SGLT3 uses glucose as the signaling molecule and responds to changes in extracellular glucose concentrations, such as stimulating pancreatic and intestinal secretions through changes in the membrane potential. SGLT3 does not bind galactose.

Figure 17.1. Cotransport (symport) by SGLT and facilitative transport by GLUT. SGLT is an Na⁺-dependent cotransporter that transports Na⁺ and glucose molecules into the cell. The higher glucose concentration gradient inside the cell triggers the facilitative transport of glucose by GLUT into the blood.

GLUTs are facilitative transporters (uniporters) (see Box 17.1) that exhibit different substrate specificities, kinetic properties, and tissue expression profiles (Wood and Trayhurn, 2003). The prototype of this family is GLUT1 (Figure 17.2). GLUT transporters contain sugar transporter signatures that consist of numerous conserved glycine, tryptophan, and tyrosine residues, which are regarded as essential for general facilitative transporter function (Joost and Thorens, 2001). There are 14 isoforms (GLUT1–12 and GLUT-14, genes SLC2A1–12 and SLCA1-14, and H⁺-coupled myo-inositol transporter (HMIT), gene SLC2A13). The functions of GLUT1–5 and their tissue distribution are well known. All 14 isoforms share common structural features, such as 12 TMDs, N-termini and C-termini facing the cytoplasm of the cell, and an N-glycosylation side within either the first (for class I and II) or the fifth (for class III) extracellular loop (Augustin, 2010).

Figure 17.2. Membrane topology of class I GLUT transporters. Residues that appear specific for class I are a glutamine (QL motif) in transmembrane helix 5 corresponding to Q161 in GLUT1 and the STSIF motif in loop 7, which is extracellular.

Based on sequence similarity, GLUT transporters are divided into three classes: class I, II, and III. Class I comprises GLUT1–4 and GLUT14, which is the product of GLUT3 gene duplication. Residues that appear specific for class I are a glutamine (QL motif) in TMD 5 corresponding to Q161 in GLUT1 and the STSIF motif in extracellular loop 7 (Augustin, 2010; Cura and Carruthers, 2012). Class II includes the "odd transporters," that is, the high-affinity fructose-specific transporter GLUT5 and three other related transporters (GLUT7, GLUT9, and GLUT11). They are all characterized by the lack of tryptophan residue in intracellular loop 10 that corresponds to tryptophan 388 in GLUT1. Class III includes the "even transporters," that is, GLUT6, GLUT8, GLUT10, and GLUT12 and the myo-inositol transporter HMIT1 (GLUT13) (Augustin, 2010). Class III GLUTs are characterized by a shorter extracellular loop 1 that lacks a glycosylation site and by the presence of such a site in the larger loop 9 (Joost and Thorens, 2001).

All GLUT transporters mediate monosaccharide transport following concentration gradient. GLUT1 is ubiquitously expressed and it mediates glucose transfer across the blood–brain barrier (BBB). GLUT2 is the major transporter of glucose across the basolateral membrane in both liver and kidney (Wright et al., 2011). Translocation of GLUT4 from the intracellular stores to the plasma membrane in response to insulin represents the rate-limiting step in insulin-controlled glucose uptake of skeletal and heart muscle as well as adipose tissue. Insulin-induced translocation of GLUT4 from the intracellular stores to the plasma membrane results in an immediate 10- to 20-fold increase in glucose transport (Bryant et al., 2002). GLUT2 functions as the glucose sensor of the insulin-secreting β cells in the pancreas (Augustin, 2010). GLUT1 also transports galactose, mannose, and glucosamine. GLUT5 is the high-affinity fructose transporter that is primarily expressed in the small intestine in human, rat, and mouse. The expression of GLUT5 is regulated by consumption of a high-sucrose and high-fructose diet. GLUT5 expression in adult rats shows a diurnal rhythm similar to that of SGLT1.

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