Sweetening with sugars has long been a favorite means of improving the acceptability of foods. The use of sugar as a sweetening agent occurred relatively late in human history. Until the development of the sugar-refining industry, sweetening agents were largely limited to honey and fruits. Approximately 10,000 years ago, the first sugar cane appeared in Papua, New Guinea (1). There was a low spread from the originating area through Asia and the Arabic countries, and it was only after The Crusades, that sucrose in the form of cane sugar became available in Europe. Later, Columbus introduced it in the New World. It was only 200 years ago that the beet root was recognized as a source of sucrose, and in Europe many factories emerged. For the production of fructose, the United States has relied principally on sugar cane (1). The political problems in the 1960s with Cuba prompted many North American companies to replace sugar cane with a substitute. At that time, technical advances made it possible to use cornstarch to produce corn syrup as a sweetening agent.
With changes in lifestyles that rely more on mass production of packaged foods, increasing amounts of simple sugars are now added to processed foods and beverages (2,3). Fructose in free form, or contained in sucrose, is appreciated for its taste and is the sweetest of all naturally occurring carbohydrates (4). In addition, fructose can enhance the perception of sweetness of other sugars. The combination of sweetness, low cost, and stable supply has made high-fructose-containing syrups (HFCS) a favored substitute for sucrose (3,5). The intake of HFCS is expected to surpass sucrose in the next decade as the primary sweetening agent of food (3). Efficient technology may further result in a change from HFCS-42 (containing 42% fructose) to sweeter tasting HFCS-55 and even syrups containing 80% to 95% fructose. In these syrups, a higher fructose-to-glucose ratio adds to the sweetness and flavor profile (4). The ease of handling this liquid, low production costs, and advances in technology have accelerated its acceptance by food and beverage producers. Quite recently, the development of crystallization processes resulted in a new-generation fructose sweetener in dry form and thus new commercial applications (4). Natural products have a wide range of fructose, glucose, and sucrose content (6,7). Over the past decades a small increase in the consumption of fructose from natural sources such as fruits, vegetables, and cereal products has been noted (3). In certain populations the increase is even more pronounced, as in the consumption of fruit (apple) juice by toddlers (4,8). Natural foods contain only the D-fructose isomer.
As a result of normal changes in feeding habits, mean daily fructose intake increases sharply after weaning. The highest body weight-adjusted intake of fructose occurs in toddlers (≈2.2 g/kg) (3). When mean fructose intake is represented as a percentage of total carbohydrate intake (16-20%) or as a percentage of total energy intake (7-9%) there is less of an age difference (3), although each age group has a wide range of intake.
FRUCTOSE IN HEALTH AND DISEASE
Absorption of ingested carbohydrates by the small intestine is accomplished through the coordinated expression of a variety of digestive and transport proteins that break down complex polysaccharides and effect the transcellular delivery of monosaccharides from the intestinal lumen to the blood. Three major dietary carbohydrates-glucose, galactose, and fructose-represent most ingested sugars. The physiology and pathologic mechanism of glucose and galactose transport have been reported on extensively (9-11), whereas fructose has been less well studied.
Investigations of human fructose absorption must be separated into studies examining the absorption of free fructose from those investigating fructose ingested in combination with other actively transported solutes. The other solutes may be free monosaccharides, in particular glucose, either as the free sugar or as the disaccharide sucrose.
In contrast to glucose, it is clear that fructose is not absorbed in the intestine by an active sodium-dependent system (12). However, the rate of transport is greater than would have been expected from simple diffusion but much less than that seen with the actively transported sugars glucose and galactose (13-16). Fructose absorption is also associated with less water and sodium absorption than glucose absorption (13). In earlier perfusion studies, investigators clearly overestimated the absorptive capacity for dietary carbohydrates (13,14,17). Results in more recent studies in healthy adults and children have demonstrated a limited intestinal absorption capacity after ingestion of fructose. Using the well-established technology of hydrogen (H2) breath tests, which can detect small-intestinal malabsorption through the resulting colonic fermentation, studies are possible in larger groups of adults and children. Breath H2 tests after ingestion of a solution clearly show a limitation of small intestinal fructose absorption (18-21). Between 37% and 80% of otherwise healthy adults experience malabsorption of 50 g of fructose administered in a 10% solution, with even a greater percentage of malabsorption when fructose is provided in a 20% solution (18). Kneepkens et al. found incomplete absorption in 71% of a group of normal children aged between 1 month and 17 years after ingestion of 2 g/kg body weight, with a maximum ingestion of 50 g (19). Using a lower 1-g/kg dose we elicited the highest percentage of malabsorption and the highest peak H2 values in children aged 1-3 years (Fig. 1) (22).
Although the breath H2 test detects the fraction of fructose that is not absorbed, it is only semiquantitative. Carbohydrate absorption can also be studied by the use of carbon-labeled substrates. The 13CO2 breath test is based on the premise that metabolic processes directly convert part of the absorbed fructose into 13CO2 and excrete it in breath over time (23). However, in our experiments using fructose-13C-6 (99% enrichment), 13CO2 excretion in breath reflects not only the absorbed fructose fraction, but also the fraction formed as a result of colonic fermentation of unabsorbed fructose. Because both processes could not be separated over time, the 13CO2 breath test appears to be of limited value in studies of fructose absorption (23). Thus, although it reflects only malabsorption, we think breath H2 may provide a more reproducible method for studying intestinal fructose transport in people and populations. In another type of study, the 13C label was valuable for investigating internal fructose metabolism (e.g., the amount of glucose synthesized from fructose and fructose oxidation) (24).
Among people with significant breath hydrogen production after fructose ingestion, symptoms of malabsorption may vary as a result of an adaptation of the intestinal bacterial flora. It appears that the colonic flora can efficiently process the nonabsorbed fructose with fermentation into short-chain fatty acids, hydrogen, methane, and carbon dioxide. These adaptive processes vary among people and may therefore account for the discrepancy in clinical symptoms produced by gas and acid in the colon (25,26). These adaptations are well illustrated in patients with congenital glucose-galactose malabsorption. Their main carbohydrate intake consists of free fructose, because its absorption is unaffected (16). In these patients, a high dietary fructose intake does not result in major symptoms, whereas hydrogen production remains high (27). In infants, viral gastroenteritis may result in extensive villus damage resulting in life-threatening intractable diarrhea with secondary intolerance of glucose-galactose, disaccharides, and polymeric glucose. In this situation, fructose was shown to be the only carbohydrate tolerated, illustrating good tolerance in an extreme situation (28).
Absorption in Combination With Other Nutrients
A number of studies have indicated that fructose absorption is greatly facilitated by the presence of glucose (13,21). These studies performed in man with intestinal perfusion techniques (13), breath hydrogen tests (19,21,29), and in the intact rat (30) demonstrate, that this facilitation occurs in a dose-dependent manner with maximal augmentation of uptake as occurs with an equimolar amount of glucose. This latter situation may reflect efficient absorption of the fructose-glucose disaccharide sucrose (15,20). Galactose has the same facilitating effect as glucose (19). Although investigators have suggested an important role for the enzyme sucrase-isomaltase for a facilitated fructose transport (20,30), our investigations in healthy children favor an alternative explanation (29). In contrast with results in the studies by Fujisawa et al. (30) in rats, sucrase-isomaltase inhibition by acarbose did not alter glucose-facilitated fructose transport in humans (29). In addition, we found that amino acids, in particular those that induce bulk water movements (e.g., L-alanine), resulted in significantly better facilitated fructose absorption when compared with that of glucose (Fig. 2) (29).
In our investigations with structurally related sorbitol, comparable results were obtained. We found an increased absorption of sorbitol by the coadministration of glucose and L-alanine (29). These data are consistent with the reported glucose-facilitated xylose transport (31). The facilitated fructose absorption probably occurs as increased fructose absorption as a consequence of glucose-induced water streaming through the mucosal layer. This process is known as solvent drag and traditionally requires the same paracellular pathways for water and solutes. Moreover, osmotic water absorption results in an increase in luminal fructose concentration caused by the removal of intraluminal water, which in turn may result in enhanced absorption by the intestinal fructose transporter. All these observations help to explain why both fructose and sorbitol are better absorbed in a meal than in a solution.
Using breath H2 tests in adults with abdominal pain, Rumessen and Gudmand-Høyer (32) reported increased fructose malabsorption when structurally related sorbitol is coadministered. They suggested competition between sorbitol and fructose at the small intestinal transporter level. Alternatively, these results may also be explained by a laxative effect of sorbitol decreasing intestinal fructose absorption through increased transit.
Chronic Diarrhea and Abdominal Pain
Chronic nonspecific diarrhea or toddler's diarrhea is a prominent problem in this age group (33). Although the pathophysiology is not completely understood, dietary factors have been shown to contribute to the occurrence or persistence of symptoms (33). These children tend to consume high amounts of simple carbohydrates in liquid form, in particular apple juice, in which high fructose concentrations (≈60 g/l) are present. The observation that only elimination of this juice from the diet makes symptoms disappear focuses on fructose malabsorption as a primary pathogenic factor (34,35). As mentioned previously, fructose malabsorption is more pronounced in the typical age group for this condition (22). However, fructose breath hydrogen in these children failed to separate these patients from healthy controls and, more important, the group with toddler's diarrhea had no diarrhea in the hours after ingesting fructose (36). In a randomized clinical trial, a group of children with a diagnosis of toddler's diarrhea could tolerate cloudy (unprocessed) apple juice, whereas the (processed) clear apple juice resulted in re-appearance of diarrhea (37). The products differ in the amount of dietary fiber and the amounts of indigestible monosaccharides and oligosaccharides. Moreover, because the amounts of fructose (and sorbitol) were identical in both products, these studies question the role of fructose malabsorption in toddler's diarrhea and underscore the complex interaction between food ingredients (38).
In a few children a specific defect of fructose transport has been reported (39-41). These patients had pronounced symptoms, with colicky abdominal pains and frequent diarrhea after ingestion of low amounts of fructose. The symptoms in these children resolved when they consumed a fructose-free diet. In addition, all had similar responses after sucrose ingestion, which suggests a sucrase-isomaltase deficiency, but measured jejunal disaccharidase levels were normal (39-41). These children may have rare but real, isolated fructose transport defects. Recently, details from a group of nine children with these symptoms were described (42). With advancing ages the symptoms in some of these children seem to improve.
Patients with general monosaccharide malabsorption, including fructose, have been described directly after birth and also after severe, acute rotavirus gastroenteritis at young age (43,44). In these latter children, virus-induced villus atrophy seems to recover without a restoration of monosaccharide transport (43). This condition has a high mortality rate and most of the surviving children remain dependent on parenteral glucose infusion (43,44).
More frequently, children (19,22) and adults (18,20,21) show a diminished tolerance for fructose, often combined with similar symptoms after ingestion of sorbitol (45-47). In older children and adults, abdominal pain is reported more frequently than diarrhea. For this condition the term diminished fructose tolerance seems to be more appropriate than fructose intolerance, to differentiate this condition from hereditary fructose intolerance, the metabolic disorder caused by hepatic aldolase B deficiency. However, this diminished fructose (and sorbitol) tolerance seems to play a role in only a minority of patients with irritable bowel syndrome (46,48). In children with chronic abdominal pain we have no epidemiologic data. In a minority, careful dietary history may suggest a relation between diminished fructose and sorbitol tolerance and symptoms. These children may considerably improve during a trial elimination of fructose and sorbitol from their diets. In a recent study of adult patients with dyspepsia, a diminished tolerance for fructose was often seen in combination with sorbitol and lactose intolerance (49). These observations suggest more a general intestinal disorder of motility or colonic fermentation than a primary transport defect.
MOLECULAR BIOLOGY OF TRANSPORT
Transcellular Transport of Fructose
Transport of dietary fructose across the intestinal epithelium is achieved through the enterocyte. The enterocyte is a polarized cell, possessing a brush border membrane in contact with the lumen, and a basolateral membrane in contact with the blood supply. Using rat brush border membrane vesicles the transporter responsible for the luminal uptake of dietary fructose has been determined to be
- energy independent and facilitative (50);
- highly stereospecific for fructose (50);
- a low-affinity, high-capacity fructose transporter with a supraphysiological Kt (substrate concentration required for half-maximal transport) of 100 to 150 mM (50,51);
- insensitive to the brush border Na+-glucose transporter inhibitor phlorizin (52);
- insensitive to the basolateral sugar transporter inhibitor phloretin (53); and
- photolabelled by the facilitative glucose transporter inhibitor cytochalasin B (54).
Fructose exits the enterocyte by transport across the basolateral membrane. Using rat basolateral membrane vesicles (53,55), the characteristics of basolateral fructose transporter has been determined to be
- energy independent and facilitative;
- a dual carrier of fructose (Kt = 16 mM) and glucose (Kt = 30 mM);
- Na+ independent; and
- sensitive to phloretin and cytochalasin B.
The membrane vesicle data have shown that the absorption of dietary fructose is achieved by the expression of two distinct transporters. Furthermore, the sensitivity of these transporters to cytochalasin B suggests that they are members of the family of facilitative hexose transporter genes (GLUT1, 2, 3, 4, and 5) (for review see reference 56).
Cloning of Intestinal GLUT5 and GLUT2
Carrier-mediated transport of hexoses in mammals is achieved by either the Na+-dependent glucose transporter (SGLT1) (57), or, by a member of the family of facilitative hexose transporter genes. To date, five facilitative hexone transporter genes have been cloned and functionally characterized (GLUT1, erythrocyte; GLUT2, hepatocyte; GLUT3, brain; GLUT4, muscle and fat; and GLUT5, small intestine). GLUT6 has also been cloned, although premature stop codons render this gene nonfunctional (58). Evidence for a sixth transporter, GLUT7, awaits functional confirmation (59).
The intestinal facilitative hexose transporters were isolated from human liver and kidney complementary DNA (cDNA) libraries using a GLUT1 cDNA probe. Using low-stringency hybridization techniques, the human liver-type GLUT2 cDNA was cloned (60) and its gene localized to chromosome 3 in the Q26-Q26.3 region (61). Human GLUT5 cDNA has also been cloned and its gene localized to the short arm of chromosome 1 in the p32-p22 region (58). The coding sequence of GLUT5 and GLUT2 clones predicts expressed proteins containing 500 to 525 amino acids. GLUT5 shows 67% to 80% homology between species, with the rabbit being the most divergent (52,62). For GLUT2, an 81% to 94% similarity between humans, rats, and mice has been determined.
Expression and Function of Intestinal GLUT5 and GLUT2
Northern blot analyses determined GLUT5 messenger RNA (mRNA) expression to be abundant in human and rodent intestinal epithelium (61,62). In situ hybridization has detected GLUT5 mRNA in the lower and midvillus regions of the intestine, with little expression in the villus tips and no detectable expression in the crypts (62). GLUT5 mRNA was also detected in the kidney, although expression levels were approximately 50% below intestinal levels. Immunohistochemical studies found the GLUT5 transporter protein to be targeted to the brush border membrane of mature enterocytes with no expression in the crypts or basolateral membranes (63). Similar to GLUT5 mRNA, GLUT2 mRNA transcripts were detected in the lower and midvillus regions of the intestine, with minimal expression detected in the villus tips or crypts (64). However, immunohistochemical studies have determined GLUT2 protein to be localized to the basolateral membrane of mature enterocytes with no protein expression in the brush border membrane or crypt (Fig. 3)(65).
The role of intestinal GLUT5 and GLUT2 could not be formally stated until their transport characteristics were analyzed in isolation. Xenopus oocytes have minimal intrinsic sugar transport capacity and have therefore provided a useful tool in understanding the transport capabilities of the individual members of the GLUT family. When human, rabbit and rat GLUT5 cDNAs were expressed in oocytes, fructose uptake increased (Kt = 6-12 mM) (52,62,66,67). In contrast to the brush border vesicle data, the increase in fructose uptake in oocytes was insensitive to cytochalasin B. Furthermore, rabbit and rat GLUT5 expressed in oocytes transported a small amount of glucose, whereas human GLUT5 did not (Fig. 4). The reasons for the differences between the vesicle and oocyte data are unclear. It is possible that variations in the coding sequence between species alter the sugar and cytochalasin B-binding sites. There is also accumulating evidence that GLUT5 activity and stereospecificity are modulated in vivo. For example, GLUT5 is highly stereospecific for fructose in rabbit brush border vesicles, whereas in oocytes, rabbit GLUT5 cRNA transports both fructose and glucose (52). Although the nature and identity of these modulators are unknown, investigators are currently pursuing this area of hexose transporter control. In agreement with the vesicle data, expression of human GLUT2 in oocytes produces an increase in fructose (Kt = 66 mM) and glucose uptake (Kt = 17-42 mM), which is inhibited by cytochalasin B (68-70) (Fig. 4).
The current consensus is that dietary fructose is transporter into the enterocyte through the brush-border membrane transporter, GLUT5. Fructose is then able to enter the blood supply by exiting the enterocyte through the basolateral membrane transporter GLUT2 (Fig. 5).
Regulation of Intestinal GLUT5 and GLUT
The development of the mammalian gastrointestinal tract can be divided roughly into fetal, postnatal, and adult phases. These developmental changes involve a number of digestive activities and appear to occur independent of alterations in dietary content (71). It has therefore been suggested that the development of the intestinal tract is of a hard-wired nature. For example, at the end of the suckling period, the rat intestine shows a significant increase in fructose transport capacity, despite the absence of dietary fructose (72). These changes in fructose transport capacity have subsequently been attributed to an alteration in the expression levels of GLUT5 and GLUT2 (62,63,73-75). In the intestine of rat fetuses, GLUT1, GLUT2, and GLUT5 are expressed from postconceptional day 10 until birth. GLUT1 expression decreases during the gestational and postnatal period and is essentially absent from the adult intestine. In contrast, GLUT5 and GLUT2 expression levels increase during the suckling phase and reach adult levels of expression after weaning. In further demonstration of the hard-wired nature of developmental expression, weaning rodents onto a high fat and carbohydrate-free diet did not prevent the induction of GLUT5 mRNA expression (74). What triggers developmental expression is still not clear to investigators. Maternal, dietary, environmental, hormonal, and neuronal cues are all probable candidates, although the predominant signaler is unclear.
Rodents are nocturnal feeders and ingest approximately 80% of their calories during the dark cycle. In anticipation of this nocturnal luminal load, several intestinal processes increase in activity before the onset of dark-cycle feeding: sucrase-isomaltase, trehalase, lactase, alkaline phosphatase, and cholesterol synthesis; glucose transport; and mitosis (75-79). This diurnal pattern of expression appears to be linked to the daily differentiation process whereby crypt cells mature into enterocytes.
Intestinal SGLT1, GLUT2, and GLUT5 mRNA are also diurnally expressed, with a peak in expression occurring around midafternoon (80). Interestingly, even with a fructose free-control diet, GLUT5 mRNA diurnality is as robust as GLUT2 and SGLT1. This suggests that diurnality is hardwired in nature. Recently, nuclear run-off assays have determined diurnal expression of SGLT1 mRNA to be controlled at the transcriptional level (81). In this study the transcriptional factor HNF-1β was suggested to be responsible for SGLT1 diurnal expression. HNF-1 domains in either GLUT2 or GLUT5 promoters have yet to be identified. The molecular mechanisms responsible for the diurnal expression of GLUT5 and GLUT2 mRNA therefore remain unknown.
GLUT5 and GLUT2 protein expression levels also vary over a 24-hour controlled-feeding period, with a peak in expression occurring at approximately the onset of dark-cycle feeding. In contrast to precursor mRNA, GLUT5 protein expression levels are kept low during the 24-hour control-feeding period, which suggests that at the posttranslational level the intestine is sensitive to dietary content.
Dietary Control of GLUT5
Intestinal carbohydrate transport in rodents is rapidly and reversibly regulated by the amount of cognate sugar in the diet (82). When Swiss-Webster mice (83) were fed a 60% to 65% fructose-enriched diet for 3 days a 2.5-fold stimulation in luminal uptake of fructose was observed. Similarly, Crouzoulon and Korieh (51) determined that feeding rats a 50% fructose-enriched diet for 3 days significantly increased the maximum velocity (Vmax) of brush border fructose transport. Because the crypt-tovillus turnover in rodents is also 3 days, it has been suggested that dietary fructose is initially sensed by the crypts. In support of this, dietary glucose has also been shown to be sensed by the crypts (84).
We (80,85,86) and others (73,87) have determined that feeding rodents a fructose-enriched diet significantly increases the intestinal GLUT5 mRNA and protein expression levels. Immunohistochemical studies of control and fructose-exposed intestines show GLUT5 and GLUT2 protein expression to be confined to the mature villus cells, with no detectable expression in the crypts (85). Thus, the intestinal response to dietary fructose is confined to the mature enterocytes, with the crypts appearing incapable of sensing and responding to fructose.
Although GLUT5 protein expression levels increase significantly within 3 hours of fructose exposure (80,85), the Vmax of brush border fructose transport does not change until the third day of fructose feeding (51). This suggests that expression and activity of the brush-border fructose transporter are not always simultaneous. Further experiments are needed to confirm these phenomena and their physiological importance.
Dietary Control of GLUT2
Because GLUT2 was originally identified as a glucose transporter, most studies have been concerned with the effects of glucose on GLUT2 expression and activity (55,88). Results in the few studies in which investigators have looked at the effects of fructose feeding on GLUT2 appear contradictory. For example, the expression of GLUT2 mRNA is minimally affected by feeding a 65% enriched fructose diet (79,86). In contrast, when animals were switched from a carbohydrate-free diet to a 55% fructose-enriched diet, GLUT2 mRNA levels were significantly increased (89). Because of the dietary switch from a low- to a high-carbohydrate diet, we think the latter study most likely reflects GLUT2 re-establishing its baseline diurnal level of expression, rather than a specific diet-induced upregulation. Indeed, in the same study SGLT1 mRNA was upregulated by dietary fructose (90).
Contradictory data have also been obtained on the posttranslational control of GLUT2 by fructose. After a 4-hour luminal perfusion of 100 mM fructose, isolated basolateral membrane vesicles showed a three- to four-fold increase in the Vmax for fructose transport (55). This increased capacity to transport fructose occurred independent of changes in GLUT2 protein expression levels. These data suggest that the activity of GLUT2 could be modulated by fructose, independent of changes in the expression levels of the protein. In contrast, a 65% fructose-enriched diet rapidly and consistently downregulated GLUT2 protein expression levels by 50% (80). The reasons for the differences in the response to luminal fructose are unclear. Moreover, these responses in the basolateral membrane could also be influenced by blood hexose concentrations.
Effects of Type 1 and Type 2 Diabetes
Type 1 diabetes can be experimentally induced in rodents by the administration of the glucose analogue, streptozotocin (STZ) (91). The rodent with STZ-induced type 1 diabetes is characterized by hyperglycemia, hypoinsulinemia, and hyperphagia. In addition, the intestine shows an increased capacity to transport sugar (92). This has been attributed in part to an increase in the expression levels of GLUT5, GLUT2, and SGLT1 transporter mRNA and protein (53,64,74). Premature activation of the hexose transporters has also been detected in the crypts, suggesting that pathophysiologic control mechanisms are different from the dietary control mechanisms (64). The signals responsible for the transformation of the normal intestine to that seen in type 1 diabetes are unknown. However, it has been suggested that the long-term absence of insulin signals to the intestine that the periphery is starved, resulting in the enhanced nutrient-absorption capacity.
We have recently assessed the expression patterns of the intestinal hexose transporters in the Zucker diabetic fatty (ZDF) rat (93). The ZDF rat has been used as a model for type 2 diabetes and is characterized by hyperphagia, hyperglycemia, and hyperinsulinemia. Surprisingly, the expression levels of the intestinal hexose transporters were unchanged in the ZDF rat (unpublished data). We have suggested that the chronic hyperinsulinemia depresses the stimulatory effects of increased feeding and hyperglycemia on transporter levels. The type 1 and 2 diabetic data suggest that in the long term, insulin is the predominant adaptive signal to the intestine, rather than glucose.
GLUT5 Expression in Tissue Culture
Biologists are interested in determining the molecular mechanisms responsible for GLUT5 expression. Unfortunately, because of the degrading power of the intestine, using intact tissue for such studies becomes problematic. An alternate route would be to use a GLUT5-expressing intestinal or kidney cell line. Caco-2 cells are derived from a human colon cancer that expresses GLUT5 (94). This cell line differentiates in culture and forms apical and basolateral membranes that are maintained by tight junctions. Similar to small intestinal GLUT5, Caco-2 GLUT5 expression is absent from proliferating cells. However, after the Caco-2 cells reach confluence, GLUT5 is expressed and targeted to the apical membrane. GLUT5 in Caco-2 cells has been found to be functional (95) and sensitive to fructose, glucose, and components of the growth medium (96). In rodents, GLUT5 expression is controlled by dietary fructose and not glucose. It is therefore unclear whether Caco-2 cells replicate whole animal intestinal function. The Caco-2 immortal cell line has also been used to assess the transcriptional control of human GLUT5. Approximately 0.8 kb of human GLUT5 promoter has been cloned, with two cyclic adenosine monophosphate response elements and a CAAT box identified (97). Although forskolin (an adenyl cyclase activator) was shown to stimulate expression of GLUT5 promoter-luciferase constructs, as yet, no fructose response elements have been documented.
The increased use of high-fructose corn syrup as a sweetener over the past few decades has increased the amount of fructose in the Western diet. In concordance, fructose-related gastrointestinal symptoms have also increased. In severely affected people with isolated fructose malabsorption, however, the molecular mechanisms responsible for malabsorption are unknown. For example, when GLUT5 DNA was sequenced, no mutations were detected (42). Although the GLUT5 gene appeared normal in these patients, it is possible that fructose malabsorption is a result of faulty expression, activity, or targeting of the GLUT5 transporter. These mechanisms of control are poorly understood but could eventually result in the determination of the molecular basis of fructose-related intestinal diseases in humans.
Understanding the molecular biology of intestinal hexose transporter expression can have profound clinical implications. For example, the knowledge that individual carbohydrates increase specific intestinal transporters suggests that inclusion of fructose in early feedings in people who have had prolonged intestinal starvation or extensive small intestinal diseases (such as short gut syndrome) could prevent fructose malabsorption when more complex meals are offered during dietary advancement. In patients with type 1 diabetes who are not under optimal control, the upregulation of glucose and fructose transporters may exacerbate the hyperglycemia by more rapid absorption of carbohydrate. Restriction of carbohydrates, as has been recommended in the past in diabetes, seems appropriate until metabolic control is restored. Finally, diurnal alterations in intestinal transporter expression could also be exploited to improve nutrition or to plan feeding in pathologic conditions.
Acknowledgments: Portions of this work were supported by The National Institute for Diabetes and Digestive and Kidney Diseases Grant DK-02170 (to CFB) and the Gastrostart Foundation of the Dutch Digestive Society (JHH).
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