690S Am J Cliii Nutr 1994;59(suppl):690S-85. Printed in USA. © 1994 American Society for Clinical Nutrition
Digestion and absorption of carbohydrates -
from molecules and membranes to humans1’2
Roy J Levin
ABSTRACT Hydrolysis in the luminal bulk fluid by se-
creted enzymes is the major pathway for the breakdown of poly-
saccharides to ohigosaccharides, and further hydrolysis is accom-
pushed by a battery of carbohydmases in the brush border of the
mature enterocytes. The glucose, galactose, and fructose pro-
duced are absorbed across the enterocytes of the upper half of
the villus. Glucose and galactose (and other glucalogues) are ac-
tively transported into the enterocyte by the Na�-glucose cotrans-
porter SGLT1 (gene on chromosome 22) via the transmembrane
electrochemical Na� gradient, and exit across the basolateral
membrane by the glucose transporter GLUT2 (gene on chro-
mosome 3). The critical importance of the correct expression of
SGLT1 for human sugar absorption is shown by the rare genetic
disease of glucose-galactose malabsorption. People with this dis-
ease cannot absorb hexoses and have severe watery diarrhea,
which, if untreated, is terminal. Fructose absorption is by an Na�-
independent transport system that has not been fully character-
ized (possibly GLUTS). Despite many kinetic and other studies
in animals, and some in humans, that suggest multiple Na�-glu-
cose transporters, only SGLT1 is expressed in enterocytes. Ab-
sorption of monosaccharides from disaccharides appears to have
a kinetic advantage (disaccharide-related transport system). Hex-
ose absorption is enhanced by dietary intake of hexoses by in-
creased activity of SGLT1 and GLUT2 and by increased entero-
cyte numbers. Am J Cliii Nutr 1994;59(suppl):690S-8S.
KEY WORDS Digestion-absorption carbohydrates, sugar
absorption, intestinal absorption, glucose-galactose malabsorp-
tion, SGLT1, GLUT2, GLUT5
Digestion of carbohydrate by the intestine
Dietary carbohydrate in humans and omnivorous animals is a
major nutrient and the alimentary tract is well adapted for its
digestion and subsequent absorption. Initially, polysaccharides
are broken down by the enzymatic hydrolysis of salivary and
pancreatic amylase mainly in the upper small bowel. Only a small
amount is hydrolyzed in the stomach (1). In humans the ohigo-
saccharides formed from starch are mostly from this cavital or
intraluminal bulk phase process (2), there is hardly any of the so-
called contact or membrane digestion where amylase has its ac-
tivity enhanced by being absorbed on brush border membranes
(3). The continued breakdown of the newly formed glycosyl oh-
gosaccharides is by the surface enzymes of the enterocyte’s brush
borders. The carbohydrases are built into the surface membranes
of the mature enterocyte’s microvilhi and are in juxtaposition to
the transport sites for the released monosaccharides (4-6). This
chose integration of digestive breakdown with transport prompted
Crane (7) to describe the brush border of the enterocytes as a
“digestive-absorptive interface.’ ‘ Dietary molecules as large as
disaccharides do not cross the small intestinal epithelium al-
though larger molecules such as polyethylene glycols can be ab-
sorbed and excreted into the urine (8). It is the high concentration
and hydrolytic efficiency of the disaccharidases in the brush bor-
der that effectively hydrolyze all the disaccharides, leaving none
to pass across intact.
The major glycosidases are shown in Table 1 [after Dahlqvist
and Semenza (9)]. In adults lactose is the only disaccharide for
which enzymic breakdown is slow and is the rate limiting factor
in its absorption. The hydrolysis of lactose into glucose and ga-
lactose is crucial for the nutrition of human infants (human milk
contains ra�200 mmol lactose/L). The capacity of the infant’s in-
testine to digest lactose is retained only by a minority of individ-
uals (10).
Development of disaccharide activity along the cryptvillas axis
Disaccharidases develop during the migration of the entero-
cytes from the crypt onto the villus. Stem cells that reside a few
cells above the base of the crypt divide into four cell phenotypes,
enterocytes (which represent > 95% of the cells on villus), goblet
cells, enteroendocrine cells, and Paneth cells. The crypt precur-
sors of the enterocytes divide several times in the crypt before
moving up onto the villus and finally being shed into the lumen
at the villus tip. This process takes 5 d in humans (11). How the
enterocytes are stimulated to produce the proteins that equip them
for their digestive and absorptive roles on the villus is not known,
but two mechanisms have been proposed. One is that the relative
abundance of mRNA is a key factor in the differential expression
of genes along the crypt-villus axis, that is, transcriptional acti-
vation of genes is an important mechanism for enterocyte differ-
entiation. The other possible mechanism is differential posurans-
lational processing of the proteins in crypt and villus cells. It is
known that there is an absence of mRNA in crypt cells of rat
intestine for a variety of genes (12-14). This suggests that tran-
‘From the Department of Biomedical Science, University of Shef-
field, Yorkshire, UK.2 Reprints not available. Address correspondence to RI Levin, Dc-
partment of Biomedical Science, University of Sheffield, Sheffield SlO2TN, Yorkshire, UK.
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For hexoses to be absorbed from the bulk phase into the blood-
rnterstitial stream they have to move through many pathways. Each of theseorserosal pathways are treated separately in the following sections. A
diagrammatic summary of the various pathways is shown in Fig-
ure 1.
INTESTINAL CARBOHYDRATE ABSORPTION 691S
TABLE 1
Major glycosidases of mammalian enterocyte brush border*
Glycosidase Complex Enzyme activity
Maltase-sucrase Sucrase-isomaltase 80% of maltase; some of a-limit dextrinase; all of sucrase; most of isomaltase
Maltase-isomaltaseMaltase-glucoamylase (2) Glucoamylase All glucoamylase; most of a-limit dextrmnase; 20% of maltase; small percentage of isomaltaseTrehalase All trehalaseLactase 13-Glycosidase All neutral lactase and cellobiaseGlucosyl-ceramidase Most of aryl-fi-glycosidase
(phloridzin hydrolase)
* Adapted from reference 9.
scription is perhaps the primary regulatory step in enterocyte dii-
ferentiation.
Sucrase-isomaltase
Sucrase-isomaltase is synthesized as a single polypeptide that
is glycosylated in the endoplasmic reticulum and Golgi apparatus
and then transported to the apical portion of the enterocytes,
where it is inserted into the membrane. Luminal proteases cleave
the protein, separating it into two functional units: isomaltase,
which is anchored in the membrane, and sucrase, which becomes
noncovalently bound to isomaltase (15). In human intestines, su-
crase-isomaltase activity is low or absent in the crypts and ap-
pears abruptly in cells at the crypt-villus junction (16). The
mRNA for sucrase-isomaltase is also low or absent in the crypts
and then appears at the crypt-villus junction. This suggests that
the level of mRNA for the enzyme is the predominant mechanism
for the differential expression of sucrase-isomaltase in crypt and
villus cells and that activation of sucrase-maltase gene transcrip-
tion is the most likely cause for the abrupt appearance of its
FIG 1. Diagrammatic representation of the pathways of solute move-ment from the bulk phase (1) of the lumenal (in vivo) or mucosal (invitro) fluid through the unstirred layer, either for transfer across the brush
border membrane (2) into the enterocyte’s intracellular compartment (3)
or to diffuse through the tight junctions into the intracellular space withor without solvent drag. The solute diffuses across the intracellular com-partment (3) to the basolateral membrane (4) to be transferred either bydiffusion or facilitated diffusion and enter the interstitial (in vivo) orserosal fluid (in vitro). In vivo, it is then cleared from the milieu of theenterocytes by the blood and lymph streams. At the basolateralmembrane there is an entry process (5) for glucose from the blood. Thismay simply be the facilitated diffusion (3) component. See text for fur-ther details.
mRNA. However, studies by Beaulieu et al (17) have produced
evidence for posttranslational control of sucrase-isomaltase cx-
pression in human jejunum crypt and villus cells. They used a
collection of monoclonal antibodies raised to human sucrase and
isomaltase to identify the presence of the cellular enzymes. The
obvious discrepancy between these two studies is difficult to cx-
plain. Traber et al (16) have suggested that it may be due to the
specificity and type oflabeling of the monoclonal antibodies used
by Beauhieu et al.
Lactase (lactase-phloridzin hydrolase)
Lactase is formed after complex glycosylation of a high mo-
lecular weight single-chain precursor (18). The exact mecha-
nisms of the synthesis are not yet known. The amino acid se-
quence of lactase has been deduced from cDNA clones (19).
There is a short signal sequence and a large ‘ ‘pro’ ‘ portion of
849 amino acids that do not appear in the mature membrane-
spanning enzyme. The membrane-spanning hydrophobic seg-
ment acts as an anchor while the short, hydrophihic segment is in
the cytosol. In rabbits and rats there is a high concentration of
lactase mRNA in the enterocytes during the perinatal period. In
humans there is plenty of lactase mRNA even in individuals in
whom the enzyme does not persist (20). The initial decline of
lactase activity during development is compatible with transcrip-
tional control of lactase expression (21). It has been suggested
that the ‘ ‘pro’ ‘ portion has a regulatory role in the posuransla-
tional processing of the pro-lactase molecule (19, 20).
Absorption of the monosaccharides
Movement from the bulk phase to the enterocyte surface
Any disaccharide or free monosaccharide formed in the bulk
phase has to diffuse across to the surface of the enterocyte before
it can be further hydrolyzed or transported (Fig 1). Water be-
comes more highly structured at surfaces and creates an unstirred
layer that extends outwards into the bulk phase. The thickness of
this unstirred layer largely depends on the type of stirring present
in the lumen of the intestine. If there is only linear flow (the type
present when fluid is circulated through the intestine of anesthe-
tized animals) the unstirred layer thickness can be remarkably
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692S LEVIN
large, but if there is turbulent flow or if the villi exhibit motility,
then the unstirred layer can be relatively thin. Early studies sug-
gested that the unstirred layer in various preparations of the small
intestine was significant and thus represented a diffusion barrier
to the passage of molecules, especially those that were highlypermeant across the mucosa (22-25). This can be an important
factor in the accurate quantitative characterization of the kinetics
involved in the transport of hexoses (22-26). Recent evaluations
of the unstirred layer in vivo, however, have suggested that it is
much smaller than originally measured, especially in unanesth-
etized animals, possibly because of the greater motility of the
intestine and its vilhi (27).
Movement across the brush border membrane
Movement across the enterocyte brush border membrane can
take place by three mechanisms: active transport, facilitated dif-
fusion, and passive diffusion.
Active transport. The mechanism of the Na� glucose cotrans-
porter of the brush border is active transport. Studies mainly with
rodent intestine incubated in vitro using a variety of preparations
showed that enterocytes could transfer not only the dietary hex-
oses glucose and galactose against a concentration gradient (ac-
tive transfer), but also various glucalogues that could not be me-
tabohized like a-methyl glucoside and 3-0-methyl glucose. This
activity was dependent not only on energy but also on the pres-
ence of Na� in the luminal fluid (28). Crane (29) proposed a
brilliantly simple mechanism. He postulated that uphill transport
occurrs via a Na�-glucose-carrier complex in the brush border
membrane of the enterocyte that is driven by the transmembrane
Na� gradient. The Na�, when bound to its site on the carrier,
enhances the affinity of the sugar site for hexoses and, when Na�
came off the carrier, the sugar site’s affinity for the bound hexose
diminishes and the hexose leaves the carrier for the inside of the
cell. Because of the movement of charge (Nat ions) with the
Na�-hexose loaded carrier, active transport of hexoses is electro-
genic and is associated with the generation of both transfer po-
tential differences and transfer currents (Fig 2). These have been
used extensively to characterize intestinal active transfer mech-
anisms, especially their kinetics, and have also been used to iden-
tify the presence of the carrier in both animal and human intestine
(23). Experiments using isolated brush border vesicles confirmed
the hypothesis and the Na�-glucose cotransporter became the ac-
cepted mechanism for hexose active transfer (30, 31). Attempts
were made to isolate and purify the cotransporter but the small
amount of protein carrier in the membrane, < 1% of the total
membrane proteins, made the task extremely difficult (31). The
breakthrough came with the advent of molecular biological tech-
niques.
Hediger et al (32) used a novel technique called expression
cloning to clone, express, and sequence the Na�-glucose cotrans-
porter (SGLT1) from rabbit intestine. Poly (A)� mRNA prepared
from rabbit enterocytes was injected into oocytes from Xenopus
laevis, which resulted in the expression in the egg of Na�-de-
pendent, phloridzin-sensitive uptake of the glucalogue a-methyl
glucoside. The mRNA coding for the cotransporter was found
and the full-length cDNA was prepared, isolated, and inserted in
a plasmid vector. A single clone was isolated that increased the
glucalogue’s Na�-sensitive uptake by > 1000-fold but had no
effect on the Nat-insensitive uptake. After its surmise 30 y pre-
viously, the Na�-glucose transporter in the intestinal brush border
had been cloned. Two years later the human cotransporter was
FIG 2. Diagram of enterocytes illustrating the concepts of linking theextracellular-intracellular Na� gradient (upper enterocyte) with activehexose transfer through the Na�-glucose cotransport carrier SGLT1 inthe brush border membrane and the outward Na� pump at the basolateralmembrane (middle enterocyte). The transintestinal potential difference
(pd) in the interdigestive phase is �3 mV (interstitial or serosal fluidpositive to lumen), which increases to � 6 mV on addition of an activelytransported hexose to the luminal fluid because of the generation of ahexose transfer pd. A nonelectrogenic carrier-mediated pathway (possi-bly GLUT 5) is shown in the bottom enterocyte whereas the glucosetransporter GLUT 2 is shown at the basolateral membrane, allowing thefacilitated movement of hexose in or out of the cell. The values are acomposite from experimental data in the reviews by Levin (22, 23). Seetext for further details. mM, mmolIL.
cloned, sequenced, and expressed (33). The human cDNA of
chromosome 22 codes for a protein of 664 amino acid residues,
86% of which are identical in the rabbit (34). There is no ho-
mology with the facilitated glucose transporters present in other
tissues (35, 36). The SGLT1 gene is located on chromosome 22
at qi 1.2 -+ qter. The actual three-dimensional structure of SGLT1
in the membrane is not known but the primary amino acid se-
quence has been arranged into a model secondary structure (Fig
3). This has the amino terminal in the cytoplasm and 12
membrane-spanning domains in a helical conformation (37). The
protein is glycosylated at one site (ASN 248) but this has little
effect on function (37). Radiation inactivation analysis of SGLT1
indicates that the functional form of the protein in the membrane
is that of a tetramer. At saturating glucose concentrations, the K,,.,
for Na� is between 10 and 40 mmohfL and the kinetic evidence
suggests that two sodium ions are coupled with each glu-
cose molecule. Interestingly, D-glucose, 3-0-methyl glucoside,
D-galactose, and a-methyl glucoside are all transported by
SGLT1 (37).
One outstanding anomaly remains in relation to many previous
kinetic studies on the Na�-hexose cotransported and SGLT1. So
far only SGLT1 has been found to be expressed in enterocytes
of rabbits and humans and there is no evidence of any other
cotransporter. Yet animal studies in rats (38-40), hamsters (41),
guinea pigs (42), rabbits (43), and human adult (44) and fetal
intestine (45) have indicated the presence of more than one car-
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INTESTINAL CARBOHYDRATE ABSORPTION 693S
FIG 3. Diagram showing the secondary structure model of the Na�-
glucose cotransporter SGLT1 . The 664 amino acid residues are formedinto 12 membrane-spanning domains (helical formation) whereas theamino terminal is in the cytoplasm. An outer glycosylation site (N linked)is shown (actually at Asn 248), it appears to have little effect on thefunction of the carrier. In glucose-galactose malabsorption, one mutationidentified results in a replacement of the aspartic acid residue at theinterface between the amino terminal in the cytoplasm and the first trans-membrane domain (helical formation). The diagram is a simplified ver-sion of that proposed by Wright et al (37).
ncr. Even the laboratory that eventually cloned SGLT1 found
kinetic evidence for heterogeneity of the carrier (46). It seems
strange that all of these studies, which used a variety of tissue
preparations in vivo and in vitro from many species, were all
incorrect and either misinterpreted or had a faulty technique.
Presently there is no genetic evidence for other cotransporters, at
least in rabbit and human enterocytes. The sgltls for rats, ham-
sters, and guinea pigs have not yet been cloned and expressed.
Therefore, we must wait for the definitive answer about the re-
markable dichotomy between the kinetic measurements and the
cloning result.
Facilitated diffusion. Evidence for the movement of hexoses
by facilitated diffusion across the intestine is based mainly on in
vivo studies with rodents in which the absorption of actively
transported hexoses appears to be mediated by both a saturable,
electrogenic, phloridzin-sensitive mechanism (47), thought now
to be SGLT1, and a nonsaturating, phlondzin-insensitive non-
electrogenic mechanism. This latter component could also have
been simple diffusion. Studies on the distribution of glucose
transporters in various tissues have shown that the glucose trans-
porter isoform known as GLUT 5 is present in highest concen-
trations in the jejunum of the small intestine. The highest relative
amounts of GLUT 5 mRNA are also found at this site (36). At
present, the properties of this glucose transporter isoform are not
available but it is probably involved in the transfer of glucose
across the brush border by facilitated transfer. GLUT 5 has 501
amino acid residues and does not show any homology with
SGLT1 (36). The GLUT 5 gene is located on chromosome 1 at
site p31. GLUT 5 is an entirely independent molecule and has
an independent transport pathway. As stated previously, although
its properties have not yet been investigated, if the features of
GLUT 5 are similar to the other glucose transporter isoforms
GLUT 1-4, GLUTS will not be sodium sensitive or blocked by
phloridzin, features of the carrier that would be needed for the
linear absorption of glucose (see above) as observed in the ex-
periments of Debnam and Levin (47).
Passive diffusion. Passive movement of the strongly hydro-
phihic hexoses across the membrane of the brush border by dif-
fusion alone would be slow and poor and would certainly be an
inadequate mechanism for the rapid absorption of the hexoses
from the lumen. The experimental evidence for such movement
is weak in that it relies on seeing whether there is any transport
left after excluding movement by facilitated diffusion and by
active transport, whether the transport is linear with increasing
concentration, and whether it matches the transport of sugars
thought to be absorbed passively (eg, sorbose). Because there is
no inhibitor or transporter for the facilitated diffusion process it
is sometimes difficult to distinguish between facilitated diffusion
(a transporter with a large K,,,) and simple passive diffusion. This
was the case in the experiments of Debnam and Levin (47) when
they measured the absorption of hexoses from the rat intestinal
lumen in vivo, in the case of Stevens et al (48) when they used
isolated rabbit brush borders in vitro, and in the case of Dawson
et al (49) when they used human jejunal biopsies in vitro.
Movement across the basolateral membrane
Sugars leave the enterocyte by moving across the basolateral
membrane, which is a significant diffusion barrier to hydrophilic
molecules. Early studies showed that glucose moved across by a
facilitated transfer process that was Na�-dependent and was
blocked by phloretin or cytochalasin B (49, 50). It was suggested
that the transfer mechanism was similar to the glucose trans-
porters in cells like liver and adipocytes. Molecular cloning iden-
tified five glucose transporter isoforms that have been designated
GLUT 1-5 in the order of their discovery (35, 36). The glucose
transporter present in the enterocyte basolateral membrane has
been identified as GLUT 2 (35, 36) and has been shown to be
localized on the basolateral membrane (51). Whereas the mRNA
for GLUT 2 in the enterocytes is identical with the mRNA for
GLUT 2 in kidney and liver, the molecular weights of the pro-
teins expressed in the various cells are different (51). The cx-
pression of the different forms is thought to be due to tissue-
specific posttranslational modification. GLUT 2 is only present
in the enterocytes on the villus (mature) and is not seen in those
in the crypts (immature) (51).
Glucose-galactose malabsorption
Humans suffering from glucose-galactose malabsorption can
absorb fructose and can breakdown lactose, sucrose, and maltose
but cannot absorb the released monosaccharides glucose and ga-
lactose (52-55). Biopsy tissue taken from intestine from such
patients cannot actively accumulate hexoses (56) and in vivo
does not show hexose-transfer potentials (57), evidence that
strongly suggests that these patients do not possess a normal Na�-
glucose cotransporter in their brush borders (Figs 2 and 3). The
condition gives rise to severe watery diarrhea in neonates that is
lethal unless glucose- and galactose-containing foods are re-
moved from the diet. Turk et al (58) succeeded in obtaining
mRNA from two sisters who were diagnosed as having glucose-
galactose malabsorption. The cDNA was synthesized from the
RNA by reverse transcriptase, and overlapping segments of
cDNA coding for the cotransporter were amplified by the poly-
merase chain reaction by using ohigonucleotide primers based on
the normal sequence. The entire cDNA coding region of one of
the sisters was sequenced and a single base change was discov-
ered at position 92, where a guanine replaced an adenine. This
change was confirmed in the other sister. One chromosome in
each parent also contained a mutation at position 92. The muta-
tion changes amino acid 28 of SGLT1 from an aspartate to an
asparagine. Expression cloning of the mutant clone was under-
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694S LEVIN
taken in Xenopus laevis oocytes and it was shown that the in-
duced transporter failed to create any enhanced uptake of sugar
into the egg, unlike wild type SGLT1. Thus the glucose-galactose
malabsorptive condition in the sisters is due to a defective gene
that creates an inactive Nat-glucose transporter because of the
substitution of one amino acid at position 28. It is thought that
in the secondary structure hypothesized for SGLT1 in the
membrane (Fig 3), the substituted amino acid is at the interface
between the amino terminal in the cytoplasm and the first trans-
membrane segment of the protein (58).
In humans, if there is no active transport of glucose by SGLT1
then glucose and galactose absorption do not proceed normally.
There appears to be little or no facilitated absorption of glucose
or galactose by GLUT 5 or little absorption of either hexose by
passive diffusion. Early perfusion studies of the absorption of
sugars in human intestine by Holdsworth and Dawson (59)
showed that although increasing concentrations of the perfused
glucose and galactose conformed to a curvilinear absorption, sug-
gesting a saturable process, sorbose and mannose (nonactively
transferred sugars absorbed by passive diffusion only) had hardly
any absorption at all, even at high luminal concentrations (60).
This evidence indicates that passive absorption of hexoses across
human intestine is much lower than that observed in animal ex-
periments (23).
Pappenheimer and his coworkers (61-64) proposed from their
experiments on rat small intestine that the solvent drag of fluid
passing between enterocytes via the intercellular pathway was
the principal route and mechanism for the absorption of glucose
from the intestinal lumen at physiological rates of fluid absorp-
tion and concentration. In their provocative hypothesis, the pri-
mary role of the Na�-glucose transporter (SGLT1) was to allow
glucose to enter the enterocyte and enhance the permeability of
the tight junction by triggering contraction of cytoskeletal pro-
teins and by providing the osmotic force or drive for the absorp-
tive fluid flow through the paracellular pathway. The hypothesis
was criticized by Ferraris et al (65) because the absorption of
dietary glucose by solvent drag was based on old estimates of
the concentration of free glucose present in the intestinal lumen
after meals. These estimates of concentration were between 50
and 500 mmol/L. When measurements were taken with greater
accuracy and better techniques it was found that the concentra-
tion of free glucose was between 0.5 and �50 mmoh/L.
Levin (23) pointed out that with the solvent drag model for
dietary glucose absorption, sufferers from glucose-galactose mal-
absorption would fail to absorb significant quantities of dietary
hexoses because they could not generate a glucose-induced con-
vective flow of fluid and neither could they induce a contraction
of the intracellular proteins by glucose entry into the enterocyte.
However, recent evaluation of the role of passive absorption of
sugars across perfused human jejunum in vivo has shown that
the passive absorptions of both L-glucose (not actively trans-
ported) and mannitol (a polyhydric alcohol ofthe same molecular
weight and volume as glucose) were poor both in the presence
and absence of D-glucose in the luminal fluid (66). It was esti-
mated that > 95% of glucose absorption from the human jeju-
num under in vivo perfusion conditions occurs by carrier-medi-
ated transport. At present it appears that in humans, practically
all glucose absorption is by SGLT1. Strangely, GLUTS does not
appear to be involved in facilitating the absorption of glucose
across the human enterocyte. What then is the function of GLUT
5? Could it be involved in fructose transport?
Fructose absorption
The absorption of fructose across both animal and human in-
testine has been reviewed by Levin (23). (This review should be
consulted for full references.) Fructose is absorbed by a mecha-
nism that is independent of SGLT1 because it is absorbed nor-
mally in sufferers from glucose-galactose malabsorption and
whereas phloridzin completely blocks glucose active transfer it
has no effect on fructose absorption. In rat and human intestine,
fructose is absorbed intact but in guinea pig and hamster intes-
tine, it is converted into glucose during its passage through the
enterocyte. It was originally thought that fructose was not ac-
tively absorbed by enterocytes but was absorbed by carrier-me-
diated facilitated diffusion. However, studies on fructose absorp-
tion across everted jejunum from starved rats have shown that it
is accumulated against its concentration gradient by an energy-
dependent and Na�-dependent process that follows saturation hi-
netics [K,,, = 0.9 mmohfL (67)]. Four individuals suffering from
diarrhea who have been reported as showing delayed fructose
absorption in vivo and whose symptoms disappeared after being
placed on a fructose-free diet may be showing a deficiency or
even an absence of the fructose carrier (68). Unfortunately, the
uptake of fructose was not studied in biopsy samples, so no ccl-
lular details of the cause of the delayed absorption are available.
The transporter for fructose has not been identified, but because
GLUT 5 does not seem to be involved in glucose absorption per
se, it may be involved in mediating fructose absorption (69).
Fructose absorption is enhanced by glucose, suggesting a glu-
cose-dependent and a glucose-independent path (59, 70). Simi-
larly, fructose from sucrose is more readily absorbed than is fruc-
tose fed alone (70). However, both results could be obtained if
fructose is significantly entrained in the fluid absorption induced
by the luminal glucose and the glucose released from sucrose.
Another possibility, discussed by Fujisawa et al (71) is that when
fructose and glucose are ingested together they could be trans-
ported by a disaccharidase-related transport system, and that fruc-
tose ingested by itself cannot be so transported.
Expression patterns for brush border proteins along the crypt
villus axis
The expression of the Nat-glucose transporter and its mRNA
along the crypt villus axis has been investigated in the rabbit
jejunum by two groups of workers. Hwang et al (72) and Smith
et al (73) both studied the localization of the mRNA by an in situ
hybridization technique. The disposition of SGLT1 was dem-
onstrated immunocytochemically in the former study and in the
latter by measuring the distribution along the vihlus of phloridzin-
sensitive active glucose uptake. Neither glucose uptake nor
SGLT1 were found in the crypt cells but whereas Hwang et al
reported a sixfold increase in mRNA from the villus base to its
tip, Smith et al found no significant change in its amount being
maximal at or near the crypt mouth. Smith et al (73) also reported
that the active uptake of glucose increased continuously from the
crypt mouth until its maximum at the villus tip whereas Hwang
et al stated that the distribution of SGLT1 by the polyclonal an-
tibody showed ‘ ‘uniform labelling of the brush border mem-
branes of enterocytes lining the intestinal villi’ ‘ although it was
also stated that ‘ ‘the intensity of the labelling decreased towards
the base of the villus’ ‘ (72). Study of the localization of SGLT1
by immunohistochemical techniques in rats also showed that
SGLT1 was distributed uniformly in each villus cell (74, 75).
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INTESTINAL CARBOHYDRATE ABSORPTION 695S
Smith et al (73) argued that SGLT1 was subject to posttranscrip-
tional control and that the relative amount of its mRNA was no
indication of its function. Hwang et al (72), however, proposed
that the SGLT1 gene is transcribed, mRNA translated, and the
manufactured SGLT1 inserted directly into the brush border
plasma membrane of the mature enterocytes in the functional
form. This expression pattern was claimed to be distinct from
that of other brush border proteins such as aminopeptidase (13)
and vilhin (76). The mRNA for both the enzyme and the structural
protein was most abundant in the cells at the crypt villus junction
with a decline towards the villus tip, yet the proteins are present
in the brush border from the base to the villus tip. Hwang et al
(72) interpreted this to indicate that the two genes are transcribed
early at the crypt villus junction and there is then a low turnover
in the expressed proteins of the brush border membranes during
the life of the enterocyte. Moreover, because of the differential
expression of the mRNA and brush border proteins, it was con-
cluded that there is no single temporal or spatial point for the
expression of all the enterocyte genes.
Absorption of the products ofdisaccharide hydrolysis
Hydrolysis of maltose, sucrose, and lactose by the brush border
disaccharidase produces glucose, galactose, and fructose. Al-
though lactose absorption may be rate limited by its slow hydro-
lysis, the rate of absorption of monosaccharides produced by hy-
drolysis of other disaccharides at the brush border membrane
should be the same as from other monosaccharide solutions of
equimolar concentration. Experiments in vitro, however, showed
that glucose liberated from sucrose was transported better than
was free glucose or glucose produced from glucose-i-phosphate,
that is, it had a ‘ ‘kinetic advantage” (4). Similar results illus-
trating this kinetic advantage were obtained with other disaccha-
rides and with other intestinal preparations. Levin (23) reviewed
the literature and found that the importance of the kinetic advan-
tage for glucose absorption from disaccharides was not clearly
defined when applied to in vivo studies; some authors found sig-
nificant increases with disaccharides whereas others did not. For
example, patients with glucose-galactose malabsorption did not
have a hydrolase-related transport system to compensate for the
primary defect (55).
Intestinal adaptations induced by changes in dietary
carbohydrate
Changes in the dietary amounts of carbohydrates can alter in-
testinal function and structure by three basic mechanisms:
changes in the number of the functional enterocytes; changes in
the carrier, enzymic, or metabolic processes of the enterocytes;
and changes in the maturation of function of the enterocytes as
they migrate from the crypts to the extrusion zone at the vil-
lus tip.
Effects of carbohydrate on intestinal enterocyte population
There is now a considerable body of experimental evidence
indicating that food in the lumen (luminal nutrition) has signifi-
cant effects on the structure and functions of the small intestine
(23, 77). Even when rats are maintained on total parenteral nu-
trition (1’PN) the small bowel atrophies (78, 79). When experi-
mental animals are progressively starved, there is a progressive
decrease in the small intestinal enterocyte population as charac-
terized by decreases in mucosal mass (wet or dry weight), entero-
cyte number, enterocyte column number, and villous height (80).
Infusion of dietary sugars and even of nonmetabolized, actively
transferred sugars (eg, 3-0-methyl glucose) can prevent the small
bowel atrophy of the starved rat and the atrophy of the rat gut
maintained by TPN (81). The infusion of disaccharides into the
starved rat gut has been found to be advantageous compared with
the free monosaccharides (82). The relevance of the rat model to
human intestine is not clear. The few studies that have examined
the functions and structure of the human gut deprived of its lumen
food supply (luminal nutrition) appear to indicate that structural
changes are not obvious, but other studies suggest that lumi-
nal nutrition may play a role in maintaining enterocyte mass
(23, 77).
Effects on intestinal enzymes
The diet of experimental animals can be modified to alter the
amounts of digestive enzymes. The literature in this field of study
is extensive and has been reviewed many times (23). In general,
researchers have found that the feeding of specific carbohydrates
or carbohydrate-rich diets increases the amount of disaccharid-
ases in the brush border and in some cases even the specific
activity of the enzyme. Thus, feeding increased amounts of su-
crose increases sucrase activity by de novo synthesis (83, 84). In
humans high dietary intakes of sucrose and fructose, but not glu-
cose, increase sucrase and maltase but not lactase activity (85,
86). The amounts and activity of metabolic enzymes inside en-
terocytes can also be changed by dietary carbohydrate intake.
Studies have shown changes, for example, in the glycolytic, ga-
lactose-metabolizing and fructose metabolizing enzymes in both
humans and animals.
Effects on intestinal hexose absorption mechanisms
The influence ofdietary carbohydrate on the absorption of sug-
ars by the small intestine has been known for > 50 y (87, 80).
Many studies have examined the effects of feeding specific sug-
ars or glucalogues to starved animals to assess their effects on
the hexose absorption processes (38, 89). The studies have been
reviewed by Levin (23), Karasov and Diamond (90), and Ferraris
and Diamond (91). More recently the effects of variation in di-
etary carbohydrate on the concentrations of SGLT1 and its
mRNA in sheep intestine have been studied. In this model glu-
cose absorption is upregulated by diet (92). Little attention, how-
ever, has been paid to the possible regulation by hexoses of the
facilitated transport mechanism for hexose on the basolateral
membrane (GLUT 2 transporter). It is known that raising the
concentration of plasma glucose (by infusion of glucose) en-
hances the transport of glucose across basolateral vesicles taken
from such treated rats but not in their brush border membranes
(93, 94). The changes have not been fully characterized (ie,
whether they are due to an increase in the number of GLUT 2
transporters or not). It was claimed that the rate-limiting step for
glucose absorption across the enterocyte was its exit across the
basolateral membrane. It has also been reported that increasing
the carbohydrate content of the diet increases the glucose trans-
port capacity at the basolateral membrane, and the change was
specific for metabolizable hexoses (95). Changes in the basolat-
eral transporter GLUT 2 may thus be another feature of the con-
trol of glucose absorption across the gut. There is no information
about whether the levels of GLUT 5 are influenced by dietary
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696S LEVIN
carbohydrate levels. With the new techniques of in situ hybridi-
zation and immunocytochemical staining using the specific an-
tibodies for SGLT1 and GLUT i-S it will be possible to follow
the actual changes of the transporters induced along the crypt
villus axis by changes in dietary carbohydrate.
Effects on intestinal secretory function
Intractable diarrhea is usually the terminal condition of victims
of famine and severe malnutrition. Ethical problems prevent con-
trolled studies to investigate the cause of the enhanced secretory
behavior of the intestine in such starved and severely malnour-
ished human victims. In the past few years it has been shown
that starvation for > 24 h induced a hypersecretory state of the
small and large intestine in rats (96-98). This starved rat model
shows many characteristics of the diarrhea of starvation and mal-
nourishment. Levin (98) reviewed the subject and proposed that
the small intestinal hypersecretory activity was caused by the
hypergiucagonemia known to occur in animal and human star-
vation and suggested a possible mechanism by which the hor-
mone glucagon could induce the changes in the enterocytes. In
support of the glucagon theory, Lane and Levin (99) have shown
that injecting glucagon into fed rats causes hypersecretory activ-
ity in both jejunum and ileum similar to that observed previously
in the starved rat intestine (96, 97). The possible importance of
(dietary) carbohydrate in influencing this hypersecretory behav-
ior of the small intestine has been shown by allowing rats to drink
isotonic glucose during the 3-d starvation period. When this oc-
curred, hypersecretory activity was ameliorated in the duodenum,
jejunum, and practically in the ileum, but the large intestine was
unaffected (100, 101). The mechanisms by which glucose feed-
ing prevents the hypersecretion from occurring are not yet known
but they could involve direct actions on the enterocytes or their
maturation, effects on the crypts, or changes in the concentrations
of hormones in the plasma (glucagon is one such obvious can-
didate). U
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