Digestion andabsorption ofcarbohydrates frommolecules andmembranes

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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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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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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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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