1 Departments of Surgery and Physiology, University of California Medical Center, Los Angeles, California 90024; and 2 Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115
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ABSTRACT |
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Traditionally, intestinal glucose absorption was thought to occur through active, carrier-mediated transport. However, proponents of paracellular transport have argued that previous experiments neglected effects of solvent drag coming from high local concentrations of glucose at the brush-border membrane. The purpose of this study was to evaluate glucose absorption in the awake dog under conditions that would maximize any contribution of paracellular transport. Jejunal Thiry-Vella loops were constructed in six female mongrel dogs. After surgical recovery, isotonic buffers containing L-glucose as the probe for paracellular permeability were given over 2-h periods by constant infusion pump. At physiological concentrations of D-glucose (1-50 mM), the fractional absorption of L-glucose was only 4-7% of total glucose absorption. Infusion of supraphysiological concentrations (150 mM) of D-glucose, D-maltose, or D-mannitol yielded low-fractional absorptions of L-glucose (2-5%), so too did complex or nonabsorbable carbohydrates. In all experiments, there was significant fractional water absorption (5-19%), a prerequisite for solvent drag. Therefore, with even up to high concentrations of luminal carbohydrates in the presence of significant water absorption, the relative contribution of paracellular glucose absorption remained low.
cell membrane permeability; small intestine; perfusion; mannitol; maltose; water absorption
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INTRODUCTION |
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EPITHELIAL TRANSPORT OF glucose in the intestine is known to occur through both active and passive mechanisms. Active transport is affected by specific membrane-associated carriers, and its rate follows saturation kinetics. In contrast, the rate of passive transport in the intestine varies linearly with solute concentration and does not obey saturation kinetics.
Until recently, it has been widely accepted that most glucose transport in the mammalian intestine occurs through active mechanisms. However, a number of recent studies have proposed that passive transport may play a dominant role in glucose absorption. In this theory, the tight junctions (TJs) are assumed to be the rate-limiting barriers for passive or paracellular glucose permeation. The activation of Na+-nutrient transporters on the cellular surface is thought to elicit cytoskeletal changes in the TJ anatomy (12, 15), mediated by alterations in Ca2+ influx into the cell and causing activation of the actin-myosin complex (2, 8). The suggested result of these cytoskeletal changes is the disruption of the TJ barrier to paracellular flow and the creation of TJ dilatations, whose existence during Na+-glucose cotransport has been observed by electron microscopy (10, 12).
Although alteration of the TJ structure during Na+-nutrient cotransport has thus been documented, the question remains as to the quantitative physiological significance of these observations. Specifically, do the changes in epithelial permeability cause an increase in paracellular transport of nutrients that is significant in comparison with active transport rates? A number of studies suggest that water movement across the altered TJ barrier results in paracellular uptake of small, luminal nutrients via solvent drag (9, 11, 12, 14-20). In some intestinal perfusion studies, glucose uptake does not follow saturation kinetics and continues above the known Michaelis-Menten constant for glucose (9, 18). Some calculated estimates of total glucose uptake capacity of rat small intestine based on transcellular transport alone are below uptakes observed in vivo (11, 17). During transcellular transport of Na+ and nutrients, inert tracers such as D-mannitol are absorbed from the intestinal lumen in a manner consistent with solvent drag (17). Finally, Na+-nutrient cotransport stimulates changes in the cellular architecture of the TJ, which would allow the passage of small molecules along the paracellular route. These types of evidence have been interpreted to support the physiological importance of paracellular transport.
The goal of the present study was to assess the physiological importance of paracellular D-glucose absorption in an unanesthetized dog model. We surgically created jejunal Thiry-Vella loops that have an intact neurovascular supply but that are isolated from luminal continuity with the remainder of the intestine. This model allows the perfusion of these intestinal loops without the confounding variables of anesthesia or acute surgical manipulation. Isotonic solutions containing L-glucose as the probe for paracellular permeability, plus D-glucose or D-isomer sugars, were given by constant infusion pump. These solutions contained carbohydrate concentrations both within the physiological range and at supraphysiological levels, aimed at maximizing any effect of paracellular transport.
In addition to testing the theory of paracellular transport in a previously untested species (the dog), our study differs from previous studies by taking account of criticisms that proponents of paracellular transport directed at previous tests in humans and rats (1, 14, 17). We used a sufficiently long perfusion period to be certain that the proposed alterations in TJ permeability really would occur, we ensured conditions adequate for solvent drag by obtaining significant water absorption, and we tested the hydrolyzable disaccharide maltose to increase local glucose concentrations at the brush-border membrane. Despite these experimental conditions designed to maximize paracellular transport, the results of our experiments indicate that paracellular transport of D-glucose still plays a minor role in total glucose transport in this dog model.
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METHODS |
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Animals.
This protocol was approved by the Animal Research Committee of the
University of California at Los Angeles. Six female mongrel dogs,
weighing 15-20 kg, underwent surgery following a 12-h fast. The
animals were anesthetized with an intravenous injection of 30 mg/kg of
pentobarbital sodium (Abbott, North Chicago, IL), intubated, and
maintained with inhalational halothane anesthesia. After midline
laparotomy, a 25-cm segment of jejunum was isolated 10 cm distal to the
ligament of Treitz. This segment was removed from continuity from the
remainder of the small bowel, while its neurovascular supply was
carefully maintained. Luminal access to the Thiry-Vella loops was
established with custom-made metal cannulas, which were inserted into
both the proximal and distal ends. The cannulas were wrapped with
omentum and delivered through the anterolateral abdominal wall through
stab incisions. Continuity of the remaining intestine was restored with
end-to-end anastomosis. The laparotomy incision was closed, and the
animals were allowed to recover. Antibiotic (60 mg Batryl; Haver,
Shawnee, KA) was administered intravenously for 5 days postoperatively.
Postoperative care of the loops included daily irrigations with 50 ml
of saline (0.15 M). The dogs were allowed to recover for 2 wk before
absorption studies were conducted. During this interval, the dogs were
conditioned to stand in modified Pavlov slings for 4-h periods. Dogs
were fed a standard laboratory diet (Harland Teklad no. 8653, Madison, WI) composed of 25% protein, 47% carbohydrate, and 9% fat (250 g dry
food · kg body
wt1 · day
1).
The carbohydrate content consisted of ground corn, soybean meal, corn
gluten, ground wheat, and beet pulp, all of which are expected to yield
glucose on hydrolysis. Thus dogs were adapted to glucose-containing
luminal contents.
Thiry-Vella loop perfusion.
These experiments were conducted using a modification of a previously
reported method (25). The dogs were fasted for a 12-h period before the
study but were allowed free access to water. The animals were placed in
Pavlov slings, and the Thiry-Vella loops were gently irrigated with
saline (0.15 M) to remove residual debris. Perfusate solutions were
then infused into the loops via a roller pump (Cole Parmer) (Fig.
1). Each solution differed in its
carbohydrate composition (D-glucose,
D-maltose, or
D-mannitol) and was buffered in
an electrolyte solution to maintain constant isotonicity (Table
1). Each liter of solution also
contained 50 µCi
L-[3H]glucose
as a marker of paracellular permeability. Polyethylene glycol (PEG)
(Sigma, St. Louis, MO) (5 g) with 10 µCi
[14C]PEG was added as
a volume marker. The perfusate solutions were adjusted to pH 7.4 and
were maintained at 37°C throughout the experiment. The final
measured osmolarity of all solutions was between 285 and 293 mosM.
Effluents were collected at 15-min intervals in separate vials after
passage through the loops. These were stored at 0°C for later
analytic determination.
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Analytic determinations. For each experiment, two infusate samples were collected from the perfusion apparatus without passage through the loops. These served as control solutions for analytic determinations. One milliliter of effluent for each sampling period was mixed with 5 ml of scintillation cocktail (Ready Safe, Beckman, Irvine, CA) and placed in scintillation vials. These were assayed simultaneously for L-[3H]glucose and [14C]PEG activities using dual-isotope liquid scintillation counting (model LS6000, Beckman). D-Glucose concentrations of samples were determined using an enzymatic assay (Stanbio Laboratories, San Antonio, TX) that relies on a two-step reaction catalyzed by hexokinase-glucose-6-phosphate dehydrogenase. Absorbance was read at 340 nm, corresponding to the reaction product (NADH).
Experimental design. Experiments were designed to determine the relative importance of paracellular transport for carbohydrate concentrations spanning the physiological range (0-50 mM) and also at the supraphysiological level (150 mM).
Physiological experiments were designed to approximate the luminal D-glucose delivery experienced by the jejunum after a meal. In humans, the postprandial concentration of D-glucose in jejunal luminal fluid ranges from 30 to 48 mM (13). In dogs, whose diet is comprised mostly of meat, the average jejunal glucose concentration is <1 mM (4). The design of this experiment used luminal glucose concentrations of 1 and 50 mM (Table 1). A higher perfusion rate (4.5 ml/min) was used to mimic the bolus delivery of luminal contents into the jejunum following a meal. A supraphysiological concentration (150 mM) of three different carbohydrates (D-glucose, D-maltose, and D-mannitol) was used in the perfusate solutions in a second set of experiments (Table 1). The purpose of using this concentration level that is so far above the physiological ones in the dog was to maximize the chances of detecting a quantitatively important contribution of paracellular transport. This contribution is expected to increase with luminal glucose concentration because rates of passive paracellular transport increase linearly but active transport levels off according to saturable kinetics. Had we omitted experiments at supraphysiological concentrations and failed to detect paracellular transport at concentrations believed to be physiological, our conclusions might have been disputed (e.g., on the grounds that we underestimated physiological concentrations or that paracellular transport was still important under certain conditions). D-Maltose was used as complex carbohydrate of D-glucose monomers, whose breakdown by brush-border hydrolases should yield higher local glucose concentrations (14). D-Mannitol serves as a nonabsorbable carbohydrate control. The NaCl composition of the perfusate solutions was altered to maintain isotonicity (Table 1). Perfusion rate of the Thiry-Vella loops was slowed to 2.5 ml/min to maximize the fractional absorption of water and glucose.Calculations. Flow rate was calculated as the average of the two control infusate sample volumes, normalized to 1 min. With the use of modifications of the standard Thiry-Vella loop equations (3), values for [14C]PEG recovery, water flux, D-glucose flux, and L-[3H]glucose flux were calculated. D-Glucose and L-[3H]glucose loads were similarly determined. Means of these parameters for each 15-min period were calculated. These were averaged over the 2-h experimental period to determine the overall value for each experiment. The fractional absorptions of water, D-glucose, and L-[3H]glucose were determined by normalizing the flux values by the respective load values.
Statistical analysis. Data are presented as means ± SE. The significance of differences between means was determined by Student's paired t-test.
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RESULTS |
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Physiological levels of D-glucose
(1-50 mM).
Results for these experiments are summarized in Table
2.
[14C]PEG recovery for
these experiments ranged from 94 ± 4 to 98 ± 3%. Perfusion
rate of the Thiry-Vella loops was kept at 4.7 ml/min to mimic
physiological conditions in the jejunum.
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Supraphysiological levels of D-glucose, D-maltose, and D-mannitol (150 mM). Results of these experiments are also shown in Table 2. [14C]PEG recovery ranged from 93 ± 4 to 103 ± 9%. Loop perfusion rates for these experiments were reduced to 2.0 ± 0.1 ml/min, to increase transit time through the loop and to maximize the absorption of water and carbohydrates. The concentration of D-glucose in the 150 mM D-mannitol solution was not detectable either before or after passage through the loop. The concentration of D-glucose in the 150 mM D-maltose solution increased from 0.004 ± 0.001 to 0.9 ± 0.1 mM after passage through the loop. This change presumably reflects the breakdown of D-maltose by brush-border hydrolases, rather than back-diffusion of D-glucose into the intestinal lumen, because glucose concentration remained undetectable in the mannitol perfusate.
The fractional absorption of D-glucose was 21 ± 4% when the 150 mM D-glucose solution was used, and the fractional absorption of D-maltose was 17 ± 7% when 150 mM D-maltose was given. Although these fractional absorption figures are not significantly different, the amount of D-glucose absorbed is greater in the 150 mM D-maltose group because each D-maltose molecule is composed of two D-glucose monomers. The fractional absorption of water was similar between the 150 mM D-glucose and D-maltose groups (19 ± 5 and 13 ± 8%, respectively). The fractional absorption of water in the 150 mM D-mannitol group was significantly lower than either the D-glucose or D-maltose groups (6 ± 4%). The passive permeation of L-glucose was not significantly altered between the 150 mM D-glucose, D-maltose, and D-mannitol groups, which yielded L-glucose fractional absorptions of 2.3 ± 0.4, 5 ± 3, and 5 ± 2%, respectively. With the use of these figures, the calculated fraction of D-glucose absorbed passively was 13 ± 5% for the D-glucose group and the fraction of D-maltose absorbed passively was also 13 ± 5% for the D-maltose group. ![]() |
DISCUSSION |
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We tested the hypothesis that, under physiological and supraphysiological conditions, paracellular transport accounts for an appreciable fraction of D-glucose absorption. We created neurovascularly isolated jejunal loops in dogs and measured the disappearance of probes from the lumen of the intestine. This model offers five unique characteristics that distinguish this study from techniques used in previous studies.
First, other studies have accessed paracellular transport by measuring the appearance of markers in the urine after ingestion of supposedly "nonabsorbable" probes. These studies have led to conflicting results. Pappenheimer et al. (16) measured the appearance of a lipid-insoluble octapeptide composed of D-amino acids in the urine of rats. When rodents drank a 5% glucose solution, nearly 50% of the octapeptide was retrieved intact in the urine, indicating absorption of this molecule. However, Schwartz et al. (21) measured the appearance of inert sugars (L-xylose, L-galactose, D-mannitol, and L-mannose) in the urine of gavaged and chow-fed rats. This study showed minimal absorption of these markers in the presence of D-glucose or chow. Perfusion techniques allow for direct measurement of probes in the perfusion solutions and avoid errors that rely on their indirect appearance in the urine.
Second, perfusion techniques allow for precise control of the tonicity of the perfusion solution. Markedly hypertonic solutions are known to damage surface epithelium, which may alter the transcellular permeability of the membrane surface. Back diffusion of water can also occur into the intestinal lumen containing a hypertonic solution, which would dilute the concentration of the measured markers.
Third, the luminal transport time in these experiments can be controlled. Previous studies, using intestinal membrane sheets mounted in Ussing chambers, have shown that in vitro alterations in TJ permeability can take up to 10 min to occur (1).
Fourth, the chronic nature of our models ensures that the dogs are free of anesthesia and acute postsurgical effects. Uhing and Kimura (23) showed in studies using anesthesia and acute surgical manipulation in the rat that active glucose transport is thereby inhibited up to 86%. Because paracellular transport, however, remained unaffected by surgery or anesthesia, the relative importance of paracellular transport becomes overestimated using anesthetized animals or ones that have been recently surgically manipulated.
Finally, species-specific differences have been blamed for some apparent contradictions seen in other studies of glucose transport. The Thiry-Vella model in the dog gives some insight into the mechanisms of glucose transport in a larger animal.
Our experimental design sought to determine the relative importance of paracellular transport under both physiological and supraphysiological concentrations of luminal carbohydrates. In the physiological experiments, the concentration of D-glucose in the perfusion solution was varied between 1 and 50 mM. These concentrations are thought to express the physiological range of glucose found in luminal aspirates from both dogs and humans (4, 13). Luminal flow rates were also increased to mimic a bolus of luminal contents experienced after a meal. These experiments showed that by increasing the luminal concentration of D-glucose from 1 to 50 mM the fractional absorption of water is slightly increased (7 ± 1 vs. 5 ± 3%). Fractional absorption of D-glucose is reduced (18 ± 3 vs. 66 ± 8%), as the efficiency of glucose transport is higher at low concentrations and a larger percentage of glucose can be absorbed. However, the fractional absorption of L-glucose was not significantly affected by the increase in luminal glucose concentration (4 ± 1 vs. 7 ± 4%), contrary to previous studies in anesthetized rats (1, 7, 8, 17, 24). We speculate that this discrepancy may be due to the already discussed effects of anesthesia. The percentage of D-glucose absorption that is passive was determined by dividing the fractional L-glucose absorption by the fractional D-glucose absorption. Although the percentage of passive D-glucose absorption is nominally increased with increased D-glucose concentrations from 1 to 50 mM (24 ± 10 vs. 9 ± 4%), this difference did not reach statistical significance (P > 0.05). This trend is expected under traditional theories of intestinal glucose absorption and does not require involving paracellular absorption for its interpretation: the trend arises as an arithmetic consequence of dividing the concentration-independent passive fractional absorption of L-glucose by total D-glucose fractional absorption, which varies with concentration because it is dominated by active absorption with saturable kinetics.
In a second set of experiments, supraphysiological concentrations (150 mM) of three different carbohydrates (D-glucose, D-maltose, and D-mannitol) were used as the perfusion solutions. It has been theorized that the local concentration of carbohydrate experienced by the jejunal brush border is much higher than samples from luminal aspirates (14), due to the breakdown of complex carbohydrates by hydrolases at the brush border. This postulated local increase in concentration would increase the amount of carbohydrates pulled across the intercellular spaces by solvent drag, thereby increasing the effect of paracellular transport. However, this postulated increase in paracellular permeation was not seen in our experiments. When 150 mM concentrations of D-glucose and D-maltose were infused, the fractional absorption of D-glucose (21 ± 4%) and D-maltose (17 ± 7%) and the fractional absorption of water (19 ± 5 and 13 ± 8%, respectively) remained relatively constant. Although exact comparisons with the experiments using physiological concentrations of D-glucose cannot be made due to differences in the experimental procedure, it is evident that the fractional absorption of carbohydrates and water remained similar between experiments. In addition, the fractional absorption of L-glucose, the marker for paracellular transport, also remained low in the 150 mM D-glucose and D-maltose groups (2.3 ± 0.4 and 5 ± 3%, respectively), contrary to the theory that supraphysiological concentrations of D-glucose at the jejunal brush border would increase the proportion of paracellular transport, which would occur through solvent drag (14). The percentage of D-glucose absorption occurring passively remained low in the 150 mM D-glucose (13 ± 5%) and D-maltose (13 ± 5%) groups and did not increase with concentration, as would be expected by linear (passive) kinetics.
The 150 mM D-mannitol solutions were used as a nonabsorbable carbohydrate control to measure paracellular transport in the absence of absorbable sugars. No measurable amount of D-glucose was found in the perfusion solution before or after passage through the loop; therefore, no measurements of D-glucose flux were possible. However, an appreciable amount of water absorption was observed, consistent with previous studies performed in the absence of glucose in the dog (unpublished observations). Interestingly, the fractional absorption of L-glucose in the D-mannitol group (5 ± 2%) was not significantly different from that seen in the 150 mM D-glucose group (2.3 ± 0.4%) or the 150 mM D-maltose group (5 ± 3%). This important observation argues that paracellular permeability is not influenced by luminal concentrations of D-glucose and thus contradicts a key tenet of the paracellular absorption theory.
These findings are consistent with other studies showing that paracellular transport plays a minor role in D-glucose absorption. Fine et al. (5) used a similar experimental design to ours, with constant perfusion of jejunal loops in humans, and used perfusion solutions with defined ratios of unabsorbable markers (L-xylose, urea, and D-mannitol) of varying molecular sizes to determine alterations in TJ permeability. They found no evidence for glucose-induced changes in paracellular transport. One criticism of this study argued that paracellular absorption was underestimated because of a low fractional absorption of water and carbohydrates from the perfusion solution. However, our experimental design afforded a higher fractional absorption of water and carbohydrates and still yielded a negligible effect on paracellular transport. By a novel experimental approach, Uhing and Kimura (22) were able to determine the importance of paracellular transport without surgical manipulation of the gastrointestinal tract. Chronic indwelling catheters were placed in the duodenum, aorta, and portal vein of rats. Test solutions were given into the duodenum containing 3-O-methylglucose and L-glucose as markers for active and passive transport, respectively. Blood samples were then drawn from the aorta and portal veins after duodenal infusion, and the portal venous-aortic concentration gradients were determined. These studies estimated that more than 90% of glucose uptake occurred by active transport mechanisms. These experiments are consistent with our findings that active, transcellular transport is the dominant mechanism of D-glucose absorption.
In conclusion, our study confirms that paracellular D-glucose absorption plays a minor role compared with carrier-mediated transport in both physiological and supraphysiological conditions. In addition, our study responds to many criticisms put forth by proponents of paracellular transport. We have used an animal model that is free of the confounding factors of surgery or anesthesia, which have been shown to increase the passive flow of nutrients (22). The animals were studied over a 2-h time frame, which allows ample time for the proposed alterations in TJ permeability to occur. Previous studies have shown that alterations in TJ architecture may take 10 min to occur (1). We have observed significant water absorption over our study period (up to 19%), which would maximize any passive flow of nutrients that may occur through "solvent drag", as this has been proposed as a dominant mechanism of paracellular flow (17). Finally, we have incorporated maltose, a disaccharide, into our study design to evaluate the effect of local breakdown of a complex carbohydrate at the intestinal brush border. It has been previously theorized that this may increase the local glucose concentration, thereby enhancing paracellular flow (14). Despite these experimental alterations aimed at maximizing paracellular permeability, our study indicates that only a small portion of D-glucose absorption occurs through the paracellular route in unanesthetized dogs.
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ACKNOWLEDGEMENTS |
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Support for this work was from National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-47326 (S. W. Ashley) and DK-39870 (M. J. Zinner).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. W. Ashley, Dept. of Surgery, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (E-mail: swashley{at}bics.bwh.harvard.edu).
Received 7 October 1998; accepted in final form 7 December 1998.
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