J Appl Physiol 95: 1132–1138, 2003.
First published May 9, 2003; 10.1152/japplphysiol.01172.2002.
Prior exercise enhances passive absorption of
intraduodenal glucose
R. Richard Pencek, Yoshiharu Koyama, D. Brooks Lacy, Freyja D. James,
Patrick T. Fueger, Kareem Jabbour, Phillip E. Williams, and David H. Wasserman
Department of Molecular Physiology and Biophysics, Diabetes Research and Training Center, and
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615
Submitted 20 December 2002; accepted in final form 5 May 2003
dogs; phloridzin; splanchnic blood flow
of insulin to stimulate
skeletal muscle (25) and liver (22) glucose uptake. This
increase in insulin sensitivity, however, does not uniformly lead to improved oral glucose tolerance (15, 18,
24). Work done by Hamilton et al. (9) showed that
failure to improve oral glucose tolerance, despite increased insulin-stimulated glucose uptake, is due to
EXERCISE ENHANCES THE ABILITY
Address for reprint requests and other correspondence: R. R. Pencek,
Dept. of Molecular Physiology and Biophysics, Vanderbilt Univ. School of
Medicine, Nashville, TN 37232-0615 (E-mail: [email protected]).
1132
increased absorption of glucose from the gut. The resulting enhancement in splanchnic bed glucose output
counterbalances the effect of increasing muscle glucose
uptake on arterial glucose levels.
The mechanism by which prior exercise enhances
the absorption from the gut is unknown. Gut glucose
absorption is both transporter mediated and passive.
Transporter-mediated gut glucose absorption occurs
via luminal sodium glucose cotransporter-1 (SGLT-1)
Na⫹-K⫹ active transporters (5, 10) and GLUT-2-mediated facilitated diffusion. Facilitated diffusion of glucose occurs when transport of glucose via SGLT-1 stimulates translocation of GLUT-2 transporters to the
luminal surface of the gut (11, 16). Transporter-mediated glucose transport encompasses 90% of total gut
glucose absorption in both conscious dogs (17, 23) and
rats (31, 32). The remaining 10% of gut glucose absorption is due to paracellular diffusion across the intestinal
wall, although this route also appears to be indirectly
dependent on intestinal SGLT-1-mediated glucose transport, at least in sedentary, conscious dogs (23).
The purpose of the present study is to determine
whether the increased absorption of intraduodenal glucose after exercise is due to increased transportermediated and/or passive glucose absorption. For this
purpose, 3-O-[3H]methylglucose (absorbed via active,
facilitative, and passive routes) and L-[14C]glucose (absorbed passively) were delivered in trace amounts in
the duodenum to determine the contributions of transporter-mediated and passive pathways to net gut glucose absorption during an intraduodenal glucose load
(3, 4).
MATERIALS AND METHODS
Animal care and surgical procedures. Fifteen mongrel dogs
of either sex, with a mean weight of 23 ⫾ 1 kg, were studied.
A subset of the sedentary dogs was published previously (23).
The dogs were housed in a facility that met the American
Association for the Accreditation of Laboratory Animals Care
guidelines. All procedures were approved by the Vanderbilt
University Animal Care and Use Committee. The dogs were
fed a standard diet of meat and chow (34% protein, 14.5% fat,
46% carbohydrate, and 5.5% fiber based on dry weight).
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. Section 1734
solely to indicate this fact.
8750-7587/03 $5.00 Copyright © 2003 the American Physiological Society
http://www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
Pencek, R. Richard, Yoshiharu Koyama, D. Brooks
Lacy, Freyja D. James, Patrick T. Fueger, Kareem Jabbour, Phillip E. Williams, and David H. Wasserman.
Prior exercise enhances passive absorption of intraduodenal
glucose. J Appl Physiol 95: 1132–1138, 2003. First published
May 9, 2003; 10.1152/japplphysiol.01172.2002.—The purpose
of this study was to assess whether a prior bout of exercise
enhances passive gut glucose absorption. Mongrel dogs had
sampling catheters, infusion catheters, and a portal vein flow
probe implanted 17 days before an experiment. Protocols
consisted of either 150 min of exercise (n ⫽ 8) or rest (n ⫽ 7)
followed by basal (⫺30 to 0 min) and a primed (150 mg/kg)
intraduodenal glucose infusion [8.0 mg 䡠 kg⫺1 䡠 min⫺1, time
(t) ⫽ 0–90 min] periods. 3-O-[3H]methylglucose (absorbed
actively, facilitatively, and passively) and L-[14C]glucose (absorbed passively) were injected into the duodenum at t ⫽ 20
and 80 min. Phloridzin, an inhibitor of the active sodium
glucose cotransporter-1 (SGLT-1), was infused (0.1
mg 䡠 kg⫺1 䡠 min⫺1) into the duodenum from t ⫽ 60–90 min
with a peripheral venous isoglycemic clamp. Duodenal, arterial, and portal vein samples were taken every 10 min during
the glucose infusion, as well as every minute after each tracer
bolus injection. Net gut glucose output in exercised dogs
increased compared with that in the sedentary group (5.34 ⫾
0.47 and 4.02 ⫾ 0.53 mg 䡠 kg⫺1 䡠 min⫺1). Passive gut glucose
absorption increased ⬃100% after exercise (0.93 ⫾ 0.06 and
0.45 ⫾ 0.07 mg 䡠 kg⫺1 䡠 min⫺1). Transport-mediated glucose
absorption increased by ⬃20%, but the change was not significant. The infusion of phloridzin eliminated the appearance of both glucose tracers in sedentary and exercised dogs,
suggesting that passive transport required SGLT-1-mediated
glucose uptake. This study shows 1) that prior exercise enhances passive absorption of intraduodenal glucose into the
portal vein and 2) that basal and the added passive gut
glucose absorption after exercise is dependent on initial
transport of glucose via SGLT-1.
PRIOR EXERCISE ENHANCES PASSIVE GUT GLUCOSE ABSORPTION
perimental period (t ⫽ 0–90 min) began with the injection of
a 150 mg/kg body wt glucose primer (20% dextrose) into the
duodenum, followed by a continuous intraduodenal glucose
infusion of 8 mg 䡠 kg⫺1 䡠 min⫺1 (20% dextrose) until t ⫽ 90 min.
The rate of the intraduodenal glucose infusion was chosen to
reproduce glucose levels commonly seen in the portal vein
after feeding. At t ⫽ 20 min, a bolus containing trace
amounts of 3-O-[3H]methylglucose and L-[14C]glucose (25
␮Ci of each isotope) was injected into the duodenum. At t ⫽
60 min, an intraduodenal bolus of phloridzin (1.97 mg/kg)
was given, followed by a continuous intraduodenal phloridzin
infusion of 0.1 mg 䡠 kg⫺1 䡠 min⫺1 for the remainder of the
study. At the start of the phloridzin infusion, an isoglycemic
clamp was initiated to maintain the arterial glucose concentration at the level seen before phloridzin infusion. At t ⫽ 80
min, a second bolus of 3-O-[3H]methylglucose and L-[14C]glucose (100 ␮Ci of each isotope), fourfold larger than the first,
was introduced into the duodenum. During the experimental
period, blood and duodenal samples were taken every 10 min.
In addition to these samples, blood and duodenal samples
were taken every minute for 5 min after administration of
each tracer bolus. Because D-glucose and 3-O-methylglucose
are transported out of the lumen, less of these sugars makes
it to the paracellular gaps, compared with L-glucose. Consequently, gradients in the ratios of 3-O-[3H]methylglucose to
L-[14C]glucose exist. Although these gradients are impossible
to measure directly, evidence suggests that they are minimal
during the period immediately after the bolus, as direct and
indirect measures of luminal sugar ratios give the same
result (23). It has been shown in our previous work (23) that
determination of the passive fraction of gut glucose absorption using this technique is quantitatively the same as is seen
in the work of Lane et al. (17), which measured the absorption of L-glucose isotopes in isolated perfused jejunal sections
over a 2-h period. At the end of the experiment, animals were
euthanized with pentobarbital sodium, and an autopsy was
performed to confirm catheter and flow probe placement.
Blood and intraduodenal sample analyses. Plasma and
intraduodenal glucose levels were determined on the day of
the experiment by using the glucose oxidase method with a
Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). ICG absorption was assessed in arterial and
hepatic vein plasma samples at 810 nm after centrifugation
(3,000 g, 30 min). Those plasma samples that were not
immediately analyzed were stored at ⫺70°C for later analysis. Whole blood and intraduodenal samples were deproteinized with barium hydroxide and zinc sulfate to assess the
radioactivity of 3-O-[3H]methylglucose and L-[14C]glucose in
blood and duodenal samples. After centrifugation (3,000 g, 30
min), the supernatant was dried and reconstituted in 1 ml of
water and 10 ml Ultima Gold scintillent (Packard, Meriden,
CT). Radioactivity was determined by using a Packard TRICARB 2900TR liquid scintillation counter. Plasma insulin
Fig. 1. Experimental protocol. Arrows indicate the injection of a tracer bolus [25 ␮Ci at time (t) ⫽ 20 min and
100 ␮Ci at t ⫽ 80 min] of 3-O-[3H]methylglucose and
L-[14C]glucose into the duodenum. Arterial plasma glucose levels were clamped from t ⫽ 60–90 min to match
concentrations from t ⫽ 20–60 min.
J Appl Physiol • VOL
95 • SEPTEMBER 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
At least 16 days before each experiment, a laparotomy was
performed under general anesthesia. Two Silastic catheters
(0.03 mm ID) were inserted into the inferior vena cava for
indocyanine green (ICG) and glucose infusions. Silastic catheters (0.04 mm ID) were inserted into the portal vein and left
common hepatic vein for blood sampling, as described previously (36). Two Silastic catheters (0.03 mm ID) were inserted
into the duodenum. The first catheter was inserted just below
the pyloric sphincter for administration of glucose, phloridzin, 3-O-[3H]methylglucose, and L-[14C]glucose. The second
duodenal catheter was inserted just before the junction of the
duodenum with the jejunum (⬃10 cm caudal to the first
duodenal catheter). A Silastic catheter (0.03 mm ID) was
inserted into the left femoral artery for blood sampling. After
insertion, the vascular catheters were filled with saline containing heparin and knotted at the free ends.
Transonic flow probes (Transonic Systems, Ithaca, NY)
were used to measure portal vein blood flow (PVF), as described previously (23). The flow probe lead and knotted
catheter ends were stored in a subcutaneous pocket made in
the abdominal region. The femoral artery catheter was stored
in a pocket in the inguinal region. One week before an
experiment, dogs for either protocol were trained to run on a
treadmill (4 mph on a 12% grade). Training consisted of 20-,
40-, and 90-min bouts to acclimate the dogs to treadmill
exercise. Dogs were not exercised 48 h before an experiment.
Only those animals that met the following criteria were used
in this study: a leukocyte count ⬍18,000/mm3, a hematocrit
⬎0.36, normal stools, and a good appetite (consuming the
entire daily ration). Animals meeting these criteria were
fasted 18 h before the beginning of the study to ensure that
all animals were postabsorptive.
Experimental protocol. The experimental protocol is shown
in Fig. 1. On the day of the experiment, the catheters and
flow probes were freed from subcutaneous pockets by using
⬃2-cm incisions made after application of 2% lidocaine. Saline was infused into the arterial sampling catheter throughout the duration of the study. Dogs were submitted to 150
min of moderate treadmill exercise (n ⫽ 8; 4 mph, 12% grade)
or an equivalent period of rest in a Pavlov stand [n ⫽ 7; time
(t) ⫽ ⫺190 to ⫺40 min]. At t ⫽ ⫺110 min, a venous infusion
of ICG was initiated and was continued for the duration of
the study. This infusion served as a backup measurement of
splanchnic blood flow in case the transonic flow probes did
not function properly. It was assumed, based on previous
work (9), that PVF is ⬃80% of splanchnic blood flow, whereas
hepatic artery blood flow represents the other 20%. ICG was
used as a substitute for transonic flow probes in 3 of the 15
experiments. At t ⫽ ⫺40 min, exercised dogs were transferred to a Pavlov harness for the remainder of the study.
From t ⫽ ⫺30 to 0 min, blood samples were taken for baseline
measurements. Because the duodenum was empty during
this period, no duodenal sample could be obtained. The ex-
1133
1134
PRIOR EXERCISE ENHANCES PASSIVE GUT GLUCOSE ABSORPTION
and glucagon and blood glucose were measured as described
previously (9).
Calculations. Total net gut glucose output (NGGO) was
calculated as described by Eq. 1
NGGO ⫽ ([P] ⫺ [A])䡠PVF
(1)
where [P] and [A] are portal vein and arterial glucose concentrations, respectively. NGGO during the duodenal glucose
infusion is represented as the average NGGO from t ⫽ 20–60
min. Calculations of the transporter-mediated and passive
components of gut glucose absorption are based on tracer
data obtained during the 5 min of sampling after administration of the tracer bolus. Previous work has shown that the
calculation of the passive fraction of gut absorption via both
direct and indirect assessment of intraduodenal radioactivity
yields the same results (23). The direct approach was used in
the present study (Eq. 2) to calculate the passive fraction of
gut glucose absorption
Fraction of gut glucose absorption that is passive
(2)
where L-GlcP and L-GlcA are the portal venous and arterial
radioactivity of L-[14C]glucose, respectively; MGP and MGA
are the radioactivities of 3-O-[3H]methylglucose in the portal
vein and the artery, respectively; and MGD and L-GlcD are
the duodenal concentrations of 3-O-[3H]methylglucose and
L-[14C]glucose, respectively. The rates of transporter-mediated and passive absorption were calculated by multiplying
the fraction of passive and transporter-mediated absorption
by NGGO (Eqs. 3 and 4, respectively).
Net rate of transporter-mediated absorption
⫽ (1 ⫺ Passive fraction) 䡠 NGGO
Net rate of passive absorption
⫽ Passive fraction 䡠 NGGO
(3)
(4)
Statistics. All data presented herein are means ⫾ SE.
ANOVA was performed to assess differences between gut
absorption, hormone, and substrate concentrations in sedentary and exercised dogs. Differences were considered significant if P ⬍ 0.05.
RESULTS
Arterial blood glucose, glucose infusion rates, plasma
hormones, and PVF. Arterial blood glucose concentrations were not significantly different in exercised (75 ⫾
3 mg/dl) and sedentary (82 ⫾ 2 mg/dl) dogs during the
basal period (Fig. 2). Arterial blood glucose levels rose
to similar levels in both exercised (110 ⫾ 7 mg/dl) and
sedentary (113 ⫾ 5 mg/dl) dogs during the intraduodenal glucose infusion. After the administration of phloridzin, arterial blood glucose levels were maintained at
levels seen before phloridzin administration with the
peripheral glucose clamp (107 ⫾ 6 exercised vs. 107 ⫾
5 mg/dl sedentary). The glucose infusion rate required
to maintain isoglycemia was not different in exercised
and sedentary dogs (5.19 ⫾ 0.70 vs. 4.67 ⫾ 0.48
mg 䡠 kg⫺1 䡠 min⫺1).
Arterial plasma insulin was significantly less in exercised compared with sedentary dogs (4 ⫾ 1 vs. 7 ⫾ 1
␮U/ml) during the baseline period, whereas glucagon
J Appl Physiol • VOL
Fig. 2. Arterial blood glucose concentrations in sedentary (䊐) and
exercised (■) dogs during the baseline sampling period (⫺30 to 0 min)
and during the intraduodenal glucose infusion in the absence (0–60
min) or presence (60–90 min) of intraduodenal phloridzin. Values
are means ⫾ SE.
was significantly higher (50 ⫾ 5 vs. 33 ⫾ 6 ng/ml).
During intraduodenal glucose infusion in the absence
of phloridzin, insulin rose approximately threefold in
each group but remained significantly lower in exercised compared with sedentary (15 ⫾ 3 vs. 24 ⫾ 5
␮U/ml) dogs. Arterial plasma glucagon in exercised
and sedentary dogs was not different during intraduodenal glucose infusion (40 ⫾ 6 vs. 30 ⫾ 5 ng/ml).
Plasma cortisol levels were significantly higher in the
baseline period in exercised dogs (5.4 ⫾ 0.9 vs. 2.4 ⫾
1.7 pg/ml). During the intraduodenal glucose infusion,
plasma cortisol levels were similar between groups
(3.8 ⫾ 0.9 vs. 3.9 ⫾ 0.7 pg/ml). Catecholamines were
not different between groups in the baseline period or
during the intraduodenal glucose infusion. Hormone
levels, in the presence of phloridzin, were not different
between groups.
PVF during the baseline period was significantly
higher in exercised dogs (25 ⫾ 3 vs. 18 ⫾ 2
ml 䡠 kg⫺1 䡠 min⫺1). However, PVF was not different during the intraduodenal glucose infusion period in the
presence (24 ⫾ 2 vs. 23 ⫾ 4 ml 䡠 kg⫺1 䡠 min⫺1) or absence
(27 ⫾ 2 vs. 21 ⫾ 3 ml 䡠 kg⫺1 䡠 min⫺1, exercised vs. sedentary dogs) of phloridzin.
NGGO, net transporter-mediated and net passive
glucose output. NGGO was negative in both rested and
exercised dogs during the baseline period, reflecting
net gut uptake of glucose from the blood (Fig. 3).
During the first 60 min of the intraduodenal glucose
load, NGGO rose in the sedentary group, averaging
4.02 ⫾ 0.53 mg 䡠 kg⫺1 䡠 min⫺1. Prior exercise caused a
significant increase in NGGO in the presence of intraduodenal glucose (5.36 ⫾ 0.46 mg 䡠 kg⫺1 䡠 min⫺1).
This increase in NGGO was, in part, due to a ⬃65%
increase in the percent contribution of passive gut
glucose absorption to total NGGO, which was ⬃11% in
sedentary dogs and 18% in exercised dogs (Fig. 4). This
increase in the percent contribution of passive absorp-
95 • SEPTEMBER 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
(L-GlcP ⫺ L-GlcA) MGD
⫽
䡠
(MGP ⫺ MGA) L-GlcD
PRIOR EXERCISE ENHANCES PASSIVE GUT GLUCOSE ABSORPTION
tion was reflected by a doubling in the net rate of
passive gut glucose absorption (0.93 ⫾ 0.06 vs. 0.45 ⫾
0.07 mg 䡠 kg⫺1 䡠 min⫺1). The rate of transporter-mediated absorption increased ⬃20% with exercise but was
not significantly different from that in sedentary dogs
(4.41 ⫾ 0.45 vs. 3.57 ⫾ 0.48 mg 䡠 kg⫺1 䡠 min⫺1). After the
administration of phloridzin, NGGO decreased in both
sedentary and exercised dogs, so that rates in neither
group were significantly different from zero (Fig. 3).
the time of the first bolus, absorption of the passive
marker, L-[14C]glucose, occurs on a background of zero
and is relatively easy to detect. The appearance of
tracers in the portal vein was assessed over a short
interval after delivery of the bolus. This was done to
minimize gradients in the ratio of tracers in the duodenal lumen. It should be noted that this technique
gives the same results for the percent contribution of
passive gut glucose absorption as previous work done
by Lane et al. (17), in which isolated jejunal segments
were perfused for 2 h.
The present studies and previous work (17, 23, 32)
assessing passive gut glucose absorption have used
L-glucose as a marker for the passive process. A considerable volume of work suggests that L-glucose does
not interact with the SGLT-1 transporter (6, 13, 17,
32). For example, in basolateral membrane vesicles
isolated from rat small intestine, the presence of 100
mM L-glucose did not inhibit radioactive D-glucose uptake, suggesting that L-glucose does not interact with
the transporter (38). Work done by Ikeda et al. (13),
using vesicles isolated from rabbit small intestine and
Xenopus oocytes expressing a cloned version of
SGLT-1, showed with competition experiments that
L-glucose had no effect on D-glucose uptake. However,
results of a study in the rat led to the conclusion that
DISCUSSION
It was shown previously that absorption of intraduodenal glucose is accelerated after a bout of prolonged,
moderate-intensity exercise (9). The increased gut glucose absorption facilitates the delivery of glucose to
glycogen-depleted tissues (liver and muscle), accelerating replenishment of these stores. The method presented here is an extension of the method described by
Uhing and Kimura (32) that we have previously
adapted for use in the dog model (23). The experimental protocol takes advantage of arteriovenous and duodenal sampling techniques, as well as isotopic tracer
methodology to determine the contributions of transporter-mediated and passive processes to the absorption of an intraduodenal glucose load in sedentary and
exercised dogs. The components of gut glucose absorption have also been measured by the disappearance of
glucose analogs from the gut (6, 17). Measuring passive
absorption via this technique is difficult, because it is a
relatively small component of total gut absorption and
is reliant on the disappearance of a small fraction of
the passive absorption marker from the gut. The appearance of tracers in the portal vein was used to
calculate the contributions of passive and transportermediated processes to total gut glucose absorption.
This method was first described by Uhing and Kimura
(31) and adapted for use in the dog (23). The advantage
of this for determination of passive transport is that, at
J Appl Physiol • VOL
Fig. 4. A: percent contribution of passive absorption to NGGO in
sedentary (open bars) and exercised (solid bars) dogs as calculated by
using Eq. 2. B: rate of passive gut glucose absorption calculated by
using Eq. 4. Values are means ⫾ SE. * P ⬍ 0.05 vs. sedentary.
95 • SEPTEMBER 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
Fig. 3. Net gut glucose output (NGGO) in sedentary (open bars) and
exercised (solid bars) dogs during the baseline sampling period and
intraduodenal glucose infusion period in the presence (⫹) and absence (⫺) of phloridzin. Negative values represent the uptake of
glucose from the blood by the gut, whereas positive values represent
absorption of glucose from the gut. Values are means ⫾ SE. * P ⬍
0.05 vs. sedentary.
1135
1136
PRIOR EXERCISE ENHANCES PASSIVE GUT GLUCOSE ABSORPTION
J Appl Physiol • VOL
body. There are several potential endocrine responses
that are known to occur during exercise that, as a
result of prolonged exposure during exercise, could
potentially affect nutrient absorption in response to
subsequent feeding. It has been reported that ␤-adrenergic stimulation of the small intestine in rats (14) and
sheep (2) by epinephrine results in increased gut glucose absorption. The primary target of such stimulation has been postulated to be the SGLT-1 transporter.
It is conceivable that this increase in catecholamines
seen during prolonged exercise could enhance gut glucose absorption during feeding after exercise. Whereas
a significant increase in transporter-mediated absorption was not observed, in the present study we do show
that the passive component of gut glucose absorption
under both sedentary and exercised conditions is indirectly dependent on SGLT-1 stimulation. In addition to
the potential role of epinephrine in stimulating gut
glucose absorption, the elevation in plasma glucocorticoid concentrations during exercise (27) could also conceivably lead to an enhancement in NGGO during an
intraduodenal glucose load. Dexamethasone treatment
in conscious rats increased the absorption of glucose by
the gut after the delivery of an oral glucose load (29).
Additionally, work done in rabbits has shown that the
injection of dexamethasone can increase gut glucose
absorption for extended periods of time after this treatment (12). During prolonged exercise, glucagon levels
rise, whereas insulin decreases (35). Previous work has
shown that elevated insulin levels increase gut glucose
absorption (30), whereas increased levels of glucagon
cause a delay in absorption (28). The intraduodenal
glucose infusion still resulted in increased NGGO in
exercised dogs, despite the prolonged exposure to reduced insulin, which persisted into the glucose infusion
period, and elevated glucagon levels. In addition to the
potential impact of these exercise-induced hormonal
changes, the impact of exercise on splanchnic blood
flow could potentially lead to alterations in gut absorption in the postexercise state. Previous work has shown
that the changes in blood flow alter gut glucose absorption (34, 37). After the period of exercise or rest, PVF
was significantly higher in exercised compared with
sedentary dogs. During the intraduodenal glucose infusion, PVF was comparable in both groups. Even
though blood flow was similar in both groups, potential
changes in the microcirculation of the blood vessels
perfusing the gut could facilitate the absorption of
glucose from the gut.
In sedentary dogs, the delivery of a tracer bolus in
the presence of phloridzin does not result in an increase in circulating radioactivity of either isotope,
indicating an impairment of passive as well as transporter-mediated absorption. This finding is consistent
with previous work that showed that a requisite
amount of active transport is required for passive
transport to occur (20, 21). In exercised dogs, where
passive glucose absorption is enhanced, absorption of
both glucose analogs is still inhibited by phloridzin
administration, indicating that the enhanced passive
glucose absorption after exercise is also dependent on
95 • SEPTEMBER 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
L-glucose is not a valid marker for passive gut glucose
absorption (26). It was suggested in this study that
differences existed in the gut absorption of L-glucose
compared with other nonmetabolized hexoses. It
should be noted that gut absorption of the hexoses was
determined by their subsequent urine collection. This
is an indirect assessment of intestinal absorption and
can be affected by differential renal handling (33).
Additionally, if L-glucose had a significant, but minor,
affinity for the SGLT-1 transporter and the changes in
gut glucose absorption with exercise could be ascribed
completely to transporter-mediated absorption, then
the increase in what we describe as the passive component should be accompanied by a large and unambiguous increase in transport-mediated gut glucose
absorption. Nevertheless, one cannot rule out from the
present study that there is a fraction of L-glucose that
is transported, and this possibility must be considered.
The work presented here shows that the increase in
NGGO after exercise is accompanied by an increase in
passive gut glucose absorption. Whereas the increase
in transporter-mediated gut glucose absorption was
not significant, it did tend to be higher as well. Despite
this tendency for an increase in transporter-mediated
absorption, its actual percent contribution to NGGO
was decreased. We observed only a 24% nonsignificant
increase in transporter-mediated absorption. A power
analysis indicated that we had the power to detect a
50% change in transporter-mediated gut glucose absorption with a power of 0.95, with n ⫽ 7, assuming
equal variance between groups. It should be noted,
however, that, based on our subject number and the
observed variance between groups, there is a ⬃18%
chance that a type II statistical error occurred, which
could have resulted in failure to detect a significant
difference between groups. In both sedentary and exercised dogs, NGGO was less than the infusion rate of
glucose into the duodenum. The differences between
the infusion rate and NGGO can be attributed to glucose metabolism by the gut and delayed absorption of
glucose over time (1). Previous work in the dog has
shown that, when a glucose load is delivered to the gut,
⬃15–18% of that load is metabolized by the gut itself
(1, 19). Additionally, previous work in the conscious
dog model showed that, in the presence of an intraduodenal glucose infusion, there was a gradual increase in
tracer-determined gut glucose absorption over time
that approached the duodenal infusion rate (19).
There are several possible mechanisms for this increase in passive NGGO during an intraduodenal glucose load. Metabolic stresses such as exercise (9) and
fasting (7) result in increased NGGO during an intraduodenal glucose load. These conditions are characterized by an increase in gut proteolysis, which serves
to increase gluconeogenic substrate supply to the liver
(8). This increased proteolysis could impair the gut’s
ability to function as a barrier during feeding when it
follows such a physiological stress.
Exercise is characterized by changes in circulating
hormone levels, which result in increased production of
glucose to meet the increasing energy demands of the
PRIOR EXERCISE ENHANCES PASSIVE GUT GLUCOSE ABSORPTION
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
We thank Deanna Bracy for valued assistance with the completion of this work, as well as the Vanderbilt University Diabetes
Center Hormone Assay Core for contribution to this work.
18.
DISCLOSURES
This work was funded by National Institute of Diabetes and
Digestive and Kidney Diseases Grant RO1 DK-50277, Diabetes Center Grant DK-20593, and Training Grant 5-T32-DK-7563–08.
19.
20.
REFERENCES
1. Abumrad NN, Cherrington AD, Williams PE, Lacy WW,
and Rabin D. Absorption and disposition of a glucose load in the
conscious dog. Am J Physiol Endocrinol Metab 242: E398–E406,
1982.
2. Aschenbach JR, Borau T, and Gabel G. Glucose uptake via
SGLT-1 is stimulated by beta(2)-adrenoceptors in the ruminal
epithelium of sheep. J Nutr 132: 1254–1257, 2002.
3. Boyd CA and Parsons DS. Effects of vascular perfusion on the
accumulation, distribution and transfer of 3-O-methyl-D-glucose
within and across the small intestine. J Physiol 274: 17–36,
1978.
4. Boyd CA and Parsons DS. Movements of monosaccharides
between blood and tissues of vascularly perfused small intestine.
J Physiol 287: 371–391, 1979.
5. Ferraris RP and Diamond J. Regulation of intestinal sugar
transport. Physiol Rev 77: 257–302, 1997.
6. Fine KD, Santa Ana CA, Porter JL, and Fordtran JS. Effect
of D-glucose on intestinal permeability and its passive absorption
J Appl Physiol • VOL
21.
22.
23.
24.
25.
in human small intestine in vivo. Gastroenterology 105: 1117–
1125, 1993.
Galassetti P, Reed E, Messina A, Lacy DB, and Wasserman
DH. Effect of prior fast duration on the appearance and disposal
of an intraduodenal glucose load. Am J Physiol Endocrinol
Metab 276: E543–E552, 1999.
Halseth AE, Flakoll PJ, Reed EK, Messina AB, Krishna
MG, Lacy DB, Williams PE, and Wasserman DH. Effect of
physical activity and fasting on gut and liver proteolysis in the
dog. Am J Physiol Endocrinol Metab 273: E1073–E1082, 1997.
Hamilton KS, Gibbons FK, Bracy DP, Lacy DB, Cherrington AD, and Wasserman DH. Effect of prior exercise on
the partitioning of an intestinal glucose load between splanchnic
bed and skeletal muscle. J Clin Invest 98: 125–135, 1996.
Hediger MA, Coady MJ, Ikeda TS, and Wright EM. Expression cloning and cDNA sequencing of the Na⫹/glucose co-transporter. Nature 330: 379–381, 1987.
Helliwell PA, Richardson M, Affleck J, and Kellett GL.
Regulation of GLUT5, GLUT2 and intestinal brush-border fructose absorption by the extracellular signal-regulated kinase, p38
mitogen-activated kinase and phosphatidylinositol 3-kinase intracellular signaling pathways: implications for adaptation to
diabetes. Biochem J 350: 163–169, 2000.
Iannoli P, Miller JH, Ryan CK, and Sax HC. Glucocorticoids
upregulate intestinal nutrient transport in a time-dependent
and substrate-specific fashion. J Gastroenterol 2: 449–457, 1998.
Ikeda TS, Hwang ES, Coady MJ, Hirayama BA, Hediger
MA, and Wright EM. Characterization of a Na⫹/glucose cotransporter cloned from rabbit small intestine. J Membr Biol
110: 87–95, 1989.
Ishikawa Y, Eguchi T, and Ishida H. Mechanism of betaadrenergic agonist-induced transmural transport of glucose in
rat small intestine. Regulation of phosphorylation of SGLT1
controls the function. Biochim Biophys Acta 1357: 306–318,
1997.
Ivy JL, Frishberg BA, Farrell SW, Miller WJ, and Sherman
WM. Effects of elevated and exercise-reduced muscle glycogen
levels on insulin sensitivity. J Appl Physiol 59: 154–159, 1985.
Kellett GL and Helliwell PA. The diffusive component of
intestinal glucose absorption is mediated by the glucose-induced
recruitment of GLUT2 to the brush-border membrane. Biochem
J 350: 155–162, 2000.
Lane JS, Whang EE, Rigberg DA, Hines OJ, Kwan D,
Zinner MJ, McFadden DW, Diamond J, and Ashley SW.
Paracellular glucose transport plays a minor role in the unanesthetized dog. Am J Physiol Gastrointest Liver Physiol 276:
G789–G794, 1999.
Leblanc J, Nadeau A, Richard D, and Tremblay A. Studies
on the sparing effect of exercise on insulin requirements in
human subjects. Metabolism 30: 1119–1124, 1981.
Moore MC, Cherrington AD, Cline G, Jones EM, Neal DW,
Badet C, and Shulman GI. Sources of carbon for hepatic
glycogen synthesis in the conscious dog. J Clin Invest 88: 578–
587, 1991.
Pappenheimer JR. Physiological regulation of epithelial junctions in intestinal epithelia. Acta Physiol Scand 571, Suppl:
43–51, 1988.
Pappenheimer JR and Reiss KZ. Contribution of solvent drag
through intercellular junctions to absorption of nutrients by the
small intestine of the rat. J Membr Biol 100: 123–136, 1987.
Pencek RR, Fueger PT, Camacho RC, Lacy DB, James F,
Jabbour K, and Wasserman DH. Prior exercise enhances
insulin-stimulated hepatic glucose uptake in response to a glucose load (Abstract). Diabetes 51, Suppl 2: 1298P, 2002.
Pencek RR, Koyama Y, Lacy DB, James FD, Fueger PT,
Jabbour K, Williams PE, and Wasserman DH. Transportermediated absorption is the primary route of entry and is required for passive absorption of intestinal glucose into the blood
of conscious dogs. J Nutr 132: 1929–1934, 2002.
Pruett EDR and Osseid S. Effect of exercise on glucose and
insulin response to glucose infusion. Scand J Clin Lab Invest 26:
277–288, 1970.
Richter EA. Glucose utilization. In: Handbook of Physiology.
Exercise: Regulation and Integration of Multiple Systems. Be-
95 • SEPTEMBER 2003 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
transport-mediated gut absorption. This suggests that
the same fundamental processes are involved.
Transporter-mediated and passive gut glucose absorption have been calculated by using both direct and
indirect estimates of intraduodenal glucose analog radioactivity because of inherent difficulties in duodenal
sampling (23). In previous work that describes these
calculations, there was no significant difference between the results obtained using different calculation
methods (23). In this experiment, only data from the
calculation of the passive fraction by using direct duodenal sampling are presented. It should be noted that
the passive fraction was calculated by using equations
both reliant on and independent of direct duodenal
sampling and that there was no difference between
results obtained with different calculation methods
(data not shown).
After exercise, the delivery of an intraduodenal glucose load resulted in an increase in total NGGO. This
was accompanied by a ⬃65% increase in the percent
contribution of the passive component of gut glucose
absorption and an associated 100% increase in the
mass of glucose absorbed by the passive process. Intraduodenal infusion of phloridzin, an inhibitor of the
SGLT-1 transporter, completely abolishes NGGO during an intraduodenal glucose load in sedentary dogs.
Here we show that NGGO during an equivalent glucose load is also not significantly different from zero in
the presence of phloridzin in exercised dogs. Additionally, the absorption of L-[14C]glucose after the administration of the second tracer bolus was completely
eliminated. These findings indicate that the added
passive gut glucose absorption in the postexercise state
is also dependent on a requisite rate of transportermediated gut glucose absorption.
1137
1138
26.
27.
28.
29.
30.
31.
PRIOR EXERCISE ENHANCES PASSIVE GUT GLUCOSE ABSORPTION
thesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 20, p.
912–951.
Schwartz RM, Furne JK, and Levitt MD. Paracellular intestinal transport of six-carbon sugars is negligible in the rat.
Gastroenterology 109: 1206–1213, 1995.
Sellers TL, Jaussi AW, Yang HT, Heninger RW, and Winder
WW. Effect of the exercise-induced increase in glucocorticoids on
endurance in the rat. J Appl Physiol 65: 173–178, 1988.
Shah P, Basu A, Basu R, and Rizza R. Impact of lack of
suppression of glucagon on glucose tolerance in humans. Am J
Physiol Endocrinol Metab 277: E283–E290, 1999.
Stojanovska LRG and Proietto J. Dexamethasone-induced
increase in the rate of appearance in plasma of gut-derived
glucose following an oral glucose load in rats. Metabolism 40:
297–301, 1991.
Stumpel F, Kucera T, Gardemann A, and Jungermann K.
Acute increase by portal insulin in intestinal glucose absorption
via hepatoenteral nerves in the rat. Gastroenterology 110: 1863–
1869, 1996.
Uhing MR and Kimura RE. The effect of surgical bowel manipulation and anesthesia on intestinal glucose absorption in
rats. J Clin Invest 95: 2790–2798, 1995.
32. Uhing MR and Kimura RE. Active transport of 3-O-methylglucose by the small intestine in chronically catheterized rats.
J Clin Invest 95: 2799–2805, 1995.
33. Ullrich KJ and Papavassiliou F. Contraluminal transport of
hexoses in the proximal convolution of the rat kidney in situ.
Pflügers Arch 404: 150–156, 1985.
34. Varro GE, Harris JA, and Geenen JE. Effect of decreased
local circulation on the absorptive capacity of a small intestine
loop in the dog. Am J Dig Dis 10: 170–177, 1965.
35. Wasserman DH. Regulation of glucose fluxes during exercise in
the postabsorptive state. Annu Rev Physiol 57: 191–218, 1995.
36. Wasserman DH, Lacy DB, Goldstein RE, Williams PE, and
Cherrington AD. Exercise-induced fall in insulin and hepatic
carbohydrate metabolism during exercise. Am J Physiol Endocrinol Metab 256: E500–E508, 1989.
37. Williams JH, Mager M, and Jacobson ED. Relationship of
mesenteric blood flow to intestinal absorption of carbohydrates.
J Lab Clin Med 63: 853–862, 1964.
38. Wright EM, van Os CH, and Mircheff AK. Sugar uptake by
intestinal basolateral membrane vesicles. Biochim Biophys Acta
597: 112–124, 1980.
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on June 18, 2017
J Appl Physiol • VOL
95 • SEPTEMBER 2003 •
www.jap.org