Pancreatic innervation is not essential for exercise-induced
changes in glucagon and insulin or glucose kinetics
Robert H.
Coker1,
Yoshiharu
Koyama1,
D. Brooks
Lacy2,
Phillip E.
Williams3,
Nathalie
Rhèaume1, and
David H.
Wasserman1
1 Department of Molecular
Physiology and Biophysics, 2 The
Diabetes Research and Training Center, and
3 Department of Surgery,
Vanderbilt University School of Medicine, Nashville, Tennessee
37232-0615
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ABSTRACT |
The purpose of this study was to determine the
role of pancreatic innervation in mediating exercise-induced changes in
pancreatic hormone secretion and glucose kinetics. Dogs underwent
surgery >16 days before an experiment, at which time flow probes were implanted on the portal vein and the hepatic artery, and Silastic catheters were inserted in the carotid artery, portal vein, and hepatic
vein for sampling. In one group of dogs (DP) all nerves and plexuses to
the pancreas were sectioned during surgery. A second group of dogs
underwent sham denervation (SHAM). Pancreatic tissue norepinephrine was
reduced by >98% in DP dogs. Each study consisted of basal (
30
to 0 min) and moderate exercise (0 to 150 min, 100 m/min, 12% grade)
periods. Isotope
([3-3H]glucose)
dilution and arteriovenous differences were used to assess hepatic
function. Arterial and portal vein glucagon and insulin concentrations
and the rate of net extrahepatic splanchnic glucagon release (NESGR)
were similar in DP and SHAM during the basal period. Arterial and
portal vein glucagon and NESGR increased similarly in DP and SHAM
during exercise. Arterial and portal vein insulin were similar during
exercise. Arterial glucose, tracer-determined endogenous glucose
production, and net hepatic glucose output were similar in DP and SHAM
during the basal and exercise periods. These results demonstrate that
pancreatic nerves are not essential to pancreatic hormone secretion or
glucose homeostasis during rest or moderate exercise.
pancreas; nerves and hormones
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INTRODUCTION |
CHANGES IN THE PANCREATIC SECRETION of glucagon and
insulin play an important role in glucoregulation during exercise (38). The factors that control glucagon and insulin release from the pancreas
have not, however, been well defined. It is known that the pancreas is
innervated by the vagus and splanchnic nerves and that the stimulation
of these nerves can alter glucagon and insulin secretion (42). Although
vagally induced insulin secretion is mediated predominantly by
muscarinic mechanisms, nonmuscarinic (possibly peptidergic) mechanisms
mediate vagally induced changes in glucagon secretion (2).
- and
-Adrenergic stimulation increases the pancreatic secretion of
glucagon (7, 23, 35).
-Adrenergic stimulation inhibits insulin
secretion, whereas
-adrenergic stimulation increases insulin release
(7, 14, 23). Even though insulin and glucagon secretion can be
regulated by nerve stimulation, the role of pancreatic innervation in
the mediation of exercise-induced changes in these hormones has not
been established.
Partial denervation of the canine pancreas has been shown to attenuate
the rise in glucagon but not the fall in insulin in response to
exercise (16). Despite the blunted glucagon response, arterial glucose
levels did not fall. Specific assessment of glucose kinetics was not
made in these studies (16). Furthermore, only the nerves that follow
the pancreatic branches of the cranial pancreaticoduodenal artery were
sectioned in these studies, and nerves that follow the caudal
pancreaticoduodenal artery were not sectioned (26). It is possible that
complete denervation of the pancreas might have resulted in more
profound differences in the glucoregulatory response to exercise.
The present study was designed to determine the role of pancreatic
innervation in mediating the exercise-induced changes in pancreatic
hormone secretion and glucose kinetics. For these purposes, nonhepatic
splanchnic and hepatic arteriovenous differences were measured and
isotopic techniques were utilized in pancreatic-denervated or
sham-denervated dogs.
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METHODS |
Animals and surgical procedures.
Experiments were performed on a total of 14 overnight-fasted mongrel
dogs (mean wt 22.0 ± 0.6 kg) of either sex that had been fed a
standard diet (Pedigree beef dinner and Wayne Lab Blox: 51%
carbohydrate, 31% protein, 11% fat, and 7% fiber based on dry wt).
The dogs were housed in a facility that met American Association for
the Accreditation of Laboratory Animal Care guidelines, and the
protocols were approved by the Vanderbilt University Animal Care
Subcommittee. At least 16 days before each experiment, a laparotomy was
performed while the dogs were under general anesthesia (0.04 mg/kg of
atropine and 15 mg/kg pentobarbital sodium presurgery and 1.0%
isofluorane inhalation anesthetic during surgery). An incision in the
neck region allowed the isolation of the carotid artery into which a
Silastic catheter (0.04 in ID) was inserted and advanced to the aortic
arch for sampling and hemodynamic measurements during experiments.
Silastic catheters (0.04 in. ID) were inserted into the portal vein and
left common hepatic vein for sampling. Silastic catheters (0.03 in. ID)
were inserted into the vena cava for infusion of
[3-3H]glucose.
Catheters were filled with heparinized saline, and the free ends were
knotted. Ultrasonic transit time flow probes were fitted and secured to
the portal vein and hepatic artery (Transonic Systems, Ithaca, NY). The
knotted catheter ends and flow probe leads were stored in a
subcutaneous pocket in the abdominal region (except for the carotid
artery catheter, which was stored in a pocket under the skin of the
neck), so that the complete closure of the skin incisions was possible.
In one group of dogs (n = 8; DP), the
pancreas was surgically denervated as outlined below. The caudal
pancreaticoduodenal artery and vein were skeletonized, and all visible
nerves and plexuses were sectioned and excised. Access to the celiac
artery and any branches of the hepatic artery supplying the main body of the pancreas were isolated and skeletonized of visible nerves and
plexuses. The splenic artery and vein were skeletonized, and all
visible nerves and plexuses were sectioned and excised. All omental
connections were dissected from all regions of the pancreas. Upon
completion of denervation, the vascular integrity and organ viability
were assessed. A second group of dogs
(n = 6) underwent sham denervation
(SHAM), in which all surgical procedures were performed with the
exception of pancreas denervation. Pancreas norepinephrine in the head,
middle, and tail was higher in SHAM (915 ± 31, 1,002 ± 312, and
1,520 ± 507 pg/mg) than in DP (18 ± 6, 6 ± 1, and 1 ± 1 pg/mg).
Beginning 7 days after surgery, dogs were acclimatized to running on a
motorized treadmill. Blood samples were drawn 3 days before the
experiment to determine the leukocyte count and the hematocrit of the
animal. Only animals with 1) a
leukocyte count below 18,000/mm3,
2) a hematocrit above 36%,
3) a good appetite (consumption of daily food ration), and 4) normal
stools were used.
All studies were conducted in dogs after an 18-h fast. The free
catheter ends and flow probe leads were accessed through small skin
incisions made under local anesthesia (2% lidocaine; Astra Pharmaceutical Products, Worcester, MA) in the abdominal and neck regions on the morning of the experiment. The contents of the catheters
were then aspirated and flushed with saline. The exposed catheters were
connected to Silastic tubing, which was secured to the back of the dog
with quick-drying glue.
Experimental procedures.
Experiments consisted of a tracer equilibration period (
130 to
30 min), a basal period (
30 to 0 min), and an exercise
period (0 to 150 min, 100 m/min, 12% grade). This exercise protocol is advantageous in that parasympathetic stimulation is undetectable [as indicated by the pancreatic polypeptide (PP) response to
exercise], thereby allowing the study of sympathetic stimulation
to the pancreas. A primed (50 µCi) infusion (0.30 µCi/min) of
HPLC-purified
[3-3H]glucose (New
England Nuclear, Boston, MA) was initiated at
t =
130 min. The
[3-3H]glucose infusion
was increased during exercise in proportion to the increased glucose
flux normally present during exercise of this intensity in both
protocols (Fig. 1) (29). Portal vein and
hepatic artery blood flows were monitored on-line throughout the
experiments.

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Fig. 1.
Protocol.
[3-3H]glucose
(%basal) was infused at a constant rate during rest and increased with
exercise in a manner proportional to the normal increase in glucose
entry into plasma.
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Blood sample collection and processing.
Arterial blood samples were drawn at t =
30,
15, 0, 2.5, 5, 7.5, 10, 15, 20, 40, 60, 80, 100,
130, and 150 min. Portal vein and hepatic vein blood samples were drawn
at the same times with the exception of
t = 2.5, 7.5, and 15 min. Dogs were
euthanized by an overdose of pentobarbitol sodium at the conclusion of
the study, and tissue samples were taken from the head, middle, and tail of the pancreas and frozen immediately in liquid
N2.
Plasma glucose concentrations were determined by the glucose oxidase
method using a glucose analyzer (Beckman Instruments, Fullerton, CA).
For the determination of plasma glucose radioactivity, samples were
deproteinized with barium hydroxide and zinc sulfate and were
centrifuged. The supernatant was then evaporated to remove 3H2O
and reconstituted in 1 ml of water and 10 ml of scintillation fluid
[Ecolite (+); ICN Biomedicals, Irvine, CA]. Radioactivity was determined on a Beckman liquid scintillation counter.
Immunoreactive insulin was measured using a double-antibody procedure
[interassay coefficient of variation (CV) of 16%] (28).
Immunoreactive glucagon (3,500 mol wt) was measured in plasma samples
containing 500 kallikrein-inhibitor units/ml aprotinin (Trasylol, FBA
Pharmaceuticals, NY) by use of a double-antibody system (CV of 8%)
modified from the method developed by Morgan and Lazarow for insulin
(28). Materials for these assays have been published previously (9). PP
was measured using a double-antibody system developed by Gingerich et
al. (15). Pancreas tissue was powdered over liquid
N2 immediately after the study and
homogenized in a 5 mM solution of 4% perchloric acid. Samples were
then centrifuged at 4°C, and the supernatant was extracted for
pancreas norepinephrine analysis by HPLC. Blood samples for
norepinephrine and epinephrine were collected in tubes containing EGTA
and glutathione and were centrifuged at 4°C; plasma was stored at
70°C for subsequent HPLC analysis. Catecholamine concentrations were calculated on the basis of linear regression using
dihydroxybenzylamine as an internal standard. The CV values with this
method were 5 and 7% for norepinephrine and epinephrine, respectively.
Plasma cortisol was measured with the Clinical Assays Gamma Coat
radioimmunoassay kit (Clinical Assays, Travenol-Genetech Diagnostics,
Cambridge, MA) with an interassay CV of 6%.
Calculations.
Net hepatic glucose output (NHGO) was determined according to the
formula HAF × ([H]
[A]) + PVF × ([H]
[P]), where
[A], [P], and [H] are the arterial,
portal vein, and hepatic vein glucose concentrations, and HAF and PVF
are the hepatic artery and portal vein blood flows. Net nonhepatic
splanchnic glucagon release (NESGR) was calculated according to the
formula ([P]
[A]) × PVF, where [P] and [A] are the portal vein and arterial
plasma glucagon concentrations. Endogenous glucose production
(Ra) and glucose utilization
(Rd) were calculated using the two-compartment approach
described by Mari (24). Changes in specific activity were minimized
during the exercise period by increasing the infusion rate of
[3-3H]glucose in
proportion to exercise-induced changes in glucose flux to increase the
accuracy of the Ra calculation
(29).
Statistical analysis.
Superanova (Abacus Concepts, Berkeley, CA) software installed on a
Macintosh Power PC was used to perform statistical analyses. Statistical comparisons between groups and over time were made using
ANOVA designed to account for repeated measures. Specific time points
were examined for significance using contrasts solved by univariate
repeated measures. Statistics are reported in the corresponding table
or figure legend for each variable. Data are presented as means ± SE. Statistical significance was defined as
P < 0.05.
 |
RESULTS |
Arterial and portal vein plasma glucagon, insulin,
glucagon-to-insulin ratio, and arterial plasma PP.
Arterial glucagon was similar during the basal period in DP (44 ± 6 pg/ml) and SHAM (47 ± 3 pg/ml). Arterial glucagon increased (P < 0.05) similarly in DP (61 ± 6 pg/ml, t = 150 min) and SHAM (59 ± 3 pg/ml, t = 150 min) during
exercise (Fig. 2). In addition, basal
portal vein glucagon was not different between DP (51 ± 6 pg/ml)
and SHAM (56 ± 6 pg/ml) and increased
(P < 0.05) to the same extent in DP
(108 ± 12 pg/ml, t = 150 min) and
SHAM (96 ± 8 pg/ml, t = 150 min)
during exercise (Fig. 2). Basal arterial insulin was not different in
DP (9 ± 1 µU/ml) or SHAM (9 ± 1 µU/ml). Arterial insulin
fell (P < 0.05) similarly in DP (5 ± 1 µU/ml, t = 150 min) and SHAM
(6 ± 1 µU/ml, t = 150 min)
during exercise (Fig. 3). Portal vein
insulin was similar in DP (17 ± 1 µU/ml) and SHAM (19 ± 1 µU/ml) during the basal period and was unchanged by exercise in both
groups (Fig. 3). The basal arterial glucagon-to-insulin ratio was not
different (P > 0.05) in DP (6 ± 1 pg/µU) and SHAM (5 ± 1 pg/µU). In addition, the arterial
glucagon-to-insulin ratio increased (P < 0.05) similarly during exercise in DP (12 ± 2 pg/µU, t = 150 min) and SHAM (10 ± 1 pg/µU, t = 150 min) (Fig.
4). The basal portal vein
glucagon-to-insulin ratio was not different (P > 0.05) between DP (4 ± 1 pg/µU) and SHAM (3 ± 1 pg/µU). The portal vein
glucagon-to-insulin ratio increased (P < 0.05) similarly in DP (9 ± 2 pg/µU,
t = 150 min) and SHAM (7 ± 2 pg/µU, t = 150 min) during exercise
(Fig. 4).

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Fig. 2.
Arterial (A) and portal vein
(B) plasma glucagon during basal and
exercise periods in pancreas-denervated dogs (DP) and sham-denervated
dogs (SHAM). Data are means ± SE;
n = 8 for DP and
n = 6 for SHAM.
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Fig. 3.
Arterial (A) and portal vein
(B) plasma insulin during basal and
exercise periods in DP and SHAM. Data are means ± SE;
n = 8 for DP and
n = 6 for SHAM.
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Fig. 4.
Arterial (A) and portal vein
(B) plasma glucagon-to-insulin ratio
during basal and exercise periods in DP and SHAM. Data are means ± SE; n = 8 for DP and
n = 6 for SHAM.
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Basal PP was similar in DP (142 ± 25 pg/ml) and SHAM (114 ± 25 pg/ml). PP was not significantly increased by exercise in either group
(Fig. 5).

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Fig. 5.
Arterial pancreatic polypeptide during basal and exercise periods in DP
and SHAM. Data are means ± SE; n = 8 for DP and n = 6 for SHAM.
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NESGR.
Basal NESGR was not significantly different between DP (88 ± 25 pg · kg
1 · min
1)
and SHAM (120 ± 25 pg · kg
1 · min
1).
NESGR was also similar in DP (482 ± 108 pg · kg
1 · min
1,
t = 150 min) and SHAM (487 ± 130 pg · kg
1 · min
1,
t = 150 min) during exercise (Fig.
6).

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Fig. 6.
Net extrahepatic splanchnic glucagon release during basal and exercise
periods in DP and SHAM. Data are means ± SE;
n = 8 for DP and
n = 6 for SHAM.
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Arterial plasma epinephrine and norepinephrine concentrations.
Basal arterial plasma epinephrine was similar in DP (104 ± 12 pg/ml) and SHAM (125 ± 14 pg/ml). Plasma epinephrine increased (P < 0.05) in both groups and was
not different in DP (531 ± 105 pg/ml,
t = 150 min) compared with SHAM (574 ± 101 pg/ml, t = 150 min) during
exercise (Fig. 7). Basal plasma
norepinephrine was similar in DP (189 ± 9 g/ml) and SHAM (205 ± 12 pg/ml). Plasma norepinephrine increased
(P < 0.05) in both groups and was
not different between DP (750 ± 92 pg/ml,
t = 150 min) and SHAM (636 ± 69 pg/ml, t = 150 min) during exercise
(Fig. 7).

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Fig. 7.
Arterial plasma norepinephrine (A)
and epinephrine (B) during basal and
exercise periods in DP and SHAM. Data are means ± SE;
n = 8 for DP and
n = 6 for sham.
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Arterial plasma cortisol.
Basal arterial cortisol was similar in DP (2 ± 0 µg/ml) and SHAM
(2 ± 1 µg/ml). Arterial cortisol increased
(P < 0.05) in both groups and was
not different in DP (8 ± 2 µg/ml,
t = 150 min) compared with SHAM (11 ± 3 ug/ml, t = 150 min) during
exercise (Fig. 8).

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Fig. 8.
Arterial plasma cortisol during basal and exercise periods in DP and
SHAM. Data are means ± SE; n = 8 for DP and n = 6 for SHAM.
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Arterial glucose concentration and kinetics.
Basal arterial plasma glucose was similar in DP and SHAM. In addition,
arterial glucose remained unchanged with exercise in both groups (Fig.
9). Basal NHGO was similar in DP (1.8 ± 0.2 mg · kg
1 · min
1)
and SHAM (2.1 ± 0.3 mg · kg
1 · min
1).
At 150 min of exercise, NHGO had risen
(P < 0.05) to 7.8 ± 1.2 mg · kg
1 · min
1
in DP and 7.0 ± 0.9 mg · kg
1 · min
1
in SHAM (Fig. 9). In agreement with arteriovenous difference measurements, basal Ra was similar
in DP (2.5 ± 0.1 mg · kg
1 · min
1)
and SHAM (2.7 ± 0.1 mg · kg
1 · min
1).
Ra increased
(P < 0.05) similarly in DP (7.8 ± 0.8 mg · kg
1 · min
1,
t = 150 min) and SHAM (7.2 ± 0.8 mg · kg
1 · min
1,
t = 150 min) during exercise (Fig.
10). Basal
Rd was similar in DP (2.5 ± 0.2 mg · kg
1 · min
1)
and SHAM (2.6 ± 0.1 mg · kg
1 · min
1).
Rd rose
(P < 0.05) during exercise and was
not different between DP (7.7 ± 0.7 mg · kg
1 · min
1,
t = 150 min) and SHAM (7.0 ± 0.9 mg · kg
1 · min
1,
t = 150 min) (Fig. 10).

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Fig. 9.
Arterial plasma glucose (A) and net
hepatic glucose output (B) during
basal and exercise periods in DP and SHAM. Data are means ± SE;
n = 8 for DP and
n = 6 for SHAM.
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Fig. 10.
Endogenous glucose production (Ra,
A) and glucose utilization
(Rd,
B) during basal and exercise periods
in DP and SHAM. Data are mean ± SE;
n = 8 for DP and
n = 6 for SHAM.
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Hepatic blood flows.
Portal vein and hepatic artery blood flows were not significantly
different between groups during the basal and exercise periods (Table
1).
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Table 1.
Portal vein and hepatic artery blood flows during basal and exercise
periods in denervated pancreas and sham dogs
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DISCUSSION |
Sympathetic nerves have been proposed to mediate the increase in
glucagon and decrease in insulin during exercise (17, 25, 35). As a
result of these divergent changes in insulin and glucagon, glucose
production is increased to match the increased rate of glucose
utilization, and glucose homeostasis is maintained (39, 40). The
results of this study show that pancreatic innervation is not essential
in the regulation of exercise-induced changes in insulin, glucagon,
NESGR, Ra, and NHGO or glucose homeostasis.
Pancreas norepinephrine levels were reduced by >98% in dogs ~17
days after denervation, substantiating the effectiveness of the
surgical technique in this study. This is consistent with previous
studies in rats that also showed that pancreas norepinephrine levels
were reduced by ~98% 1 wk after surgical pancreatic denervation (43). The virtual elimination of pancreas norepinephrine supports the
premise that denervation removed all of the sympathetic innervation of
the pancreas. It is important to note that parasympathetic nerve fibers
lie in close proximity with sympathetic nerve fibers as they innervate
the pancreas via the cranial and caudal pancreaticoduodenal arteries
(27). Because parasympathetic and sympathetic nerves are parallel in
their anatomic arrangement, it was presumed that parasympathetic fibers
would also be removed by surgical denervation. Reinnervation of
pancreas tissue by parasympathetic and sympathetic nerves requires
~13 wk (22) and should not, therefore, be a factor in these studies
in which experiments were conducted ~2.5 wk after surgery.
Stimulation of PP secretion is thought to be under vagal control so
that changes in PP levels directly correspond to changes in vagal
activity (1, 36). Despite the use of surgical procedures designed to
remove sympathetic and parasympathetic innervation to the pancreas,
preliminary studies have demonstrated increases in PP in response to
overt hypoglycemia in dogs that have undergone the same surgical
pancreatic denervation procedure utilized in this study (37). This
suggests that parasympathetic fibers may remain intact, even when
sympathetic fibers have been eliminated. Although stimulation of PP
release has been shown during exercise in some experiments (6, 19), the
exercise protocol used in the present study does not result in an
increase in arterial PP. This may be due to differences in the
intensity of the exercise protocols used (19). Because parasympathetic
stimulation of the pancreas does not appear to be increased, as judged
by the lack of an increase in arterial PP concentration, it seems
unlikely that the possible presence of some parasympathetic innervation is a major complication in the interpretation of the results from the
present study.
The findings of the present study (similar exercise-induced glucagon
and insulin responses in DP and SHAM) are surprising, because vagal and
splanchnic nerve stimulation can modulate pancreatic hormone secretion
(2, 35). Splanchnic nerve stimulation releases norepinephrine and
inhibits insulin secretion from the
-cell (27). Stimulation of
2-receptors by norepinephrine
has an inhibitory effect on insulin release, whereas stimulation of
-adrenergic receptors increases insulin release. However, the action
of norepinephrine on
2-receptors predominates, and
insulin secretion is normally reduced during exercise (42). Electrical
stimulation of the splanchnic nerve can simultaneously activate
-
and
-adrenergic receptors on the
-cell and increase glucagon
secretion (3, 42). However, specific surgical denervation of the
pancreas in the present study did not affect exercise-induced changes
in the arterial and portal vein concentrations of glucagon or arterial insulin. These findings suggest that although nerves are capable of
controlling changes in pancreatic hormones, they are not essential to
the exercise response.
The present study contrasts with experiments performed in dogs with a
partial pancreatic nerve section (3 wk before study). These animals had
a blunted arterial glucagon response to exercise after pancreatic
denervation (16). The interpretation of these earlier studies is
complicated by an increase in plasma glucose concentrations compared
with the response in the same dogs before denervation. The elevation in
plasma glucose might have attenuated the increment in glucagon that
would normally have resulted. In addition, the denervation procedure
used in the previous study was only partial, as it did not remove
nerves that followed the caudal pancreaticoduodenal artery. Portis et
al. (32) reported an elevation instead of a gradual fall in arterial
insulin during exercise in long-term islet cell-autografted dogs
compared with sham dogs. The paradoxical increase in insulin during
exercise in these studies lends support to the premise that the normal insulin response to exercise is under autonomic control. Nevertheless, the arterial plasma glucagon and glucose responses to exercise were
similar. It is important to note that the catecholamine levels were
higher in the islet cell-autografted dogs and could have compensated
for the lack of pancreatic innervation. A recent study in pancreas
transplant patients (presumably free of pancreatic innervation)
reported alterations in glucagon, C-peptide, and insulin during
exercise (33). No significant difference was reported in arterial
plasma glucose between the two groups. The use of a patient population
(33) complicates the interpretation of these studies. The absolute work
intensity (33 W) in these pancreas transplant patients may have been
too low to elicit significant pancreatic hormone responses.
Although the nerves that innervated the pancreas were sectioned during
surgery, pancreatic adrenergic receptors and adrenal glands remained
intact. There is only limited evidence for supersensitivity of the
denervated pancreas to catecholamines (30). Nevertheless, such an
adaptation could make the role of circulating catecholamines more
prominent. Therefore, exercise-induced increases in epinephrine could
have influenced glucagon and insulin secretion. However, adrenodemedullated rats infused with saline or epinephrine replacement to achieve normal physiological levels have similar pancreatic hormone
levels during exercise (4). Although pancreatic denervation in the
present study, adrenodemedullation in rodents (4), and adrenalectomy in
humans (18, 20) alone do not seem to affect pancreatic hormone
secretion during exercise, a combination of the these procedures may
impair the pancreatic hormone response. For example, changes in
glucagon and insulin are diminished in adrenodemedullated rats that
were also chemically sympathectomized with 6-hydroxydopamine (34). The
physiological importance of adrenergic drive is also supported by
pharmacological evidence. For example, inhibition of insulin release
can be reversed by
-adrenergic receptor blockade during exercise,
and the blockade of
- and
-adrenergic receptors can diminish the
exercise-induced increase in glucagon (20, 23). The catecholamine and
glucagon responses to exercise are closely correlated in DP and SHAM,
which is consistent with a possible role of circulating catecholamines in control of exercise-induced changes in glucagon secretion (see Figs.
2 and 7). On the basis of these observations, circulating catecholamines may stimulate changes in pancreatic hormones during exercise in combination with neural input, when pancreatic nerves are
left intact, or as a compensatory mechanism when the pancreas is denervated.
Although arterial insulin fell gradually in DP and SHAM during
exercise, portal vein insulin did not fall in either group. This would
appear to suggest that increased hepatic insulin clearance may be a
cause of the reduced arterial insulin levels during exercise. In fact,
a rise in insulin clearance during exercise has been demonstrated
through the simultaneous measurement of insulin and C-peptide in humans
(41). Previous studies in our laboratory have shown both a decrease in
portal vein insulin (5, 39) and unchanged portal vein insulin (8) in
response to exercise. The reason for the variation in the portal vein
insulin response may be due to potential errors with portal vein
insulin sampling, coupled with difficulties in detecting small
differences in insulin. Streaming of newly secreted insulin can
confound the precise measurement of portal vein insulin and possibly
glucagon, particularly when portal vein blood flow is laminar (21).
Therefore, the full interpretation of portal vein insulin requires
consideration of portal vein blood flow dynamics.
In addition to catecholamine-mediated changes in islet cell function,
galanin is a neurotransmitter that may affect hormone secretion (10,
11, 13). Galanin is released from extrapancreatic and pancreatic
sympathetic nerves and inhibits insulin and stimulates glucagon
secretion in the dog (13). Because nonhepatic splanchnic norepinephrine
spillover (an index of sympathetic drive) increases during exercise in
the normal dog (8), and galanin is co-released with norepinephrine
(13), one would expect portal vein galanin levels to be higher. It is
interesting to note that immunoneutralization of galanin eliminated the
swimming-induced inhibition of insulin in rats (12). Only the
pancreatic nerves were sectioned in the present study, and the
increased release of galanin from nonpancreatic sources during exercise
may have contributed to changes in pancreatic hormonal secretion.
In conclusion, exercise-induced changes in insulin and glucagon were
maintained despite the elimination of pancreas sympathetic nerves
(>98% reduction in pancreas norepinephrine). As a result, exercise-induced increases in NHGO and
Ra were not affected, and glucose
homeostasis was preserved. It seems plausible that exercise-induced changes in circulating catecholamines or some other factor may serve as
the mediator of pancreatic hormone secretion or as part of a
compensatory glucoregulatory mechanism that can compensate for the
absence of sympathetic nerves. The preservation of normal exercise-induced changes in glucagon and insulin despite pancreatic denervation has important implications for pancreas transplant and
islet cell transplant patients who wish to take advantage of the health
benefits of regular exercise.
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ACKNOWLEDGEMENTS |
We are grateful to Deanna Bracy, Eric Allen, Pamela Venson, and
Wanda Snead for excellent technical assistance.
 |
FOOTNOTES |
This research was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant R01-DK-50277. Part of this work was
presented at the 58th Annual Meeting of the American Diabetes
Association, Chicago, IL in June, 1998. Robert H. Coker was the
recipient of a Postdoctoral Fellowship Award from the Juvenile Diabetes
Foundation International.
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 correspondence and reprint requests: R. H. Coker, 220 Turner Center, Dept. of Exercise Science, University of Mississippi,
University, MS 38677 (E-mail: rhcoker{at}olemiss.edu).
Received 11 February 1999; accepted in final form 17 August 1999.
 |
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