Division of Metabolism, Endocrinology, and Nutrition, Seattle Veterans Affairs Puget Sound Health Care System, and the University of Washington, Seattle, Washington 98108
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We investigated the relationship between autonomic
activity to the pancreas and insulin secretion in chronically
catheterized dogs when food was shown, during eating, and during the
early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were
measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity,
respectively. The relation between autonomic activity and insulin
secretion was confirmed by autonomic blockade. Showing food to dogs
initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting
2-adrenergic mediation, which was confirmed by
-adrenoceptor blockade. Eating initiated a second transient insulin
response, which was only totally abolished by combined muscarinic and
-adrenoceptor blockade. During absorption, insulin increased to a
plateau. PP output showed the same pattern, suggesting parasympathetic
mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory
sympathetic neural tone. We conclude that 1) the insulin
response to showing food is mediated by the
2-adrenergic
effect of Epi, 2) the insulin response to eating is mediated
both by parasympathetic muscarinic stimulation and by the
2-adrenergic effect of Epi, and 3) the insulin
response during early absorption is mediated by parasympathetic
activation, with possible contribution of withdrawal of sympathetic
neural tone.
cephalic phase of insulin release; feeding; pancreatic polypeptide
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
FOOD INTAKE is generally considered as the
primary physiological stimulus for insulin secretion. In this view,
nutrients, such as glucose, are absorbed into the systemic circulation
and play the major role in stimulating the pancreatic -cell to
secrete insulin. However, careful analysis of the time course of
insulin secretion during carbohydrate ingestion has shown that insulin secretion can start even before glucose is actually absorbed (11, 34).
This so-called early insulin response (EIR) is initiated through
stimulation of sensory receptors in the oropharyngeal region as well as
through visual and olfactory stimulation (21). This afferent neural
input is conveyed to the central nervous system, which mediates
autonomic outflow to the pancreatic islet
-cell, resulting in a
rapid, transient increase in insulin release.
The EIR is traditionally attributed to parasympathetic stimulation of
pancreatic -cells, because, at least in rats, muscarinic blockade
diminishes the EIR (4, 19, 31, 32, 33). However, pancreatic endocrine
function is under control of both the parasympathetic and the
sympathoadrenal branch of the autonomic nervous system. Sympathetic
stimulation of
2-adrenoceptors on pancreatic islets, most profoundly by circulating epinephrine (Epi), can also increase insulin secretion (25, 41), even though
2-adrenoceptor
stimulation, most profoundly by neurally released norepinephrine (NE),
leads to inhibition of insulin secretion (31). Sympathetic activation has been reported during feeding (7, 30). Therefore, it is possible
that sympathoadrenal stimulation of
2-adrenoceptors could also play a part in meal-related stimulation of insulin secretion.
It was the aim of this study to determine the autonomic contribution to meal-related insulin secretion in dogs. To this end, two sets of experiments were performed. In the first set, pancreatic norepinephrine spillover (PNESO), pancreatic polypeptide (PP) output, circulating catecholamines (Epi and NE), and pancreatic insulin output were determined in conscious dogs bearing chronically implanted arterial and pancreatic venous catheters. This was done during the following three phases of the meal: 1) when food was shown to the dogs, without allowing them to eat; 2) during actual eating; and 3) during the early absorptive phase.
PNESO was used as an index for sympathetic neural activity to the pancreas. The measurement of PNESO during hypoglycemia in anesthetized dogs (14, 15), and recently in conscious dogs as well (9), demonstrates the activation of the sympathetic nerves innervating the pancreas during this type of stress. Pancreatic ACh spillover would provide an index for parasympathetic neural activity to the pancreas. However, the extremely rapid degradation of ACh by cholinesterases in plasma and in tissue precludes this option. Measurement of PP output provides an alternative. PP is secreted by pancreatic F cells and is predominantly under vagal control, because muscarinic blockade with atropine as well as vagotomy prevents almost all PP responses (26, 27, 37). PP output has been used as an index for parasympathetic activity to the pancreas and has been correlated with the EIR (26, 37). Finally, circulating Epi serves as an index for adrenal medullary activity. Comparison of the time courses of PNESO, PP output, and Epi with that of insulin secretion during the three phases of feeding should allow one to decide if pancreatic sympathetic nerves, pancreatic parasympathetic nerves, or the adrenal medullary neurohormone Epi could mediate the observed insulin responses.
Proving the suspected mediator, however, would require blockade of the
appropriate autonomic receptors. This was performed in a second set of
experiments in conscious dogs bearing only arterial catheters. In these
experiments, arterial concentrations of PP and insulin were determined
during the three phases of a meal in dogs that were treated with the
muscarinic blocker methylatropine and/or the -adrenoceptor blocker timolol.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All surgical and experimental protocols were approved by The Seattle Veterans Affairs Puget Sound Health Care System Animal Use Committee.
Animals and Surgical Preparation
After an overnight fast (~18 h), adult male dogs (28-34 kg) were anesthetized with the short-acting barbiturate thiamylal sodium (thiopental; Parke-Davis, Morris Plains, NJ). Anesthesia was subsequently maintained with isoflurane (2.0%) administered from a calibrated vaporizer (Draeger) by mechanical ventilation with pure oxygen.All animals (experiments 1 and 2) had indwelling catheters (Tygon microbore S-54-HL, ID 0.5 mm, OD 1.5 mm) inserted in the right omocervical vein and artery. The tips of the catheters were advanced in the pulmonary artery for drug infusion and in the descending aorta for blood sampling and blood pressure measurement (23). The catheters were tunneled subcutaneously and externalized in the midscapular region. There they were secured to arterial valve connectors (Harvard Apparatus) and sutured to the skin.
Dogs used for the experiments involving direct measurement of pancreatic hormone output and neurotransmitter spillover (experiment 1) received a midline laporotomy and had an additional indwelling catheter (Tygon microbore S-54-HL, ID 2.0 mm, OD 3.0 mm) inserted in the main duodenal input to the superior pancreaticoduodenal vein (SPDV). The tip of this catheter was placed 1 mm proximal to the junction of the main duodenal input with the SPDV, allowing unrestrained blood flow from the duodenal lobe of the pancreas into the SPDV. Additionally, an ultrasonic blood flow probe (Transonic Systems) was positioned around the SPDV 1 cm proximal to the junction of the SPDV with the portal vein. Both the catheter and the wire of the blood flow probe were tunneled subcutaneously and externalized in the midscapular region.
The catheters were kept patent by daily flushing with heparinized (50 U/ml) saline, whereafter they were filled with heparin (1,000 U/ml). The arterial catheters remained patent for months; the pancreatic venous catheters remained patent for up to 1 mo.
The combination of simultaneous sampling of arterial and pancreatic venous blood with blood flow measurement in the pancreatic vein allowed the calculation of hormone output and neurotransmitter spillover from the right lobe (duodenal lobe and uncinate process) of the canine pancreas (35-50% of the total canine pancreas).
Experimental Protocols
To avoid novelty stress, the dogs were habituated to the laboratory surroundings and personnel and were trained to stand in a Pavlovian sling before the start of the actual experiments. To minimize external influences, the dogs were habituated to the moderate sound level of a radio. To avoid excitatory visual stimulation during muscarinic blockade, the experimental room was dimly lit.Experiment 1.
The first set of experiments was designed to test whether the adrenal
medulla, the pancreatic parasympathetic, or the pancreatic sympathetic
nerves were activated during the three phases of a meal. After an
overnight fast, the dogs (n = 7) entered the experimental room and were placed in a Pavlovian sling. The arterial catheter was,
via a blood pressure transducer (Statham P23Db), connected to a blood
pressure monitor (Propac 106 EL; Protocol Systems) for
measurement of mean arterial pressure (MAP). The socket of the blood
flow probe was connected to the blood flowmeter (T101 ultrasonic
bloodflow meter; Transonic Systems) to measure pancreatic venous blood
flow. After a cooldown period of ~60 min, during which MAP had
stabilized, baseline arterial and pancreatic venous blood samples were
taken [time (t) = 10 and
1 min]. At t = 0, food [2 cans of Western Family Chicken Flavored Dog Food (protein >8%, fat >3%, fiber >1%, water <78%, ash <5%) +50 ml of
D50 glucose)] was shown to the animals, without allowing them to eat.
Blood samples were then taken at t = 2 and 4 min. At t = 5 min, the animals were allowed to eat the meal. In general,
the dogs finished the meal within 3 min. When the meal was not
finished at t = 11 min, the remaining food was taken away to
maintain clear separation between the eating phase and the early
absorptive phase. Additional blood samples were taken during eating
(t = 7.5 and 10 min) and early absorption
(t = 12.5, 15, 20, 25, and 35 min).
Experiment 2.
The second set of experiments was designed to determine which autonomic
input mediated the insulin responses to the sight and smell of the
food, to eating the food, and early during absorption of the food. To
this end, each dog participating in this study underwent a series of
four experiments: one with muscarinic blockade, one with
-adrenoceptor blockade, one with combined muscarinic and
-adrenoceptor blockade, and one, as a control, without blockade. Each dog (n = 8) underwent these four experiments in a random order. Muscarinic blockade was induced using methylatropine (0.5 mg/kg + 0.5
mg · kg
1 · h
1;
Sigma; see Ref. 23);
-adrenoceptor blockade was induced using timolol (0.2 mg/kg + 0.2
mg · kg
1 · h
1;
Sigma; see Ref. 23). Drugs were dissolved in saline and were administered through the cannula in the pulmonary artery. Infusion of
saline alone served as the control. The experimental protocol was
similar to the one used for experiment 1. A baseline sample was
taken at t =
15 min, whereafter blockade was induced and maintained throughout the experiment. Baseline blood samples were then
taken at t =
7.5 and
1 min. At t = 0, food was
shown to the animals, and blood samples were taken at t = 2 and
4 min. At t = 5 min, the animals were allowed to eat
the meal (see above for the procedure). Additional blood samples were
taken during eating (t = 7.5 and 10 min) and during early
absorption (t = 12.5, 15, 20, 25, and 35 min).
Assays
Blood samples were immediately placed on ice in tubes containing EDTA for determination of immunoreactive insulin, glucose, and PP and in tubes containing glutathione and EGTA for catecholamine determination. Samples were centrifuged (20 min at 2,600 g and 4°C), whereafter the plasma was decanted and frozen atPlasma insulin and PP concentrations were determined using RIAs described previously (6, 36). Plasma NE and Epi concentrations were determined in duplicate with a highly sensitive and specific radioenzymatic assay (10). The intra- and interassay coefficients of variation for the plasma catecholamine assay in this laboratory are 6 and 12%, respectively. Plasma glucose concentration was determined using a glucose oxidase technique.
Data Analysis
Pancreatic insulin and PP output were calculated using the formula
![]() |
Duodenal glucose absorption was calculated as
![]() |
![]() |
![]() |
![]() |
|
Data are expressed as means ± SE for experiment 1 and
as mean change ± SE from baseline [delta ()] obtained
at t =
1 min for experiment 2. Wilcoxon's
matched-pairs signed-rank test was used to test for significant changes
from baseline at t =
1 min (experiment 1). ANOVA and
the Mann-Whitney U-test were used to test for significant
differences between responses in the control experiment and those
during autonomic blockade (experiment 2). The level of
significance was set at P < 0.05.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Experiment 1
Figure 1 shows that insulin output increased when food was shown to the animals, even though they were not yet allowed to eat. This increase was transient; insulin output had already returned to the baseline by t = 4 min. When the animals were allowed to eat (t = 5 min), insulin output increased again (+24.0 mU/min at t = 7.5 min). After this second transient increase, insulin output declined below the baseline (t = 12.5-15 min). Twenty minutes after the onset of the meal (t = 25 min), a third more modest but more sustained increase in insulin output was recognized (P < 0.05 at t = 2, 7.5, 12.5, 15, and 20-35 min).
|
The arterial insulin concentration increased when food was shown and increased further immediately after the onset of the meal before returning toward the baseline. Twenty minutes after the onset of the meal, arterial insulin increased again and remained elevated throughout the experiment (P < 0.05 at t = 2-12.5 and 20-35 min).
Duodenal glucose absorption was negligible before feeding and was not affected by the sight and smell of the food. Eating had no immediate effect on duodenal glucose absorption. However, duodenal glucose absorption increased significantly at t = 10 min, i.e., 5 min after the start of the meal, and was elevated throughout the remainder of the experiment. It is noteworthy that the increase in duodenal glucose absorption occurred after the second transient increase in insulin output, in fact when insulin output was declining.
The arterial glucose concentration increased progressively above the baseline level when the food was shown to the animals and later when the animals ate the food. Then it declined before another sustained increase occurred. The first increase of plasma glucose occurred before the increase of duodenal glucose absorption; the second increase of plasma glucose occurred during the increase of duodenal glucose absorption.
PP output was not significantly affected by the sight and smell of food
(Fig. 2). However, eating the meal did
initiate a large increase in PP output that reached a maximal value of
492 ± 128 ng/min at t = 7.5 min before it declined to 135 ± 31 ng/min at t = 15, still significantly above baseline.
Thereafter, it increased modestly again and remained elevated for the
duration of the experiment. After the start of the meal, the time
course of PP output was similar to that of insulin output. Arterial PP showed a significant and sustained increase from t = 7.5 min
throughout the remainder of the experiment.
|
PNESO was not significantly affected by the presentation of the food or immediately by eating the meal. However, at t = 10 min, PNESO had decreased below baseline and remained suppressed throughout the experiment.
Showing food did not significantly affect SPDV blood flow. However, during eating, SPDV blood flow increased significantly. Thereafter, it gradually declined to reach a value of 83 ± 13 ml/min at t = 25 min, still significantly above baseline (P < 0.05 at t = 7.5-35 min).
The arterial Epi concentration (Fig. 3)
increased sharply when food was shown. Thereafter, it gradually
declined to return to baseline at t = 12.5 min, where it
remained for the rest of the experiment (P < 0.05 at
t = 2-7.5 min). Arterial NE also increased when food was
shown, but unlike Epi it increased further when the animals were
allowed to eat (P < 0.05 at t = 2-10 min).
NE reached its maximal value at t = 7.5 min (vs.
t = 2 min for Epi). Thereafter, it declined to reach the
baseline at t = 12.5 min. The time course of MAP was similar to
that of NE; MAP increased when food was shown to the animals, increased
further when the food was actually eaten, and reached its maximum at
t = 7.5 min (P < 0.05 at t = 2, 7.5, and
10 min).
|
Experiment 2
The arterial insulin response to showing food to the animals was not reduced by muscarinic blockade (Fig. 4). In contrast, the arterial insulin response to the sight and smell of food was significantly reduced by
|
|
|
The immediate arterial insulin response to eating was significantly
reduced, but not totally abolished, after either muscarinic blockade or
-adrenoceptor blockade (P < 0.05 at t = 5
min). Combined muscarinic and
-adrenoceptor blockade, however,
totally prevented the eating-induced increase of arterial insulin
(P < 0.05 at t = 5 and 7.5 min).
During the early absorptive phase (t = 10-35 min), the
insulin response was not affected by -adrenoceptor blockade (Fig. 5). Muscarinic blockade and combined muscarinic and
-adrenoceptor blockade prevented insulin from increasing during the early absorptive phase (P < 0.05 at t = 25 and 35 min).
No significant differences in the arterial PP responses were observed
between the experiment with -adrenoceptor blockade and the control
experiment (Fig. 5). Muscarinic blockade with or without
-adrenoceptor blockade, on the contrary, totally prevented the
responses in arterial PP to eating and during the early absorptive phase (P < 0.05 a t = 7.5-35 min).
In the experiment with muscarinic blockade (Fig. 4), the arterial blood
glucose response during the early absorption phase was significantly
decreased compared with that in the control experiment
(P < 0.05 at t = 20-35 min). In the
experiment with -adrenoceptor blockade (Fig. 5) and in the
experiment with combined
-adrenoceptor and muscarinic blockade (Fig.
6), the blood glucose response during eating and during the early
absorptive phase was significantly increased compared with the glucose
response in the control experiment (P < 0.05 at
t = 7.5-15 and 25-35 min for the experiment with
-adrenoceptor blockade and P < 0.05 at
t = 10-20 min for the experiment with combined blockade).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We have examined the meal-related insulin responses in dogs and have
assessed which branch of the autonomic nervous system mediates these
responses. We separated the insulin responses to a meal into the
following three phases: 1) the response to the sight and smell
of food [when the food was shown to the animals without allowing them
to eat (t = 2 and 4 min)], 2) the immediate response
to eating the meal (t = 7.5 and 10 min), and 3) the
response to the early absorptive phase after eating
(t = 12.5-35 min). We sought to characterize the
autonomic contribution to each of these insulin responses. We found
that showing food to the animals induced a rapid and transient increase
in insulin secretion. Surprisingly, the data suggest that this response
is not mediated by either glucose or direct parasympathetic stimulation
but rather by circulating Epi. When the animals ate the meal, a second
rapid and transient insulin response occurred. The data suggest that
this response is mediated by combined parasympathetic, muscarinic, and
sympathetic 2-adrenergic stimulation. During the early
phase of absorption, a third, and now sustained insulin response
occurred. Surprisingly, the data suggest that this response is mediated
by parasympathetic stimulation rather than by glucose. Thus, in dogs,
all three early insulin responses to a meal appear to be autonomically mediated.
Showing food to the dogs, without allowing them to eat, induced a rapid and transient insulin response. Such an early insulin response to the sight and smell of food has been observed in a variety of species, including humans (24, 28, 29, 42). It has been suggested to be mediated by a conditioned increase in parasympathetic activity (24, 29, 42). However, in the experiments presented here, PP output did not increase when food was shown, suggesting that vagal activity to the pancreas had not increased at that moment. This conclusion was confirmed by the failure of methylatropine to block or even reduce the arterial insulin response to showing food. Thus, in dogs, the insulin response to the sight and smell of food cannot be attributed to increased parasympathetic cholinergic stimulation.
Although the plasma glucose concentration rose slightly when food was shown, it is unlikely that this increase triggered the insulin response. First, at that time, there was no increase in glucose absorption from the duodenum (see Fig. 1). Second, the arterial insulin response to showing food was still present after muscarinic blockade, even though plasma glucose did not increase.
Another possible mediator of the insulin response to the sight and
smell of food could be withdrawal of inhibitory sympathetic neural
tone. Such tone is apparently present in rats, since -adrenergic blockade increases plasma insulin concentrations (3, 31). However, in
the present experiments, PNESO, an index for sympathetic neural
activity to the pancreas (9, 14, 15), did not decrease significantly
when food was shown, suggesting that any inhibitory sympathetic neural
tone was still present. Alternatively, because our measurement of NE
spillover includes both pancreas and attached duodenum, one could argue
that NE spillover from the proximal duodenum might have increased,
masking a potential decrease of NE spillover from the pure pancreatic
tissue. However, duodenal dilution of pancreatic blood is estimated at
only 24% (9), making the above explanation unlikely.
Ruling out parasympathetic stimulation, withdrawal of sympathetic tone
and stimulation by plasma glucose as the mediators of the insulin
response to showing food leaves sympathoadrenal 2-adrenoceptor (18) stimulation as the likely mediator.
Arterial NE is increased in response to showing food, despite unchanged PNESO, indicating that the sympathetic nerves to other organs beside
the pancreas, for example the heart, are activated. This observation
confirms the poor relation between circulating NE and sympathetic drive
to individual organs, in particular the pancreas (8). Arterial Epi is
also increased in response to showing food, indicating that the adrenal
branch of the sympathetic system was activated as well.
Feeding-associated activity of the sympathoadrenal system has been
reported for dogs (7) and for rats (30) and has been related to the
increased energy expenditure noticed during the cephalic phase of
feeding (7). A direct link to the stimulation of feeding-associated
insulin secretion, however, has to the best of our knowledge not been
made before. Still, we would argue that the increase in insulin
secretion is due to
2-adrenoceptor-mediated stimulation,
with the arterial insulin response to the sight and smell of food being
blocked by the
-adrenoceptor antagonist timolol, despite the higher
arterial glucose concentration present during
-blockade.
The 2-adrenoceptor-mediated stimulation of insulin
secretion is most likely to be mediated via Epi rather than via NE,
because
2-adrenoceptors have a much higher affinity for
Epi than for NE (17). This means that Epi at low
concentrations, such as present in the current experiments, has
profound
2-adrenoceptor-stimulating properties and can
stimulate insulin secretion (2). Epi is released primarily in
situations having excitatory emotional components (12), a situation
clearly reflected in the behavior of the animals when food was
presented without allowing them to eat.
-Adrenoceptor-mediated stimulation of insulin secretion is suggested to prevent total
-adrenoceptor-mediated suppression of insulin release during sympathetic (neural) activity, thus securing a minimal release of
insulin (35).
Eating induces a rapid and transient insulin response similar to that produced by just showing the food. This early insulin response to eating has been observed in a variety of species, including humans (4, 7, 11, 16, 30-35, 36, 39). Like the insulin response to showing food, the early response to eating has been attributed to a neural reflex, because it is also observed in response to sham feeding conditions (4, 5, 38) or taste stimulation (20, 21). This reflex has been associated with hypothalamically mediated parasympathetic stimulation of the pancreas (22). In rats, the insulin response to eating can be prevented by vagotomy (19) or atropinization (34), confirming the parasympathetic mediation in that species.
In dogs, the mechanism underlying the immediate increase in insulin
during eating appears to be more complex. As in other species, there is
activation of the parasympathetic nervous system, as indicated by a
rapid increase of the arterial PP concentration. This parasympathetic
activation does contribute to the meal-induced increase of the arterial
insulin concentration, since methylatropine abolishes the PP response
and reduces the insulin response to eating. However, some of the
eating-induced insulin response remains during muscarinic blockade (see
Fig. 4). This remaining insulin response is not due to a decrease in
pancreatic sympathetic nervous activity, since PNESO dropped only after
the insulin response to eating had already peaked. Rather, it is due to
-adrenergic stimulation of the
-cell, because the addition of
-adrenoceptor blockade to muscarinic blockade abolished the insulin
response to eating. This total suppression of the eating-induced
insulin response occurs despite the higher glucose levels present
during combined blockade. This observation excludes the small increase in plasma glucose, which is observed immediately at the start of
eating, as a mediator of the immediate insulin response. However, the present experiments do not rule out the alternative possibility that the effect of the small rise of plasma glucose to contribute to
eating-induced insulin secretion is inhibited by the unopposed
-adrenergic effect of catecholamines during
-adrenoceptor blockade.
During eating in the control experiment, a small increase in glucose
can be recognized, although glucose absorption has not yet increased.
This small increase in glucose in the control experiment is probably
mediated by direct or indirect (via glucagon) sympathoadrenal stimulation of hepatic glucose production (13). Epi, a potent stimulus
for glucagon, is still increased during eating. The elevated glucose
concentrations during eating after combined blockade were most likely
allowed by the decrease in baseline insulin, resulting from the
combined withdrawal of -adrenoceptor and muscarinic stimulation of
the
-cell, leaving unopposed
-adrenoceptor-mediated inhibition of
insulin secretion.
After the immediate response to eating, insulin output fell rapidly
below the baseline and then rose slowly. This slow rise occurred during
increasing glucose absorption and is traditionally thought to be due to
the rising arterial glucose level. However, the importance of the small
increase in circulating glucose for stimulation of insulin secretion
can be argued. Based on a vast number of in vitro studies, it is beyond
dispute that glucose directly stimulates insulin secretion. However, it
is also true that most of the in vitro studies challenged the -cells
with glucose concentrations that by far exceed the small increase of the arterial glucose concentration observed in the present study.
Alternatively, stimulation of insulin secretion during the early
absorption phase could be due to parasympathetic stimulation of the
-cell, either directly or indirectly via interaction with gastrointestinal hormones, because PP remains elevated during this
early absorptive phase. The blockade of the PP response and the
lowering of the insulin level by methylatropine during this phase are
consistent with this hypothesis. However, muscarinic blockade also
lowers the glucose level, probably by impairing glucose absorption.
Therefore, it is unclear from these data if it is the decrease in
parasympathetic stimulation or the decreased glucose level that causes
the decreased insulin response during early absorption in the
experiments with muscarinic blockade. However, combined muscarinic and
-adrenoceptor blockade totally abolishes the insulin response during
absorption, despite higher glucose levels (see Fig. 6). Therefore, it
is our current opinion that the insulin response during absorption is
mediated by increased parasympathetic activity rather than by the small
rise in glucose level. One cannot exclude, however, that small
increases in glucose may still play a role in potentiating the
-cell
response to parasympathetic stimulation. Another possible contributor
to this insulin response could be the withdrawal of
inhibitory pancreatic sympathetic neural tone, since PNESO appears to
be decreased throughout this time period (see Fig. 2).
Based upon these results, we conclude that, in the dog, 1) the
insulin response to showing food is mediated by the
2-adrenergic effects of Epi; 2) the immediate
insulin response to eating is mediated both by parasympathetic
cholinergic stimulation and by the
2-adrenergic effects
of Epi; and 3) the insulin response during early absorption is
mediated via parasympathetic cholinergic stimulation, with a possible
contribution of withdrawal of sympathetic neural tone.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Richard Chang, Ruth Hollingworth, Rix Kuester, Hong Nguyen, and Jira Wade for expert technical assistance.
![]() |
FOOTNOTES |
---|
This research was supported by the Medical Research Service of the Department of Veterans Affairs and by the National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-12829, DK-12047, and DK-50154. L. Benthem was supported by an Albert Renold Fellowship awarded by the European Association for the Study of Diabetes and by a grant from the Diabetes Foundation Netherlands.
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: L. Benthem, Dept. of Human Biology, University of Maastricht, PO Box 616, NL-6200 MD Maastricht, The Netherlands (E-mail: B.Benthem{at}HB.UNIMAAS.NL).
Received 10 May 1999; accepted in final form 4 November 1999.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ahren, B,
Dunning BE,
Havel PJ,
Veith RC,
and
Taborsky Jr GJ.
Extraction of epinephrine and norepinephrine by the dog pancreas in vivo.
Metabolism
37:
68-73,
1988[ISI][Medline].
2.
Ahren, B,
Veith RC,
and
Taborsky Jr GJ
The effects of epinephrine on islet hormone secretion in the dog.
Int. J. Pancreat.
3:
375-388,
1988[ISI].
3.
Benthem, L,
van der Leest J,
Steffens AB,
and
Zijlstra WG.
Metabolic and hormonal responses to adrenoceptor antagonists in exercising rats.
Metabolism
44:
245-253,
1995[ISI][Medline].
4.
Berthoud, HR,
and
Jeanrenaud B.
Sham feeding-induced cephalic phase insulin release in the rat.
Am J Physiol Endocrinol Metab
242:
E280-E285,
1982
5.
Bruce, DG,
Storlien LH,
Furler SM,
and
Chrisholm DJ.
Cephalic phase metabolic responses in normal weight adults.
Metabolism
36:
721-725,
1987[ISI][Medline].
6.
Chance, RE,
Moon NE,
and
Johnson MG.
Human pancreatic polypeptide (HPP) and bovine pancreatic polypeptide (BPP).
In: Methods of Hormone Radioimmunoassay. New York: Academic, 1979, p. 657-672.
7.
Diamond, P,
and
LeBlanc J.
Hormonal control of postprandial thermogenesis in dogs.
Am J Physiol Endocrinol Metab
253:
E521-E529,
1987
8.
Dunning, BE,
Havel PJ,
Veith RC,
and
Taborsky Jr GJ.
Pancreatic and extrapancreatic galanin release during sympathetic neural activation.
Am J Physiol Endocrinol Metab
258:
E436-E444,
1990
9.
Dunning, BE,
Scott MF,
Neal DW,
and
Cherrington AD.
Direct quantification of norepinephrine spillover and hormone output from the pancreas of the conscious dog.
Am J Physiol Endocrinol Metab
272:
E746-E755,
1997
10.
Evans, MI,
Halter JB,
and
Porte Jr D.
Comparison of double- and single-isotope enzymatic derivative methods for measuring catecholamines in human plasma.
Clin Chem
24:
567-570,
1978
11.
Fischer, U,
Hommel H,
Fiedler H,
and
Bibergeil H.
Reflex mechanism on insulin secretion.
Endocrinol Exp
8:
137-146,
1974[ISI][Medline].
12.
Frankenhaeuser, M.
Experimental approaches to the study of catecholamines and emotion.
In: EmotionsTheir Parameters and Measurement, edited by Levi L.. New York: Reaven, 1976, p. 209-234.
13.
Havel, PJ,
Scott M,
Allen E,
and
Neal D.
Rapid increase of hepatic glucose output in response to meal anticipation and to feeding in dogs; mediation via increased glucagon secretion.
Diabetes
44, Suppl 1:
90A,
1995.
14.
Havel, PJ,
and
Taborsky Jr GJ.
The contribution of the autonomic nervous system to changes of glucagon and insulin secretion during hypoglycemic stress.
Endoc Rev
10:
332-350,
1989[ISI][Medline].
15.
Havel, PJ,
Veith RC,
Dunning BE,
and
Taborsky Jr GJ.
Pancreatic noradrenergic nerves are activated by neuroglucopenia but not hypotension or hypoxia in the dog.
J Clin Invest
82:
1538-1545,
1988[ISI][Medline].
16.
Jong, A de,
Strubbe JH,
and
Steffens AB.
Hypothalamic influence on insulin and glucagon release in the rat.
Am J Physiol Endocrinol Metab
235:
E380-E388,
1977.
17.
Lands, AM,
Arnold A,
Mcauliff JP,
Luduena FP,
and
Brown G.
Differentiation of receptor systems activated by sympathomimetic amines.
Nature Lond
214:
597-598,
1967[ISI][Medline].
18.
Loubatières, A,
Mariani M-M,
Sorel G,
and
Savi L.
The action of -adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of
-receptor.
Diabetologia
7:
127-132,
1971[ISI][Medline].
19.
Louis-Sylvestre, J.
Preabsorptive insulin release and hypoglycemia in rats.
Am J Physiol
230:
56-60,
1976[ISI][Medline].
20.
Niijima, A,
Togiyama T,
and
Adachi A.
Cephalic phase insulin release induced by taste stimulus of monosodium glutamate (unami tatste).
Physiol Behav
48:
905-908,
1990[ISI][Medline].
21.
Powers, MA,
Schiffman SS,
Lawson DC,
Pappas TN,
and
Taylor IL.
The effect of taste on gastric and pancreatic responses in dogs.
Physiol Behav
47:
1295-1297,
1990[ISI][Medline].
22.
Powley, TL.
The ventromedial hypothalamic syndrome, satiety, and the cephalic phase hypothesis.
Physiol Rev
84:
89-126,
1977.
23.
Roossien, A,
Brunsting JR,
Nijmeijer A,
Zaagsma J,
and
Zijlstra WG.
Effects of vasoactive intestinal polypeptide on heart rate in relation to vagal cardioacceleration in conscious dogs.
Cardiovasc Res
33:
392-399,
1997[ISI][Medline].
24.
Roozendaal, B,
Oldenburger WP,
Strubbe JH,
Koolhaas JM,
and
Bohus B.
The central amygdala is involved in the conditioned but not in the meal-induced cephalic insulin response in the rat.
Neurosci Lett
116:
210-215,
1990[ISI][Medline].
25.
Samols, E,
and
Weir GC.
Adrenergic modulation of pancreatic A, B, and D cells.
J Clin Invest
63:
230-238,
1979[ISI][Medline].
26.
Schwartz, TW.
Pancreatic polypeptide: a hormone under vagal control.
Gastroenterology
85:
1411-1425,
1983[ISI][Medline].
27.
Schwartz, TW,
Holst JJ,
Fahrenkrug J,
Lindkær Jensen S,
Nielsen OV,
Rehfeld JF,
Schaffalitzky OB,
and
Stadil F.
Vagal, cholinergic regulation of pancreatic polypeptide secretion.
J Clin Invest
61:
781-789,
1978[ISI][Medline].
28.
Simon, C,
Schlienger JL,
Sapin R,
and
Imler M.
Cephalic phase insulin secretion in relation to food presentation in normal and overweight subjects.
Physiol Behav
36:
465-469,
1986[ISI][Medline].
29.
Sjøstrøm, L,
Garellick G,
Krotkiewsky M,
and
Luyckx L.
Peripheral insulin in response to the sight and smell of food.
Metabolism
29:
901-909,
1980[ISI][Medline].
30.
Steffens, AB,
Van Der Gugten J,
Godeke J,
Luiten PGM,
and
Strubbe JH.
Meal-induced increases in parasympathetic and sympathetic activity elicit simultaneous rises in plasma insulin and free fatty acids.
Physiol Behav
37:
119-122,
1986[ISI][Medline].
31.
Strubbe, JH.
Central nervous system and insulin secretion.
Neth J Med
34:
154-167,
1989[ISI][Medline].
32.
Strubbe, JH.
Parasympathetic involvement in rapid meal-associated conditioned insulin secretion in the rat.
Am J Physiol Endocrinol Metab
263:
ER615-R618,
1992.
33.
Strubbe, JH,
Prins AJA,
Bruggink J,
and
Steffens AB.
Daily variation of food induced changes in blood glucose and insulin in the rat and the control by the suprachiasmatic nuscleus and the vagus nerve.
J Auton Nerv Syst
20:
113-119,
1987[ISI][Medline].
34.
Strubbe, JH,
and
Steffens AB.
Rapid insulin release after ingestion of a meal in the unanesthetized rats.
Am J Physiol
229:
1019-1022,
1975[ISI][Medline].
35.
Strubbe, JH,
and
Steffens AB.
Neural control of insulin secretion.
Horm Metab Res
25:
507-512,
1993[ISI][Medline].
36.
Taborsky Jr, GJ.
Evidence of a paracrine role for pancreatic somatostatin in vivo.
Am J Physiol Endocrinol Metab
245:
E598-E603,
1983
37.
Taylor, IL,
Impicciatore M,
Carter DC,
and
Walsh JH.
Effect of atropine and vagotomy on pancreatic polypeptide response to a meal in dog.
Am J Physiol Endocrinol Metab
235:
E443-E447,
1978[ISI][Medline].
38.
Teff, KL,
Levin BE,
and
Engelman K.
Oral sensory stimulation in man: effects on insulin, C-peptide, and catecholamines.
Am J Physiol Regulatory Integrative Comp Physiol
265:
R1223-R1230,
1993
39.
Teff, KL,
Mattes RD,
and
Engelman K.
Cephalic phase insulin release in normal weight males: verification and reliability.
Am J Physiol Endocrinol Metab
261:
E430-E436,
1991
40.
Teff, KL,
Mattes RD,
Engelman K,
and
Mattern J.
Cephalic-phase insulin in obese and normal-weight men: relation to postprandial insulin.
Metabolism
42:
1600-1608,
1993[ISI][Medline].
41.
Woods, SC,
and
Porte Jr D.
Neural control of the endocrine pancreas.
Physiol Rev
54:
596-619,
1974
42.
Woods, SC,
Vasselli JR,
Kaestner R,
Szakmary GA,
Milburn P,
and
Vitiello MV.
Conditioned insulin secretion and meal feeding in rats.
J Clin Endocrinol Metab
55:
1114-1117,
1982[Abstract].