Amplitude Modulation of Pulsatile Insulin Secretion by Intrapancreatic Ganglion Neurons
Lei Sha,
Johanna Westerlund,
Joseph H. Szurszewski, and
Peter Bergsten
From the Department of Medical Cell Biology (J.W., P.B.), Uppsala
University, Uppsala, Sweden; and the Department of Physiology and Biophysics
(L.S., J.H.S.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
Address correspondence and reprint requests to Dr. Peter Bergsten, Department
of Medical Cell Biology, Uppsala University, Box 571, SE-751 23 Uppsala,
Sweden. E-mail:
peter.bergsten{at}medcellbiol.uu.se
.
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ABSTRACT
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Neuron activity and insulin release were measured simultaneously from 33
preparations of intrapancreatic canine ganglia and pancreatic parenchyma
adjacent to the ganglia. The electrical activity of single neurons of the
ganglia was recorded with intracellular microelectrodes, and insulin release
from the attached islets was determined with an enzyme-linked immunosorbent
assay. Insulin release was 62 ± 18 fmol preparation/min in the presence
of 10 mmol/l glucose and pulsatile (3.7 ± 0.4 min/pulse). Corresponding
measurements of neuronal electrical activity showed a stable membrane
potential of -53.5 ± 0.6 mV. Short, high-frequency (20 Hz)
preganglionic nerve stimulation evoked action potentials and, in 46% of the
preparations, a threefold rise in the insulin secretory rate associated with
increased amplitude of the insulin pulses. The effects were blocked by 10
µmol/l tetrodotoxin (TTX). In other preparations, continuous low-frequency
(0.05-0.5 Hz) preganglionic nerve stimulation evoked action potentials and, in
50% of the preparations, a gradual increase of insulin release associated with
augmentation of insulin pulse amplitude without alteration of the duration.
The effects were blocked by 50 µmol/l hexamethonium (HEX). In the remaining
preparations, no change in insulin release was observed during nerve
stimulation. In the absence of stimulation, neither TTX nor HEX affected the
membrane potential or insulin secretion. These first simultaneous measurements
of intrapancreatic ganglion activity and insulin secretion are consistent with
amplitude modulation of pulsatile insulin secretion induced by changes in
electrical activity in a population of intrapancreatic ganglion neurons.
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INTRODUCTION
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Arise in plasma glucose concentration increases insulin concentration by
modulating the amplitude of the regular variations in the plasma insulin
concentrations
(1,2).
The importance of the increase in the insulin pulse amplitude is illustrated
by the hyperglycemia-induced rise in plasma insulin in type 2 diabetic
patients (2). In these
individuals, the increase is mainly nonpulsatile, with irregular plasma
insulin oscillations with small amplitudes. This deranged plasma insulin
pattern is believed to be an important factor leading to receptor
downregulation (3) and insulin
resistance (4). Indeed,
pulsatile insulin delivery has greater hypoglycemic effect than nonpulsatile
delivery
(5,6).
Understanding the mechanisms regulating the amplitude of plasma insulin
oscillations is therefore crucial in attempts to restore normal oscillatory
plasma insulin in diabetic patients.
Amplitude regulation of plasma insulin oscillations depends on the
modulation of the insulin pulse amplitude from the isolated islet
(7). Glucose and other
secretagogues increase insulin release from the isolated islet by increasing
the insulin pulse amplitude. However, to obtain pulsatile release from the
pancreas (8), coordination of
the secretory activities of the islets is required. Although no effect has
been observed on plasma insulin oscillations in the presence of drugs
affecting the central nervous system
(9), amplitude modulation of
plasma insulin oscillations does occur in response to cholinergic and
adrenergic blockade, thereby indicating a role of the autonomic nervous system
(1,10).
In this context, it has been suggested that the intrinsic ganglia of the
pancreas play a role in the generation of pulsatile insulin release, possibly
by synchronizing the secretory activities of the islets
(11,12,13).
The role of these ganglia in pulsatile insulin secretion has been difficult to
evaluate, because the ß-cells receive neuronal input from these ganglia
as well as from many other nerves of the autonomic nervous system
(14). Furthermore, the
secretory activity of the ß-cells is also influenced by intestinal
peptides released in response to activation of the autonomic nervous system
(15).
To determine the role of the intrapancreatic neurons for pulsatile insulin
secretion, we isolated individual ganglion together with adjacent
islet-containing pancreatic parenchyma. Simultaneous measurements of neuronal
activity and insulin release revealed that intrapancreatic ganglia may play a
role in amplitude regulation of pulsatile insulin release.
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RESEARCH DESIGN AND METHODS
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Reagents. Reagents of analytical grade and deionized water were
used. Aprotinin, bovine serum albumin (fraction V), hexamethonium (HEX),
tetramethylbenzidine, tetrodotoxin (TTX), and insulin peroxidase were
purchased from Sigma Chemicals (St. Louis, MO). The rat insulin standard was
obtained from Novo Nordisk (Bagsvaerd, Denmark). IgG-certified microtiter
plates were purchased from Nunc (Roskilde, Denmark). The antibodies to insulin
were raised in guinea pigs.
Preparation and perifusion of cells. Adult dogs (20-25 kg) of both
sexes were anesthetized with 30 mg/kg body wt sodium pentobarbital i.v. (Fort
Dodge Laboratories, Fort Dodge, IA) and killed by exsanguination. Dogs were
obtained from a U.S. Department of Agricultureapproved supplier (Triple
C, St. Joseph, IL). The use of dogs and the experimental methods used in this
study were approved by the Institutional Animal Care and Use Committee (Mayo
Clinic). Through a midline abdominal incision, the pancreas was removed and a
section of the head region of the pancreas was dissected and pinned to the
Sylgard-coated floor of a tissue bath. The tissue was superfused with modified
Krebs solution bubbled with 97% O2 and 3% CO2 (pH 7.4).
The composition of the Krebs solution was as follows (in mmol/l): NaCl 120,
KCl 5.9, MgCl2 1.2, CaCl2 2.5, NaHCO3 15.5,
NaH2PO4 1.2, and glucose 10. Pancreatic ganglia were
identified in the interlobular connective tissue with a microscope
(magnification x15). An individual ganglion, attached nerve trunks, and
a piece of pancreatic parenchyma attached to the ganglion were dissected
together. One such preparation was prepared from each pancreas. A total of 33
pancreata were used for the study. Each piece of pancreas was approximately 1
x 2 mm in size and 0.5 mm or less in thickness, to limit
diffusion-related problems. Nerve trunks were identified as central or
peripheral, based on their location relative to the ganglion as it would lie
in the pancreas, as previously described
(13). The preparation was
pinned to the Sylgard-coated floor of a recording chamber (500 µl) and
perifused at a flow rate of 800 µl/min using gravity as the driving force
with the same buffer as the one used during dissection. After a 2-h
perifusion, the buffer was supplemented with albumin (1 mg/ml) and aprotinin
(500 kallikrein inhibitor units [KIU]/ml), the flow rate was reduced to 500
µl/min using a peristaltic pump as the driving force, and the preparation
was perifused for another hour.
Electrical neuronal recordings. Intracellular recordings were made
with 3 mol/l KCl-filled microelectrodes (40-80 M
resistance) connected
to an electrometer with an active bridge circuit that allowed passage of
depolarizing or hyperpolarizing current through the recording electrode. The
membrane potential and intracellular current injections were displayed on an
oscilloscope (Tektronix 513), and permanent records were made on a chart
recorder (Gould Brush 220) and an FM tape recorder (Hewlett Packard 3968A).
Satisfactory impalements resulted in a stable resting membrane potential of
-40 mV or a more negative potential. Central nerve trunks were stimulated by
bipolar platinum wire electrodes connected to a stimulator (Grass S88) and a
stimulus isolation unit (Grass SIU5). A high-frequency stimulation (20 Hz, 100
V), with a pulse duration of 0.5 ms and a train duration of 30 s and a
sustained low-frequency stimulation (0.05-0.5 Hz, 60 V) with a pulse duration
of 0.5 ms were used to evoke action potentials in the impaled ganglion
neurons. The duration of the high-frequency stimulation was restricted to 30
s, because a prolonged stimulation period would cause damage to the nerve
trunk.
Insulin release measurements. Insulin release was measured in the
perifusate, which was collected in 30-s fractions and immediately cooled on
ice. Determinations of insulin were made by a competitive enzyme-linked
immunosorbent assay (ELISA) with the insulin-capturing antibody immobilized
directly in the solid phase and with inter- and intra-assay variation <10%
(7). The amounts of insulin
were calculated from linear standard curves in semilogarithmic plots. Insulin
release in the presence of 10 mmol/l glucose varied between 9 and 211 fmol per
preparation and minute, corresponding to the secretory rate from 3 to 70
isolated islets, respectively
(7). Because of this
variability in endocrine secretion from the pancreatic preparations, insulin
release during the first 5 min of perifusion of each preparation was
normalized to 100 arbitrary units. The cross-reactivity of canine insulin with
the insulin assay was 70%. Data and statistical analysis. The
occurrence and duration of insulin pulses were assessed from power spectra
obtained by Fourier transformation of the original data. Average secretory
rates were calculated using moving averages of three consecutive sample
points. Analyses of the frequencies and average rates were performed with Igor
software (Wave Metrics, Lake Oswego, OR). Data are presented as means ±
SE. Differences in secretory rates were evaluated with analysis of
variance.
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RESULTS
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Insulin release and neuronal activity were recorded simultaneously from 33
preparations consisting of an intrapancreatic ganglion and pancreatic
parenchyma adjacent to the ganglion. In the presence of 10 mmol/l glucose,
insulin release was 62 ± 18 fmol preparation/min and was pulsatile with
a pulse duration of 3.7 ± 0.4 min/pulse. The corresponding measurements
of neuronal electrical activity showed a stable membrane potential of -53.5
± 0.6 mV with no spontaneous electrical activity. Only occasional
excitatory postsynaptic potentials (EPSPs) or action potentials were observed
(1 EPSP/3.1 ± 0.4 min). An example of simultaneous recording of insulin
release and neuronal activity is shown in
Fig. 1.

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FIG. 1. Simultaneous recordings of membrane potential of a pancreatic ganglion
neuron (A) and insulin release from an attached piece of pancreatic
parenchyma (B) in the presence of 10 mmol/l glucose. Intracellular
recordings were obtained with a high-resistance glass microelectrode. Insulin
release was measured in the perifusate by ELISA. Representative of 27
experiments.
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Neuronal activity and insulin release in the presence of 10 mmol/l glucose
were recorded simultaneously during high-frequency (20 Hz) preganglionic
stimulation of the centrally attached nerve trunk in the absence and presence
of 10 µmol/l of the Na+ channel blocker TTX
(16) in 13 preparations. In
the absence of TTX, nerve stimulation induced a train of action potentials and
a more than threefold augmentation of insulin release associated with
increased amplitude of the insulin pulses in six preparations
(Fig. 2;
Table 1). In the presence of TTX,
both the neuronal response and the associated increase in the amplitude of
insulin release observed in the absence of TTX were blocked in these
preparations. In the remaining seven preparations, no change in insulin
release was observed during high-frequency stimulation in the absence of TTX.
In all 13 preparations, in the absence of nerve stimulation, TTX had no effect
on the membrane potential of the ganglion neurons and no effect on the
amplitude or duration of the insulin pulses
(Table 1).

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FIG. 2. Simultaneous recordings of membrane potential of a pancreatic ganglion
neuron (A) and insulin release from an attached piece of pancreatic
parenchyma (B) at 10 mmol/l glucose in the absence or presence of
TTX. Arrows indicate periods of high-frequency (20 Hz) preganglionic
electrical stimulation of a central nerve trunk attached to the ganglion; the
bar indicates addition of 10 µmol/l TTX to the perifusion medium (TTX).
Membrane potential recordings during electrical stimulation are expanded in
the absence and presence of TTX. Data are representative of six
experiments.
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Neuronal activity and insulin release in the presence of 10 mmol/l glucose
were also recorded during continuous low-frequency (0.05-0.5 Hz) stimulation
of the centrally attached nerve trunk in the absence and presence of 50
µmol/l of the nicotinic receptor blocker HEX
(17) in 14 preparations.
Low-frequency nerve stimulation evoked action potentials and an increase in
insulin release in seven preparations (Fig.
3; Table 2). Based on
control experiments, this increase could not be explained by an increase in
nonpulsatile insulin release, but was at least partially related to
augmentation of the insulin pulse amplitude. In these control experiments,
individual islets were perifused under the same conditions used in this study
(500 µl chamber and a flow rate of 500 µl/min). Similar insulin release
patterns to those observed in Fig.
3 before stimulation were obtained from these islets. When a
constant amount of insulin was added to each fraction of perifusate, the
pulsatility of insulin release was almost completely obscured. The addition of
insulin approximately doubled the amount of insulin in the fraction. When HEX
was present, nerve stimulation failed to evoke postsynaptic action potentials
in these preparations (Fig. 3).
There was a concomitant gradual decline of insulin release associated with a
decrease in the insulin pulse amplitude, but with no change in the pulse
duration. After a 10-min perifusion in the presence of HEX, insulin release in
the presence of electrical stimulation was no longer different from that of
control (Table 2). In the
remaining seven preparations, no change in insulin release was observed when
low-frequency stimulation was applied in the absence of HEX. The effect that
adding HEX to the perifusion medium had on the membrane potential of the
neuron and insulin release when no electrical stimulation was applied was
investigated in six preparations (Table
2). Neither the membrane potential nor the amplitude or duration
of the insulin pulses was affected by HEX under these conditions.

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FIG. 3. Simultaneous recordings of membrane potential of a pancreatic ganglion
neuron (A) and insulin release from an attached piece of pancreatic
parenchyma (B) at 10 mmol/l glucose in the absence and presence of
HEX. Bars indicate low-frequency (0.05-0.5 Hz) preganglionic electrical
stimulation (S) of a central nerve trunk attached to the ganglion and addition
of 50 µmol/l HEX to the perifusion medium (HEX). Membrane potential
recordings during electrical stimulation are expanded in the absence (first
two stimulations) and presence (last two stimulations) of HEX. Data are
representative of seven experiments.
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DISCUSSION
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The influence of the parasympathetic and sympathetic nervous systems on
blood insulin concentration has been studied extensively
(18,19,20,21,22).
Apart from these two branches of the autonomic nervous system, the enteric
system of the gastrointestinal tract may also play an important role in
regulating insulin release. A population of enteric ganglion neurons project
from the distal stomach and proximal duodenum to the pancreas, where they
synapse with islet cells directly or via intrapancreatic ganglia
(23). Although the
intrapancreatic neurons are likely to influence the secretory activity of the
islet cells, very little is known about how they affect the plasma insulin
oscillations.
Plasma insulin is oscillatory not only in normal subjects
(1,24),
but also in individuals with a transplanted pancreas
(25). The latter observation,
together with the pulsatile insulin release from the isolated perfused
pancreas (8), indicates that
the intrinsic intrapancreatic ganglion neurons may play a role as coordinators
of the secretory activities of the islets in the pancreas. The rhythmic
occurrence of spontaneous electrical activity in neurons of interconnected
intrapancreatic ganglia, with similar frequency as in insulin release, further
supports a role of the ganglia in the synchronization of the islets
(13). When ganglionic activity
was inhibited by TTX, the duration of the insulin oscillations from the
perfused isolated pancreas was altered
(11). Indeed, after prolonged
perfusion with the neurotoxin, insulin release from the isolated pancreas was
essentially nonoscillatory and sustained
(26). These observations
indicate that frequency modulation of pulsatile insulin release could occur
via the intrapancreatic ganglia. However, when agents affecting the central
(9) or peripheral nervous
system
(1,10)
were administered in healthy individuals, no changes in the duration of the
plasma insulin oscillations were observed. Instead, alterations in the
amplitude of the regular variations in plasma insulin concentration were
recorded. This preferred modulation of the amplitude of insulin oscillations
has been observed in response to different secretagogues in the isolated
perfused pancreas (8) and
isolated islets (7).
Insulin release from islets of Langerhans connected to an intrapancreatic
ganglion in the present study was pulsatile when the neurons showed a steady
membrane potential, and the amplitude was modulated when the ganglion was
electrically stimulated. The results demonstrate that pulsatile insulin
release from individual islets does not require intermittent neural input from
the intrapancreatic ganglia. Also, the denervated isolated islet has pulsatile
insulin release (7). Although
it has been suggested that pulsatile insulin from the isolated islet is
controlled by an intrinsic islet nervous system that is sensitive to TTX
(27), this was not confirmed
in a more recent study (26).
Furthermore, in the present study, neither TTX nor HEX had any effect on
insulin release by themselves. However, TTX and HEX did block the increase in
insulin release during orthodromic stimulation, which strongly suggests that
the increase was mediated by the pancreatic ganglion. In some of the
experiments in our study, there was no change in secretory activity during
orthodromic nerve stimulation. This was interpreted as indicating that the
islet cells of these experiments were not innervated by the particular
pancreatic ganglion neurons under study.
The property of the isolated islet to release insulin intermittently may be
related to an oscillatory metabolism. Regular variations in the ATP/ADP ratio
(28), with a frequency similar
to the insulin oscillations
(1,7,8),
support this notion. Because exocytosis of insulin granules is an
energy-requiring process (29),
it has been suggested that the oscillations in the ATP/ADP ratio could be
responsible for the insulin oscillations
(28,30.
Indeed, we recently demonstrated that the regular variations in insulin
release are synchronous with oscillations in oxygen tension in the isolated
islet (31). The
intrapancreatic ganglia may serve as coordinators of these intrinsic rhythmic
secretory activities of the individual islets of Langerhans in the pancreas
and explain the pulsatile release of insulin from the pancreas
(8,11,12).
The stimulation of preganglionic nerves of extrinsic origin and perhaps
also nerve fibers of intrapancreatic ganglion neurons is mediated by nicotinic
transmission in the intrapancreatic ganglia
(17), leading to transmitter
release from the intrapancreatic ganglion neurons. Although intrapancreatic
ganglion cells have been reported to contain peptides that inhibit insulin
release (32), the observed
increase in the amplitude of insulin release indicates the significance of
acetylcholine in the transmitter release. Acetylcholine causes an inositol
triphosphateinduced release of Ca2+ from intracellular
stores via the cholinergic receptors, which leads to an elevation of the
cytoplasmic calcium concentration ([Ca2+]i) in the
pancreatic ß-cells (33).
Although this elevation is not oscillatory, it may increase the amplitude of
the insulin pulses in the same way as secretagogues, which also induce
nonpulsatile elevation in [Ca2+]i, cause rises in the
amplitude of the pulsatile insulin release from isolated islets
(34,35,36).
The present results are the first stimultaneous measurements of electrical
activity of intrapancreatic ganglion neurons and insulin release from attached
islets and are consistent with a role of the ganglia in the amplitude
regulation of insulin pulses. It can be speculated that intrapancreatic
neuronal discharge could be an important factor for the normalization of blood
glucose levels by increasing the amplitude of plasma insulin oscillations.
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ACKNOWLEDGMENTS
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This study was supported by grants from the National Institutes of Health
(DK-17632), the Swedish Medical Research Council (72X-14NNN), the
Göran Gustafsson Foundation, the Novo Nordisk
Foundation, the Swedish Diabetes Association, the Marcus and Amalia Wallenberg
Foundation, and the Family Ernfors Foundation. The authors thank Jan
Applequist for her assistance in preparing the manuscript.
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FOOTNOTES
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[Ca2+]i, cytoplasmic calcium concentration; ELISA,
enzyme-linked immunosorbent assay; ESPS, excitatory postsynaptic potential;
HEX, hexamethonium; TTX, tetrodotoxin.
Received for publication June 7, 1999
and accepted in revised form September 14, 2000
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