Vol. 281, Issue 5, R1540-R1544, November 2001
Physiological effect of circulating glucagon on the hepatic
membrane potential
Thomas A.
Lutz1,
Alois
Estermann1,
Nori
Geary2, and
Erwin
Scharrer1
1 Institute of Veterinary Physiology, University of Zurich,
8057 Zurich, Switzerland; and 2 E. W. Bourne Behavioral Research Laboratory, New York Presbyterian
Hospital and Weill Medical College of Cornell University, White
Plains, New York 10605
 |
ABSTRACT |
The pancreatic hormone glucagon hyperpolarizes the
liver cell membrane under various conditions. Here we investigated the physiological relevance of this effect by testing the influence of
infusions of glucagon antiserum on the liver cell membrane potential in
vivo. Intracellular microelectrode recordings of liver cells (up to
60/rat over 2 h) were done in anesthetized male rats. Livers were
fixed in place, and recordings were done 10-30 min after
intraperitoneal injections of glucagon or hepatic portal vein infusions
of glucagon or specific polyclonal glucagon antibodies raised in
rabbits. The isotonic lactose vehicle was used as a control for
glucagon, and equal amounts of nonimmunized rabbit IgG were used as a
control for glucagon antibodies. Intraperitoneal glucagon (400 µg/kg)
hyperpolarized the liver cell membrane up to 12 mV, and intraportal
glucagon (10 or 60 µg/kg) dose dependently hyperpolarized the liver
cell membrane by 3-7 mV. Intraportal infusion of glucagon
antiserum (in vitro binding capacity of 4 ng glucagon/rat)
significantly depolarized the liver cell membrane by ~2.5 mV. The
effects of both glucagon and glucagon antiserum reversed after
60-90 min. We conclude that glucagon is a physiologically important modulator of the liver cell membrane potential.
food intake; glucagon antiserum
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INTRODUCTION |
THE CONTROL OF MEAL
SIZE appears to number among the physiological roles of the
pancreatic hormone glucagon (12, 13, 29). Feeding
transiently stimulates pancreatic glucagon secretion (3, 7,
24). Intraperitoneal injection and systemic intravenous or
intraportal infusion of glucagon dose dependently inhibit feeding (14, 28, 35, 46). The physiological importance of this effect is underlined by experiments demonstrating that prandial intraperitoneal injection or intraportal infusion of glucagon antiserum, presumably blocking endogenous glucagon, stimulates feeding
(15, 25, 30). Because these inhibitory actions of glucagon
on feeding are expressed as changes in meal size, glucagon is
considered a physiological control of satiation.
The liver appears to be the major site for glucagon's satiating
effect. First, glucagon infused in the portal vein produced a more
potent satiating effect than glucagon administration via other routes
(11, 28, 46). Second, hepatic branch vagotomy blocked the
inhibitory effect of intraperitoneally or intraportally delivered
glucagon (15, 17, 34). Third, lesions of the nucleus of
the solitary tract, the initial central projection target of hepatic
vagal afferents, blocked intraperitoneal glucagon's inhibitory effect
on feeding (45). Fourth, hepatic branch vagotomy blocked the stimulatory effect of intraportal infusion of glucagon antiserum on
feeding (15). Fifth, brief infusions of glucagon decreased meal size when delivered intraportally but not when delivered in the
vena cava near the junction of the hepatic vein (15). It
is important to note, however, that some tests of hepatic vagotomy (2, 44) and of varied routes of glucagon administration
(43) suggest that glucagon may act outside the liver to
control feeding under some conditions.
The transduction mechanism initiating glucagon's satiating
action in the liver is not well understood. One interesting possibility arises from recent evidence that some of glucagon's actions may be
related to its actions on the liver cell membrane potential (22). According to Russek's (41)
potentiostatic hypothesis, the hepatocyte membrane potential regulates
food intake by modulating the activity of hepatic afferent nerves,
with hepatocyte hyperpolarization inhibiting feeding and hepatocyte
depolarization increasing feeding. Consistent with this, glucagon
hyperpolarizes the liver cell membrane in vitro (10, 38).
Furthermore, this effect of glucagon can be counteracted by treatment
with the antidiabetic drug metformin, which depolarizes the liver cell
membrane (32) and increases food intake in rats
(8). In view of these results, we wanted to test whether
glucagon also hyperpolarizes the liver cell membrane in vivo and
especially whether antagonism of endogenous glucagon with glucagon
antibodies at doses that increase feeding (15, 25, 30)
depolarizes the liver cell membrane in vivo.
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MATERIALS AND METHODS |
Animals and maintenance.
Adult male Sprague-Dawley rats (OFA; BRL, Füllinsdorf,
Switzerland) with an approximate body weight of 250 g were used.
Rats had ad libitum access to a diet containing 18% fat, 46%
carbohydrate, 13% protein, 4% mineral mix, 3% vitamin mix, and 16%
nondigestible components (33, 40) for at least 2 wk before
experiments. Water was always available ad libitum.
Protocol.
Rats were tested in the diurnal phase of the lighting cycle, without
food deprivation. Each rat was tested in one condition. In the first
experiment, rats were injected intraperitoneally with 100 or 400 µg/kg glucagon (Novo Nordisk, Küsnacht, Switzerland) dissolved
in isotonic lactose solution (1 ml/kg) or with isotonic lactose alone
(n = 6/group). Although intraperitoneal injection of
100 µg/kg glucagon inhibited feeding in some prior experiments (14, 16), the threshold for a satiating action in our rat strain appears nearer to 400 µg/kg (23). Rats were
anesthetized with a mixture of ketamine (Ketavet; Parke-Davis; 66 mg/kg) and xylazine (8 mg/kg; Rompun; Bayer) ~20 min later, and
recordings began 10 min later, i.e., 30 min postinjection. The liver
cell membrane potential was measured in the left lateral liver lobe, as
described previously (5, 31). Briefly, the rat was
laparotomized, and the left lateral lobe of the liver was fixed in
nictating membrane forceps. The abdominal cavity, including the liver,
was covered in warmed (37°C) Krebs-Henseleit buffer (in mmol/l:
118.00 NaCl, 4.70 KCl, 1.25 CaCl2 · 2H2O, 0.60 MgCl2 · 6H2O, 1.20 NaH2PO4 · H2O, and 25.00 NaHCO3), which was replaced every 5 min to maintain tissue
euthermia. The membrane potential was measured using conventional open-tip microelectrodes in liver cells on the part of the parietal surface of the liver that was exposed in the open loop of the upper
limb of the forceps. The reference electrode was placed in the
abdominal cavity. Up to 60 consecutive impalements were made over
2 h in each rat.
In the second experiment, after laparotomy, the intestines were lifted
momentarily to expose the hepatic portal vein, which was then
cannulated with a 25-gauge butterfly needle. The intestines and portal
vein were then returned to their normal positions, and 0, 10, or 60 µg/kg glucagon was infused intraportally (0.5 ml/rat infused over
1-2 min). Previously, these doses inhibited feeding after
intraportal infusion (28, 35, 46). The recording then
proceeded as described above. The third experiment followed the same
procedure as the second, except that intraportal infusions of
polyclonal glucagon antiserum (0.5 ml/rat infused over 1-2 min;
Peninsula Laboratories; Belmont, CA) were done. The in vitro binding
capacity of the antiserum was 4 ng glucagon/rat, which presumably
blocks all circulating glucagon. This dose of antiserum previously
stimulated feeding when administered before meals (25, 30). Control infusions were saline containing an appropriate amount of normal rabbit serum.
Measurement of membrane potential.
Open-tip microelectrodes were drawn in a horizontal puller
(Sachs-Fleming Micropipette Puller PC-84; Sutter Instrument, San Raphael, CA) from microfilament glass capillaries (OD 1.5 mm; ID 0.86 mm; A-M Systems, Everett, WA). Pipettes were filled with 0.5 M KCl. The
microelectrode was connected by an Ag-AgCl half cell to a high-input
impedance preamplifier (1013 
, VF 180; Biologic,
Echirolles, France). The reference electrode (Ag-AgCl) was placed in
the abdominal cavity filled with Krebs-Henseleit solution (see above).
Voltage was measured with a digital voltmeter and an oscilloscope (COS
5020; Kibusui, Kawasaki City, Japan) and was recorded on a two-channel
recorder (B-281-L; Rikadenki, Kogyo, Japan). Criteria for valid
micropipette impalements of liver cells were 1) a rapid
deflection of the voltage trace on advancing the microelectrode in the
liver; 2) a stable voltage trace within ±2 mV for at least
10 s; and 3) return of the voltage trace to within ±2
mV of the baseline when the microelectrode was withdrawn. Resistance of
open-tip microelectrodes (20-50 M) was measured one time before
every impalement by passing alternating current pulses (1 nA; frequency
1,000 Hz).
At each time point, the membrane potential of five liver cells was
measured consecutively within ~90-120 s. The mean of these five
values was calculated. One such mean was obtained at each time point
from each animal and used for further analysis. The mean coefficient of
variation for the membrane potential measured in different cells of a
liver lobe was 4.0 ± 0.5%. Because up to 12 time points were
measured in an experiment, the liver of each animal was impaled up to
60 times.
Statistical evaluation.
All values are presented as means ± SE (n = no.
of animals/group; see RESULTS for details). Data were
analyzed by repeated-measures two-way ANOVA (repeated for the time
factor; treatment as the main effect). The Student-Newman-Keuls post
hoc test was used for pairwise comparisons between individual means
after significant ANOVA effects. In all cases, a P value
<0.05 was considered significant.
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RESULTS |
Glucagon.
Intraperitoneal injection of 400 µg/kg glucagon, but not of 100 µg/kg glucagon, significantly hyperpolarized the liver cell membrane
(repeated-measures ANOVA: P < 0.01 for effect of
treatment; Fig. 1). The hyperpolarization
60 min postinjection of ~12 mV appeared to be larger than that
recorded 30 or 90 min postinjection, but this difference was not
statistically significant. Intraportal infusion of 10 or 60 µg/kg
glucagon elicited a dose-dependent hyperpolarization of the liver cell
membrane (repeated-measures ANOVA: P < 0.001 for
effect of treatment; Fig. 2). These doses produced relatively steady, long-lasting hyperpolarizations of ~3 and
7 mV, respectively, between 30 and 90 min postinfusion. The difference
between the effects of the two doses was significant at every time
point except one. These hyperpolarizing effects appeared to be fully
reversible because the liver cell membrane potential returned to
baseline within 100-110 min after glucagon infusion.
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Fig. 1.
Influence of glucagon (100 and 400 µg/kg body wt)
injected intraperitoneally (ip) on liver cell membrane potential in
anesthetized rats. Injection of isotonic lactose solution served as
control. Values are means ± SE. ***Significant difference between
glucagon (400 µg/kg) and control, or glucagon (400 µg/kg) and
glucagon (100 µg/kg), at respective time point (P < 0.001; repeated-measures ANOVA with the Student-Newman-Keuls post hoc
test; n = 6 animals for all groups).
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Fig. 2.
Influence of glucagon (10 and 60 µg/kg body wt) infused
intraportally (ipv) on liver cell membrane potential in anesthetized
rats. Infusion of isotonic lactose solution served as control. Values
are means ± SE. Different letters indicate significant difference
between groups at respective time point [P < 0.05;
repeated-measures ANOVA with the Student-Newman-Keuls post hoc test;
n = 12 animals for control, n = 6 for
glucagon (10 µg/kg) and glucagon (60 µg/kg)].
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Glucagon antiserum.
Intraportal infusion of glucagon antiserum significantly depolarized
the liver cell membrane by ~2.5 mV 40-50 min postinfusion (repeated-measures ANOVA: P < 0.01 for the effect of
treatment; Fig. 3). The depolarizing
effect was reversible within ~60 min after the infusion of glucagon
antiserum. The magnitude and time course of the effect of intraportal
glucagon antiserum infusion was replicated in another group of rats
(data not shown).
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Fig. 3.
Influence of glucagon antiserum (in vitro binding
capacity ~4 ng glucagon/rat) infused ipv on liver cell membrane
potential in anesthetized rats. Infusion of saline containing normal
rabbit serum served as control. Values are means ± SE.
Significant difference between glucagon antiserum and control at
respective time point: *P < 0.05 or
***P < 0.001 (repeated-measures ANOVA with the
Student-Newman-Keuls post hoc test; n = 6 animals for
all groups).
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DISCUSSION |
These experiments extend previous reports that glucagon
administration hyperpolarizes the liver cell membrane (Refs.
9, 10, 38 and unpublished
observations) by demonstrating 1) that exogenous glucagon
has a hyperpolarizing effect in vivo under conditions where it
decreases feeding, 2) that intraportal infusion of glucagon
requires lower doses to hyperpolarize liver cells than intraperitoneal
injection, and 3) that antagonism of endogenous glucagon
with glucagon antiserum depolarizes the liver cell membrane in vivo.
The latter result indicates that endogenous glucagon has a necessary
role in the maintenance of the liver cell membrane potential. The
results do not, however, reveal the physiological function of changes
in the liver cell membrane potential.
The parallelism of our present findings with previous analyses of
glucagon's satiating action is consistent with the possibility that
glucagon's action on the liver cell membrane potential is related to
its satiating action. That is, we observed a similar dose-response
relationship for intraportal glucagon's effect on the liver cell
membrane as has been observed for glucagon's satiating effect in rats
(11, 14, 29). Also, as in the feeding experiments, higher
doses were necessary for intraperitoneally than for intraportally injected glucagon to elicit an effect (11, 15, 17).
Furthermore, a dose of glucagon antiserum that increased food intake in
rats (15, 25, 30) also depolarized the liver cell membrane
in the present study. Finally, the durations of the effects of glucagon and glucagon antiserum on the liver cell membrane potential match their
respective effects on food intake in rats (17, 25). These
parallels are in principle consistent with Russek's hypothesis (41) that glucagon may affect feeding by virtue of its
effect on the liver cell membrane potential, but do not prove it.
Furthermore, one aspect of the data, the latency of the effect of
glucagon antibodies on feeding and on the liver cell membrane
potential, does not fit this interpretation well. Prandial glucagon
administration or glucagon antagonism appears to have selective effects
on meal size that occur within minutes (16, 28, 30, 46).
In the present experiments, glucagon administration had similarly rapid effects on the liver cell membrane potential (i.e., within 10 min).
Glucagon antibody administration, however, clearly required >30 min to
elicit a significant effect. Further research is necessary to determine
whether this is because glucagon's effect on the liver cell membrane
potential is not involved in its satiating action or whether the
apparent discrepancy was caused by some procedural difference in the
test situations. One such methodological factor could be our use of
anesthetized rats here, since both ketamine and xylazine can increase
glucagon release and induce hyperglycemia (6, 26), which
may have reduced the functional potency of infused glucagon antibodies.
It also may have been important that the animals were not
simultaneously feeding in the present study because glucagon's
satiating action appears to involve an obligatory synergism with other
food stimuli (27).
It is interesting to note that, despite the sensitivity of the liver
cell membrane potential to infusions of glucagon antiserum, only large,
supraphysiological (23) intraperitoneal glucagon doses
affected it. This also parallels previous feeding studies (14,
17, 23). Thus, according to the usual endocrine criteria, the
antagonist data are strong evidence for a physiological effect of
glucagon on the liver cell membrane potential, whereas the agonist data
mitigate against such a role. There are several possible explanations
for this (12). For example, under the conditions in the
present experiments, circulating endogenous glucagon may have nearly
saturated the signaling mechanisms for glucagon's effect on the liver
cell membrane potential (perhaps because of anesthesia-induced glucagon
secretion), thus necessitating unusually large amounts of exogenous
glucagon to elicit an additional effect. Another possible explanation
for intraperitoneal glucagon's poor potency is that the rate of
increase of plasma glucagon concentration may affect the biological
response (12). This would explain the greater potency of
intraportal than intraperitoneal glucagon. In either case, however, the
fact that blocking endogenous glucagon with glucagon antibodies
produced a depolarizing effect on the liver cell membrane indicates
that the signaling system is very sensitive in the opposite direction.
This favors the idea of a physiologically important role of glucagon in
the regulation of the liver cell membrane potential.
The hyperpolarization of the liver cell membrane by glucagon also fits
with Niijima's (37) observation that intraportal glucagon
administration reduced the discharge rate of vagal afferents. This is
in principle consistent with a hepatic vagal afferent glucagon
signaling system. It is as yet unclear, however, whether and how liver
cells and hepatic afferent nerve endings communicate, especially in
rats (for review, see Ref. 42). In contrast to many other
species, the liver parenchyma in rats appears to be only poorly
innervated, and the innervation seems to be confined largely to intra-
and extrahepatic bile duct cells, hepatic paraganglia, and the portal
vein (4). Nevertheless, the hepatocytes are extensively
coupled by gap junctions and are in close proximity to vagal afferents
in the intrahepatic bile ducts (4, 39). Thus a functional
coupling of the hepatocyte membrane potential and the activity in
hepatic vagal afferents, whether direct or indirect, might be possible
(also see Ref. 42). Potentially, this coupling could be
chemical in nature, i.e., it might involve the potential-dependent
release of some signaling substance from the liver cells acting on
vagal afferents.
Glucagons's influence on the hepatic membrane potential may also be
related to its other physiological and metabolic effects. This may
apply especially to the control of gluconeogenesis from amino acids
because the intracellular uptake of amino acids, e.g., alanine and
glutamine, occurring by Na+ cotransport, depends on the
membrane potential (21, 36, 47). Glucagon's effects on
the uptake of bile salts by liver cells and on bile secretion also seem
to be mediated by its effect on the membrane potential
(36).
Finally, the influence of glucagon on the hepatic membrane potential
may be related to cell volume regulation. The opening of nonselective
cation channels, which are present in liver cells (1), by
glucagon's intracellular second messenger cAMP (20) could
trigger a Ca2+ influx in the liver cells, leading to an
opening of K+ channels and subsequently hyperpolarization
of the liver cell membrane (33). Because of a coupling of
K+ channels, Na+-K+-ATPase, and
Cl
efflux, this could result in net Na+ and
Cl efflux, osmotic water loss, and cell shrinking, which
may contribute to increased glycogenolysis and proteolysis (18,
19).
In summary, we have shown that glucagon hyperpolarizes and that
glucagon antiserum depolarizes the liver cell membrane under in vivo
conditions. This points to a physiologically important role of glucagon
as a modulator of the liver cell membrane potential. It is possible
that glucagon's satiating or metabolic effects may depend in part on
this action of the hormone on liver cell membrane potential.
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FOOTNOTES |
Address for reprint requests and other correspondence: T. A. Lutz, Institute of Veterinary Physiology, Univ. of Zurich,
Winterthurerstrasse 260, 8057 Zurich, Switzerland (E-mail:
tomlutz{at}vetphys.unizh.ch).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 27 March 2001; accepted in final form 18 July 2001.
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ABSTRACT
INTRODUCTION
