Perspectives in Diabetes
Galanin-Sympathetic Neurotransmitter
in Endocrine Pancreas?
BETH ELAINE DUNNING AND GERALD J. TABORSKY, JR.
The effects of sympathetic neural activation on basal
pancreatic hormone secretion cannot be explained
solely by the actions of the classic sympathetic
neurotransmitter norepinephrine. The nonadrenergic
component may be mediated by the 29-amino acid
peptide galanin in that this neuropeptide meets
several of the criteria necessary to be considered a
sympathetic neurotransmitter in the endocrine
pancreas. 1) Galanin administration inhibits basal
insulin and somatostatin secretion and stimulates
basal glucagon secretion from the pancreas,
qualitatively reproducing the effects of sympathetic
nerve stimulation. These sympathomimetic effects
appear to be mediated by direct actions of galanin on
the islet. 2) Galanin-like immunoreactivity exists in
fibers that innervate pancreatic islets. 3) Galanin is
released during electrical stimulation of pancreatic
nerves. The quantity released is sufficient to reproduce
sympathetic nerve stimulation-induced effects on
insulin secretion and to contribute to the neural effects
on somatostatin and glucagon release. 4) Whether
interference with galanin action or release reduces
the islet response to sympathetic nerve stimulation
remains to be determined. We hypothesize that galanin
and norepinephrine act together to mediate the islet
response to sympathetic neural activation. If galanin
is a sympathetic neurotransmitter in the endocrine
pancreas, it may contribute to the inhibition of insulin
secretion that occurs during stress and thereby to the
hyperglycemic response. Moreover, the local presence
of this potent p-cell inhibitor in the islet leads to
speculation on galanin's contribution to the
impairment of insulin secretion that occurs in noninsulin-dependent diabetes mellitus and therefore on
the potential utility of a galanin antagonist in the
treatment of this disease. Diabetes 37:1157-62, 1988
From the Division of Endocrinology, Metabolism, and Nutriton, Department
of Medicine, Un~versityof Washington and VA Medical Center, Seattle, Washington
Address correspondence and reprint requests to Dr Beth Elaine Dunning,
D~visionoi Metabolism. Endocrinology, and Nutrition (151), VA Medical Center,
Seattle. N'A 98108
Rece~vedfor publ~cation2 May 1988 and accepted 5 May 1988.
DIABETES, VOL. 37, SEPTEMBER 1988
cores of neuropeptides have been discovered
over the past 30 years, and many of them can
I influence metabolism through actions on the endocrine pancreas under certain experimental conditions. However, knowledge of a peptide's effects on insulin
or glucac!on secretion is by itself of limited use in understanding the physiologic or pathophysiologic role of that
peptide, because the ability of an exogenous peptide toalter
islet hormone secretion does not necessarily reflect a physiologic fu~ictionin the pancreas. For this reason it may be
more use'ul to begin by inquiring what functions cannot be
explained by the actions of previously known regulators and
therefore what functions might be subserved by an endogenous neuropeptide. We consider one example.
System c stress or direct electrical stimulation of the sympathetic nerves to the pancreas inhibits insulin and stimulates glucagon release. Such changes of pancreatic hormone secretion are thought to serve an important role to
defend b l ~ o dglucose levels under conditions of increased
demand f3r or decreased availability of metabolic fuels. Although the classic sympathetic neurotransmitter norepinephrine is usually assumed to mediate sympathetic neural
influence: on islet function, direct tests of this assumption
have procuced some surprising results. For example, direct
pancreatic: arterial infusion of norepinephrine, in a wide
range of doses, failed to reproduce the inhibition of basal
insulin relt?aseseen during sympathetic nerve stimulation in
anesthetized dogs ( I ) , although the infusion could inhibit
arginine-stimulated insulin release. Furthermore, moderate
doses of iorepinephrine did stimulate basal glucagon secretion, allhough to a lesser extent than did nerve stimulation.
A second independent approach revealed that combined
adrenergi~: blockade had little effect on sympathetic nerve
stimulatiori-induced changes of basal pancreatic hormone
release (2).These studies suggested that sympathetic
neural regulation of basal islet hormone secretion was a
function in which neuropeptides may serve an important role.
One recently discovered neuropeptide, galanin, stands out
as a particularly good candidate to mediate nonadrenergic
neural influences on the islet.
Galanin is a29-amino acid peptide with a C-terminal amide
characteristic of many biologically active peptides. Galanin
was originally isolated from porcine intestinal extracts by
virtue of its C-terminal amide and was so named for its Nterminal glycine and C-terminal alanine residues (3). Galanin
has little homology with other known peptides, but like other
peptides it is synthesized as a large-molecular-weight precursor and then enzymatically cleaved to the 29-amino acid
form. A 60-amino acid galanin message-associated peptide
(GMAP) neighbors the galanin sequence (4). Because
GMAP (as well as galanin) appears to be highly conserved
across species, it is thought to have as yet unknown biologic
functions (5). The first effects of galanin were reported in
1983: galanin was found to contract smooth muscle preparations from the rat and produce hyperglycemia in conscious dogs (3). The hyperglycemic effect of galanin led to
investigation of its influence on the endocrine pancreas, and
galanin was found to markedly reduce peripheral insulin levels in response to parenteral glucose in conscious dogs (6).
This action of galanin was reminiscent of stress and spurred
our interest in this peptide as a possible mediator of nonadrenergic sympathetic neural influences on the endocrine
pancreas.
Historically, proof that a substance had a physiologic role
as a neurotransmitter required a demonstration that it fulfilled
a set of criteria. We have borrowed from the tenets of classic
neurobiology and modified the criteria to be specific for a
proposed function in the pancreas (Fig. 1).To be considered
a sympathetic neurotransmitter in the endocrine pancreas,
galanin must 1 ) have direct actions on islet function that
mimic the effect of sympathetic neural activation, 2) be localized in islet sympathetic nerves, and 3 ) be released by
sympathetic neural activation in quantities sufficient to evoke
an islet response. In addition, interference with the release
or actions of galanin must alter the islet response to neural
activation (Fig. 1).
DOES EXOGENOUS GALANIN MIMIC EFFECTS O F
SYMPATHETIC NEURAL ACTIVATION THROUGH
DIRECT ACTIONS O N ISLETS?
Early reports that systemic administration of galanin produced hyperglycemia and prevented the expected increase
of insulin levels during endogenous or exogenous hyperglycemia were consistent with an effect of this peptide to inhibit
insulin secretion (3,6). Further tests of synthetic porcine galanin in anesthetized dogs with the use of sampling of the
pancreatic venous effluent demonstrated marked inhibition
of basal insulin output, modest stimulation of basal glucagon
output, and significant suppression of pancreatic somatostatin output (7), effects qualitatively identical to those produced by electrical act~vationof the local sympathetic nerves
to the pancreas (1,8). Galanin has since been reported to
inhibit basal insulin secretion and the acute insulin response
to both glucose and nonglucose secretagogues in vivo and/
or in vitro in rats, mice, and dogs (9-15). The potency of
galanin, the consistency of the observed effects, and the
ability of the porcine form of galanin to inhibit insulin release
in all species examined (i.e., the ability to cross species
1 . Golonin must mimic the effects of sympothetic neurol octivotion
through direct octlon on the islet.
--_..-.
2. Golonin must be localized in the sympothetic nerves of the islets.
3. Golonin must be released during neurol octivotion in quantities
sufficient to evoke on islet response.
4. Interference with golonin oction or releose must olter the
poncreatic response to neurol octivotion.
FIG. 1. Schema of 4 criteria for acceptance of galanin as sympathetic
neurotransmitter in endocrine pancreas.
boundaries) set this peptide apart from other possible candidates. For example, the effects of neuropeptide Y (NPY)
and calcitonin gene-related peptide (CGRP) on islet function
seem to vary with species and experimental system (1619).
The evidence that galanin's inhibitory influence on insulin
secretion is mediated by a direct action of this peptide on
the p-cell is substantial. Mediation by an extrapancreatic
effect of galanin was ruled out by demonstration that galanin,
given directly into the pancreatic circulation in vivo (at a
systemically ineffective dose), markedly inhibits insulin output (7) and that galanin inhibits insulin release from the isolated perfused pancreas in vitro (15). Galanin does not
appear to inhibit insulin release by influencing local pancreatic neural activity, because galanin administration does
not change pancreatic venous norepinephrine levels in vivo
(7) and because neither adrenergic nor cholinergic blockade prevents galanin-induced inhibition of insulin secretion
in the perfused dog pancreas in vitro (15). Galanin also
inhibits insulin release from isolated mouse islets (13) and
DIABETES, VOL 37. SEPTEMBER 1988
from monolayer cultures of neonatal rat pancreatic cells (1 O),
strongly supporting a direct effect. Finally, the demonstration
of specific receptors for galanin on membranes from a hamster p-cell tumor (20) and the recent report that galanin activates ATP-sensitive K + channels in an insulin-secreting rat
islet cell line (21) provide information regarding the cellular
mechanisms by which galanin directly inhibits insulin release. Thus, all available evidence supports the conclusion
that the sympathomimetic effect of galanin to inhibit insulin
secretion reflects its direct action on the p-cell.
In contrast to galanin's consistent effects on insulin secretion, observations of this peptide's influence on glucagon
secretion have been more varied. We find that galanin modestly stimulates pancreatic glucagon output when administered either systemically or locally into the pancreatic artery
in vivo in dogs (7); a similar moderate increase of both basal
and stimulated glucagon levels in response to systemic galanin was found in mice (13). However, galanin has also been
reported to have no effect on peripheral glucagon levels in
conscious dogs (6) and no effect on glucagon release from
the per-fusedrat pancreas in vitro (I 1). Finally, although moderate doses of galanin had little effect on glucagon secretion
from the isolated perfused dog pancreas, high doses elicited
an inhibitory effect (15).
Although it is difficult to reconcile the divergent reports of
the effects of galanin on glucagon secretion, clarification
may b e provided by considering galanin's effect on pancreatic somatostatin secretion. Galanin markedly inhibits
pancreatic somatostatin release from the dog pancreas in
vivo (711, as does sympathetic nerve stimulation (8). A similar
degree of somatostatin suppression has been suggested to
remove a paracrine restraint on the a-cell, resulting in increased glucagon secretion (22). The inhibitory tone of local
somatostatin on the a-cell is reflected by pancreatic somatostatin output; it appears high in dogs in vivo and substantially lo'ur~erin vitro in both the isolated dog and rat pancreas.
Thus, it is reasonable to suggest that a net stimulatory effect
of galanin occurs when the pancreatic somatostatin tone is
initially high and is then markedly reduced by galanin administration. Conversely, in experimental preparations in which
pancreatic somatostatin secretion is low, e.g., perfused pancreas and isolated islets, there is little paracrine restraint to
remove, and a weak direct inhibitory effect on the a-cell
becom'es apparent when high doses of galanin are administered. This interpretation is consistent with our findings that
galanin stimulates glucagon release in vivo (7) but inhibits
glucagon release from monolayer cultures of rat pancreatic
cells (unpublished observations). Additionally, galanin-induced inhibition of insulin secretion could also contribute
indirectly to the stimulation of glucagon release observed in
vivo by reducing putative local endocrine restraint of the acell by insulin (23).
Because of galanin's apparently variable effects on glucagon secretion, its potential contribution to the a-cell response to sympathetic nerve stimulation is difficult to
estimate. However, because galanin does increase glucagon output in vivo, it may augment norepinephrine's direct
stimulatory effect on glucagon secretion, possibly via its action to suppress pancreatic somatostatin and insulin secretion.
DIABETES. VOL. 37, SEPTEMBER 1988
IS GALANIN LOCALIZED IN ISLET
SYMPATHETIC NERVES?
Galanin-like immunoreactivity has been detected in extracts
of pancreatic tissue from pigs, rats (24), mice (25), humans
(S.M. Gabriel, unpublished observations), dogs, and rabbits
(unpublished observations). The galanin-like immunoreactivity in the dog pancreas dilutes in parallel with synthetic
porcine standards in radioimmunoassay and elutes from
Sephadex G-50 in a position very similar to that of synthetic
porcine galanin, suggesting there is significant similarity between the canine and porcine forms of the molecule (30).
However, the levels of galanin in pancreatic extracts are
much lower than those in intestinal or hypothalamic extracts
(26). The low pancreatic content of galanin may lead to an
erroneous assumption that this peptide cannot serve an important function within the pancreas. However, the islet-specific location of galanin nerves may reconcile the low levels
of galanin in pancreatic extracts with an important but highly
localized function in that islets represent only 1-2% of total
pancreatic mass.
lmmunofluorescent staining for galanin in the dog pancreas revealed galanin-like immunoreactivity only in nerve
fibers and primarily in those that innervate the islets, as opposed to the fibers innervating acinar tissue and blood vessels (7). This selective islet innervation again sets galanin
apart from other pept~despresent in canine pancreas, e.g.,
NPY, vasoactive intestinal polypeptide, and CGRP, which do
not exhibit such selective localization (16,27; unpublished
observations). Galanin-like immunoreactivity was not found
in the intrapancreatic ganglia, also in contrast to NP Y (16),
suggesting that galanin nerves may be sympathetic in character, because pancreatic sympathetic fibers are extrinsic
(i.e., their ganglia reside outside the pancreas), whereas
parasympathetic fibers are intrinsic (i.e., they arise from intrapancreatic ganglia). An extrapancreatic location of galanin cell bodies is also consistent with the recent failure to
detect galanin mRNA in rat pancreatic tissue (5). Thus, galanin appears to be present in sympathetic-like fibers innervating the dog islet. Similar localization studies of pancreatic
galanin-like immunoreactivity in other species are necessary
to establish the generality of this observation. Furthermore,
it would be of interest to determine if galanin and norepinephrine are colocalized.
It is important to note that all available information regarding both galanin's presence in the pancreas and its release
during neural activation is based on immunologic techniques
with the use of antibodies generated against porcine galanin.
Because there is species variability in the C-terminal part of
the galanin molecule (5), we and others have found that the
detection of galanin in nonporcine species is often enabled
only by the use of a non-C-terminally directed antibody (28).
Therefore, a comparison of pancreatic content or localization
of galanin-like immunoreactivity between species must take
into account the specificity of the antibody employed.
IS GALANIN RELEASED DURING PANCREATIC NEURAL
ACTIVATION IN QUANTITIES SUFFICIENT
TO EVOKE AN ISLET RESPONSE?
Galanin's proposed role as a local neurotransmitter would
dictate that pancreatic neuronal spillover is not l~kelyto make
1159
a significant contribution to circulating galanin levels. For
this reason, and because circulating levels of galanln have
been reported to be very low ( < I 0 fmollml in humans; 29),
documentation of galanin release dur~ngpancreatic nerve
stimulation necessitates direct access to pancreatic venous
blood and a sensitive assay for galanin in plasma. Recently,
using a non-C-terminally directed antibody to measure
galanin in dog plasma, researchers found that electrical
stimulation of the pancreatic autonomic nerves markedly
increased the concentration of galanin-like immunoreactivity
in the pancreatic venous effluent. Calculated pancreatic spillover (arteriovenous concentration difference x plasma flow)
increased by >15-fold (30), and the galanin-like immunoreactivity released by pancreatic nerve stimulation coeluted
with synthetic porcine galanin. As predicted, this spillover
did not influence peripheral levels of galanin. Because pancreatic galanin spillover increases to a similar degree during
stimulation of the splanchnic nerves (the sympathetic input
to the splanchnic bed; 31), the galanin appearing in the
pancreatic vein during mixed autonomic nerve stimulation
probably arises from the sympathetic nerves.
To determine if the amount of galanin released during
neural activation is sufficient to evoke an islet response, galanin was infused directly into the pancreatic artery of dogs
at a rate that reproduced the increment of pancreatic venous
galanin observed during local nerve stimulation. Although it
is difficult to estimate the amount of galanin present at its
site of action during nerve stimulation, the local islet concentration of galanin must equal or exceed that present in
the pancreatic venous effluent. Therefore, reproducing the
neurally induced increment of pancreatic venous galanin by
infusing exogenous peptide is a conservative approach to
evaluation of the potential actions of endogenous galanin.
Such local matched infusions of galanin decreased basal
insulin output by >50%, equivalent to the inhibition induced
by pancreatic nerve stimulation (30). Pancreatic somatostatin output also decreased to a degree similar to that induced by nerve stimulation. Glucagon output increased, but
the magnitude of the response was less than that induced
by nerve stimulation. Because norepinephrine is also released under these conditions and because exogenous norepinephrine has been found to stimulate glucagon output,
it seems plausible that these two neurotransmitters act in
concert to mediate the a-cell response to neural activation.
Indeed, an interaction of norepinephrine and galanin to influence basal insulin and somatostatin secretion also remains a possibility. In addition, their interaction to impair
glucose-stimulated insulin release is likely because each
individually inhibits this response. Nonetheless, the amount
of galanin released during nerve stimulation appears sufficient to account for the neurally induced inhibition of basal
insulin secretion and to contribute to the changes of basal
somatostatin and glucagon secretion.
DOES INTERFERENCE WITH GALANIN ACTION OR
RELEASE ALTER PANCREATIC RESPONSE
TO NEURAL ACTIVATION?
'This final criterion is the most critical for acceptance of galanin as a sympathetic neurotransmitter in the endocrine pancreas, but it is the most difficult to fulfill because the
1160
experimental tools to address this criterion are lacking. We
therefore discuss theoretical approaches.
The actions of galanin could be blocked by several types
of molecules including 7 ) a competitive antagonist, 2) an
antibody to the galanin receptor, and 3) an antibody to galanin itself. There has been considerable success in the design of competitive antagonists to some peptides (e.g..
vasopressin and parathyroid hormone) with the use of various fragments and analogues to define the portion of the
amino acid sequence (domain) responsible for receptor
binding (necessary but not sufficient to exert bioactivity) and
the domain that is actually responsible for the biologic effect.
These domains, once defined, may be chemically modified
to enhance receptor binding but eliminate intrinsic bioactivity. Although such structure-binding-activity studies are best
performed with in vitro screening techniques in view of the
large numbers of peptides that are necessary to test, parallel
in vivo testing of the most promising candidates is necessary
because antagonists that are potent and effective in vitro
have sometimes been found to be ineffective or even to exert
agonistic properties in vivo. There is no known antagonist of
galanin action, and the studies defining the receptor-binding
and bioactive domains are just beginning.
Antibodies to the galanin receptor could antagonize galanin action and provide the additional benefit of a longduration effect. Thus, a galanin-receptor antibody might be
useful for longer-term animal studies to elucidate galanin's
physiologic role. However, the galanin receptor has not yet
been isolated or purified for use as an antigen to generate
galanin-receptor antibodies. Furthermore, certain anti-receptor antibodies can be receptor agonists, not antagonists
(32).
A third method for blocking galanin action is immunoneutralization of the neurally released galanin with an antibody
to galanin itself. The advantage of this approach is that such
antibodies are available. The disadvantage is that immunoglobulins may be too large to easily penetrate the pancreatic vasculature and reach the site of galanin action in
high enough concentrations to neutralize the locally released
galanin. However, despite the theoretical limitations, some
studies have successfully demonstrated a role for other neuropeptides with this technique (33,34).
Finally, this criterion could be addressed by preventing
galanin release-either by prior depletion of galanin from
nerve terminals or by actual blockade of release. Pharmaceuticals capable of depleting or block~ngthe release of the
classic neurotransmitters norepinephrine and acetylcholine
have been available for some time and have proved to be
extremely valuable tools to define the physiologic roles of
these neurotransmitters. However, this approach to determining galanin's role is remote in that the mechanisms controlling its release are not yet understood. Furthermore, this
approach requires selective release of galanin, which may
not be possible if it is costored with norepinephrine. Evidence
for such colocalization in the pancreas is not yet available.
SUMMARY AND SPECULATION
We have hypothesized that galanin is a sympathetic neurotransmitter in the endocrine pancreas and acts, in addition
to norepinephrine, to mediate the influence of the local sympathetic nerves on the secretion of insulin, glucagon, and
DIABETES. VOL. 37, SEPTEMBER 1988
\\
~
INSULIN
NERVE
4
GLUCAGON
+
FIG. 2. Schema of hypothetical role for galanln as sympathetic
neurotransmitter In endocrine pancreas. It is proposed that both
galanln (G) and noreplnephrine (NE) are released during activation
of pancreatic sympathetic nerves. Galanln potently inhiblts (-) Islet
p-cell (0) and 6-cell (D) secretion. Both G and NE modestly stimulate
( + ) a-cell (A). Net result is galanin-induced inhibition of basal insulin
and somatostatin secretlon and synergistic stimulation of glucagon
secretion by NE and G. Note that lack of NE eflect on p-cell refers
specifically to basal Insulin secretion and not to glucose-stimulated
Insulln secretion.
somatostatin (Fig. 2). We have discussed the criteria that
must be met before this hypothesis can be accepted, the
evidence that galanin meets said criteria, and approaches
that rlay be of use in obtaining further evidence.
In summary, 1 ) exogenous galanin potently inhibits insulin
secretion, in various species, by a direct action on the pcell; galanin also markedly inhibits pancreatic somatostatin
secretion and, at least in vivo, modestly stimulates glucagon
release. 2) Galanin-like immunoreactivity is located in fibers
innervating the dog islet. Further studies are needed to demonstrate similar innervation in other species and to prove its
sympathetic character. 3) Preliminary reports suggest that
galanin is released during electrical activation of pancreatic
nerves in the dog and that the concentrations achieved are
high enough to restrain insulin and somatostatin release and
augment glucagon release.4) The critical demonstration that
the effects of sympathetic neural activation are reduced by
interference with galanin release or action awaits further
studies and may necessitate the development of new experimental tools.
We have evaluated a specific hypothesis related to galanin's potential role in the endocrine pancreas. However,
galanill, like many other neuropeptides, is widely distributed
in the mammalian nervous system. It is present in the hypothal,amusand other brain areas; the posterior pituitary; the
spinal cord; the nerves of the respiratory, genitourinary, and
gastrointestinal tracts; and the adrenal medulla (35). Exogenous galanin can influence pituitary hormone secretion,
food intake, neuronal transmission, and smooth muscle tone
(35). It is therefore likely that galanin has many local functions
in addition to that proposed herein. Work in other areas may
not only clarify galanin's diverse roles but may also provide
general information about, for example, the mechanism of
galaniri release and action, which may in turn accelerate the
development of the pharmacologic tools needed to further
elucidate galanin's function in the pancreas.
However, even rigorous proof that galanin is a pancreatic
sympathetic neurotransmitter would represent only the first
step toward understanding this peptide's physiologiclpathophysiologic function in the pancreas. The role of the sym-
DIABETES VOL. 37. SEPTEMBER 1988
pathetic nervous system as a whole in the regulation of
endocrine pancreatic secretion is not well understood. For
example, although it has generally been accepted that the
sympathetic nervous system plays an important role in the
endocrine pancreatic response to stress, it has only recently
been documented that any stress in fact activates pancreatic
sympathetic nerves (36). Nonetheless, it is tempting to speculate that pancreatic galanin is released during stress, restrains insulin secretion, and thereby contributes to the
integrated metabolic response.
The potent inhibitory effect of galanin on insulin secretion
may also lead to speculation on galanin's role in other states
in which p-cell function is impaired, e.g., diabetes. Whereas
the impairment of insulin secretion in insulin-dependent
diabetes mellitus results from destruction of p-cells, the
impairment in non-insulin-dependent diabetes mellitus
(NIDDM) is more complicated. Although many theories tenter on the potential interaction of insulin resistance with a
reduction of p-cell mass, the presence of a potent endogenous inhibitor of p-cell secretion in the fibers that innervate
the islets suggests that galanin could contribute to or exacerbate the impairment of insulin secretion in NIDDM. If this
were so, a galanin antagonist could be useful in the treatment
of this disease. Even if elevated levels of endogenous galanin
or enhanced islet sensitivity to galanin does not contribute
to the development of NIDDM, blocking normal "galaninergic
tone" might still be expected to improve islet function.
Clearly, there is much left to learn about the neuropeptide
galanin and its role in the endocrine pancreas. From our
perspective, however, continued effort seems warranted.
ACKNOWLEDGMENTS
We thank our colleagues at the Veteran's Administration
Medical Center and the University of Washington for critical
review of the concepts contained in the manuscript.
This study was supported in part by the Research Service
of the Veterans Administration and by USPHS Grants AM12829, AM-1 7047, and AM-07526.
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DIABETES, VOL 37, SEPTEMBER 1988