Am J Physiol Endocrinol Metab 295: E751–E761, 2008.

First published July 22, 2008; doi:10.1152/ajpendo.90295.2008. Review

Insulin as a physiological modulator of glucagon secretion

Pritpal Bansal1 and Qinghua Wang1,2,3
1
Department of Physiology, 2Department of Medicine, and 3Division of Endocrinology and Metabolism, Li Ka-Shing
Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
Submitted 15 March 2008; accepted in final form 15 July 2008

Bansal P, Wang Q. Insulin as a physiological modulator of glucagon secretion.

Am J Physiol Endocrinol Metab 295: E751–E761, 2008. First published July 22,
2008; doi:10.1152/ajpendo.90295.2008.—Glucose homeostasis is regulated pri-
marily by the opposing actions of insulin and glucagon, hormones that are secreted
by pancreatic islets from ␤-cells and ␣-cells, respectively. Insulin secretion is
increased in response to elevated blood glucose to maintain normoglycemia by
stimulating glucose transport in muscle and adipocytes and reducing glucose
production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion
is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting
hepatic glucose production and ultimately raising blood glucose levels. Diabetic
hyperglycemia occurs as the result of insufficient insulin secretion from the ␤-cells
and/or lack of insulin action due to peripheral insulin resistance. Remarkably,
excessive secretion of glucagon from the ␣-cells is also a major contributor to the
development of diabetic hyperglycemia. Insulin is a physiological suppressor of
glucagon secretion; however, at the cellular and molecular levels, how intraislet
insulin exerts its suppressive effect on the ␣-cells is not very clear. Although the
inhibitory effect of insulin on glucagon gene expression is an important means to
regulate glucagon secretion, recent studies suggest that the underlying mechanisms
of the intraislet insulin on suppression of glucagon secretion involve the modulation
of KATP channel activity and the activation of the GABA-GABAA receptor system.
Nevertheless, regulation of glucagon secretion is multifactorial and yet to be fully
understood.
diabetes; hyperglycemia; ␥-aminobutyric acid; adenosine 5⬘-triphosphate-sensitive
K⫹ channel

INSULIN AND GLUCAGON ARE PRIMARY ENDOCRINE FACTORS respon-
sible for regulating the blood glucose levels (146). During
periods of hyperglycemia (i.e., after meal ingestion), whereas
insulin secretion is increased, glucagon secretion is reduced.
Insulin promotes anabolism through facilitation of glucose
transport in skeletal muscle and adipose tissue and stimulation
of hepatic glycogen synthesis (41, 124). Glucagon protects the
body against hypoglycemia to maintain an adequate level of
blood glucose. This procedure is important particularly during
fasting, because glucose is the primary fuel source of the
central nervous system (146).
Glucagon Production and Secretion
Glucagon is a 29-amino acid peptide synthesized and se-
creted by pancreatic ␣-cells, which comprise ⬃20 –30% of all
islet cells (7, 23). The human proglucagon gene is a 9.4-kb
sequence located on chromosome 2 (85), and translation of this
gene in the pancreas, gut, and brain creates a precursor peptide
(85) that is differentially processed by a set of prohormone
covertases, depending on the cell type (70). In the ␣-cell,
proglucagon is cleaved into glucagon by prohormone conver-
tase 2 (120).
Address for reprint requests and other correspondence: Q. Wang, Dept. of
Medicine, Univ. of Toronto, St. Michael’s Hospital, 30 Bond St., Rm. 7005,
Toronto, ON, Canada M5B 1W8 (e-mail: qinghua.wang@utoronto.ca).
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Both the insulin-producing ␤-cells and the glucagon-secret-
ing ␣-cells are electrically excitable; however, each cell type
features a unique set of ion channels (72, 89). Unlike in ␤-cells,
␣-cells are electrically silent in the presence of insulin-stimu-
latory glucose concentrations (56). Regulation of glucagon
secretion is mediated by electrical machinery comprised of ion
channels and is modulated by glucose and paracrine factors
(Fig. 1). The ␣-cells contain a large tetrodotoxin (TTX)-
sensitive Na⫹ current that inactivates at intermediate voltages
(56, 119) and are equipped with two types, low-voltage acti-
vated (T-type) (56, 88) and high-voltage activated (L- or
N-type) (11, 56, 88, 89, 95, 104, 156), of voltage-gated Ca2⫹
channels. T-type Ca2⫹ channels are partly responsible for
initiation of the depolarization cascade that is required to elicit
exocytosis (56, 72). Activated by the mild depolarization
caused by activation of the T-type Ca2⫹ channel, the TTX-
sensitive Na⫹ channel continues the depolarization cascade
(56) to trigger the influx of Ca2⫹ ions via either the L-type (56)
or N-type Ca2⫹ channel (55, 59, 95, 104), although in some
cases blockade of the L-type Ca2⫹ channel has no effect on
␣-cell secretion (55, 95, 104). In comparison, pancreatic
␤-cells also express TTX-sensitive Na⫹ channels (20, 37, 54,
149), but they are half-maximally inactivated at a more nega-
tive voltage (Vh ⫽ ⫺100 mV) (54, 89) compared with TTX-
sensitive Na⫹ channels in ␣-cells (Vh ⫽ ⫺47 mV) (56, 89).
Mouse ␤-cells lack low-voltage-activated Ca2⫹ channels (89) and
possess only L-, P/Q-, N-, and R-type Ca2⫹ channels (149),
E751
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E752 INSULIN ACTION ON ␣-CELL SECRETION

Fig. 1. Electrical machinery of glucagon secretion in mouse ␣-cells. Glucagon secretion requires the initiation of a full depolarization cascade, which begins
when T-type Ca2⫹ channels are activated and depolarize the cell to an intermediate membrane potential. The tetrodotoxin (TTX)-sensitive Na⫹ channels then
open and allow an influx of Na⫹ ions to further depolarize the ␣-cell, leading to activation of the L- or N-type Ca2⫹ channels and generation of sustained Ca2⫹
influx that triggers the glucagon granule exocytosis. The cell membrane is repolarized by the opening of voltage-gated delayed rectifier K⫹ channels (KDR), and
the depolarization cascade recurs (56, 95). The ␣-cell ATP-sensitive K⫹ (KATP) channel activity within a “narrow window” is critical for allowing the operation
of this machinery; at low glucose concentrations, a subpopulation of the total number of KATP channels present on the ␣-cell is open and sets the membrane
potential to ⫺60 mV, causing activation of the T-type Ca2⫹ channels and subsequent depolarization cascades (56, 95). An elevation in glucose concentration
and a rise in the intracellular ATP/ADP ratio results in a closure of the KATP channels (56, 61, 95) that depolarizes the ␣-cell membrane potential beyond the
narrow window, causing voltage inactivation of ion channels involved in the depolarization cascade. Of note, in the rat ␣-cells the ATP/ADP ratio does not
increase in high glucose conditions (35), whereas in isolated ␣-cells glucose-induced closure of KATP channels stimulates glucagon release (42, 104). Therefore,
during hyperglycemia the paracrine modulators (i.e., insulin, Zn2⫹, and GABA) appear to be predominant in suppressing glucagon secretion presumably through
either direct interference of the KATP channel activity (42, 61, 75, 87, 132) or the ␣-cell membrane potential (118, 153, 157). [Ca2⫹]i, intracellular free Ca2⫹
concentration.

whereas a recent study using human ␤-cells found that they
lack N- or R-type Ca2⫹ channels and express the T-type
isoform (20). Rat ␤-cells express T- and L-type Ca2⫹
channels (6).
Both ␣-cells and ␤-cells possess ATP-sensitive K⫹ (KATP)
channels, which are weakly inwardly rectifying K⫹ channels
that are gated by the intracellular levels of adenosine triphos-
phate (ATP) (121). The KATP channels set the resting mem-
brane potential of the cell (17, 56, 72) and thus link the
metabolic state of a cell to its electrophysiological activity. In
the ␤-cells, a postprandially increased blood glucose concen-
tration enhances glucose metabolism (i.e., increases the
[ATP]i) (137). As a result, the KATP channels close, leading to
membrane depolarization and subsequent activation of voltage-
gated Ca2⫹ channels (137). The increased Ca2⫹ entry triggers
insulin release (137). Both the ␣-cell and ␤-cell KATP channels
are comprised of the SUR1 (sulphonylurea receptor) (138) and
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Kir6.2 (pore-forming) subunits (17, 138) yet were thought to
be operated differently in the ␣-cells (61). Interestingly, it has
been demonstrated by Olsen et al. (104) that the glucagon
secretion pathway in isolated rat ␣-cells mimics the stimulus-
secretion mechanism in ␤-cells. In these studies the authors
found that prolonged treatment of 20 mM glucose causes
closure of KATP channels and stimulates glucagon exocytosis
(104). This effect is glycolysis dependent and mimicked by
treatment with the KATP channel blocker tolbutamide (104).
Similar results were obtained by Franklin et al. (42). Although
one must be cautious when interpreting results from experi-
ments on isolated ␣-cells because they are removed from any
potential paracrine regulation from neighboring ␤-cells or
somatostatin-secreting ␦-cells, these findings suggest that glu-
cose metabolism and increased ATP production in ␣-cells
leads to KATP channel closure, ␣-cell membrane depolariza-
tion, and glucagon secretion (104). However, a biphasic effect
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INSULIN ACTION ON ␣-CELL SECRETION
of KATP channel activity on glucagon secretion has recently
been demonstrated in isolated mouse islets, because low doses
of tolbutamide stimulate glucagon secretion (95) while inhib-
iting glucagon secretion at high concentrations (61, 95). These
findings suggest that a certain degree (i.e., narrow window) of
␣-cell KATP channel activity sets the ␣-cell membrane poten-
tial within a range that is critical for the operation of the
machinery of glucagon secretion (Fig. 1). Nevertheless, the
effects of modulating ␣-cell KATP channels are complex and
yet to be fully understood. It is clear that the ␣-cell must be
subject to a regulatory mechanism other than the direct action
of glucose (i.e., paracrine or intraislet) to ensure that glucagon
secretion is inhibited during hyperglycemia.
Physiological Role of Glucagon
Glucagon exerts a variety of biological actions via the
activation of the glucagon receptor, which is a member of a
subfamily of G protein-coupled receptors. Glucagon receptors
are present in the islet ␤-cells and a wide array of tissues,
including the liver, kidney, adipose tissue, brain, adrenal gland,
duodenum, and heart (24). Glucagon has been shown to mod-
ulate heart muscle contractility (108), ghrelin secretion (5), and
gastrointestinal motility (102), among other actions (Table 1).
Most importantly, glucagon protects against hypoglycemia by
stimulating net hepatic glucose production through promotion
of glycogenolysis and gluconeogenesis and simultaneous inhi-
bition of glycolysis and glycogenolysis (70, 146).
Generation of mouse models featuring a whole body knock-
out of the glucagon receptor gene (Gcgr⫺/⫺) has advanced our
understanding of glucagon signaling and its roles in the regu-
lation of glucose homeostasis. For instance, Gcgr⫺/⫺ mice
display reduced fasting blood glucose levels and improved
glucose tolerance compared with the wild-type mice (50, 106).
Interestingly, despite lacking glucagon action, these mice still
retain their counterregulatory capacity since their glucose lev-
Table 1. Effects of glucagon signaling in various organs
Receptor
Location Effect
Liver Stimulates glycogenolysis and glyconeogenesis
Inhibits glycolysis and glycogenesis
Adrenal gland Inhibits ACTH-stimulated cortisol production
Kidney Stimulates bicarbonate secretion
Reduces urinary acidification
Increases glomerular mesangial cell proliferation
Promotes natriuresis
Stimulates K⫹ excretion
Increases glomerular filtration rate
Adipose tissue Stimulates brown fat thermogenesis
Stimulates brown fat cell growth
Duodenum Inhibits gastrointestinal motility
Promotes relaxation of Sphincter of Oddi
Stomach Stimulates ghrelin secretion
Heart Increases heart rate and myocardial contractility
and improves atrioventricular conduction
Brain Suppresses ghrelin secretion
Stimulates somatostatin release from
hypothalamus
Stimulates neuronal ketone metabolism
Suppresses feeding
Stimulates sympathetic nervous activity
␤-Cell Promotes glucose-stimulated insulin secretion
␣-Cell Stimulates ␣-cell exocytosis
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E753
els could be restored to the basal levels within 60 min during
hypoglycemia induced by insulin injection (50). The clear
counterregulatory mechanism functioning in the lack of gluca-
gon action has yet to be determined; however, a remarkable
increase in basal cAMP signaling in Gcgr⫺/⫺ liver and en-
hanced responsiveness to epinephrine in the Gcgr⫺/⫺ hepato-
cytes and white adipose tissues might be, in part, responsible
for this compensation (50). The presence of marked ␣-cell
hyperplasia in Gcgr⫺/⫺ islets also suggests that glucagon
signaling is required for the preservation of normal islet cell
growth and function (50, 131). These islets also exhibit im-
paired insulin secretion when treated with insulin secreto-
gogues such as arginine and carbachol, indicating that loss of
glucagon signaling may impact the insulin secretion pathway
(131). Interestingly, whole body insulin sensitivity in Gcgr⫺/⫺
mice was enhanced as indicated by hyperinsulinemic euglyce-
mic clamp studies (131), which may represent a compensatory
mechanism for a reduction in ␤-cell function. Furthermore, one
such compensatory pathway could be the elevation of gluca-
gon-like peptide 1 (GLP-1) signaling as a consequence of
increased production of the hormone by the ␣-cells in the face
of whole body glucagon resistance (31, 50). GLP-1 is an
insulinotropic hormone that exerts a variety of biological
actions in mammals, including simulation of insulin secretion,
promotion of ␤-cell growth, improvement of peripheral insulin
sensitivity, and moderation of body weight gain (39). It is thus
not surprising that the elevated levels of GLP-1 may explain
why Gcgr⫺/⫺ mice are protected against streptozotocin-in-
duced ␤-cell destruction and high-fat diet-induced obesity (31).
However, it is not clear whether the improved action of insulin
on glucose clearance in Gcgr⫺/⫺ mice is a result of direct
glucagon action or indirect GLP-1 action on the insulin-
sensitive tissues. It is important to note that the remarkable
elevation of glucagon levels in the Gcgr⫺/⫺ mice might have
further facilitated the GLP-1 signaling, because glucagon can,
although with reduced affinity and efficacy, bind and activate
the GLP-1 receptor (32).
Hyperglucagonemia Causes Diabetic Hyperglycemia
Ref. No.
Hyperglucagonemia has been established as a major contrib-
70 utor to the development of diabetic hyperglycemia (128, 143).
70
98
A recent study using mice that were administered glucagon via
101 osmotic minipump for 28 days showed that chronic hyperglu-
34 cagonemia caused elevated blood glucose levels, impaired
90 glucose tolerance, and glomerular abnormalities (91), symp-
80
3
toms that are representative of early-stage type 2 diabetes.
2 Humans with type 2 diabetes have day-long plasma glucagon
15 concentrations that are higher than normal (116), and this
14 hyperglucagonemia causes inappropriate elevation of hepatic
102 glucose output due to enhanced gluconeogenesis (48) and
26
73 glycogenolysis (48, 127). Interestingly, clinical studies have
108 demonstrated that challenge with glucagon results only in a
transient and small rise in the glucose and insulin levels of
5 healthy individuals (117). However, in insulin-withdrawn dia-
129
betes patients, the glycemic response to hyperglucagonemia is
76 five to 15 times greater than in nondiabetic controls (128).
67 These findings suggest that the action of glucagon is diabeto-
83 genic only under the conditions of insulin deficiency (117, 128,
66 143). Studies in human subjects with type 1 diabetes, a disease
94
characterized by insufficient insulin production due to autoim-
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E754 INSULIN ACTION ON ␣-CELL SECRETION
mune destruction of the ␤-cells, have demonstrated that hyper-
glucagonemia could develop even after an oral glucose chal-
lenge (1, 145). However, administration of exogenous insulin
in these patients is able to suppress excessive glucagon secre-
tion induced by hyperglycemia (136) or other stimuli such as
arginine (51). Therefore, the insulin action is essential to exert
the suppressive effect of glucose on ␣-cells since, in its
absence, glucose is unable to suppress glucagon release in vivo
(58, 64). These studies provide an explanation underlying the
observation of unsuppressed glucagon secretion in diabetes
despite the presence of hyperglycemia, presumably due to
relatively insufficient insulin levels in the internal environment
of the islet or as a result of ␣-cell insulin resistance (68,
91, 141).
Intraislet Insulin Action on Glucagon Secretion
Actions of insulin are initiated by binding of the hormone to
its receptor at the cell surface in insulin-responsive tissues,
which activates a signaling complex through recruitment of
adaptor molecules, including the insulin receptor substrate
family. Upon tyrosine phosphorylation, these proteins interact
with signaling molecules through their SH2 domains, which
results in the activation of diverse signaling pathways, includ-
ing phosphatidylinositol (PI) 3-kinase/Akt signaling and
MAPK activation. These pathways act in a coordinated manner
to regulate glucose transport, protein and lipid synthesis, and
mitogenic responses (12).
Within the islets, the ␣-cells are major targets of insulin
action. Studies on islet microvasculature have suggested that
the ␣-cells lie downstream from the ␤-cells and are therefore
presumably bathed by high concentrations of insulin (18). It is
thought that the islet is arranged such that a core of ␤-cells is
surrounded by a thin layer of ␣- and ␦-cells (7, 18, 25, 84, 105).
The directionality of microvascular perfusion within the islet
has been investigated in perfused rat (125), dog (134), rhesus
monkey (135), and human (133) pancreas by infusing insulin-
neutralizing antibodies through the arterial and venous systems
of the organ, representing anterograde and retrograde perfu-
sion, respectively. The perfusate was then analyzed for pan-
creatic hormone secretions, using radioimmunoassays to deter-
mine the directional effects of abolishing insulin signaling on
␣- and ␦-cell secretion. These “passive immunization” exper-
iments demonstrated a ␤ 3 ␣ 3 ␦ directionality of islet blood
flow and strongly suggested that intraislet insulin regulates
hormone secretion from ␣-cells.
Consistent with an important role for insulin in the ␣-cell,
insulin receptor and the insulin-signaling molecules are ex-
pressed highly in pancreatic ␣-cells (13, 71, 77, 107, 147) at
levels that are similar to those in the hepatocytes (42). The
insulin receptor plays a role in modulating ␣-cell function, as
siRNA-mediated “knockdown” of the insulin receptor abol-
ishes glucose-regulated glucagon secretion from the ␣-cells
(36). Action of insulin on suppression of glucagon secretion
has been demonstrated directly using cultured clonal glucagon-
secreting ␣-cell lines, including ␣TC6 and In-R1-G9 cells (71,
77, 157). These studies have demonstrated that insulin-induced
suppression of glucagon secretion could be blocked by the PI
3-kinase inhibitor wortmannin (71, 157) or ablation of Akt
kinase activity using dominant negative approaches (157),
suggesting that insulin-suppressed glucagon secretion is medi-
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ated by the PI 3-kinase-/Akt-dependent signaling pathway.
Although results derived from clonal cell lines may not nec-
essarily be representative of actual ␣-cell physiology, insulin
also inhibits glucagon secretion in isolated rat islets treated
with pyruvate, an intermediate of glycolysis that selectively
stimulates glucagon secretion (69). The role of intraislet insulin
in suppressing glucagon secretion from the ␣-cells has been
illustrated further in studies using isolated rat and human islets
and islet hormonal RIAs (157). In these studies, challenging
islets with 20 mM glucose results in insulin secretion associ-
ated with suppressed glucagon secretion; however, blockade of
insulin signaling by the PI 3-kinase inhibitor wortmannin pre-
vents glucose from suppressing glucagon secretion, whereas the
glucose-stimulated insulin secretion is not affected, indicating that
the insulin-signaling pathway mediates the glucose-induced glu-
cagon secretion in the islets (157). Studies in rat pancreata have
shown that glucose-induced suppression of glucagon secretion is
blocked in the presence of insulin-neutralizing antibodies (96),
further supporting the physiological role of insulin in mediating
glucose effect on the ␣-cells. These findings may provide a
mechanism underlying the well-characterized push-pull phenom-
enon between the secretion of insulin and glucagon in response to
glucose challenge (144) (Fig. 2). Thus, it is hypothesized that
defects in the intraislet insulin-signaling pathway may contribute
to the development of diabetic hyperglucagonemia and hypergly-
cemia, because ␣-cells with insulin resistance imposed by chronic
treatment with high glucose and insulin displayed reduced insulin
responsiveness, including blunted insulin-stimulated Akt phos-
phorylation and insulin-suppressed glucagon secretion in the
␣-cells (157). Therefore, it is conceivable that the postprandial
hyperglucagonemia in type 2 diabetes may be due to the loss of
intraislet postprandial suppression of glucagon secretion driven by
insulin (144). This hypothesis has recently been verified by
in vivo studies using pigs treated with or without alloxan (79,
100), a chemical that selectively destroys ␤-cells and causes
diabetic hyperglycemia. Postprandial insulin secretion induced a
suppression of glucagon secretion via inhibition of glucagon pulse
mass (100); on the contrary, the postprandial insulin-driven sup-
pression of glucagon secretion was lost in the pigs treated with
alloxan, which caused a reduction of ␤-cell mass and a deficit in
postprandial insulin secretion (100). Despite this, it has been
shown that glucose can inhibit glucagon secretion at concentra-
tions below that required to elicit insulin secretion (95, 104, 123),
indicating that glucose may directly inhibit glucagon secretion in
the ␣-cells.
Hypoglycemia is a serious acute complication in type 1
diabetic patients undergoing intensive insulin therapy (33).
Defects in glucose counterregulation have been attributed to
tonic inhibition of ␣-cell activity due to intraislet hyperinsu-
linemia (9), which prevents a decrement in intraislet insulin
during hypoglycemia that would normally act as the switch for
␣-cells to secrete glucagon (114). This “switch-off” hypothesis
has been supported by studies in rats rendered diabetic via
treatment with the ␤-cell-selective toxin streptozotocin (159)
as well as by using isolated rat and human islets (65) and a rat
model of spontaneous type 1 diabetes (161). These studies
demonstrated that cessation of exogenous insulin administra-
tion prior to induction of hypoglycemia produces a glucagon
secretory response that would otherwise be absent during
continuous insulin infusion (65, 159, 161). A clincal study in
nondiabetic humans attributed a 30% decrease in the counter-
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INSULIN ACTION ON ␣-CELL SECRETION
regulatory glucagon response to hypoglycemia after somatosta-
tin infusion was administered to abolish any decrement in
intraislet insulin during hypoglycemia (57), indicating that
there may be other mechanisms involved in triggering gluca-
gon secretion in humans. However, the specificity of the
switch-off hypothesis has become broad, since a recent study
has suggested that a decrease in the intraislet concentration of
Zn2⫹ and not insulin is the switch required to trigger glucagon
secretion during hypoglycemia in rats (160). The effects of
Zn2⫹ on ␣-cell function are discussed later in this review, but
these results highlight the importance of ␤-cell secretory prod-
ucts on ␣-cell glucagon secretion.
Intraislet Insulin Modulates ␣-Cell KATP Channels
Insulin’s action as a negative regulator of glucagon secretion
may involve diverse machineries, including modulating the
␣-cell KATP channel activity. As mentioned above, glucagon
secretion requires ␣-cell depolarization to trigger the release of
glucagon-containing granules. Conversely, hyperpolarization
of the ␣-cell as a consequence of KATP channel activation can
block glucagon secretion (61). Insulin has been shown to
activate KATP channels in hypothalamic neurons in rats (132)
and isolated mouse ␤-cells (75), resulting in membrane hyper-
polarization and cessation of electrical activity (75, 132).
Interestingly, a recent study showed that, in isolated mouse
␤-cells, glucose could directly enhance KATP channel conduc-
tance by upregulating KATP channel plasma membrane local-
ization (158). Furthermore, it has also been demonstrated that
activation of ERK2 enhanced the activity of KATP channels in
HEK-293 cells transiently transfected with the KATP channels
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E755
Fig. 2. The reciprocal response of insulin (䊐) and
glucagon (E) to changes in glucose concentration in
the perfused dog pancreas (144). Figure is reproduced
from the article by Dr. R. H. Unger (144) with
permission from the author.
through phosphorylation of the Kir6.2 subunit, leading to a
decrease in ATP sensitivity (92). It is interesting to note that
ERK2 is a component in the Ras-MAPK pathway that is
activated by insulin (139). Since the Ras-MAPK pathway is PI
3-kinase independent, it is plausible that insulin modulates
KATP channel function via PI 3-kinase-dependent and/or -in-
dependent pathways.
Treatment of isolated rat ␣-cells with insulin can also tran-
siently enhance KATP-mediated currents (42), suggesting that
insulin-mediated suppression of glucagon secretion from the
␣-cells could occur via modulation of KATP currents. Interest-
ingly, this effect is not blocked by wortmannin (42), which
suggests the potential involvement of nonclassical PI 3-kinases
in glucagon secretory competence. Studies in transgenic mice
expressing green fluorescent protein under the control of the
mouse insulin promoter, which facilitates differentiation be-
tween ␤-cells and non-␤-cells within the pancreatic islet (89),
have characterized the KATP channels in ␣-cells to be five
times more sensitive to intracellular ATP-mediated channel
inhibition than ␤-cell KATP channels, although the densities of
KATP channels found in both cell types are equal (89). In
isolated ␣-cells from mice expressing insulin promoter-green
fluorescent protein, insulin markedly reduces the sensitivity of
KATP channels to ATP in a wortmannin-sensitive fashion (87).
Interestingly, although glucose can dose-dependently modulate
the intracellular [ATP] in the ␤-cells, glucose has no effect on
(35) or increases the intracellular [ATP] less efficiently in
␣-cells compared with ␤-cells (69). Therefore, it is conceivable
that glucose-induced suppression of glucagon secretion could
occur through insulin-mediated desensitization of ␣-cell KATP
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E756 INSULIN ACTION ON ␣-CELL SECRETION
channels to ATP inhibition, increasing channel activity and
causing the ␣-cell to become hyperpolarized. It is of great
interest to further determine how insulin precisely reduces the
␣-cell KATP channel sensitivity and its downstream cascades.
Intraislet Insulin Promotes GABAergic Inhibition
of Glucagon Secretion
␥-Aminobutyric acid (GABA) is a major inhibitory neu-
rotransmitter in the mammalian central nervous system and
is synthesized from glutamic acid by glutamic acid decar-
boxylase (82). Three types of the GABA receptor (GABAR)
have been identified: type A GABAR (GABAAR), a hetero-
pentameric ligand-gated Cl⫺ channel that is antagonized by
the compound bicuculline (93); GABABR, a heterodimeric
G protein-coupled receptor (19, 28); and GABACR, which is
also a ligand-gated Cl⫺ channel; however, it is bicuculline
insensitive, homopentameric, and active at lower concentra-
tions of GABA than GABAAR (28). Activation of GABAAR
results in membrane hyperpolarization as a consequence of
an inward Cl⫺ flux (78). Although GABAergic signaling is
an essential regulatory component of neural excitability
accounting for 20 –30% of all synaptic signaling in the
mammalian brain (154), GABA also modulates the endo-
crine function of the pancreas (43, 74). Pancreatic ␤-cells
contain high concentrations of GABA (21, 46, 140) and
glutamic acid decarboxylase (45, 53). GABA is localized in
both synaptic-like microvesicles (21) and the insulin-con-
taining large dense core vesicles (22, 44) within the ␤-cells.
The functional GABAARs are expressed in both ␣-cells (63,
118) and ␤-cells (38).
The GABA-GABAAR system has been suggested to nega-
tively regulate glucagon secretion (118, 153). GABA admin-
istered to isolated mouse and rat islets, as well as to perfused
rat pancreas, can inhibit the release of glucagon (52), whereas
inhibition of the GABAAR by bicuculline (47, 118) or
SR95531 (153) prevents GABA-mediated suppression of glu-
cagon secretion from the ␣-cells but does not affect the insulin
secretion (157). However, although controversial (47), the
release of GABA from the ␤-cells does not appear to be
stimulated by glucose (130, 151, 155), or the increase in
GABA release by high glucose may be too small to detect
(118). However, the failure to detect an increase in GABA
release from the ␤-cells in response to increased glucose
concentrations does not exclude the possibility that there is an
increase in the responsiveness of GABAARs on ␣-cells. Evi-
dence supporting this idea is the finding that GABAARs can be
phosphorylated directly by Akt, the important insulin-signaling
molecule, resulting in translocation of the receptors from
intracellular pools to the cell surface (152). Furthermore, a
recent study also suggested that, at postreceptor levels, glucose
can modulate GABAAR activity through increasing cell sur-
face abundance of the GABAARs (8). Consistent with the role
of insulin in modulating GABAergic signaling in the central
nervous system (148, 150, 152), insulin enhances inhibitory
GABA currents in clonal glucagon-secreting ␣-cells and iso-
lated rat ␣-cells upon phosphorylation of the ␤-subunit of
GABAAR and plasma membrane recruitment of the GABAARs
by insulin (157). The rapid regulation of neurotransmitter
receptor numbers in the postsynaptic domain by direct receptor
phosphorylation is an important means of modulating synaptic
AJP-Endocrinol Metab • VOL
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plasticity (30, 152). Increasing cell surface abundance of
GABAARs in pancreatic ␣-cells, as a result of direct modula-
tion by glucose or indirectly by insulin, in response to in-
creased glucose concentrations may be a major mechanism
underlying glucose-induced suppression of glucagon secretion.
This conception is in accord with a recent study using a
well-designed in situ patch-clamp recording technique that
illustrates that GABA released from the ␤-cells could diffuse
across the islet interstitium to activate GABAARs in neighbor-
ing cells (153). It is interesting to note that, in vitro, high
glucose concentrations stimulate glucagon secretion from iso-
lated rat ␣-cells via the glucose-sensing pathway as used by the
␤-cells (104), further emphasizing the crucial importance of
islet paracrine signaling in the regulation of glucagon release in
vivo. The intraislet insulin pathway and these modulators
appear to constitute precise regulatory networks that operate to
regulate glucagon release and, hence, to control glucose ho-
meostasis. Given that in diabetic individuals, insulin deficiency
is associated with elevated glucagon levels, which rapidly
return to normal with insulin treatment, it is possible that
defects in this pathway may contribute to diabetic hyperglu-
cagonemia and subsequent hyperglycemia. This pathway may
also partly explain that type 1 diabetic hypoglycemia that
occurs in insulin-treated patients may be due to a lack of
suppression by endogenous insulin that may potentially render
the ␣-cells hypersensitive to the suppression induced by exog-
enous insulin (9).
Insulin Suppresses Glucagon Gene Expression
Transcriptional regulation of the glucagon gene by insulin
appears to be an important way to regulate glucagon pro-
duction and secretion. The inhibitory effects of insulin on
glucagon biosynthesis are mediated through a downregula-
ton of proglucagon gene expression (29, 109, 110) that
requires activation of PI 3-kinase and Akt (126). The insulin
response element that mediates insulin effects on glucagon
gene transcription is located in the proximal promoter re-
gion of the proglucagon gene (111), and several proteins
have been identified to act in trans with this region to
facilitate insulin-induced transcriptional alterations (49,
111, 126). Furthermore, it has recently been identified that
FoxO1, a member of the forkhead transcription factor fam-
ily, is required for the regulation of proglucagon gene
expression by insulin by direct binding of FoxO1 to a
forkhead consensus binding site in the preproglucagon gene
promoter region (99). In vitro studies in clonal glucagon-
secreting cells have demonstrated that insulin induced nu-
clear exclusion of FoxO1 and a subsequent reduction in
proglucagon gene transcription. Experiments employing di-
rect-site mutagenesis and RNA interference have also dem-
onstrated that diminishment of FoxO1 binding eliminated
transcriptional regulation by glucose or insulin, whereas
FoxO1 silencing abolished the acute regulation by insulin,
but not glucose, of glucagon secretion. (99). Therefore,
these studies further support that intraislet insulin is a key
modulator of ␣-cell function. However, this transcriptional
regulation may be more critical for long-term maintenance
of ␣-cell glucagon content instead of for short-term re-
sponses to changes in blood glucose levels.
295 • OCTOBER 2008 • www.ajpendo.org

INSULIN ACTION ON ␣-CELL SECRETION
Regulation of Glucagon Secretion is Multifactoral
Although the intraislet insulin-mediated suppression of gluca-
gon secretion plays an important role in modulating glucagon
secretion via mechanisms involving protein-protein interactions,
signal transduction, receptor translocation, and transcriptional reg-
ulation (Fig. 3), it should be noted that factors other than intraislet
insulin, such as Zn2⫹, may also influence glucagon secretion from
␣-cells. Insulin molecules are complexed with Zn2⫹ ions to
permit stable storage of insulin within large dense core vesicles
(81). Zn2⫹ is coreleased with insulin from the ␤-cells (113) and
may be an important inhibitor of glucagon secretion (42, 69).
Upon liberation, Zn2⫹ is transported into the ␣-cells via Ca2⫹
channels and Zn2⫹ transporters (62). Zn2⫹ has been shown to
inhibit pyruvate-stimulated glucagon secretion in perfused rat
pancreas (69), reduce the release of glucagon in isolated ␣-cells
when incubated in the absence of glucose (42), and inhibit
glucagon release from ␣TC6 cells as well as mouse islets at low
glucose concentrations (62). Also, a recent study in rats has found
that a decrement in intraislet Zn2⫹ is required for a normal
glucagon secretory response to hypoglycemia (160). Zn2⫹ may
Review
E757
inhibit glucagon secretion by binding directly to two histidine
residues on the SUR1 subunit (10) of the KATP channel and
enhancing their activity (42, 112), as it has been reported to
enhance KATP channel-mediated current in clonal rat ␤-cells (16);
however, studies in mouse ␣-cells have shown no effect of Zn2⫹
on KATP channels (62, 87). These findings potentially explain why
ZnCl2 has no effect on intracellular Ca2⫹ oscillations or glucagon
secretion in isolated mouse ␣-cells in the absence of glucose
(115), since mouse ␣-cells express fewer KATP channels than rat
␣-cells (11, 115).
Furthermore, there are a number of reported regulators/
modulators that may participate in the process of glucagon
secretion. Among them are sympathetic and parasympathetic
nerves (4), somatostatin (27), ghrelin (122), L-glutamate (142),
and GLP-1 (97). However, L-glutamate (40, 86) and GLP-1
(103) are also known to stimulate insulin secretion, which
suggests that, in vivo, the effects of these molecules on the
␣-cells may be indirectly caused by raising intraislet insulin
concentrations. For a thorough and up-to-date review of the
effects these substances have on ␣-cells, refer to Ref. 60.

Fig. 3. Proposed mechanisms of intraislet insulin suppression of glucagon secretion. Insulin secreted from ␤-cells acts in a paracrine manner to activate the
insulin-signaling cascade in ␣-cells. This has 3 main consequences: 1) activation of KATP channels, 2) enhancement of type A GABA receptor (GABAAR)-
mediated GABA current, and 3) inhibition of proglucagon gene transcription. First, insulin decreases the ␣-cell KATP channel sensitivity to ATP inhibition in
a phosphatidylinositol 3-kinase-dependent manner, causing an increase in the efflux of K⫹ ions from the ␣-cell and hyperpolarizing the ␣-cell membrane
potential. The resultant cessation of action potentials prevents an increase in cytosolic [Ca2⫹] and inhibits glucagon secretion. Second, activation of the insulin
receptor (IR) promotes membrane translocation of GABAAR and enhances GABA-mediated Cl⫺ influx. The ␣-cell membrane potential becomes hyperpolarized,
and glucagon secretion is suppressed. Finally, insulin inhibits proglucagon gene transcription, possibly representing a long-term mechanism for regulating ␣-cell
function. Other modulators of ␣-cell glucagon secretion, including Zn2⫹ and somatostatin, are not shown.

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Review
E758 INSULIN ACTION ON ␣-CELL SECRETION
Conclusion
As a counterregulatory hormone for insulin, glucagon plays
a critical role in maintaining glucose homeostasis. Glucagon
increases hepatic glucose output by enhancing glycogenolysis
and gluconeogenesis in the liver. In diabetic subjects, abnormal
secretion of not only insulin but also glucagon leads to hyper-
glucagonemia and altered insulin-to-glucagon ratios, which
predominantly contribute to diabetic hyperglycemia. Given
that insulin is a physiological suppressor of glucagon secretion,
understanding the precise molecular mechanism of glucagon
secretion by intraislet insulin may facilitate our effort to de-
velop strategies to combat diabetic hyperglycemia and to
prevent hypoglycemia in insulin-treated patients.
ACKNOWLEDGMENTS
We thank L. Ding, J. Zhang, and Dr. K. Chen for the credit in artwork.
GRANTS
Researchers in Dr. Wang’s laboratory are supported by grants from the
Canadian Institute for Health Research (CIHR), Canadian Diabetes Associa-
tion (CDA), and Juvenile Diabetes Research Foundation. Q. Wang was a CDA
Scholar and is presently supported by the New Investigator Program from
CIHR.
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