1842 Diabetes Volume 71, September 2022

Cross Talk Between Insulin and Glucagon Receptor

Signaling in the Hepatocyte
Kirk M. Habegger
Diabetes 2022;71:1842–1851 | https://doi.org/10.2337/dbi22-0002

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While the consumption of external energy (i.e., feeding) work by Burger, Brandt, and Kramer (4–6) identified the
is essential to life, this action induces a temporary dis- liver as the primary target of glucagon-stimulated hypergly-
turbance of homeostasis in an animal. A primary exam- cemia. Finally, in 1948 Sutherland and de Duve (7) pub-
ple of this effect is found in the regulation of glycemia. lished the first evidence that glucagon was produced from
In the fasted state, stored energy is released to maintain the pancreatic a-cells, closing the loop between its initial
physiological glycemic levels. Liver glycogen is liber- discovery as a pancreatic hormone and its primary target
ated to glucose, glycerol and (glucogenic) amino acids tissue, the liver.
are used to build new glucose molecules (i.e., gluconeo-
DIABETES SYMPOSIUM

Since this early codiscovery, the contrasting roles of insu-

genesis), and fatty acids are oxidized to fuel long-term lin and glucagon have been studied in detail, often with an
energetic demands. This regulation is driven primarily by
emphasis on the pathophysiological role of unopposed gluca-
the counterregulatory hormones epinephrine, growth hor-
gon action in diabetes (8–12). However, emerging preclinical
mone, cortisol, and glucagon. Conversely, feeding indu-
studies have highlighted potential insulin-sensitizing effects
ces a rapid influx of diverse nutrients, including glucose,
that disrupt homeostasis. Consistently, a host of hor-
of glucagon receptor (GCGR) agonism, both alone and in
monal and neural systems under the coordination of insu- combination with other incretin signals (i.e., glucagon-like
lin are engaged in the transition from fasting to prandial peptide 1 [GLP-1] and glucose-dependent insulinotropic
states to reduce this disruption. The ultimate action of polypeptide [GIP]) (13–20). Consistently, clinical studies of
these systems is to appropriately store the newly acquired a single-molecule GCGR/GLP-1R coagonist uncovered re-
energy and to return to the homeostatic norm. Thus, at duced glucose excursion during a mixed-meal challenge
first glance it is tempting to assume that glucagon is (21). Although individual receptor contributions to this ef-
solely antagonistic regarding the anabolic effects of insu- fect were not specifically investigated, similar findings have
lin. We have been intrigued by the role of glucagon in the also been reported for single-molecule GCGR/GLP-1R/GIPR
prandial transition and have attempted to delineate its triagonists (22). Hence, a new emphasis has emerged on
role as beneficial or inhibitory to glycemic control. The fol- understanding the mechanisms and applications of GCGR
lowing review highlights this long-known yet poorly un- agonism, especially in metabolic diseases.
derstood hormone.
GLUCAGON SECRETION
Five main cell types (i.e., a-, b-, d-, g-, and e-cells) make
THE DISCOVERY OF GLUCAGON AND INSULIN up the endocrine pancreas and are clustered into island-
In 1921 Banting and Best (1) identified insulin, a life- like structures called islets of Langerhans (23). Like insu-
saving therapeutic for millions of individuals with diabe- lin, glucagon is produced by the endocrine pancreas and se-
tes, which set a new course for our understanding of glu- creted in response to changing nutritional demands (23).
cose metabolism. Two years later Kimball and Murlin (2) Glucagon is encoded by the proglucagon gene, which also
described the second hormone, glucagon, which appeared encodes GLP-1, GLP-2, oxyntomodulin, glicentin, and the
to oppose insulin and elevate blood glucose (3). Subsequent metabolically inert cleavage products glucagon-reactive

Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and © 2022 by the American Diabetes Association. Readers may use this article
Metabolism, Department of Medicine, University of Alabama at Birmingham, as long as the work is properly cited, the use is educational and not for
Birmingham, AL profit, and the work is not altered. More information is available at https://
Corresponding author: Kirk M. Habegger, kirkhabegger@uabmc.edu www.diabetesjournals.org/journals/pages/license.

Received 11 March 2022 and accepted 19 May 2022 See accompanying articles, pp. 1834 and 1852.
diabetesjournals.org/diabetes Habegger 1843

polypeptide and major proglucagon fragment (24). Pancre- insulin, GABA, and amylin. Conversely, in healthy individuals
atic a-cells preferentially express prohormone convertase-2, GIP stimulates glucagon secretion in a glucose-dependent
which is essential in processing the proglucagon peptide to manner (i.e., during hypoglycemia) (60,61). Reciprocally,
produce the 29-amino-acid (AA) native glucagon peptide glucagon acts in a paracrine manner to increase insulin
(25–27). Glucagon is secreted from the a-cells, which make secretion through activation of both b-cell GCGR and
up 15–20% of total rodent islet cells (23) but 30–45% of GLP-1R (19).
the human islet (28). Thus, in human islets there is far Finally, glucagon secretion is directly mediated by
greater interaction (i.e., more contact) between a- and the autonomic nervous system. Via their effects on in-
b-cells than in rodent islets. These compositional differ- sulin secretion, vagal stimulation (parasympathetic) in-
ences in islet morphology suggest that glucagon plays a hibits (62), whereas splanchnic (sympathetic) stimulation
greater physiological role in humans than in rodents. increases, glucagon secretion (63–66). Together, these find-
Glucagon secretion is influenced by nutritional state and ings clearly support the idea that glucagon secretion is reg-
is best known in the context of fasting and hypoglycemia ulated in response to multiple stimuli and systems. Among

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(29,30). a-Cells preferentially express the low-Km glucose them is a potential cosecretion with insulin in the early
transporter 1 (GLUT1) (31) and ATP-sensitive potassium prandial state. Together these observations support a more
(KATP) channels (32). Glucose-dependent increases in cellu- complex role for glucagon beyond simple counterregulation
lar ATP levels close KATP channels, depolarizing the cell and of insulin in glucose homeostasis.
inhibiting glucagon secretion (33,34). Intriguingly, the reg-
ulation of glucagon secretion is not restricted to glucose GCGR TISSUE DISTRIBUTION AND HEPATIC
alone. SIGNALING
Free fatty acids (FFA) may stimulate glucagon secretion. GCGR is a member of the class B family of G protein–
However, this regulation appears to be dependent on the coupled receptors (67). Gcgr mRNA is primarily expressed
FFA characteristics and if the FFA source was exogenous or in the liver, with low-level expression in the kidney, adipose
endogenous (30). AAs, excluding the branched-chain AAs, tissue, pancreas, spleen, lymphoblasts, brain, gastrointestinal
stimulate glucagon secretion in dogs (35). This was consis- tract, and adrenal gland (68). Hepatic Gcgr expression and
tent with the observation that high-protein meals (36–38), subsequent metabolic actions are restricted to the periportal
arginine (39,40), and alanine (41,42) stimulate glucagon se- area (69), where they overlap with INSR (Insr) expression
cretion in humans. Importantly, the stimulatory effects of (70). Hepatic GCGR signaling stimulates two intracellular
these AAs on glucagon secretion are far greater than those cascades (Fig. 1), a cAMP stimulatory G protein, Gs, and a
observed during hypoglycemia (20) yet are attenuated Gq protein that signals via Ca21 (29,30). Canonical Gs sig-
(43,44) or abolished (44) in the presence of hyperglycemia. naling activates adenylate cyclase to produce cAMP. This
Reciprocally, glucagon increases ureagenesis in hepatocytes second messenger stimulates both protein kinase A (PKA)
to regulate AA metabolism (45). Insulin-resistant and stea- and Rap guanine nucleotide exchange factor 3 (RAPGEF3;
totic individuals exhibit hyperaminoacidemia, leading to also known as EPAC1). EPAC1 activation stimulates the
hyperglucagonemia and disruption of the liver–a-cell axis small GTPase Rap1 and the AMP-dependent protein ki-
in humans (45). Likewise, inhibition of hepatic GCGR sig- nase (AMPK) (71). Concomitantly, PKA phosphorylates
naling results in increased circulating AAs and a-cell hyper- the cAMP response element-binding protein (CREB) and
plasia of both endogenous mouse islets and human islet stimulates protein phosphatase 2B-dependent dephos-
transplants (46). Importantly, a-cell hyperplasia can be phorylation of the CREB-regulated transcription coactiva-
mimicked by culturing islets in high concentrations of AAs, tor 2 (Crtc2) (72). CREB/CRTC2 signaling is associated with
especially L-glutamine (46). By extension, lipid-induced dis- gluconeogenic and glycogenolytic gene expression (e.g.,
ruption of hepatic glucagon sensitivity has been postulated glucose-6-phosphatase [G6pc], phosphoenolpyruvate ki-
to contribute to impaired AA homeostasis, hyperglucagone- nase [Pck1], and peroxisome proliferator-activated recep-
mia, and eventually to type 2 diabetes (T2D) (47). tor g coactivator 1-a [Ppargc1a]) (30). GCGR-stimulated
Glucagon secretion is also regulated via endocrine/ Ca21 signaling occurs downstream of Gq activation and
paracrine factors, including insulin, amylin, zinc, GABA, is associated with hepatic glycogen phosphorylase activa-
GLP-1, GIP, and somatostatin. a-Cells express both insulin tion, bile acid homeostasis, and liver regeneration (73).
receptors (INSR) and GABA receptors (48,49). Consistently, Termination of signaling is equally important to meta-
insulin and GABA from neighboring b-cells both inhibit bolic regulation. GCGR signaling is terminated by internali-
glucagon secretion (50–52). However, work in rat islets zation of the ligand–receptor complex and occurs primarily
supports that the key inhibitory factor from b-cells may be via clathrin- and arrestin-facilitated endocytosis. Intrigu-
zinc bound to the insulin protein (53). Similarly, somato- ingly, sustained GCGR signaling has been described after
statin of the d-cells inhibits glucagon secretion (54). Only a internalization, suggesting a second wave of signaling from
minority (
20%) of mouse, rat, and human a-cells express this receptor (30). However, the biological relevance of this
GLP-1R (55,56). Thus, inhibition via GLP-1 (57–59) is intracellular signaling has yet to be fully elucidated. Intra-
likely secondary to GLP-1R–stimulated release of zinc- cellular GCGR palmitoylation and ubiquitination have been
1844 INSR and GCGR Signaling Cross Talk in Hepatocytes Diabetes Volume 71, September 2022

GCG

GCGR

Adenylate
Phospholipase β cyclase
C Gαq β ATP
Gαq γ Gαs Gαs
PIP2 γ
GDP
GTP GDP
IP3 cAMP

cAMP
cAMP
p38K Glycolysis Protein
INSP3R1 EPAC
kinase A
Ca2+

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CREB RAP1

Intrahepatic
Mitochondrial Fatty
Acid Oxidation mTORC1
Ppargc1a
Pck1
P
Gluconeogenesis G6pc REB

Glycogenolysis

Figure 1—Overview of GCGR signaling pathways in the regulation of hepatic glucose homeostasis. Figure created with BioRender.com.

observed and may also contribute to signal termination exogenous glucagon elevates glycemia (77). Moreover, ge-
(30). Intriguingly, glucagon stimulates both GCGR internal- netic Gcgr deficiency and neutralizing antibodies targeting
ization and deubiquitination, facilitating rapid recycling of glucagon are sufficient to reduce glycemia (78–80). In con-
the receptor (74). trast, the antidiabetic effects of Gcgr knockout in strepto-
zotocin (STZ)-treated mice are lost when STZ is
METABOLIC ACTIONS OF HEPATIC GCGR administered prior to Gcgr ablation (81). These rodent
SIGNALING data must be interpreted with some caution, as GCGR an-
As introduced above, the best-known actions of GCGR sig- tagonists clearly lower glycemia in individuals with T1D
naling involve its counterregulatory effect on insulin ac- (82). Together, these findings highlight the complex and
tion. In the context of glucose metabolism, GCGR signaling context-dependent relationship between glucagon and
stimulates hepatic glycogenolysis and gluconeogenesis (GNG) insulin in glucose homeostasis.
with concomitant inhibition of glycogen synthesis (29). In addition to its effects on glucose metabolism, mount-
GCGR signaling rapidly increases hepatic glycogenolysis ing evidence suggests hepatic glucagon is a potent regulator
via a signaling cascade involving the canonical cAMP–PKA of energy balance, lipid homeostasis, and fat mass mobiliza-
pathway. This signaling activates glycogen phosphorylase tion (30). In the context of energy balance, glucagon both
kinase and subsequent activation of glycogen phosphory- stimulates energy expenditure and suppresses food intake,
lase. GCGR signaling (via PKA) likewise inhibits glycogen as highlighted by the negative energy balance observed in
synthase, preventing hepatic glycogen synthesis (75). glucagonoma patients (83). This stimulation of energy ex-
GCGR regulation of hepatic GNG occurs via both transcrip- penditure and thermogenesis is conserved across a range of
tional induction and allosteric modulation of GNG enzymes. species (29). However, the conservation of this system in
PKA-dependent phosphorylation of phosphofructokinase 2 humans is still controversial, with reports observing both in-
and pyruvate kinase shifts metabolic flux from glycolysis to creased and unchanged energy expenditure (84,85). Energy
GNG. GCGR signaling stimulates CREBSer133 phosphorylation expenditure regulation in mice is dependent upon hepatic
coupled with dephosphorylation and nuclear translocation of GCGR signaling and is mechanistically associated with he-
its coactivator, Creb-regulated transcription coactivator 2 patic FXR activity and endocrine FGF21 action (14,15,86).
(Crtc2). These actions not only stimulate the induction of Glucose futile cycling may also contribute to the upregu-
target GNG genes G6pc, Pck1, Ppargc1a and hepatocyte nu- lation of energy expenditure following GCGR agonism
clear factor 4 (Hnf4a) but also regulate GNG-associated tran- (87,88). Intriguingly, glucagon administration also de-
scription factors FOXO1 and PGC-1-a via modulation of creases hunger and food intake in both rats (89) and hu-
their acetylation states (30). Additionally, GCGR-stimulated man subjects (90,91). Consistently, GCGR agonism in
Ca21 signaling activates glycogenolysis and GNG via p38 diet-induced obese mice suppressed food intake; how-
kinase (76). Consistent with these signaling events, ever, this effect was preserved in mice lacking hepatic
diabetesjournals.org/diabetes Habegger 1845

Gcgr expression, suggesting that the liver is not the tis- INSR then phosphorylates intracellular substrates, including
sue of origin for this regulation (14). members of the insulin/insulin-like growth factor 1 receptor
Glucagon also regulates multiple components of lipid me- substrate (IRS) protein family, Gab-1, DOK1, Cbl, SH2B2
tabolism (29). Gcgr is expressed by rodent adipocytes (92). (APS), SHP2, and isoforms of Shc (104). Canonical insulin
Consistently, glucagon mediates rodent white adipose tissue regulation of hepatic glucose and lipid metabolism involves
lipolysis (93). Conversely, evidence of Gcgr expression in hu- subsequent IRS-dependent activation of phosphatidylinositol-
man adipocytes is lacking (94), as is that for glucagon- 3-kinase, 30 -phosphoinositide–dependent kinase 1 (PDK1),
induced lipolysis at physiological levels in patients (95). In and AKT/PKB (104). AKT is a central node of hepatic insulin
rodents, glucagon-mediated white adipose tissue lipolysis signaling and is crucial for both glucose and lipid metabolism.
(96,97) via hormone-sensitive lipase results in the liberation This serine/threonine kinase is activated by phosphorylation
of nonesterified fatty acids (NEFA) (98). The majority of on two residues, Thr308 and Ser473. Thr308 phosphorylation
these NEFAs are catabolized. However, in the liver, NEFAs occurs in a PDK1-dependent manner and is essential for
may be alternatively converted to ketone bodies to provide AKT kinase activity. Ser473 is phosphorylated by the rapamy-

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energy during times of glucose deficiency (99,100). Consis- cin-insensitive mTOR complex (mTORC2) and is permissive
tent with this shift to lipid energy substrates, glucagon for full kinase activity (104). Importantly, the mechanisms of
exposure inhibits hepatic lipogenesis while stimulating mTORC2 regulation remain uncertain. AKT activation leads
FA transport and oxidation (101). Inhibition of hepatic li- to subsequent phosphorylation of forkhead box–containing
pogenesis occurs via two potential mechanisms: 1) CREB- protein, O subfamily (FOXO). FOXO proteins (especially
mediated induction of insulin-induced gene 2 (Insig2) and members 1 and 6) are transcription factors that induce
sequestration of the lipogenic sterol regulatory element GNG. AKT-dependent phosphorylation triggers nuclear ex-
binding protein (SREBP) transcription factor (102) and 2) clusion and, thus, is inhibitory to this action (106).
Ca21-dependent activation of p38 kinase and subsequent Insulin also regulates hepatic Ca21 signaling. INSR acti-
inhibition of SREBP (76). GCGR agonism is also a potent vation stimulates phospholipase Cg, generating inositol-
regulator of bile acid metabolism, stimulating robust changes 1,4,5-triphosphate (InsP3). Increased InsP3 levels stimu-
in the expression of bile acid enzymes and the composition late InsP3 ligand–gated Ca21 channels of the endoplasmic
of circulating bile acids (14). As introduced above, emerging reticulum and thus increase intracellular Ca21 levels. In-
data support that hepatic GCGR signaling is a crucial regula- creased hepatic Ca21 levels further stimulate INSR-depen-
tor of AA metabolism. GCGR agonism stimulates hepatic AA dent activation of the mitogen-activated protein kinase
uptake and urea production and subsequently induces hypoa- signaling cascade and activation of transcription factors (e.g.,
minoacidemia (103). Together these pieces of evidence point MYC, FOS, and JUN) in this mitogenic pathway (107).
to glucagon as a potent regulator of AA and lipid homeosta- Diabetes, whether type 1 (T1D) or type 2 (T2D), is de-
sis, energy balance, and fat mass mobilization. fined by hyperglycemia and is ultimately the result of in-
sufficient insulin action. In the case of T1D, this deficiency
INSULIN, INSULIN ACTION, AND HEPATIC INSR is caused by destruction of the pancreatic b-cell and there-
SIGNALING fore a lack of the insulin hormone. In T2D, insulin resis-
Insulin is a powerful anabolic factor, stimulating growth tance accumulates to a point where b-cell compensatory
and energy accrual throughout the organism. This pleio- hypersecretion is insufficient to counteract the resistance
tropic hormone is essential to glucose metabolism and (108). In the liver, this insufficiency is manifested as a fail-
crucial to lipid and AA metabolism. Insulin action in the ure to suppress hepatic glucose output (i.e., GNG and gly-
liver stimulates lipogenesis and glycogen synthesis while cogenolysis). Intriguingly, in T2D this resistance is often
concomitantly inhibiting glycogenolysis, GNG, and liver incomplete, resulting in a preservation of insulin-stimu-
fatty acid oxidation (104). lated lipogenesis (108). Consistent with its counterregula-
Insulin signals via the INSR, a member of the receptor tory role, both fasting and postprandial plasma glucagon
tyrosine kinase family, and, to a lesser extent, the insulin- levels are elevated in diabetes (109). However, these obser-
like growth factor 1 receptor. These receptors are endoge- vations have been made in individuals with established
nously inhibited by the recently discovered Inceptor pro- cases of diabetes, and thus the causality of hyperglucagone-
tein in mouse b-cells (105). Insr is expressed in the central mia is difficult to assign.
nervous system and a wide range of peripheral tissues. Un-
like Gcgr, hepatic Insr expression is found in both peripor- OVERLAPPING HEPATIC GCGR AND INSR
tal and perivenous zones (70). The role of this essential ACTIONS
hormone and INSR signaling (summarized in Fig. 2) has As a counterregulatory hormone with a role in maintain-
been extensively covered, including the following review ing fasting blood glucose, it is tempting to assume that
(104). Therefore, this Perspective will focus on hepatic sig- glucagon opposes all actions of insulin. Consistent with
naling and biological functions arising from INSR activation. this hypothesis, circulating glucagon levels are elevated in
INSR signaling is initiated when insulin binds to the recep- all known instances of T1D or T2D, including animal
tor, derepressing the receptor’s intrinsic kinase activity. models of the disease (77). Likewise, preclinical GCGR
1846 INSR and GCGR Signaling Cross Talk in Hepatocytes Diabetes Volume 71, September 2022

Insulin

Shc IRS
PIP2 PIP3
Ras
PLCγ

PDK1 mTORC2
Raf
Ca2+
PI3K
p308 p473
MEK
Akt

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MAPK Glycogenolysis
Signaling FOXO
Gluconeogenesis
Lipogenesis
Cell Proliferation Glycogen Synthesis

Figure 2—Overview of INSR signaling pathways in the regulation of hepatic glucose homeostasis. MAPK, mitogen-activated protein ki-
nase; PI3K, phosphatidylinositol 3-kinase; PLCg, phospholipase Cg. Figure created with BioRender.com.

ablation or pharmacological GCGR inhibition (including INSR and GCGR signaling also converge at the hepato-
neutralizing antibodies against glucagon) in individuals cyte. Our group described the unexpected enhancement
with diabetes is sufficient to reduce glycemia and HbA1c. of insulin action in db/db mice following chronic (7-day)
However, many of these strategies have been slowed due treatment with the long-acting GCGR agonist IUB288
to adverse effects on liver transaminases, liver fat, and (86). This initial observation was followed by more de-
dyslipidemia (30). tailed investigation of acute (i.e., 60-min) GCGR agonism
Conversely, the increased concentrations and action of and its beneficial effect on insulin sensitivity (114). This
glucagon in the fasting state are well suited to potentiate work identified enhanced insulin-dependent signaling
subsequent insulin-mediated glucose control. To this point, in the phosphorylation of AKTSer473 in mice treated with
glucagon acts in a paracrine manner to increase insulin se- IUB288 60 min prior to insulin and was exclusive of
cretion through activation of both b-cell GCGR and GLP- PDK1-dependent phosphorylation (Thr308) (114). This
1R (19). Likewise, postprandial elevations of glucagon and single, acute IUB288 treatment increased insulin sensitiv-
GLP-1 contribute to the improved postprandial glucose ity, as defined by increased glucose infusion rate and im-
profile observed in Roux-en-Y gastric bypass patients (110) proved insulin-stimulated suppression of hepatic glucose
and rodent models of this powerful intervention (111). output during hyperinsulinemic-euglycemic clamps (114).
Importantly, these physiological conditions are all charac- These observations suggest GCGR and INSR signaling
terized by their heightened insulin sensitivity. Regarding intersect via a TORC2-dependent phosphorylation of
glucagon enhancement of insulin action, the use of the bi- AKTSer473. Our observation was quickly followed by work
onic pancreas (glucagon and insulin) must be mentioned by Besse-Patin et al. (115). This elegant study confirmed
(112). This technology was hypothesized to prevent life- glucagon-enhanced AKTSer473 phosphorylation and identi-
threatening hypoglycemic episodes in people with diabe- fied glucagon-dependent induction of Ppargc1a as a tran-
tes. Beyond reducing hypoglycemic episodes, the bihormo- scriptional regulator of relative levels of hepatocyte
nal (glucagon and insulin) pump reduced average glycemia IRS1:IRS2 ratios (115). This shift toward IRS2 favors insu-
while requiring a similar total daily insulin dose in adoles- lin-dependent suppression of hepatic glucose output (115)
cents (112). Likewise, 13-h glucagon infusion increased and is consistent with our observations in hyperinsuline-
both glucose appearance and disappearance in patients, mic-euglycemic clamps (114). Congruous with our study
suggesting that its regulation of human glucose metabo- and interpretation, Besse-Patin et al. concluded that gluca-
lism is not restricted to increasing hepatic glucose output gon (via PGC-1-a) primes the liver for subsequent insu-
(113). Together, these observations support the hypothe- lin action.
sis that glucagon, released during fasting and the prandial However, an importation caveat to these studies is that
response, acts to prime metabolic tissues for the subse- the observations of Besse-Patin et al. were made 4 h after
quent nutrient challenge of feeding. Moreover, it positions glucagon treatment. Subsequent observations in cultured
cooperative actions of glucagon and insulin as crucial to hepatocytes suggest GCGR signaling transiently stimulates
this physiology. protein synthesis via an mTORC1-dependent action (116).
diabetesjournals.org/diabetes Habegger 1847

This effect was also observed to be convergent with insulin blocking antibody REGN1193 was sufficient to normalize
signaling and dependent on EPAC activity (116). Addition- blood glucose and b-hydroxybutyrate levels in these mice
ally, work by Perry et al. (117) identified enhanced glucose (118). Subsequent clinical investigation uncovered reduc-
tolerance and insulin sensitivity in rats infused with gluca- tions in fasting plasma glucose and HbA1c in REGN1193-
gon for 3.5 weeks. This work supported a role for inositol treated T2D patients (119). Similar benefits in mice have
triphosphate receptor 1 (INSP3R1)-mediated calcium sig- been reported for the monoclonal antibody and competi-
naling downstream of GCGR activation. In this model, the tive GCGR antagonist REMD 2.59 (120). Moreover, GCGR
benefits of GCGR signaling on glucose metabolism are re- antagonism, when combined with GLP-1R agonism, stimu-
lated to hepatic mitochondrial oxidation (117). In sum- lates cell regeneration in STZ-treated mice (121). However,
mary, emerging data support a beneficial role for GCGR enthusiasm for GCGR antagonism is offset by observa-
signaling in hepatic insulin glucose metabolism. While the tions of dose-dependent increases in hepatic aminotrans-
precise mechanisms have yet to be elucidated, data support ferases (122) and induction of profound dyslipidemia
roles for mTORC1, mTORC2, and PCG1a-IRS2 as potential (79). Conversely, the benefits of GCGR agonism on energy

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points for cross talk with hepatic insulin signaling (Fig. 3). expenditure, hepatic steatosis, and lipid homeostasis are of
INSP3R1 may also represent a mechanism by which he- great therapeutic interest. Intriguingly, coupling of the anti-
patic GCGR signaling benefits glucose metabolism sec- diabetic properties of GLP-1R agonism with GCGR agonism
ondary to its regulation of mitochondrial oxidation. profoundly enhances the therapeutic action of both recep-
tors (17,18,123). The mechanisms underlying these benefits
GCGR AND INSR CROSS TALK IN EMERGING are still the focus of intense investigation. GLP-1/GCGR dual
THERAPEUTICS agonism drives weight loss in a synergistic manner. This
As introduced above, GCGR ablation/antagonism is benefi- weight loss is likely due to GCGR stimulation of energy ex-
cial for glucose metabolism (78,79). Of note, treating mice penditure and GLP-1R inhibition of gastric emptying (124),
with the INSR antagonist S961 induces severe insulin re- the latter also contributing to slower glucose uptake into the
sistance, hyperglycemia, and ketonemia, yet the GCGR- circulation. It is also likely that these compounds increase

Insulin
GCG

IRS
PIP2 PIP3
mTORC2
PDPK1
?
p110

p85
P P
PI3K Akt

Gluconeogenesis
Glycogenolysis

IRS1
PGC-1-alpha
Irs2 P
CREB
IRS2
Direct Regulation
Indirect Regulation
Ppargc1a P
CREB

Figure 3—Potential and reported cross talk in hepatic glucagon (GCG) and INSR signaling. PI3K, phosphatidylinositol 3-kinase. Figure
created with BioRender.com.
1848 INSR and GCGR Signaling Cross Talk in Hepatocytes Diabetes Volume 71, September 2022

glucose-stimulated insulin secretion via activation of GCGR 10. Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time
and GLP-1R at the b-cell while concomitantly enhancing in- course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes
sulin action via GCGR agonism at the liver. Based on this Care 2008;31:1403–1404
11. Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and
hypothesis, coupling GCGR agonism with other known in-
postprandial hyperglycemia in type 2 diabetes and therapeutic implications.
sulin secretagogues should have similar effects. This hy-
Endocr Rev 2007;28:253–283
pothesis is supported by the observation in mice that 12. Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas:
tolbutamide enhanced glucagon-stimulated decreases in gly- 35 years of research but the enigma remains. Endocr Rev 2007;28:84–116
cemia (19). It should be noted that while GLP-1/GCGR dual 13. Kim T, Holleman CL, Nason S, et al. Hepatic glucagon receptor
agonism drives weight loss and improves glucose homeosta- signaling enhances insulin-stimulated glucose disposal in rodents. Diabetes
sis in both preclinical and clinical studies (21,125), clinical 2018;67:2157–2166
application of these molecules has targeted treatment of 14. Kim T, Nason S, Holleman C, et al. Glucagon receptor signaling regulates
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ease (e.g., cotadutide) (125). factor 21. Diabetes 2018;67:1773–1782

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Acknowledgments. I thank Dr. Teayoun Kim, Dr. Shelly Nason, and peptide triagonist corrects obesity and diabetes in rodents. Nat Med
Jessica Antipenko (Comprehensive Diabetes Center and Division of Endocri- 2015;21:27–36
nology, Diabetes, and Metabolism, Department of Medicine, University of Ala- 19. Capozzi MEWJ, Wait JB, Koech J, et al. Glucagon lowers glycemia when
bama at Birmingham, Birmingham, AL) for helpful discussion. b-cells are active. JCI Insight 2019;5:e129954
20. Finan B, Capozzi ME, Campbell JE. Repositioning glucagon action in the
Funding. The project described in this work was supported by National In-
physiology and pharmacology of diabetes. Diabetes 2020;69:532–541
stitutes of Health grant 1R01DK112934 (K.M.H.).
21. Ambery P, Parker VE, Stumvoll M, et al. MEDI0382, a GLP-1 and
Duality of Interest. No potential conflicts of interest relevant to this
glucagon receptor dual agonist, in obese or overweight patients with type 2
article were reported.
diabetes: a randomised, controlled, double-blind, ascending dose and phase
Prior Presentation. Parts of this work were presented at the 82nd
2a study. Lancet 2018;391:2607–2618
Scientific Sessions of the American Diabetes Association, New Orleans, LA,
22. Bossart M, Wagner M, Elvert R, et al. Effects on weight loss and
3–7 June 2022.
glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/
GCG receptor triagonist. Cell Metab 2022;34:59–74.e10
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