- -

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Received: 23 August 2022 Revised: 2 December 2022 Accepted: 30 December 2022

DOI: 10.1002/dmrr.3609

REVIEW ARTICLE

Glucagon in type 2 diabetes: Friend or foe?

Irene Caruso | Nicola Marrano | Giuseppina Biondi |

Valentina Annamaria Genchi | Rossella D'Oria | Gian Pio Sorice |
Sebastio Perrini | Angelo Cignarelli | Annalisa Natalicchio | Luigi Laviola |
Francesco Giorgino

Department of Precision and Regenerative

Medicine and Ionian Area, Section of Internal
Medicine, Endocrinology, Andrology and
Metabolic Diseases, University of Bari Aldo
Moro, Bari, Italy
Correspondence
Francesco Giorgino, Department of Precision
and Regenerative Medicine and Ionian Area,
Section of Internal Medicine, Endocrinology,
Andrology and Metabolic Diseases, University
of Bari Aldo Moro, Bari, Italy.
Email: francesco.giorgino@uniba.it
Abstract
Hyperglucagonemia is one of the ‘ominous’ eight factors underlying the pathogen-
esis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining
glucose homoeostasis by increasing hepatic glucose output to counterbalance in-
sulin action. Long neglected, the introduction of dual and triple agonists exploiting
glucagon signalling pathways has rekindled the interest in this hormone beyond its
classic effect on glycaemia. Glucagon can promote weight loss by regulating food
intake, energy expenditure, and brown and white adipose tissue functions through
mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be
further investigated. Moreover, the role of glucagon in the development of T2D
micro‐ and macro‐vascular complications is elusive. Mounting evidence suggests its
beneficial effect in non‐alcoholic fatty liver disease, while few studies postulated its
favourable role in peripheral neuropathy and retinopathy. Contrarily, glucagon re-
ceptor agonism might induce renal changes resembling diabetic nephropathy, and
data concerning glucagon actions on the cardiovascular system are conflicting. This
review aims to summarise the available findings on the role of glucagon in the
pathogenesis of T2D and its complications. Further experimental and clinical data
are warranted to better understand the implications of glucagon signalling modu-
lation with new antidiabetic drugs.

KEYWORDS
cotadutide, diabetic kidney disease, dual agonists, glucagon, NAFLD, type 2 diabetes

1 | INTRODUCTION
Glucagon is a peptide hormone mainly produced by pancreatic α‐
cells.1 This hormone is involved not only in maintaining glucose
homoeostasis and counterbalancing insulin actions but also in the
regulation of lipids and amino acids metabolism, autophagy, food
intake, body weight, and cardiovascular (CV) functions.1 Its role in
the pathogenesis of type 2 diabetes (T2D) has first been postulated
by Unger and Orci in the ‘bi‐hormonal theory’.2 To date, whether the
are implicated in the pathogenesis of T2D and its micro‐ and mac-
rovascular complications have not been extensively studied. More-
over, little is known about the effect of the commonly used
antidiabetic drugs on fasting and postprandial glucagon levels,
especially following chronic treatment.1
Neglected for several years, the recent introduction in the
therapeutic arsenal against T2D of dual and triple agonists that take
advantage of glucagon receptor (GCGR) activity has rekindled the

-
interest of the scientific community in the complex relationship be-
pleiotropic effects of glucagon, besides those on glucose metabolism, tween glucagon and T2D.

Diabetes Metab Res Rev. 2023;e3609. wileyonlinelibrary.com/journal/dmrr © 2023 John Wiley & Sons Ltd. 1 of 16
https://doi.org/10.1002/dmrr.3609

2 of 16
- CARUSO
The aim of this narrative review is to summarise the available
evidence concerning the involvement of glucagon in the multifaceted
pathogenesis of T2D, addressing β‐cell function, peripheral insulin
sensitivity, food intake regulation, micro‐ and macro‐vascular com-
plications, and the therapeutic implications thereof.
2 | THE ROLE OF GLUCAGON IN THE
PATHOGENESIS OF TYPE 2 DIABETES
2.1 | The role of glucagon in β‐cell function: A
somewhat neglected friendship
In an almost exclusively insulin‐centric vision, dysregulation of the β‐
cell functional mass has always been regarded as the key mechanistic
factor in the onset and progression of diabetes.3 However, in 1975,
Unger and Orci2 recognised that impaired glucagon secretion and α‐
cell function also contribute to the pathogenesis of T2D, proposing
the ‘bi‐hormonal theory’, which suggested the coexistence of both
relative or absolute hypoinsulinemia and relative hyperglucagonemia
in T2D patients.
2.1.1 | Physiology
In humans, α‐ and β‐cells account for ~30%–40% and ~50%–60% of
the endocrine islet cells, respectively, and are intermingled
throughout the islet.4 Under physiological conditions, α‐ and β‐cells
influence each other: while the ability of insulin, as well as of other β‐
cells secretory products (e.g. zinc, gamma‐aminobutyric acid [GABA],
serotonin), to inhibit glucagon secretion is widely recognised,5,6 the
effects of glucagon to stimulate insulin secretion is a less‐known and
somewhat paradoxical event.7 Nevertheless, the insulinotropic effect
of glucagon has been demonstrated in several studies with different
model systems, such as pig pancreatic islets,8 rat islets cells,9 and
10
human pancreatic islets. Islets with higher α‐cell content displayed
improved glucose‐stimulated insulin secretion (GSIS) compared with
islets with lower α‐cell content, a difference that could be eliminated
by the addition of exogenous glucagon.11 Similarly, the response of
isolated pancreatic β‐cells to a glucose stimulus is improved by the
presence of α‐cells or glucagon.12 Moreover, the genetic deletion of
glucagon from α‐cells,13 genetically engineered inhibition of glucagon
secretion,14 and α‐cells ablation15 impaired insulin secretion in
mouse and human islets13 and resulted in hyperglycaemia and
14,15
glucose intolerance in mice in vivo.
Glucagon may act on β‐cells through the activation of glucagon
and glucagon‐like peptide‐1 receptors (GCGRs and GLP‐1Rs,
respectively)7 on the β‐cell surface.16,17 These class B G protein‐
coupled receptors promote the generation of cyclic AMP (cAMP),
and thus the activation of the cAMP/protein kinase A (PKA)/ex-
change protein directly activated by the cAMP (EPAC) system, which
in turn potentiates GSIS.13,18 Importantly, this potentiation only oc-
curs in the presence of mildly hyperglycaemic conditions, when the β‐
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ET AL.
cell membrane is already depolarised via the glucose‐induced closure
of ATP‐sensitive K+ leak channels and the insulin secretory ma-
chinery is already in motion,7,19 whereas the activation of GCGRs and
GLP‐1Rs is unable to trigger insulin secretion on its own.18 Conse-
quently, glucagon stimulates insulin secretion in the post‐prandial
phase but not during fasting, when the counter‐regulatory and
hyperglycaemic effects of glucagon are required.
The importance of GCGRs and GLP‐1Rs in glucagon‐potentiated
GSIS has been broadly demonstrated. The genetic deletion of the
GCGRs or GLP‐1Rs from β‐cells,13,20 as well as the blockade of GLP‐
1Rs by its antagonist exendin (9–39),13,20,21 resulted in decreased
insulin secretion in response to nutrient stimulation of mouse and
human islets.13,20 Interestingly, while in healthy mice the lack of
GCGRs and GLP‐1Rs at β‐cellular level did not affect glucose toler-
ance, α‐cells‐secreted glucagon seemed to be essential to maintain
glucose tolerance during the metabolic stress induced by a high‐fat
diet, suggesting that the communication between α‐ and β‐cells is
essential for metabolic adaptation to high‐fat feeding and obesity.13
In line with this evidence, the overexpression of GCGRs in murine
pancreatic β‐cells enhanced GSIS and increased β‐cell mass and
pancreatic insulin content, protecting from high‐fat diet‐induced
impaired glucose tolerance and hyperglycaemia.22 Also, transgenic
mice overexpressing GCGRs were resistant to streptozotocin‐
induced β‐cell injury partially due to enhanced intra‐islet action of
both glucagon and insulin on β‐cell function.23
Although several studies with mouse and human islets indicated
that intra‐islet glucagon stimulated insulin release primarily by acti-
vating β‐cell GLP‐1R,13,14 only the combined blockage of both re-
ceptors significantly reduced insulin secretion.20
Thus, the available evidence highlighted a paradoxical action of
glucagon: under hyperglycaemic conditions, glucagon is able to
potentiate insulin secretion and consequently glucose lowering, while
it has also been associated with increased hepatic glucose production
concurring with hyperglycaemia. However, these two opposite ef-
fects do not occur simultaneously due to the tonic inhibition (without
full suppression) of glucagon secretion by a combination of somato-
statin, GABA and serotonin in the post‐prandial phase, keeping
glucagon levels sufficiently low to exert its paracrine effects on the β‐
cells, without increasing hepatic glucose output.7
2.1.2 | Type 2 diabetes
In T2D, both fasting and post‐prandial hyperglucagonemia may occur,
maintaining an inadequately high rate of hepatic glucose production
in the fasting state, thus contributing to hyperglycaemia.5,24 Hyper-
glucagonemia could result from the impaired regulation of α‐cell
function by β‐cells5: the loss of β‐cell functional mass in T2D may
cause decreased insulin‐mediated inhibition of glucagon secretion; in
addition, β‐cells might de‐differentiate to progenitor pluripotent cells
able to release glucagon, causing a further increase in glucagon
levels.25–27 However, the decrease in β‐cell mass in T2D might be too
small to explain the excessive glucagon secretion,28 and
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CARUSO ET AL.
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hyperglucagonemia may also result from α‐cell insulin resistance.29
Also, the impaired function of insulin‐degrading enzyme, which has
been associated with T2D in genome‐wide association and genetic
polymorphism studies, caused hyperplasia and dysregulated glucagon
30
secretion in mice α‐cells.
To date, whether hyperglucagonemia precedes β‐cell failure or
31
vice versa in T2D pathogenesis is still under debate. Jamison et al.
demonstrated that hyperglucagonemia preceded the decline in insulin
secretion and caused hyperglycaemia in chronically glucose‐infused
rats by raising glucose hepatic production and increasing the ‘basal
workload’ of β‐cells until their exhaustion. In turn, Solomon et al.32
showed that experimental hyperglycaemia acutely impaired β‐cell
function but not α‐cell glucagon secretion in normal glucose‐tolerant
subjects. In type 1 diabetes, the total loss of β‐cell function was
accompanied by complete dysregulation of glucagon secretion, while
in T2D with residual β‐cell function, hyperglucagonemia did not occur
in all patients.5 In fact, glucagon release from pure human α‐cells be-
comes affected by glucose only if α‐cells are reaggregated with β‐
33
cells. Conversely, it has been demonstrated that α‐cell mass in-
creases during the development of insulin resistance and
hyperinsulinemia and that the lack of α‐cell mass expansion and
glucagon secretion may cause secondary inability of the β‐cell mass to
adapt to peripheral insulin resistance in mice under conditions of
nutrient overload.34,35 Accordingly, mice with a complete knockout of
the glucagon gene displayed defective islet development and impaired
β‐cell glucose competence.36,37 Hence, intra‐islet glucagon likely plays
an important role in the maintenance of β‐cell mass homoeostasis and
β‐cell competence.38
Overall, these data suggest the possibility that at the pancreatic
islet level, T2D is an example of ‘paracrinopathy’39 in which distur-
bances in the physiological secretion of glucagon and insulin are both
the cause and consequence of each other (Figure 1).
2.2 | The role of glucagon in peripheral tissues
A growing body of evidence currently indicates that glucagon exerts
its effect in several organs, including the liver, the adipose tissue, and,
marginally, the skeletal muscle, thus affecting peripheral insulin
sensitivity (Figure 2).

F I G U R E 1 The role of glucagon in β‐cell function under physiological (upper panels) and diabetic (lower panel) conditions. Upper panel,
left: under physiological fasting, the potentiation of insulin secretion from glucagon cannot occur due to the non‐activation of the triggering
pathway by the glucose. Upper panel, right: in the physiological post‐prandial phase, high glucose levels depolarise the β‐cell membrane by
closing the ATP‐sensitive K+ leak channels (KATP channel), thus activating the insulin secretory machinery; this triggering pathway allows the
glucagon to amplify insulin secretion by activating the GCGRs and GLP‐1Rs and favoring the generation of cAMP, and the activation of the
EPAC system; in this phase, however, glucagon levels are kept low by glucose and the counter‐regulatory action of insulin. Lower panel:
regardless of fasting or post‐prandial condition, in type 2 diabetes, hyperglucagonemia occurs as a result of both insulin resistance and
alteration of the glucose effect on the α‐cell; high glucagon levels together with high glucose levels abnormally stimulate insulin secretion in
the β‐cell; therefore, after a phase of compensatory hyperinsulinemia, the β‐cell becomes exhausted and no longer able to release insulin in
concentrations sufficient to maintain euglycemia. cAMP, cyclic AMP; EPAC, exchange protein directly activated by cAMP; GCGRs, glucagon
receptors; GLP‐1Rs, glucagon‐like peptide‐1 receptors.
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4 of 16
- CARUSO ET AL.

2.2.1 | Liver glucagon enhances hepatic lipolysis, sustains cytosolic gluconeogen-

The first activity attributed to glucagon was its activation of
hepatic glycogenolysis and gluconeogenesis to counteract hypo-
glycaemia.40 In particular, glucagon binds to GCGR resulting in
the activation of glycogen phosphorylase kinase and glycogen
phosphorylase through the cAMP‐PKA pathway, allowing the
breakdown of glycogen and generation of glucose‐6‐phosphate,
the key substrate for glucose production.40 Moreover, glucagon
fosters the activity of the glucose 6‐phosphatase (G6Pase)
enzyme increasing glucose release and inhibits glycogen syn-
thase.41 Also, a transcriptome‐wide analysis of human hepatocytes
showed that glucagon might facilitate gluconeogenesis by acti-
vating a plethora of target genes of proliferator‐activated recep-
tor gamma coactivator 1‐alpha (PGC1α).42
Hepatic intracellular signalling pathways of insulin and glucagon
converge on Foxo1, a mediator involved in glucose and lipid meta-
43 44
bolism, with opposite effects. Glucagon induces the phosphory-
lation of Foxo1 on Ser276 determining its nuclear retention via a
cAMP and PKA‐dependent pathway, impairing the insulin‐induced
Foxo1 ubiquitination and degradation.45
New insights on glucagon biology in the liver showed that
through the inositol 1,4,5‐triphosphate receptor type 1 (INSP3R1)
esis, and increases calcium‐dependent mitochondrial energy expen-
diture (EE), reducing ectopic lipids.46,47 In vitro studies demonstrated
that glucagon is also able to stimulate ketogenesis by enhancing
hepatic fatty acid oxidation especially under low circulating insulin
levels, increasing β‐hydroxybutyrate and acetoacetate production by
about 150%.48
Hence, the hepatic functions of glucagon are activation of
glycogenolysis, gluconeogenesis and lipolysis, increasing mitochon-
drial EE, and inhibition of glycogenosynthesis.
2.2.2 | Muscle
In vivo experiments in rodents found that glucagon administration for
6 h inhibited protein synthesis in muscles following a period of
feeding.49 Indeed, glucagon may promote the oxidation of L‐leucine
in human skeletal muscle under different metabolic conditions,
determining a whole‐body irreversible loss of this amino acid.50,51 L‐
leucine oxidation leads to reduced activation of target of rapamycin
(TOR) protein and TOR complex 1 (TORC1),52 hindering muscle
protein synthesis as observed in patients with severe muscle wasting
affected by glucagonoma53 and hyperglucagonaemia.54

F I G U R E 2 Principal peripheral responses evoked by glucagon. Principal peripheral responses evoked by glucagon: (i) glycogenolytic/
gluconeogenic and anti‐glycogenic effects on hepatocytes; (ii) reduction of muscle mass; (iii) browning and increased BAT activity; (iv)
stimulation of brain areas controlling anorexigenic responses; (v) uncertain effect on ghrelin secretion and gut contractility. ↑, increase; ↓,
decrease. AgRP, agouti‐related protein; ARC, arcuate nucleus; cAMP, cyclic AMP; CaMKKβ/AMPK, Ca2+−calmodulin‐dependent protein
kinase kinase β/AMP‐activated protein kinase; FGF21, fibroblast growth factor 21; Foxo1, forkhead box protein O1; GCGR, glucagon receptor;
GP, glycogen phosphorylase; GPK, glycogen phosphorylase kinase; G6Pase, glucose 6‐phosphatase; GS, glycogen synthase; pACC,
phosphorylated acetyl‐CoA carboxylase; PKA, protein kinase a; TORC1, target of rapamycin complex 1.

CARUSO ET AL.
Beyond the effects on muscle mass, conflicting evidence hints at
an indirect effect of glucagon on glucose metabolism in the skeletal
muscle. A study conducted in depancreatised dogs on nutritional
support reported that chronic exposure to high glucagon levels
impaired muscle glucose disposal, fuelling the development of insulin
resistance as well as the aggravation of glucose tolerance.55 In
humans, intravenous infusion of glucagon has often been associated
with enhanced glucose uptake during positron emission tomography
(PET), yet a retrospective study by Yasuda et al. failed to detect any
increase in glucose uptake in the gluteal muscle.56
In light of these data, the regulation of protein synthesis appears
to be a definite effect of glucagon in skeletal muscle, whereas the role
of this hormone in the control of glucose metabolism in this tissue
needs further elucidation.
2.2.3 | Adipose tissue (WAT, BAT)
Long‐standing evidence supports the hypothesis that glucagon might
increase EE even though the underlying mechanism is still debated.
One of the main contributors to EE is brown adipose tissue (BAT)‐
mediated thermogenesis in which process glucagon may play a crit-
ical role.57
Early evidence indicated that glucagon increased the rate of
oxygen consumption and free fatty acids (FFAs) release from BAT58
as well as inducing heat generation.59 In addition, glucagon appears
to be involved in the mechanisms of cold tolerance. In particular,
glucagon secretion changes according to ambient temperature, as
observed in both rodents and humans, with increased circulating60
and within BAT61 glucagon levels under cold temperatures. Indeed,
mice with the abrogation of proglucagon‐derived peptides (GCGKO)
exhibited a greater decrease in rectal temperature as well as poor
response to β‐adrenergic stimuli and reduced expression of ther-
mogenic proteins (e.g. uncoupling protein 1 [UCP1], iodothyronine
deiodinase 2, and PGC1α) under cold exposure, all restored after
glucagon supplementation.62
The effect of glucagon on EE is mediated by multiple direct and
indirect GCGR‐dependent mechanisms.63 Glucagon actions on BAT
might be mediated via the central control of sympathetic activity, as
revealed by the fact that experimental denervation of BAT or phar-
macological inhibition of β‐adrenergic signalling, the main transducer
of BAT activity, led to a consistent reduction of glucagon‐induced
64
augmentation of EE. Also, animal studies hinted at fibroblast
growth factor 21 (FGF21) as a mediator of glucagon‐induced BAT
activation,65 though this finding was not replicated in humans.66
Interestingly, results in mice with BAT‐specific GCGR knockdown
indicated that the beneficial effects of glucagon on body weight (BW),
EE, and metabolic adaptation to cold and high‐fat diet do not require
63
BAT GCGR and thermogenic mediators such as UCP‐1.
Moreover, several studies have demonstrated that glucagon
may activate browning within the white adipose tissue (WAT), even
though with a negligible clinical impact. In mice, WAT‐specific
GCGR abrogation was associated with lower levels of cold‐
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- 5 of 16
induced markers of browning (e.g. Ucp1, Prdm16, and Cidea), as
well as lower circulating levels of FGF21.28 Similarly, Townsend
et al. showed that mice with WAT‐specific GCGR knockout dis-
played attenuated induction of Ucp1, Cidea, and Fgf21 mRNA levels
under cold exposure, despite a modest increase in browning indices
at room temperature, providing evidence that glucagon signalling is
required for cold acclimation.67
Finally, recent findings suggested that glucagon might play an
anti‐adipogenic role, inhibiting adipose stem cell proliferation,
increasing apoptosis and reducing accumulated lipids.68 Of note,
supraphysiological concentrations of glucagon were used in these in
vitro experiments (10–100 nM), higher than those achieved in the
presence of obesity and diabetes.69,70 However, the anti‐lipogenic
and catabolic actions of glucagon had already been observed in
mature adipocytes, in which the hormone led to increased phos-
phorylation of acetyl‐CoA carboxylase (ACC) which in turn dimin-
ished lipid synthesis via the activation of the Ca2+−calmodulin‐
dependent protein kinase β/AMP‐activated protein kinase (CaMKKβ/
AMPK) cascade.71
Human studies in healthy volunteers confirmed that glucagon
infusion may increase EE by enhancing carbohydrate and FFAs
oxidation.72 Yet, Salem et al. hypothesised the presence of other still
unidentified pathways through which glucagon might affect EE, as a
18
F‐FDG PET/CT study in healthy male volunteers showed that
glucagon increased EE to the same extent as cold exposure but
without any changes in sympathetic activation, BAT thermogenesis
and glucose uptake.73
Taken together, these data highlight the weight‐lowering po-
tential of glucagon, through increases in EE, enhancement of BAT
thermogenesis and probably other pathways yet to be discovered, as
well as anti‐adipogenic and lipolytic effects.
2.3 | The role of glucagon in food intake regulation
2.3.1 | Central
Glucagon is also able to affect the brain regions involved in the
control of satiety and hunger. Indeed, GCGR is widely expressed in
the central nervous system (CNS)74 and several studies have ascribed
an anorexigenic role to glucagon, supporting its pharmacological use
in the treatment of obesity.75 In mice, intracerebroventricular infu-
sion of glucagon exerted a weight‐lowering effect by decreasing
appetite.76 Accordingly, rats treated with antibodies against glucagon
exhibited increased meal sizes.77 These effects appear to be medi-
ated by a hepatic‐neuronal loop: in a rat model, the activation of
hypothalamic glucagon signalling prevented hyperglycaemia through
the inhibition of hepatic glucose output via vagal nerve pulse control,
suggesting that hypothalamic glucagon resistance might contribute
to the disruption of glucose homoeostasis in diabetes.78 Similarly,
animals with hepatic vagotomy did not experience modifications in
their feeding behaviour after central infusion of glucagon, suggesting
the essential role of the hepatic branch and the CNS areas dedicated

6 of 16
- CARUSO
to the regulation of food consumption in promoting glucagon‐
induced satiety.79,80
Recent in vivo studies have also reported that glucagon displayed
anorexigenic actions by regulating the PKA/Ca2+−calmodulin‐
dependent protein kinase kinase β/AMP‐activated protein kinase/
Agouti related protein (PKA/CaMKKβ/AMPK/AgRP) signalling
pathway within the hypothalamic arcuate nucleus (ARC).81 However,
the anorexigenic effects of glucagon are lost in an obesogenic envi-
ronment, as in rats fed a high fat diet, due to a disruption in its hy-
81
pothalamic signalling downstream of PKA. In the same model,
glucagon action was restored after inactivation of CaMKKβ in the
ARC, suggesting the critical role of this protein in mediating obesity‐
81
induced glucagon resistance.
Considering these central effects, glucagon may reasonably play
a role in the management of obesity and prevention of T2D.
2.3.2 | Peripheral (stomach and intestine)
GCGRs have been detected throughout the gastrointestinal tract,
where glucagon acts through the activation of a cAMP‐dependent
pathway. In particular, an in vivo analysis indicated that GCGRs are
predominantly expressed in the lamina propria mucosae of rat
stomach. Glucagon intravenous infusion or direct administration to
the isolated stomach was associated with acute release and increased
synthesis of ghrelin, an important orexigenic hormone involved in
food intake regulation.82,83 Similarly, Gagnon et al. demonstrated
that glucagon induces the release of ghrelin from a dispersed gastric
cell culture model through a mechanism dependent on mitogen‐
84
activated protein kinases and EPAC. Contrarywise, glucagon
administration was associated with the inhibition of ghrelin secretion
65,85
in human studies.
Also, glucagon appears to regulate the enteric activity. The
spasmolytic action of glucagon has been well‐documented by
several early studies, demonstrating that its continuous intravenous
infusion resulted in jejunal dilatation and increased mean transit
86,87
time in humans, independent of its effect on carbohydrate
metabolism.84 Nevertheless, Mochiki et al. observed that glucagon
might also increase phase III‐like contractions in the duodenum and
jejunum, suggesting a potential side effect of glucagon‐based ther-
apy.84 The enteric effects of glucagon appeared to be related to the
dose used as well as to the route of administration. Indeed, Pascaud
et al. observed that low concentrations of glucagon (25 μg/kg)
stimulated contractile activity in the jejunum, while higher doses
(100 μg/kg) induced an immediate and significant decrease in
motility.88 Also, clinical trials suggested that the anti‐peristaltic ef-
fect of glucagon was more evident following intravenous rather
than intramuscular administration.89
Overall, the effects of glucagon on the gastroenteric system
remain elusive. Expanding the knowledge regarding the effects of
glucagon on intestinal motility could be useful to understand the
relative implication of glucagon‐based therapies on nutrient ab-
sorption and gastric fullness perception.
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ET AL.
3 | THE ROLE OF GLUCAGON IN THE
PATHOGENESIS OF TYPE 2 DIABETES
COMPLICATIONS
3.1 | The role of glucagon in CV complications of
type 2 diabetes
Expression of the GCGR has been detected in certain regions of the
heart57,90,91 and several animal and human experiments have
demonstrated that glucagon exerts direct cardiac actions.25,26
Glucagon facilitated the atrio‐ventricular conduction, exhibiting a
positive chronotropic and anti‐arrhythmogenic effect.25,92 In addi-
tion, glucagon also exerted a positive inotropic effect, which is
stronger in the ventricle rather than in the atrium,25 partially due to
site‐specific differential GCGR expression.93 These actions are
mediated by increased cAMP concentration and the inotropic effect
persists in the presence of β‐blockers.25,94 Being an inotropic and
chronotropic agent, glucagon increases cardiac oxygen consumption,
lipolysis, and lipid β‐oxidation.91 In animal studies, cardiac infusion of
glucagon‐promoted glycolysis and glucose oxidation, like insulin, and
these effects were mediated via phosphatidylinositol 3‐kinase‐
dependent and adenylate cyclase‐ and cAMP‐independent path-
ways.25,95 Hence, cardiac glucagon and insulin actions may overlap in
regard to the regulation of fuel metabolism.25
These findings suggest to consider glucagon as a useful resource
in the treatment of heart failure.96 Nonetheless, while glucagon
infusion improved cardiac index and left ventricular ejection fraction
in patients without heart failure undergoing diagnostic coronary
catheterisation,97 evidence on a direct inotropic effect in patients
with low cardiac output is lacking.98 However, glucagon was associ-
ated with reduced peripheral and lung vascular resistances, reducing
cardiac workload and indirectly improving cardiac performance.98
Knowledge about the direct effects of glucagon on the heart under
pathological conditions is still limited and controversial, with heart‐
specific activation of GCGR signalling reported to be either benefi-
cial or harmful, depending on the experimental or clinical context.99 Ali
et al. demonstrated that exogenous glucagon administration directly
impaired the recovery of ventricular pressure in nondiabetic ischaemic
mouse hearts ex vivo and increased mortality from myocardial
infarction (MI) after left anterior descending coronary artery ligation
in mice in a p38 MAPK‐dependent manner.99 Accordingly,
cardiomyocyte‐specific inactivation of GCGR significantly improved
overall survival and reduced hypertrophy and infarct size following
MI.99 These effects were associated with a marked reduction in long‐
chain acylcarnitines in both aerobic and ischaemic hearts following
high‐fat feeding, suggesting an essential role of GCGR signalling in the
control of cardiac fatty acid utilisation.99 Moreover, Gao et al.
observed that treating mice with the anti‐GCGR antibody REMD 2.59
following MI was able to blunt cardiac hypertrophy, fibrotic remod-
elling and contractile dysfunction after 4 weeks.100 In addition, the
administration of REMD 2.59 at the onset of or after pressure over-
load significantly reduced cardiac hypertrophy and chamber dilation
with marked preservation of cardiac systolic and diastolic function.100

CARUSO ET AL.
Similarly, Sharma et al. demonstrated that treatment with REMD 2.59
preserved fractional shortening and ejection fraction in the Leprdb/db
101
T2D mice model. Furthermore, GCGR antagonism was also able to
prevent declines in the early diastolic filling peak velocity/late filling
peak velocity (E/A) ratio, cardiac output, as well as left ventricular
developed pressure.101 REMD 2.59‐treated Leprdb/db mice were also
protected from the increase in isovolumic relaxation time (IVRT) and
101
T2D‐associated hypertrophy. Also, REMD 2.59 lowered several
toxic ceramide species, including C16:0 and C18:0 ceramides, and was
associated with a trend towards improved AMPK activation involved
101
in cardiac lipid metabolism.
Finally, it should be recalled that relative hyperglucagonemia is
involved in the pathogenesis of glycaemic variability, which repre-
sents a predictor of all‐cause mortality, especially non‐cancer mor-
102–104
tality, in patients with T2D. In addition, hyperglucagonemia
also impairs lipid and amino acid metabolism, which in turn, along
with glycaemic disorders, fuel the pathogenesis of diabetes, obesity,
non‐alcoholic fatty liver disease (NAFLD)105 and the related adverse
106
CV outcomes.
These experimental data suggest that hyperglucagonemia might
play a role in the CV complications of T2D triggering lipotoxic con-
ditions and thus the development of insulin resistance, providing
proof‐of‐concept evidence that GCGR antagonism might be poten-
tially efficacious in preventing heart failure and ischaemic heart
disease.
3.2 | The role of glucagon in microvascular
complications of type 2 diabetes
In mice, the knockout of the GCGR gene was associated with a late‐
onset loss of retinal function, visual acuity, and eventually retinal cell
90
death. Likewise, deficiency of peptides derived from the glucagon
gene was associated with peripheral neuropathy in mice.107 Indeed,
glucagon could exert a protective effect on the nervous system, as
107
shown in the setting of post‐traumatic brain injury. In a model of
diabetic neuropathy, represented by neuronal cells from the dorsal
root ganglion (DRG) treated with methylglyoxal (MG), which causes
intracellular accumulation of advanced glycated end products, reac-
tive oxygen species (ROS) and apoptosis, glucagon mitigated MG‐
induced mitochondrial ROS production, apoptosis and overall cyto-
107
toxicity. Additionally, treatment of DRG neurons with physiolog-
ical doses of glucagon, in the absence of MG, stimulated the cAMP/
PKA pathway and promoted neurite outgrowth.107
However, there are no clinical data on the role of glucagon in
diabetic retinopathy and neuropathy, while a larger body of evidence
covers the relationship between glucagon and kidney.
Glucagon is involved in the disposal of the nitrogen waste
products of protein metabolism, stimulating ureagenesis and gluco-
neogenesis from amino acids in the liver and urea excretion in the
kidney following a protein‐rich meal or amino acids infusion.108,109
The renal effects of glucagon are only partially mediated by
GCGR, which is abundantly expressed in the kidney, specifically in
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- 7 of 16
the thick ascending tubule, distal tubule and collecting duct.108
Glucagon induces glomerular hyperfiltration by modulating the
characteristics of the tubular fluid at the macula densa by simulta-
neously reducing the resorption of water, electrolytes and urea in the
proximal tubule and increasing NaCl resorption in the thick
ascending tubule, decreasing the tubulo‐glomerular feedback (TGF)
signal, and increasing glomerular filtration rate (GFR).109 While the
effect of glucagon on the thick ascending tubule is directly mediated
by the GCGR, the effect on the proximal tubule is mediated by the
circulating cAMP produced by the liver under the influence of
glucagon and insulin.109 Insulin facilitates the degradation of
glucagon‐induced cAMP, hence, it is the insulin/glucagon ratio rather
than the absolute concentration of glucagon to determine the
amount of circulating cAMP and the extent of the indirect effects of
glucagon.108
Of note, studies using mouse GCGR knockout models reported
no major impairments of kidney function.90 In non‐diabetic rodents,
infusion of glucagon was associated with moderately increased sys-
tolic blood pressure, high fasting blood glucose and impaired glucose
tolerance, glomerular hypertrophy and hyperfiltration, due to blunted
TGF,109 increased albuminuria, mesangial expansion and deposition
of extracellular matrix.110 These effects were mediated by the
phosphorylation of ERK1/2 and Akt, under euglycaemic conditions,
following the activation of PKA and the phospholipase C (PLC)
pathways leading to angiotensin II synthesis.106,110 Angiotensin II is a
powerful contributor to the synthesis of extracellular matrix in
mesangial cells.111 Also, glucagon has been shown to exert a positive
effect on renal blood flow.90 Interestingly, in rats with
streptozotocin‐induced diabetes mellitus, the injection of glucagon
antibodies significantly reduced GFR within 2 h without effects on
glycaemia, confirming the role of glucagon as a direct mediator of
glomerular hyperfiltration also in the setting of diabetes.109
Of note, glucagon relies almost entirely on renal clearance, rising
by 2‐to‐4‐fold in end‐stage renal disease.112 Accordingly, a Chinese
study conducted on 326 T2D individuals confirmed the linear in-
crease in fasting plasma glucagon levels across the stages of chronic
kidney disease (CKD).112 In 357 T2D patients, Wang et al. found that,
after a 75 g glucose oral load, glucagon levels were significantly
higher in patients with albuminuria and/or reduced eGFR, and the
glucagon peak was delayed compared to patients with preserved
kidney function.113 In addition, the glucagon/insulin ratio was higher
in patients with eGFR <60 ml/min/1.73 m2 compared to those with
>60 ml/min/1.73 m2.113 The degree of insulin resistance and eGFR
explained 22.8% of the variance in fasting glucagon levels.112 Hence,
the higher levels of glucagon in nephropathic T2D patients might be
explained by both the altered regulatory effects of insulin and
glucose on pancreatic α‐cells and the decreased renal clearance of
glucagon.113 This association was confirmed in a wider cohort of
2436 T2D patients undergoing an oral glucose tolerance test: both
fasting and post‐challenge glucagon were mildly correlated with
eGFR and urinary albumin:creatinine ratio (UACR).106 Moreover,
patients in the higher quartile of fasting and post‐challenge plasma
glucagon exhibited a 1.52‐ and 2.06‐fold increase in the likelihood of

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diabetic kidney disease compared to those in the lower quartile,
respectively.106 This association persisted even in the subgroup of
106
patients with optimal glycaemic control (HbA1c <7%).
In another study on 209 T2D patients, the increase in plasma
glucose following glucagon injection (glucagon stimulation test) not
only was directly related to GFR at baseline, but was also indepen-
dently associated with eGFR after 1 year at multiple regression
114
analysis. Therefore, responses to the glucagon stimulation test
might allow us to evaluate not only the hepatic glucose output but
also nephron functionality, as gluconeogenesis in the kidney also
114
contributes.
All in all, hyperglucagonemia might contribute to kidney disease by
both glucose‐dependent and glucose‐independent mechanisms.
Indeed, hyperglucagonemia is associated not only with fasting hyper-
glycaemia but also with GCGR‐dependent proliferation of glomerular
mesangial cells and increased deposition of extracellular matrix.106
Further mechanistic studies are warranted to further understand the
role of glucagon in the pathogenesis of diabetic kidney disease.
3.3 | The role of glucagon in NAFLD
NAFLD is defined by the detection of hepatic steatosis either on
imaging or histology in the absence of secondary causes of hepatic
lipid accumulation.115 T2D is a major risk factor for NAFLD and its
progression to NASH (non‐alcoholic steatohepatitis).115 A recent
meta‐analysis estimated 55.48% and 37.33% worldwide prevalence
115
of NAFLD and NASH in T2D patients, respectively. Conversely,
the prevalence of T2D is 22.5% and 43.6% in patients with NAFLD
and NASH, respectively, which is much higher than the 8.5% preva-
lence in general population.116
Glucagon is involved in the liver‐α‐cell axis, regulating urea-
genesis and hepatic amino acid metabolism, while in turn amino acids
stimulate pancreatic α‐cells proliferation and glucagon secretion.117
Moreover, glucagon increases endogenous glucose production mainly
by activating glycogenolysis rather than gluconeogenesis and induces
117,118
lipolysis, fatty acid β‐oxidation, and autophagy.
Notably, in an animal model of high fat diet‐induced hepatic
steatosis, GCGR density and glucagon‐mediated intracellular signal-
ling in hepatocytes were reduced, hampering liver response to
glucagon.117,119 Using several animal models, Winther‐Sørensen et al.
showed that hepatic steatosis, GCGR antagonists and genetic
knockout of GCGR similarly increased glucagon levels and reduced
ureagenesis through both transcriptional and rapid non‐
120
transcriptional mechanisms. Fat‐induced hepatic glucagon resis-
tance results in reduced ureagenesis, leading to hyperaminoacidemia
which in turn induces hyperglucagonemia.117,121 A weakened biolog-
ical effect of glucagon is associated with reduced SIRT‐1 activity,
consequently reducing its anti‐inflammatory and anti‐fibrotic effects,
down‐regulating NF‐κB and modulating TGF‐β signalling pathway.122
Furthermore, hyperaminoacidemia and hepatic glucagon resistance
contribute to impaired hepatocyte autophagy, resulting in increased
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ET AL.
oxidative stress and intracellular triglyceride accumulation, fuelling a
vicious circle that sustains the progression of NAFLD.117
Some T2D patients have high fasting and post‐prandial levels of
glucagon, but this could be related to the degree of hepatic steatosis
rather than diabetes per se.118 Indeed, Junker et al. demonstrated
that patients with biopsy‐proven NAFLD had hyperglucagonemia
regardless of the presence of T2D.123 In 4937 T2D patients, Wang
et al. found that higher glucagon levels were associated with prob-
able inflammatory progression of NAFLD to NASH but not to wors-
ening fibrosis; however, probable NASH was defined by the
simultaneous presence of NAFLD and metabolic syndrome, and
fibrosis was assessed with the NAFLD fibrosis score rather than
providing histological confirmation.124 Accordingly, in a small study
conducted on non‐obese Asian males with new‐onset T2D treated
with metformin, fasting glucagon levels were higher in patients with
NAFLD and were independently associated with markers of trunkal
subcutaneous and visceral adiposity.125 Nonetheless, in a cross‐
sectional study conducted on 172 hospitalised patients with T2D,
relative hyperinsulinemia, expressed by lower fasting and post-
prandial glucagon‐to‐insulin ratios, was significantly associated with
ultrasound‐detected NAFLD.126
Interestingly, in 33 obese individuals undergoing bariatric sur-
gery, the liver‐α cell axis was similarly disrupted irrespective of
NAFLD severity, whereas at 12 months after surgery only patients
with NASH or fibrosis at baseline exhibited persistent hyper-
glucagonemia despite significant improvements in BW and liver his-
tology. This suggests a role of structural liver abnormalities and/or
mechanisms of metabolic memory in determining glucagon levels.127
As demonstrated in a pancreatic clamp study in patients with
biopsy‐proven NAFLD versus lean individuals, the presence of
NAFLD hampered the effects of glucagon on amino acid metabolism
but not on glucose metabolism,117,121 probably due to the fact that
the glycogenolytic pathway is clearly separated from that of gluco-
neogenesis and ureagenesis.118 The glucagon‐alanine index, obtained
by multiplying glucagon and alanine plasma concentrations, has been
suggested as a marker of glucagon resistance.118 In 79 young women,
most of whom had preserved glucose tolerance, Gar et al. found that
the glucagon‐alanine index was associated with MRI‐determined
hepatic steatosis; this association was independent of the degree of
insulin resistance and was already detectable at slightly increased
liver fat content (>0.5%).128 As expected, the glucagon‐alanine index
was also significantly related to fasting and post‐prandial glucose
(PPG) levels and insulin resistance (HOMA‐IR).128
Impaired glucagon signalling may be held accountable of the
bidirectional relationship between NAFLD and diabetes,117 contrib-
uting to the pathogenesis and progression of NAFLD alongside
obesity, insulin resistance, and inflammation.129 Hence, restoration of
glucagon signalling could be beneficial in NAFLD, as suggested by the
weight loss and reversal of hepatic steatosis produced by chronic
activation of the GCGR in diet‐induced obese mice130 and by the
encouraging evidence arising from clinical studies with dual or triple
agonists activating glucagon signalling.

CARUSO ET AL.
4 | USE OF GLUCAGON IN TYPE 2 DIABETES
THERAPY
Until recently, glucagon as a therapeutic agent had been recom-
mended solely in the management of severe hypoglycaemia, now
available in a nasal, needle‐free formulation (Baqsimi®) for the
131
management of severe hypoglycaemic episodes.
On the other hand, in agreement with the ‘bi‐hormonal theory’
accounting for the dysregulation of glucagon secretion and function
in T2D, GCGR antagonists (GRAs) have been proposed as glucose‐
lowering agents.2 Interestingly, short‐term use of several effica-
cious anti‐diabetic drugs, such as metformin, DPP‐4 inhibitors and
GLP‐1 receptor agonists (GLP‐1RAs), has been associated with
reduced glucagon levels132,133 without hindering the physiological
1
response to hypoglycaemia. In experimental models, the inhibition
of GCGR has been associated with reduced plasma glucose and tri-
glycerides and increased GLP‐1 levels.134 GRAs can be small mole-
cules or antibodies interfering with the GCGR or antisense
131,134
oligonucleotides reducing the expression of the GCGR. Further
clinical development of GRAs was hampered by long‐term adverse
events such as increased BW, liver fat content, systolic blood pres-
sure, LDL‐cholesterol, and transaminase levels, associated with α‐
cells hyperplasia and severe hypoglycaemia.131,134 Also, GRA
135
LY2409021 did not improve PPG following a mixed meal test and
paradoxically reduced glucose tolerance following an oral glucose
tolerance test without restoring the incretin effect compared to
placebo in 10 T2D patients.136 GCGR antagonism was associated
with stable fasting insulin levels, despite the amelioration of glucose
control, and increased insulin levels during oral glucose tolerance
test with a subsequent greater post‐load decrease in glucose, sug-
gesting improved insulin sensitivity both in the fasting and fed
134
states. Further research is required to understand the mechanisms
underlying GRA adverse events and their clinical relevance before
approval for use.
Surprisingly, in the context of incretin‐based multiagonists,
agonism of GCGR could also be beneficial for T2D management.137
GLP‐1RAs have been proven safe and effective in achieving glucose
control and preventing some diabetes complications, such as CV dis-
eases. Their gastrointestinal side effects may limit the use of higher
137
doses to maximise weight loss and glucose control. The combi-
nation of GLP‐1 with glucagon and/or glucose‐dependent insulino-
tropic polypeptide (GIP) agonism opens thrilling possibilities in the
field of obesity and diabetes management.75,137 Indeed, glucagon may
enhance the effects of GLP‐1RAs on satiety and further promote
weight loss by increasing EE, thermogenesis and lipolysis.137 In
addition, glucagon and GLP‐1 both facilitate insulin secretion and the
combination of the two agonisms may allow to counteract the
glucagon‐dependent increase in hepatic glucose output.137 The syn-
ergistic effects of glucagon and GLP‐1 are not surprising, being both
138
encoded by the Gcg gene. The addition of GIP to these multi-
agonists is corroborated by human studies highlighting that co‐
infusion of GIP and GLP‐1 increased first‐phase insulin secretion in
diabetic patients, and animal studies showing a greater reduction of
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- 9 of 16
BW, food intake, HbA1c and lipids compared to GLP‐1RA.137 The
similarities in primary and secondary structures between glucagon,
GLP‐1 and GIP allowed the synthesis of hybridised molecules with
multiple epitope regions and a size comparable to that of the native
peptides.137 These compounds can be characterised by balanced or
preferential agonism in favour of one receptor over the others.137
Glucagon, GLP‐1 and GIP exert their effects by binding to different G
protein‐coupled receptors; though cross‐reactivity has been
demonstrated, their differential tissue‐specific distribution facilitate
a broader synergistic effect.137
Nowadays, both dual and triple agonists incorporating glucagon
agonism are under development for clinical use.75,131,137 Experi-
mental studies conducted in diet‐induced obese mice showed that
dual GLP‐1/GCGR agonists induced weight loss, improved lipid and
glycaemic profile, increased EE, and reduced food intake.75,131 In
humans, co‐infusion studies confirmed the favourable effects of this
therapeutic strategy. In healthy overweight or obese volunteers, co‐
infusion of glucagon and GLP‐1 allowed glucagon‐dependent in-
crease in EE and the reduction of food intake without affecting
plasma glucose excursion.72,76 Among the many GLP‐1/GCGR ago-
nists under development,131 the balanced agonist cotadutide
(MEDI0382) is the most advanced. The phase 1 trial demonstrated a
dose‐dependent reduction in blood glucose and food intake in
healthy individuals, with gastrointestinal adverse events at the
highest dose.139 In phase 2a randomised, placebo‐controlled, double‐
blind trials conducted in overweight and obese T2D patients, cota-
dutide reduced HbA1c and both fasting and PPG following a mixed
meal tolerance test at 41–49 days, as opposed to long‐acting GLP‐
1RA reducing mainly fasting glucose.140,141 Furthermore, up to 40%
of patients lost ≥5% of their BW.140,141 Enhanced insulin secretion
and delayed gastric emptying have been proposed as the main
mechanisms behind short‐term amelioration of glucose control with
cotadutide.140 In a phase 2b study, cotadutide was similar to lir-
aglutide 1.8 mg in terms of HbA1c lowering both at 14 and 54 weeks,
while only cotadutide 300 μg outperformed liraglutide 1.8 mg in
terms of weight loss both at 14 (LS mean [95% CI] – 5.01 [−5.57,
−4.45] vs. −3.44 [−4.20, −2.68], p = 0.001) and 54 weeks (LS mean
[95% CI] – 5.02 [−5.78, −4.26] vs. −3.33,142 p = 0.009).143 Inter-
estingly, a recent phase 2a trial showed that treatment with cota-
dutide for 32 days was associated with a 51% decrease in albumin‐
to‐creatinin ratio compared to placebo in T2D patients with
albuminuria.144
Another dual GLP‐1/GCGR agonist, SAR425899, was associated
with a greater post‐prandial glycaemic control compared to liraglu-
tide, due to enhanced β‐cell responsiveness.145
Moreover, in order to mimic the effects of GLP‐1, GIP, and
glucagon contributing to the major metabolic advantage of bariatric
surgery, the development of triple GLP‐1/GIP/GCGR agonists has
been pursued.131 Adding both incretins to glucagon hampers its ef-
fect on hepatic glucose output, allowing to maximise its salutary ef-
fects on liver and BW.75 Indeed, in diet‐induced obese rodents, the
administration of a triple agonist was associated with a greater
benefit on weight loss and glucose levels than liraglutide and a

10 of 16
- CARUSO
GLP‐1/GIP coagonist, comparable to that observed following bar-
iatric surgery in the same experimental setting.
Besides their remarkable effects on glucose control and BW
reduction, the combination of GLP‐1 and GCGR monoagonists or
GLP‐1, GIP and GCGR monoagonists has been associated with a
greater improvement than high dose liraglutide in NAFLD activity
146
score despite producing the same extent of weight loss. An
exploratory MRI analysis of a phase 2a trial demonstrated that
administration of cotadutide reduced hepatic fat content in over-
weight or obese T2D patients compared to placebo.147 Nahra et al.
showed that cotadutide 200 and 300 μg significantly lowered
aspartate (AST) and alanine (ALT) transaminases compared to pla-
cebo, while only cotadutide 300 μg induced a greater reduction in
ALT levels compared to liraglutide 1.8 mg at 54 weeks.143,148 In the
same study, liraglutide 1.8 mg and all investigated doses of cotadu-
tide produced a greater decrease in fatty liver index with respect to
placebo. Instead, higher doses of cotadutide reduced FIB‐4 (fibrosis‐4
index), NFS (NAFLD fibrosis score) and PRO‐C3 (propeptide of type
145
III collagen), while liraglutide had no effect on these endpoints.
Indeed, in mice models of NASH, treatment with cotadutide
improved liver fibrosis to a greater extent than liraglutide despite
inducing a similar weight loss.149 The beneficial effects of cotadutide
in NAFLD/NASH are likely to be mediated by the GCGR‐dependent
enhancement of mitochondrial turnover and reduced de novo
lipogenesis.145
Finan et al. showed that a balanced GLP‐1/GIP/GCGR triple
agonist induced amelioration of liver fat content and hepatocytes
vacuolation to a greater extent than GLP‐1/GIP dual agonists.150
More recently, in mice models of NASH, the triple agonist
LY3437943 decreased circulating ALT levels and hepatic tri-
glycerides content. Accordingly, the triple agonist HM15211 out-
performed both acylated GLP‐1 and GLP‐1/GIP on all the
subcomponents of the NAFLD activity score (hepatocytes ballooning,
lobular inflammation, and steatosis).148
These results encourage the use of such dual and triple agonists
for the treatment of NAFLD/NASH. Further studies on patients with
biopsy‐proven NAFLD/NASH and fibrosis are awaited.
5 | CONCLUSIONS
Increased glucagon secretion by α‐cells is one of the eight compo-
nents of the ‘ominous octet’ of factors underlying T2D pathogen-
esis.151 It is still unclear whether hyperglucagonemia results from β‐
cell dysfunction and its inability to suppress α‐cell secretion or from
α‐cells insulin resistance. In this regard, T2D could likely be consid-
ered as a ‘paracrinopathy’, where α‐ and β‐cells influence each other
in a vicious circle. Hyperglucagonemia sustains hyperglycaemia by
151
increasing hepatic glucose output, however its role in T2D path-
ogenesis might not be as straightforward (Figure 3). Indeed, GCGR
agonism harbours a relevant weight‐lowering potential since it exerts
anorexigenic actions on the hypothalamic ARC81 and has been linked
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ET AL.
to increased EE,57 anti‐adipogenic and lipolytic effects.68,71 Also,
human studies suggested that glucagon may inhibit the secretion of
the orexigenic peptide hormone ghrelin,152 but this association and
its involvement in the modulation of gastrointestinal motility are still
controversial.
Accordingly, the role of glucagon in the development of T2D
complications is cryptic (Figures 3 and 4). Glucagon administration
was able to induce glomerular hyperfiltration and hypertrophy,
mesangial expansion, and albuminuria with both glucose‐dependent
and independent mechanisms,110 while the restoration of GCGR
signalling has strongly been associated with the prevention of NAFLD
worsening130 (Figure 4).
The role of glucagon in the CV system is still elusive because
despite encouraging preliminary evidence regarding its anti‐
arrhythmic and inotropic effects, glucagon administration has not
been proven beneficial in patients with low cardiac output.98
Interestingly, GCGR antagonism has been associated with improved
systolic and diastolic performance, and amelioration of fibrosis and
hypertrophy in several pathological settings.99 Additional studies
using both GCGR agonism and antagonism, as well as GCGR
ablation models, are needed to shed light on the biology of
glucagon, which still appears enigmatic not only from a patho-
physiological perspective but also from a therapeutic point of view.
Finally, the paucity of studies investigating the effect of glucagon
signalling in the development of microvascular complications does
not allow to draw conclusions, but a beneficial role of GCGR
agonism in peripheral neuropathy and retinopathy could be
cautiously hypothesised.
Most of the commonly used antidiabetic drugs, except SGLT‐
2i, are able to lower glucagon levels,1 and yet the development of
targeted GRA has been halted by long‐term complications.134
Instead, the development of dual and triple GLP‐1/GCGR and
GLP‐1/GIP/GCGR agonists has been welcomed enthusiastically,
particularly due to significant weight‐ and glucose‐lowering po-
tential and the amelioration of hepatic steatosis.137 Clinical studies
conducted so far failed to detect relevant adverse events other
than the expected mild‐to‐moderate nausea, but further evidence
is awaited.75
In the light of the future availability of drugs able to modulate
GCGR signalling, a better understanding of the involvement of
glucagon in the pathogenesis of T2D and particularly of its tissue‐
specific effects and role in diabetes complications is eagerly awaited.
A UT H O R CO N T R I B U T I O N S
Conceptualisation: Irene Caruso. Writing – original draft preparation:
Irene Caruso, Nicola Marrano, Giuseppina Biondi, Valentina Anna-
maria Genchi and Rossella D'Oria. Writing – review and editing: Irene
Caruso, Angelo Cignarelli, Annalisa Natalicchio and Francesco Gior-
gino. Supervision: Angelo Cignarelli, Gian Pio Sorice, Annalisa Nata-
licchio, Sebastio Perrini, Luigi Laviola and Francesco Giorgino. All
authors have read and agreed to the published version of the
manuscript.
 15207560, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.3609 by Cochrane Germany, Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CARUSO ET AL.
- 11 of 16

F I G U R E 3 The role of glucagon in the pathogenesis of T2D and its complications: friend or foe? Glucagon has both favourable and
unfavourable effects on some of the mechanisms underlying the pathogenesis of T2D. Glucagon increases glucose‐dependent insulin secretion,
favourably affecting post‐prandial excursions. It might also contribute to controlling body weight, by regulating satiety through the reduction
of ghrelin levels and gastrointestinal motility in a dose‐dependent manner, and by increasing energy expenditure, likely via enhanced browning
and thermogenesis. Conversely, glucagon sustains hepatic glucose output contributing to fasting plasma glucose increase. It also reduces
peripheral insulin sensitivity by increasing lipolysis and probably reducing glucose uptake by skeletal muscles. The role of glucagon in T2D
complications is still vague. The reduction of peripheral vascular resistance is likely beneficial in patients with heart failure; however, clinical
evidence supporting its role in heart failure management is lacking and preclinical studies showed that glucagon might mediate cardiac fibrosis,
hypertrophy, and diastolic dysfunction. Glucagon might reduce the progression of NAFLD and improve peripheral diabetic neuropathy.
Conversely, glucagon has been associated with glomerular hyperfiltration and mesangial proliferation, while its effects on hard kidney
outcomes are still unknown. BW, body weight; DPN, diabetic peripheral neuropathy; FPG, fasting plasma glucose; GI, gastrointestinal; HF,
heart failure; MI, myocardial infarction; NAFLD, non‐alcoholic fatty liver disease; PPG, post‐prandial glucose; T2D, type 2 diabetes; ↑, increase;
↓, decrease.

F I G U R E 4 The putative role of glucagon in T2D complications. Green arrow, GCGR agonism; Red arrow, GCGR antagonism or knock‐out
or deficiency of glucagon gene‐derived peptides. GCGR, glucagon receptor; NAFLD, non‐alcoholic fatty liver disease; NASH, non‐alcoholic
steatohepatitis; NDRG, neurons from the dorsal root ganglion; T2D, type 2 diabetes.

12 of 16
- CARUSO
A CK N O WL ED GE M EN T S
This research received no external funding.
C O N F L IC T S O F IN T ER E S T
I.C., N.M., G.B., V.A.G., R.D., S.P., A.C. and G.P.S. declare no relevant
conflict of interest. A.N. has received speaker fees from AstraZeneca,
Novo Nordisk, and Sanofi. L.L. received speaker fees from Abbott,
AstraZeneca, Boehringer Ingelheim, Eli Lilly, Medtronic, Menarini,
Merck Sharp & Dohme, Novo Nordisk, Roche Diabetes Care, and
Sanofi and provided advisory services to Abbott, AstraZeneca,
Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Roche Diabetes Care,
Sanofi and Takeda. F.G. provided advisory services to AstraZeneca, Eli
Lilly, Novo Nordisk. Roche Diabetes Care, Sanofi, received speaker
fees, served as a consultant for Boehringer Ingelheim, Lifescan, Merck
Sharp & Dohme, Sanofi, AstraZeneca, MedImmune, Roche Diabetes
Care, Sanofi, Medtronic and received research support from Eli Lilly
and Roche Diabetes Care.
D A TA A V AIL AB IL I T Y S T A T EM E N T
Data sharing not applicable to this article as no datasets were
generated or analysed during the current study.
E T H IC S S T AT E M E N T
Ethics approval is not applicable because the present study is based
solely on published literature.
O R C ID
Valentina Annamaria Genchi https://orcid.org/0000-0001-8188-
9638
Gian Pio Sorice https://orcid.org/0000-0001-9489-1534
Francesco Giorgino https://orcid.org/0000-0001-7372-2678
PE ER R E VI E W
The peer review history for this article is available at https://publons.
com/publon/10.1002/dmrr.3609.
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How to cite this article: Caruso I, Marrano N, Biondi G, et al.
Glucagon in type 2 diabetes: friend or foe? Diabetes Metab Res
Rev. 2023;e3609. https://doi.org/10.1002/dmrr.3609