NEWS & VIEWS
OBESITY
A new paradigm for treating
obesity and diabetes mellitus
Andr J. Scheen and Nicolas Paquot
Refers to Finan, B. etal. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21,
2736 (2015)
An innovative strategy that uses a well-balanced monomeric peptide
triagonist to target three metabolically related hormone receptors
has been developed. This strategy seems to be the most effective
pharmacological approach to reverse obesity and its metabolic
comorbidities in rodents and could open new ways to tackle the dual
burden of obesity and diabetes mellitus in humans.
The management of patients with obesity
and type2 diabetes mellitus (T2DM) is
challenging in clinical practice. The recur-
rent failure of lifestyle changes and avail-
able pharmacological approaches in the
management of these patients has led to
many patients undergoing bariatric surgery
and has stimulated the search for new
pharmacological strategies.1
this strategy has the
potential to reverse obesity and
related metabolic disorders
Finan and colleagues have reported the
discovery of a new agonist that simultane-
ously targets three key metabolically related
peptide hormone receptorsthe recep-
tors for glucagon-like peptide1 (GLP1),
glucose-d ependent insulinotropic poly-
peptide (GIP) and glucagon (Figure1). 2
This monomeric peptide exerts a balanced
agonist effect and was proved to be remark-
ably effective at reducing body weight,
improving glucose control and reversing
hepatic steatosis in various rodent models
of either diet-induced or genetically
determined obesity and/or diabetesmellitus.
Through elegant studies in which knock-
out mice for the individual receptors were
used, Finan and colleagues were able to
demonstrate that the unimolecular tri
agonist targeted each of the three receptors.2
The researchers were also able to ascertain
how much blocking each receptor contrib-
uted to the overall metabolic benefits of the
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 11 | APRIL 2015
monomeric peptide. They found that the
overall metabolic efficacy of the new drug
predominantly resulted from synergis-
tic glucagon action that increased energy
expenditure, GLP1 action that reduced
caloric intake and improved glucose control
and GIP action that potentiated the so-
called incretin effect. Interestingly, the last
two actions buffer against the diabetogenic
effect of the inherent glucagon-mimicking
activity of the peptide. Thus, these preclini-
cal studies in rodents suggest that this uni-
molecular, polypharmaceutical strategy has
the potential to reverse obesity and related
metabolic disorders.2 Further studies should
confirm whether this innovative pharmaco
logical approach, which proved superior to
therapy with any existing dual coagonists
and best-in-class monoagonists in rodents,
might be effective and safe for the treatment
of obesity and T2DM in humans and thus
ultimately offer a valuable pharmacological
alternative to bariatric surgery.3
The dramatic rise of the twin epidem-
ics of T2DM and obesity is associated with
increased mortality and morbidity and is
one of the most important public-health
challenges worldwide. 1 Striking parallel
increases in the prevalence of the two enti-
ties reflect the importance of body fatness
as a contributing factor to the incidence of
T2DM and its complications. Despite the
importance of strategies to control weight in
the prevention and management of T2DM,
long-term results with lifestyle or avail-
able drug interventions are generally dis
appointing.1 Notably, therapeutic attempts
2015 Macmillan Publishers Limited. All rights reserved
GLP-1
Enhanced insulin
secretion
(incretin effect)
Reduced glucagon
secretion
Anorectic effects
GIP
Enhanced Triagonist
Glucagon
insulin secretion Increased hepatic
(incretin effect)
Buffered
glucose production
Increased energy
diabetogenic expenditure
effects of glucagon
Figure 1 | Complementary (but also
Nature Reviews | Endocrinology
opposing) effects of the individual
components of a peptide triagonist targeting
GLP1, GIP and glucagon receptors that could
be used to treat obesity and type2 diabetes
mellitus. Abbreviations: GIP, glucose-
dependent insulinotropic polypeptide; GLP1,
glucagon-like peptide1.
to normalize body weight and glycaemia
with single agents have generally had poor
results.1 Furthermore, most of the classic
glucose-lowering agents are accompanied
by weight gain, which increases the chal-
lenge of managing most individuals with
T2DM who are overweight or have obesity.1
Incretin-based therapies are increas-
ingly being used in clinical practice for
the management of T2DM. 4 The dipep
tidyl peptidase4 (DPP4) enzyme rapidly
degrades GLP1 and GIP, two gastrointesti-
nal hormones that potentiate insulin secre-
tion in response to a meal.4 Therapeutic
approaches for enhancing incretin action
include degradation-resistant GLP1 recep-
tor agonists (incretin mimetics) and inhibi-
tors of DPP4 activity (incretin enhancers).4
In addition to its incretin effect, GLP1 sup-
presses glucagon secretion, inhibits gastric
emptying and reduces appetite and food
intake.5 Both oral DPP4 inhibitors (known
as gliptins) and injectable GLP1 receptor
agonists exert a glucose-lowering effect with
no or only a minimal risk of hypoglycaemia,
with the injectable agents being more potent
than the oral compounds.4 Furthermore,
DPP4 inhibitors are weight-neutral,
whereas GLP1 receptor agonists reduce
body weight. 4 However, the amount of
weight lost is generally moderate and cannot
compete with the drastic weight reduction
NEWS & VIEWS
Practice point
Whereas inhibition of glucagon is classically
considered as a potential target for treating
diabetes mellitus, activating glucagon
receptors simultaneously with GLP1 and
GIP receptors has the potential of treating
both hyperglycaemia and excess weight,
a strategy that opens a new paradigm in
the management of obesity and type2
diabetesmellitus.
induced by bariatric surgery. The benefits
of bariatric surgery, however, extend well
beyond weight loss and include dramatic
improvement of T2DM. By mimicking the
profound changes in the enteroendocrine
responses that are secondary to changes
in gastrointestinal anatomy, drugs based
on gut hormones represent an exciting
possibility for the treatment of T2DM and
obesity.1,3 Emerging data from preclinical
studies supports the feasibility of using two
or more agonists, or single co-agonists, for
the treatment of obesity and T2DM.3
The therapeutic value of the triagonist
developed by Finan and colleagues cannot
be accurately determined from these pre-
clinical studies. One crucial feature that
needs to be established before using such
a triagonist in humans is a well-balanced
stimulation of the glucagon receptor.
Indeed, glucagon is a counter-regulatory
hormone that has a potent hyperglycaemic
effect, as it increases hepatic glucose output
through the stimulation of both glycogeno
lysis and gluconeogenesis.6 Some experi-
mental data suggest that suppression or
inactivation of glucagon might provide
therapeutic advantages over insulin mono-
therapy.6 Many attempts have been made to
inhibit glucagon secretion and/or action,
with the aim of improving glucose control
in T2DM, but without obvious success so
far (except for incretin-based therapies7).
The activation of the glucagon receptor
proposed by Finan and colleagues drasti-
cally contrasts with previous attempts to
inhibit the action of glucagon. The theory
is that glucagon could have some beneficial
activities, whereas its diabetogenic effects
might be counteracted by the co-activation of
APRIL 2015 | VOLUME 11  www.nature.com/nrendo
View publication stats
GLP1 and GIP receptors. Glucagon, at least
partly by inhibiting secretion of orexinA,
might increase energy expenditure and thus
promote weight loss, as shown in animals and
humans, irrespective of changes in levels of
glucose or insulin.8 Furthermore, data from
the past 2years have shown that coadminis
tration of GLP1 during glucagon infusion in
humans results in increased energy expendi
ture, reduction in food intake and ameli
oration of hyperglycaemia.9,10 Thus, GLP1
protects against glucagoninducedhyper
glycaemia and the glucagon-induced increase
in energy expenditure is maintained. These
observations support the concept of GLP1
and glucagon dual agonism as a possible
treatment for obesity and T2DM. Of note,
GIP action to potentiate the incretin effect,
as present in the new triagonist, could also
contribute to the buffer against the diabeto
genic effect of inherent stimulation of the
glucagon receptor.5 Finan and colleagues are
confident that the glucagon activity of the
triagonist can be selectively fine-tuned with
minimal structural or chemical changes.2
If this fine-tuning is possible, the ability to
choose among several options that differ
in their inherent molecular pharmacology
would certainly increase the likelihood of
success in humans.
such studies open a new
paradigm for the management
ofT2DM
The pharmacological outcomes of target
ing a particular pathway in humans are often
difficult to predict from results in animal
models and safety issues are always critical
in humans. Cardiovascular safety is becom-
ing a major concern for the development of
any new antidiabetic agents and glucagon is
known to have some cardiovascular effects
in humans that still need to be investigated.
Furthermore, humans have a different meta
bolic profile to that of rodents5 and many
promising strategies to treat obesity and/or
diabetes mellitus in rodents are not success-
ful in humans.1 Whether novel mechanisms
identified in preclinical studies, such as that
2015 Macmillan Publishers Limited. All rights reserved
by Finan and colleagues,2 have potential
translational relevance for the treatment of
human disease requires extensive research.3
Nevertheless, such studies targeting gluca-
gon simultaneously with GLP1 and GIP
receptors open a new paradigm for the
management of T2DM, especially when
associated withobesity.
Division of Diabetes, Nutrition and Metabolic
Disorders, Department of Medicine, CHU Lige,
University of Lige, Lige, Belgium (A.J.S., N.P.).
Correspondence to: A.J.S.
andre.scheen@chu.ulg.ac.be
doi:10.1038/nrendo.2015.3
Published online 27 January 2015
Competing interests
A.J.S. has received lecturer/advisor/investigator
fees from AstraZeneca/BMS, Boehringer Ingelheim,
Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis,
NovoNordisk, Sanofi and Takeda. N.P. has
receivedlecturer fees from Merck Sharp & Dohme
andNovoNordisk.
1. Scheen, A.J. & Van Gaal, L.F. Combating the
dual burden: therapeutic targeting of common
pathways in obesity and type2 diabetes.
Lancet Diabetes Endocrinol. 2, 911922
(2014).
2. Finan, B. etal. A rationally designed monomeric
peptide triagonist corrects obesity and
diabetes in rodents. Nat. Med. 21, 2736
(2015).
3. Sadry, S.A. & Drucker, D.J. Emerging
combinatorial hormone therapies for the
treatment of obesity and T2DM. Nat. Rev.
Endocrinol. 9, 425433 (2013).
4. Neumiller, J.J. Incretin-based therapies.
Med.Clin. North Am. 99, 107129 (2015).
5. Campbell, J.E. & Drucker, D.J. Pharmacology,
physiology, and mechanisms of incretin
hormone action. Cell Metab. 17, 819837
(2013).
6. Unger, R.H. & Cherrington, A.D.
Glucagonocentric restructuring of diabetes:
apathophysiologic and therapeutic makeover.
J. Clin. Invest. 122, 412 (2012).
7. Lund, A., Bagger, J.I., Christensen, M.,
Knop,F.K. & Vilsbll, T. Glucagon and type2
diabetes: the return of the cell. Curr. Diab.
Rep. 14, 555 (2014).
8. Arafat, A.M. etal. Glucagon regulates orexinA
secretion in humans and rodents. Diabetologia
57, 21082116 (2014).
9. Tan, T.M. etal. Coadministration of glucagon-
like peptide1 during glucagon infusion in
humans results in increased energy
expenditure and amelioration of hyperglycemia.
Diabetes 62, 11311138 (2013).
10. Cegla, J. etal. Coinfusion of low-dose GLP1
and glucagon in man results in a reduction in
food intake. Diabetes 63, 37113720 (2014).