The Journal of Physiology,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 22, 2024
Abstract
The
incretin
hormones
glucagon‐like
peptide‐1
(GLP‐1)
and
glucose‐dependent
insulinotropic
polypeptide
(GIP)
play
critical
roles
in
co‐ordinating
postprandial
metabolism,
including
modulation
of
insulin
secretion
food
intake.
They
are
secreted
from
enteroendocrine
cells
the
intestinal
epithelium
following
ingestion,
act
at
multiple
target
sites
pancreatic
islets
brain.
With
recent
development
agonists
targeting
GLP‐1
GIP
receptors
for
treatment
type
2
diabetes
obesity,
ongoing
new
incretin‐based
drugs
with
improved
efficacy,
there
is
great
interest
understanding
physiology
pharmacology
these
hormones.
image
Nature Metabolism,
Journal Year:
2024,
Volume and Issue:
6(10), P. 1866 - 1885
Published: Aug. 19, 2024
The
introduction
of
the
highly
potent
incretin
receptor
agonists
semaglutide
and
tirzepatide
has
marked
a
new
era
in
treatment
type
2
diabetes
obesity.
With
normalisation
glycated
haemoglobin
levels
weight
losses
around
15-25%,
therapeutic
goals
that
were
previously
unrealistic
are
now
within
reach,
clinical
trials
have
documented
these
effects
associated
with
reduced
risk
cardiovascular
events
premature
mortality.
Here,
I
review
this
remarkable
development
from
earliest
observations
glucose
lowering
modest
native
glucagon-like
peptide
(GLP)-1
short
acting
compounds,
to
recent
active
formulations
molecules.
will
classify
agents
as
GLP-1-based
therapies
understanding
compounds
or
combinations
may
actions
on
other
receptors
well.
physiology
GLP-1
is
discussed
well
its
mechanisms
obesity,
particular,
role
sensory
afferents
brain.
provide
details
regarding
for
anti-obesity
therapy
discuss
possible
mechanism
behind
their
beneficial
adverse
events.
Finally,
highlight
pharmacological
developments,
including
oral
agents,
important
questions
maintenance
therapy.
Molecular Metabolism,
Journal Year:
2025,
Volume and Issue:
95, P. 102118 - 102118
Published: Feb. 28, 2025
Glucose-dependent
insulinotropic
polypeptide
(GIP)
was
the
first
incretin
identified
and
plays
an
essential
role
in
maintenance
of
glucose
tolerance
healthy
humans.
Until
recently
GIP
had
not
been
developed
as
a
therapeutic
thus
has
overshadowed
by
other
incretin,
glucagon-like
peptide
1
(GLP-1),
which
is
basis
for
several
successful
drugs
to
treat
diabetes
obesity.
However,
there
rekindling
interest
biology
recent
years,
great
part
due
pharmacology
demonstrating
that
both
GIPR
agonism
antagonism
may
be
beneficial
treating
obesity
diabetes.
This
apparent
paradox
reinvigorated
field,
led
new
lines
investigation,
deeper
understanding
GIP.
In
this
review,
we
provide
detailed
overview
on
multifaceted
nature
discuss
implications
signal
modification
various
diseases.
Following
its
classification
hormone,
emerged
pleiotropic
hormone
with
variety
metabolic
effects
outside
endocrine
pancreas.
The
numerous
render
interesting
candidate
development
pharmacotherapies
obesity,
diabetes,
drug-induced
nausea
bone
neurodegenerative
disorders.
Molecular Metabolism,
Journal Year:
2024,
Volume and Issue:
88, P. 102006 - 102006
Published: Aug. 10, 2024
Obesity
represents
a
global
health
crisis
with
significant
patient
burdens
and
healthcare
costs.
Despite
the
advances
glucagon-like
peptide-1
(GLP-1)
receptor
agonists
in
treating
obesity,
unmet
needs
remain.
This
study
characterizes
novel
glucose-dependent
insulinotropic
polypeptide
(GIPR)
peptide
antagonist,
AT-7687,
evaluating
its
potential
to
enhance
obesity
treatment.
We
assessed
vitro
potency
pharmacokinetics
of
alongside
therapeutic
effects
when
administered
subcutaneously
(SC)
alone
combination
liraglutide
high-fat-diet-fed
obese
non-human
primates
(NHP).
The
spanned
42-day
treatment
period
15-day
washout
period.
AT-7687
demonstrated
subnanomolar
cAMP
antagonistic
(pKB
9.5)
HEK-293
cells
27.4
h
half-life
NHPs.
It
effectively
maintained
weight
stability
monkeys,
whereas
placebo
recipients
had
an
8.6%
increase
by
day
42
(P
=
0.01).
Monotherapy
resulted
12.4%
reduction
compared
0.03)
combining
led
16.3%
0.0002).
therapy
significantly
improved
metabolic
markers,
reducing
insulin
levels
52%
0.008),
glucose
30%
0.02),
triglycerides
39%
0.05),
total
cholesterol
29%
0.03),
LDL
48%
0.003)
placebo.
was
well
tolerated
not
associated
any
side
effects.
underscores
as
promising
addition
current
treatments.
Peptides,
Journal Year:
2025,
Volume and Issue:
187, P. 171380 - 171380
Published: March 11, 2025
Recent
studies
with
peptide-based
incretin
herapies
have
focussed
mainly
on
the
glucagon-like
peptide-1
(GLP-1)
receptor
agonist
semaglutide
and
dual
tirzepatide
that
engages
receptors
for
GLP-1
glucose-dependent
insulinotropic
polypeptide
(GIP).
Randomised
clinical
trials
'real-world'
confirmed
marked
glucose-lowering
weight-lowering
efficacy
of
these
agents
across
diverse
populations.
These
include
different
ethnic
groups,
young
elderly
individuals
without
diabetes
and/or
overweight
or
obesity.
also
protections
against
development
progression
cardiovascular
renal
diseases
are
additive
to
benefits
conferred
by
improved
control
blood
glucose
body
weight.
Emerging
evidence
suggests
therapies
could
additionally
ameliorate
fatty
liver
disease,
chronic
inflammation,
sleep
apnea
possibly
degenerative
bone
disorders
cognitive
decline.
New
incretin-based
peptide
in
a
long-acting
glucagon
(LY3324954),
GLP-1/glucagon
agonists
(survodutide,
pemvidutide,
mazdutide,
G49),
triple
GLP-1/GIP/glucagon
(retatrutide,
efocipegtrutide),
combination
amylin
analogue
cagrilintide
(CagriSema),
unimolecular
GLP-1/amylin
(amycretin),
GIP
antibody
agonism
(MariTide).
The
creation
multi-targeting
synthetic
peptides
provides
opportunities
management
type
2
obesity
as
well
new
therapeutic
approaches
an
expanding
list
associated
co-morbidities.
aim
review
is
acquaint
reader
developments
field
from
2023
present
(February
2025).
Diabetologia,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 10, 2025
Abstract
Aims/hypothesis
An
intronic
variant
(rs10830963)
in
MTNR1B
(encoding
the
melatonin
receptor
type
2
[MT2])
has
been
shown
to
strongly
associate
with
impaired
glucose
regulation
and
elevated
diabetes
prevalence.
However,
missense
variants
have
conflicting
results
on
diabetes.
Thus,
we
aimed
gain
further
insights
into
impact
of
coding
prevalence
related
phenotypes.
Methods
We
conducted
a
cross-sectional
study,
performing
burden
testing
glycaemic
phenotypes
(
N
=248,454,
without
diabetes),
other
cardiometabolic
=330,453)
(case–control
study;
=263,739)
UK
Biobank.
Similar
was
performed
Danish
Inter99
participants
=5711),
(DD2
cohort
serving
as
cases
[
=2930]
controls
=4243]).
Finally,
evaluated
effects
melatonin-induced
response
recall-by-genotype
study
individuals
Results
In
Biobank,
were
not
associated
phenotypes,
including
prevalence,
except
that
carriers
causing
MT2
signalling
exhibited
higher
HbA
1c
levels
compared
non-carriers
(effect
size,
β,
0.087
SD
[95%
CI
0.039,
0.135]).
Similarly,
no
significant
associations
observed
population.
impairing
demonstrated
nominally
lower
glucose-stimulated
insulin
(β
−0.47
−0.82,
−0.11]).
A
reduced
also
−476.0
−928.6,
−24.4])
or
rs10830963
−390.8
−740.1,
−41.6])
after
treatment.
Conclusions/interpretation
The
previously
impairment
replicated
yet
had
levels.
Data
availability
(Inter99
study)
are
available
reasonable
request
from
corresponding
author.
Requests
for
DD2
data
through
application
form
at
https://dd2.dk/forskning/ansoeg-om-data
.
Access
Biobank
can
be
requested
website
https://www.ukbiobank.ac.uk/enable-your-research
).
Graphical
Frontiers in Endocrinology,
Journal Year:
2025,
Volume and Issue:
16
Published: March 17, 2025
Glucose-dependent
insulinotropic
polypeptide
(GIP)
is
one
of
two
incretin
hormones
playing
key
roles
in
the
control
food
intake,
nutrient
assimilation,
insulin
secretion
and
whole-body
metabolism.
Recent
pharmacological
advances
clinical
trials
show
that
unimolecular
co-agonists
target
receptors
for
incretins
-
GIP
glucagon-like
peptide
1
(GLP-1)
offer
more
effective
treatment
strategies
obesity
type
2
diabetes
mellitus
(T2D)
compared
with
GLP-1
receptor
(GLP1R)
agonists
alone,
suggesting
previously
underappreciated
regulating
intake
body
weight.
The
mechanisms
by
which
regulates
energy
balance
remain
controversial
as
both
agonism
antagonism
(GIPR)
produce
weight
loss
improve
metabolic
outcomes
preclinical
models.
studies
have
shown
GIPR
signalling
central
nervous
system
(CNS),
especially
regions
brain
regulate
balance,
essential
its
action
on
appetite
regulation.
This
finding
has
sparked
interest
understanding
engages
circuits
to
reduce
In
this
review,
we
present
knowledge
around
actions
regulation
potential
GIPR/GLP1R
may
balance.
Medicina,
Journal Year:
2025,
Volume and Issue:
61(4), P. 664 - 664
Published: April 3, 2025
The
heterogeneity
among
patients
with
obesity
is
particularly
evident
in
the
weight
loss
response
to
interventions
such
as
diets,
drugs,
devices
and
surgery.
Obesity
can
be
“catalogued”
into
four
phenotypes:
hungry
brain
(abnormal
satiety
for
alteration
of
gut–brain
axis),
emotional
hunger
(hedonic
eating),
gut
duration
faster
gastric
emptying)
slow
burning
(slowing
metabolic
rate).
Phenotypes
are
grafted
onto
this
complexity,
recognition
which
allows
personalized
medicine
increasingly
targeted
therapies.
Although
there
no
standardized
treatment
protocols,
we
present
management
options
consisting
lifestyle
modifications
pharmacologic
Nutritional
advice
encouragement
adequate
physical
activity
lead
increased
self-efficacy
promote
a
sense
well-being
when
coupled
psychological
approaches
involving
mindful
eating.
In
summary,
has
complex
pathophysiology
best
addressed
through
therapeutic
process
suited
phenotype
encountered
synergy
multifactorial
interventions.
Pharmacology & Therapeutics,
Journal Year:
2025,
Volume and Issue:
unknown, P. 108846 - 108846
Published: April 1, 2025
Class
B
G
protein-coupled
receptors
(GPCRs)
are
a
subfamily
of
15
peptide
hormone
with
diverse
roles
in
physiological
functions
and
disease
pathogenesis.
Over
the
past
decade,
several
novel
therapeutics
targeting
these
have
been
approved
for
conditions
like
migraine,
diabetes,
obesity,
many
which
ground-breaking
first-in-class.
Most
agonist
analogues
modified
endogenous
sequences
to
enhance
receptor
activation
or
stability.
Several
small
molecule
monoclonal
antibody
antagonists
also
late-stage
development.
Differences
sequence
structure
therapeutic
ligands
lead
distinct
signalling
profiles,
including
biased
behaviour
inhibition
specific
pathways.
Understanding
this
pharmacology
offers
unique
development
opportunities
improving
efficacy
reducing
adverse
effects.
This
review
summarises
current
knowledge
on
ligand
bias
class
GPCR
drugs,
highlights
strategies
refine
exploit
their
pharmacological
discusses
key
considerations
related
structure,
localisation,
regulation
developing
new
therapies.
