Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 17, 2025
Abstract
The
use
of
incretin
analogues
has
emerged
in
recent
years
as
an
effective
approach
to
achieve
both
enhanced
insulin
secretion
and
weight
loss
type
2
diabetes
(T2D)
patients.
Agonists
which
bind
stimulate
multiple
receptors
have
shown
particular
promise.
However,
off
target
effects,
including
nausea
diarrhoea,
remain
a
complication
using
these
agents,
modified
versions
with
optimized
pharmacological
profiles
and/or
biased
signaling
at
the
cognate
are
increasingly
sought.
Here,
we
describe
synthesis
properties
molecule
binds
glucagon-like
peptide-1
(GLP-1)
glucose-dependent
insulinotropic
polypeptide
(GIP)
(GLP-1R
GIPR)
enhance
secretion.
HISHS-2001
shows
increased
affinity
GLP-1R,
well
tendency
towards
reduced
internalization
recycling
this
receptor
versus
FDA-approved
dual
GLP-1R/GIPR
agonist
tirzepatide.
also
displayed
significantly
greater
bias
cAMP
generation
β-arrestin
recruitment
compared
In
contrast,
G
αs
was
lower
tirzepatide
but
higher
GIPR.
Administered
obese
hyperglycaemic
db/db
mice,
circulating
whilst
lowering
body
HbA1c
similar
efficacy
substantially
doses.
Thus,
represents
novel
improved
profile.
Язык: Английский
In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist
Diabetes Obesity and Metabolism,
Год журнала:
2022,
Номер
24(11), С. 2090 - 2101
Опубликована: Июнь 9, 2022
Abstract
Aims
To
describe
the
in
vitro
characteristics
and
antidiabetic
vivo
efficacy
of
novel
glucagon‐like
peptide‐1
receptor
agonist
(GLP‐1RA)
GL0034.
Materials
Methods
Glucagon‐like
(GLP‐1R)
kinetic
binding
parameters,
cyclic
adenosine
monophosphate
(cAMP)
signalling,
endocytosis
recycling
were
measured
using
HEK293
INS‐1832/3
cells
expressing
human
GLP‐1R.
Insulin
secretion
was
cells,
mouse
islets
islets.
Chronic
administration
studies
to
evaluate
weight
loss
glycaemic
effects
performed
db/db
diet‐induced
obese
mice.
Results
Compared
leading
GLP‐1RA
semaglutide,
GL0034
showed
increased
affinity
potency‐driven
bias
favour
cAMP
over
GLP‐1R
β‐arrestin‐2
recruitment.
secretory
responses
similar
for
both
ligands.
(6
nmol/kg)
led
at
least
as
much
lowering
blood
glucose
did
semaglutide
a
higher
dose
(14
nmol/kg).
Conclusions
is
G
protein‐biased
that
shows
powerful
mice,
may
serve
promising
new
patients
with
type
2
diabetes.
Язык: Английский
Development of a novel Fc fusion protein dual glucagon‐like peptide‐1 and gastric inhibitory polypeptide receptor agonists
Diabetes Obesity and Metabolism,
Год журнала:
2023,
Номер
25(11), С. 3356 - 3365
Опубликована: Авг. 14, 2023
Abstract
Aim
To
develop
and
investigate
an
imbalanced
dual
gastric
inhibitory
polypeptide
receptor
(GIPR)/glucagon‐like
peptide‐1
(GLP‐1
R)
agonist
with
Fc
fusion
protein
structure.
Methods
We
designed
constructed
that
is
a
(HEC‐CG115)
empirically
optimized
potency
ratio
for
GLP‐1R
GIPR.
The
long‐term
effects
of
HEC‐CG115
on
body
weight
glycaemic
control
were
evaluated
in
diet‐induced
obese
mice
diabetic
db/db
mice.
Repeat
dose
toxicity
assays
performed
to
the
safety
profile
Sprague‐Dawley
rats.
Results
displayed
high
GIPR
relatively
low
GLP‐1R,
we
labelled
it
‘imbalanced’.
In
animal
models,
(3
nmol/kg)
led
more
loss
than
semaglutide
at
higher
(10
model
(one
every
3
days)
reduced
fasting
blood
glucose
glycated
haemoglobin
levels
similar
those
after
(once
daily)
same
dose.
4‐week
subcutaneous
study
conducted
assess
biosafety
HEC‐CG115,
no
observed
adverse
effect
level
was
determined
be
mg/kg.
Conclusion
novel
agonism
shows
superior
loss,
metabolic
improvement
has
optimal
according
repeat‐dose
study.
Therefore,
use
appears
safe
effective
treatment
obesity
type
2
diabetes.
Язык: Английский
RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis
Journal of Molecular Endocrinology,
Год журнала:
2023,
Номер
70(4)
Опубликована: Март 21, 2023
G
protein-coupled
receptors
(GPCRs)
have
a
critical
role
in
energy
homeostasis,
contributing
to
food
intake,
expenditure
and
glycaemic
control.
Dysregulation
of
can
lead
metabolic
syndrome
(abdominal
obesity,
elevated
plasma
triglyceride,
LDL
cholesterol
glucose,
high
blood
pressure),
which
is
associated
with
an
increased
risk
developing
diabetes
mellitus,
non-alcoholic
fatty
liver
disease
cardiovascular
complications.
As
the
prevalence
these
chronic
diseases
continues
rise
worldwide,
there
need
understand
molecular
mechanisms
by
regulated
facilitate
development
effective
therapeutic
strategies
treat
prevent
conditions.
In
recent
years,
drugs
targeting
GPCRs
been
focus
efforts
improve
treatments
for
type-2
GLP-1R
agonists
particular
success.
this
review,
we
on
nine
roles
homeostasis
that
are
current
emerging
targets
obesity
diabetes.
We
discuss
findings
from
pre-clinical
models
clinical
trials
challenges
must
be
overcome
before
routinely
used
clinics.
also
describe
new
insights
into
how
signal,
including
accessory
proteins,
biased
signalling,
complex
spatial
signalling
could
provide
unique
opportunities
develop
more
efficacious
therapies
fewer
side
effects.
Finally,
combined
therapies,
multiple
targeted,
may
outcomes
reduce
off-target
Язык: Английский
Sustained metabolic benefits of ΔTRTX‐Ac1, a tarantula venom‐derived peptide, when administered together with exenatide in high‐fat fed mice
Diabetes Obesity and Metabolism,
Год журнала:
2023,
Номер
26(1), С. 329 - 338
Опубликована: Окт. 11, 2023
Abstract
Aim
The
aim
of
the
present
study
was
to
assess
long‐term
therapeutic
efficacy
a
recently
discovered
28
amino
acid
peptide,
Δ‐theraphotoxin‐Ac1
(Δ‐TRTX‐Ac1),
originally
isolated
from
venom
Aphonopelma
chalcodes
tarantula.
Δ‐TRTX‐Ac
has
previously
been
shown
improve
pancreatic
beta‐cell
function
and
suppress
appetite.
Materials
Methods
Δ‐TRTX‐Ac1
administered
twice
daily
in
high‐fat
fed
(HFF)
mice
with
streptozotocin
(STZ)‐induced
insulin
deficiency,
namely
HFF/STZ
mice,
for
days
both
alone
combination
venom‐derived
glucagon‐like
peptide‐1
(GLP‐1)
mimetic,
exenatide.
Results
Initial
pharmacokinetic
profiling
ΔTRTX‐Ac1
revealed
plasma
half‐life
2
h
also
evidenced
pancreas
12
post‐injection.
Accordingly,
HFF‐STZ
received
twice‐daily
injections
Δ‐TRTX‐Ac1,
exenatide
or
peptides
days.
As
anticipated,
presented
hyperglycaemia,
impaired
glucose
tolerance,
decreased
disturbed
islet
morphology.
Administration
reduced
body
weight,
improved
tolerance
augmented
content
while
decreasing
glucagon
content.
Exenatide
had
similar
benefits
on
weight
hormone
reducing
circulating
glucose.
energy
expenditure
day
whereas
no
impact.
All
treatment
regimens
restored
area
towards
lean
control
levels,
which
linked
significantly
elevated
proliferation
rates.
In
terms
combined
over
individual
agents,
there
augmentation
ambulatory
activity
therapy,
these
increased
glucagon.
Conclusion
These
data
highlight
promise
diabetes,
suggestion
that
could
be
enhanced
through
administration
Язык: Английский
Metabolic State Determines Central and Peripheral Mechanisms of Liraglutide-Enhanced Insulin Secretion
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 25, 2024
Abstract
While
liraglutide
effectively
treats
type
2
diabetes
(T2D)
and
obesity,
its
mechanism
of
action
across
disease
progression
remains
poorly
understood.
Liraglutide
selectively
enhances
GSIS
in
islets
from
glucose-intolerant
donors
exposed
to
prediabetic
conditions,
but
not
normoglycemic
or
T2D
islets.
In
healthy
mice,
liraglutide's
insulinotropic
effect
requires
tanycyte-mediated
central
transport,
whereas
glucose
intolerance
it
acts
directly
on
Additionally,
reduces
blood
mice
through
insulin-independent
mechanisms
involving
decreased
gluconeogenesis
enhanced
peripheral
uptake.
These
findings
demonstrate
that
the
therapeutic
window
for
pancreatic
effects
may
be
optimal
during
prediabetes,
while
actions
predominate
other
metabolic
states.
Язык: Английский
Comparative Analysis of the Anti-Inflammatory Effects of Liraglutide and Dulaglutide
International Heart Journal,
Год журнала:
2024,
Номер
65(3), С. 548 - 556
Опубликована: Май 14, 2024
Inflammation
plays
a
pathophysiological
role
in
atherosclerosis
and
its
clinical
consequences.
In
addition
to
glycemic
control,
glucagon-like
peptide-1
receptor
agonists
(GLP-1RAs)
are
of
wide
concern
for
cardioprotective
effects.
The
structure,
half-life,
homology,
efficacy
GLP-1RAs
exhibit
remarkable
disparity.
Several
studies
have
compared
the
disparities
anti-inflammatory
effects
between
daily
weekly
GLP-1RAs.
This
study
aimed
compare
similarities
differences
liraglutide
dulaglutide
terms
inhibiting
atherosclerotic
inflammation
improving
co-cultured
endothelial
cell
function.
expression
markers
was
examined
by
immunofluorescence,
Western
blotting,
real-time
PCR.
tube-forming
ability
cells
tested
on
Matrigel.
results
verify
that
10/50/100
nmol/L
100
markedly
suppressed
inflammatory
factors
LPS-induced
after
24
72
hours,
respectively.
Moreover,
they
promoted
polarization
M1
macrophages
toward
M2
phenotype
improved
function
cells.
Both
ameliorate
development.
difference
two
resided
extended
intervention
duration
required
observe
effect
dulaglutide,
demonstrated
superior
dose-dependent
manner.
We
provide
potential
strategy
understand
dynamics
drug
action
possible
timing
administration.
Язык: Английский