Diabetes Obesity and Metabolism,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 26, 2024
Abstract
Obesity
is
a
chronic
condition
demanding
effective
treatment
strategies,
among
which
pharmacotherapy
plays
critical
role.
As
glucagon‐like
peptide‐1
(GLP‐1)
agonist
approved
by
the
Food
and
Drug
Administration
(FDA)
for
long‐term
weight
management
in
adults
with
obesity,
liraglutide
semaglutide
have
great
loss
effect
through
reducing
food
intake
delaying
gastric
emptying.
The
emergence
of
unimolecular
polypharmacology,
utilizes
single
molecules
to
simultaneously
target
multiple
receptors
or
pathways,
marked
revolutionary
improvement
GLP‐1‐based
obesity
pharmacotherapy.
dual
tirzepatide
activates
both
GLP‐1
glucose‐dependent
insulinotropic
polypeptide
(GIP)
has
shown
enhanced
potency
compared
conventional
mono
agonist.
Furthermore,
emerging
data
suggests
that
GLP‐1/glucagon
(GCG)
agonist,
as
well
GLP‐1/GIP/GCG
triple
may
offer
superior
efficacy
over
This
review
summarizes
comprehensive
mechanisms
underlying
pronounced
advantages
GLP‐1/GIP
GLP‐1/GCG
reduction
obese
without
type
2
diabetes.
A
deeper
understanding
these
multitargeting
agonists
will
provide
insights
their
clinical
application
guide
development
new
drugs
treatment.
Molecular Metabolism,
Год журнала:
2025,
Номер
95, С. 102118 - 102118
Опубликована: Фев. 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.
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.
Gut,
Год журнала:
2024,
Номер
unknown, С. gutjnl - 334023
Опубликована: Ноя. 26, 2024
Clinically
effective
pharmacological
treatment(s)
for
metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD)
and
its
progressive
form
steatohepatitis
(MASH)
represent
a
largely
unmet
need
in
medicine.
Since
glucagon-like
peptide-1
receptor
agonists
(GLP-1RAs)
have
been
licensed
the
treatment
of
type
2
diabetes
mellitus
obesity,
they
were
one
first
drug
classes
to
be
examined
individuals
with
MASLD/MASH.
Successful
phase
randomised
clinical
trials
these
agents
resulted
progression
3
(principally
testing
long-term
efficacy
subcutaneous
semaglutide).
Over
last
few
years,
addition
GLP-1RAs,
newer
glucose-dependent
insulinotropic
peptide
and/or
glucagon
agonist
functions
tested,
increasing
evidence
from
histological
improvements
MASLD/MASH,
as
well
benefits
on
MASLD-related
extrahepatic
complications.
Based
this
background
evidence,
single,
dual
or
triple
incretin
are
becoming
an
attractive
promising
option
MASLD
MASH,
particularly
coexisting
obesity
mellitus.
In
narrative
review,
we
examine
rapidly
expanding
body
supporting
role
incretin-based
pharmacotherapies
delaying
reversing
MASH
progression.
We
also
discuss
biology
incretins
putative
hepatoprotective
mechanisms
managing
MASH.
Nutrients,
Год журнала:
2024,
Номер
16(19), С. 3245 - 3245
Опубликована: Сен. 25, 2024
Background:
Obesity
is
a
global
issue,
the
development
of
which
depends
on
many
interacting
factors.
Among
these,
hormones
secreted
in
gastrointestinal
tract
play
an
important
role.
The
aim
this
review
was
to
assess
impact
these
functions
adipose
tissue.
Methods:
analysis
based
latest
research
concerning
both
tissue
and
hormones.
Results:
It
found
that
can
significantly
affect
tissue,
directly
indirectly.
Some
hormones,
when
excess,
stimulate
formation
processes,
while
others
inhibit
them.
location
type
as
well
physiological
state
body.
should
also
be
noted
no
hormone
acts
isolation
but
close
cooperation
with
other
Conclusions:
relationship
between
their
role
obesity,
complex
evolving
field
study.
Further
necessary,
particularly
into
interactions
factors,
mutual
interactions.
Diabetes Obesity and Metabolism,
Год журнала:
2025,
Номер
27(3), С. 1507 - 1514
Опубликована: Янв. 6, 2025
Abstract
Aims
To
explore
the
relationship
between
weight
loss
and
insulin
sensitivity
in
response
to
tirzepatide
or
semaglutide.
Materials
Methods
We
conducted
a
post
hoc
exploratory
analysis
of
28‐week,
double‐blind,
randomized
trial
people
with
type
2
diabetes
treated
metformin,
15
mg,
semaglutide
1
mg
placebo.
evaluated
change
body
determined
from
hyperinsulinemic
euglycemic
clamp
(
M
value),
mixed‐meal
tolerance
testing
(Matsuda
index).
Results
Tirzepatide
was
associated
greater
improvement
than
assessed
using
clamps
p
<
0.001).
With
tirzepatide,
improvements
were
percent
R
=
−0.656,
0.0001).
semaglutide,
less
strongly
correlated
−0.268,
0.0820;
0.0242
vs.
tirzepatide).
In
regression
analyses,
slope
value
statistically
different
0.0461).
These
relationships
also
Matsuda
index
as
metric
sensitivity,
fat
mass
determinant
sensitivity.
Conclusions
Improvement
proportional
loss,
strength
association
tirzepatide.
analysis,
per
unit
The
following
treatment
not
simply
attributable
loss.
