12 research outputs found
Estimulación del sistema incretina en el remodelado cardiaco inducido por diabetes tipo 2 e isquemia/reperfusión experimentales
Full text linkTesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 20-02-2015La
enfermedad
cardiovascular
es
la
principal
causa
de
muerte
en
el
mundo
actual.
Estudios
clínicos
y
experimentales
han
demostrado
que
la
diabetes
per
se,
independientemente
de
otras
patologías
cardiovasculares
asociadas,
puede
inducir
un
daño
crónico
en
el
miocardio.
Esta
nueva
entidad
recibe
el
nombre
de
miocardiopatía
diabética
y
está
caracterizada
por
alteraciones
moleculares
de
origen
metabólico
y
eventos
de
apoptosis,
hipertrofia
y
fibrosis,
que
tienen
como
consecuencia
la
aparición
de
disfunción
diastólica
y
sistólica,
que
pueden
dar
lugar
a
episodios
de
insuficiencia
cardiaca
e
infarto
agudo
de
miocardio.
Sin
embargo,
los
mecanismos
intracelulares
involucrados
no
están
completamente
descritos,
lo
que
conlleva
la
ausencia
de
un
tratamiento
específico.
Además,
a
pesar
de
los
avances
significativos
en
la
terapia
médica
y
las
mejoras
en
la
prevención
primaria
y
secundaria
de
la
enfermedad
arterial
coronaria,
el
infarto
agudo
de
miocardio
continúa
siendo
la
principal
causa
de
muerte
en
estos
pacientes
y
a
nivel
global.
La
reperfusión
precoz
del
miocardio
infartado,
bien
por
intervención
percutánea
coronaria
o
bien
por
trombolisis,
es
la
terapia
actual
efectiva
para
reducir
el
tamaño
del
infarto,
preservar
la
función
sistólica
del
ventrículo
izquierdo
y
reducir
la
morbilidad
y
mortalidad
cardiovascular
en
los
pacientes.
Mientras
que
el
tamaño
de
infarto
es
un
importante
predictor
de
mortalidad,
la
insuficiencia
cardiaca
y
el
remodelado
deletéreo
del
ventrículo
izquierdo
son
determinantes
del
pronóstico
de
la
función
cardiaca
y
eventos
cardiovasculares
futuros.
Fármacos
basados
en
la
estimulación
del
sistema
incretina
como
los
inhibidores
de
la
dipeptidil
peptidasa-‐4,
y
los
agonistas
de
GLP-‐1,
son
una
nueva
clase
de
drogas
antidiabéticas
que
podrían
ejercer
una
acción
dual
sobre
la
sensibilidad
a
insulina
y
directamente
sobre
la
célula
cardiaca.
En
un
modelo
experimental
de
miocardiopatía
diabética,
las
ratas
diabéticas
tipo-‐2
presentaron
hiperglucemia,
hiperlipemia,
resistencia
a
insulina,
disfunción
cardiaca,
remodelado
(hipertrofia
y
fibrosis)
y
apoptosis
miocárdica.
El
tratamiento
con
sitagliptina,
un
inhibidor
de
la
DPP-‐4,
mejoró
el
control
glucémico
y
el
perfil
lipídico
mediante
el
aumento
de
GLP-‐1
endógeno
y
el
consiguiente
incremento
de
los
niveles
de
insulina.
Además,
mejoró
la
función
cardiaca
y
redujo
los
niveles
de
expresión
de
moléculas
profibróticas,
hipertróficas
y
apoptóticas.
En
particular,
en
miocitos
y
fibroblastos
cardiacos
en
cultivo,
altas
concentraciones
de
glucosa
o
de
ácido
palmítico
estimularon
la
expresión
de
moléculas
profibróticas,
proceso
que
fue
revertido
con
el
pretratamiento
con
GLP-‐1
exógeno.
Este
efecto
podría
estar
mediado
por
la
activación
de
PPARβ/δ,
receptor
nuclear
de
ácidos
grasos
que
actúa
como
factor
de
transcripción
y
que
podría
controlar
la
expresión
de
genes
profibróticos
como
fibronectina.
Por
otra
parte,
el
metabolito
mayoritario
de
la
degradación
de
GLP-‐1,
GLP-‐1(9-‐36),
produjo
similares
efectos
antifibróticos
que
GLP-‐1
lo
que
podría
reforzar
el
efecto
insulino-‐independiente
del
sistema
incretina
sobre
el
corazón.
Por
otro
lado,
el
tratamiento
con
un
agonista
del
receptor
de
GLP-‐1
en
un
modelo
experimental
de
daño
por
isquemia/reperfusión
en
cerdo
presentó
efectos
cardioprotectores
reduciendo
el
tamaño
de
infarto
y
mejorando
la
función
sistólica
del
ventrículo
izquierdo.
Este
tratamiento
redujo
el
remodelado
cardiaco
medido
por
la
presencia
de
hipertrofia
cardiaca
y
celular
compensatoria,
y
fibrosis
intersticial.
Estos
datos
sugieren
que
la
inducción
del
sistema
incretina
podría
reducir
el
daño
miocárdico
tanto
a
nivel
crónico
en
la
miocardiopatía
diabética
como
en
eventos
agudos
como
el
infarto
agudo
de
miocardioCardiovascular
diseases
are
currently
the
leading
causes
of
death
in
the
world.
Experimental
and
clinical
studies
have
demonstrated
the
existence
of
heart
failure
in
diabetic
patients
independently
of
any
vascular
disease
or
hypertension.
Diabetic
cardiomyopathy
is
characterized
by
molecular
alterations
due
to
metabolic
changes
and
events
of
apoptosis,
hypertrophy
and
fibrosis,
which
can
lead
to
heart
dysfunction
and
failure
and
acute
myocardial
infarction.
However,
the
intracellular
mechanisms
involved
are
not
fully
described,
which
entails
the
absence
of
specific
treatment.
Moreover,
despite
the
significant
advances
in
medical
therapy
and
improvements
in
primary
and
secondary
prevention
of
coronary
artery
disease,
acute
myocardial
infarction
remains
the
leading
cause
of
death
in
these
patients.
Early
reperfusion
of
infarcted
myocardium
by
either
percutaneous
coronary
intervention
or
thrombolysis
are
effective
in
reducing
infarct
size,
preserving
left
ventricular
systolic
function
and
reducing
cardiovascular
morbidity
and
mortality.
However,
ischemia/reperfusion
leads
to
myocardial
remodeling
which
includes
deletereous
responses
like
apoptosis
and
fibrosis.
These
events
will
be
determinants
of
heart
function
and
future
cardiovascular
events.
Drugs
based
on
incretin
system
stimulation,
inhibitors
of
dipeptidyl
peptidase-‐4
and
GLP-‐1
agonists,
are
a
new
class
of
antidiabetic
drugs
that
could
exert
a
dual
action,
raising
insulin
sensitivity
and
also
directly
affecting
the
cardiac
cell.
In
an
experimental
model
of
diabetic
cardiomyopathy,
type-‐2
diabetic
rats
showed
hyperglycemia,
hyperlipidemia,
insulin
resistance,
cardiac
dysfunction,
remodeling
(hypertrophy
and
fibrosis)
and
myocardial
apoptosis.
Treatment
with
sitagliptin,
a
DPP-‐4
inhibitor,
controlled
glycemia
and
lipidemia
through
the
stabilization
of
endogenous
GLP-‐1
and
increasing
insulin
levels.
In
addition,
it
improved
cardiac
function
and
reduced
levels
of
expression
of
fibrotic,
hypertrophic
and
apoptotic
molecules.
During
in
vitro
studies
with
cardiac
myocytes
and
fibroblasts,
high
concentrations
of
glucose
or
palmitic
acid
increased
the
expression
of
profibrotic
molecules.
This
effect
was
reversed
by
the
pretreatment
with
exogenous
GLP-‐1,
and
likely
mediated
by
PPARβ/δ
activation,
a
fatty
acid
nuclear
receptor
that
acts
as
a
transcription
factor
and
could
control
the
expression
of
profibrotic
genes
such
as
fibronectin.
Moreover,
the
major
metabolite
of
GLP-‐1,
GLP-‐1
(9-‐36),
produced
similar
antifibrotic
effects
to
those
of
GLP-‐1,
which
might
reinforce
the
insulin-‐independent
effect
of
the
incretin
system
on
the
heart.
In
this
regard,
treatment
with
a
GLP-‐1
receptor
agonist,
exenatide,
significantly
reduced
the
infarct
size
in
an
experimental
model
of
ischemia/reperfusion
injury
in
pigs.
Furthermore,
this
drug
reduced
cardiac
remodeling
measured
by
cardiac
hypertrophy
and
interstitial
fibrosis,
and
improved
left
ventricle
systolic
and
mechanical
function
at
one
week
and
one
month
after
myocardial
infarction.
These
data
suggest
that
the
stimulation
of
the
incretin
system
could
reduce
diabetic
cardiomyopathy
and
ischemia/reperfusion
associated
cardiac
damage
Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms
Get PDFBackground:Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart.Methods:Goto-Kakizaki (GK) rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin) or vehicle (n=10, each). After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays.Results:Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36), alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells.Conclusions:Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36) promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actionsThis work was supported by national funding from Ministerio de Educación y Ciencia (SAF2009-08367), Comunidad de Madrid (CCG10-UAM/
BIO-5289), and a unrestricted grant from by Merck/MS
Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: Role of GLP-1 isoforms in Glut4 receptor trafficking
Full text linkBackground: The distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization. Methods: Type-II diabetic GK (Goto-Kakizaki), sitagliptin-treated GK (10 mg/kg/day) and wistar rats (n = 10, each) underwent echocardiographic evaluation, and positron emission tomography scanning for [ 18 F]-2-fluoro-2-deoxy-d-glucose ( 18 FDG). Hearts and plasma were isolated for biochemical approaches. Cultured cardiomyocytes were examined for receptor distribution after incretin stimulation in high fatty acid or high glucose media. Results: Untreated GK rats exhibited hyperglycemia, hyperlipidemia, insulin resistance, and plasma GLP-1 reduction. Moreover, GK myocardium decreased 18 FDG assimilation and diastolic dysfunction. However, sitagliptin improved hyperglycemia, insulin resistance, and GLP-1 levels, and additionally, enhanced 18 FDG uptake and diastolic function. Sitagliptin also stimulated the sarcolemmal translocation of the glucose transporter-4 (Glut4), in detriment of the fatty acyl translocase (FAT)/CD36. In fact, Glut4 mRNA expression and sarcolemmal translocation were also increased after GLP-1 stimulation in high-fatty acid incubated cardiomyocytes. PI3K/Akt and AMPKα were involved in this response. Intriguingly, the GLP-1 degradation metabolite, GLP-1(9-36), showed similar effects. Conclusions: Besides of its anti-hyperglycemic effect, sitagliptin-enhanced GLP-1 may ameliorate diastolic dysfunction in type-II diabetes by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysisThis work was supported by national grants from Ministerio de Educación
y Ciencia (SAF2009-08367), Comunidad de Madrid (CCG10-UAM/BIO-5289),
and PIE13/00051 and PI14/00386 (IS. Carlos III). Merck Sharp and Dohme
(Darmstadt, Germany) provided sitagliptin and partial financial support to the
conduct of the stud
Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
Full text linkCardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying
mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor
blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the
fatty-acid accumulation and apoptotic responses have not been revealed.
Methods: Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker
Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was
examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes
were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose
exposed cells.
Results: In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis
and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis.
Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes,
high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation
of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and
apoptosis were also significantly ameliorated by eplerenone.
Conclusions: By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and
subsequent remodelling and diastolic dysfunction in obese/type-II diabetic ratsThis work was supported by national grants from Ministerio de Educación y
Ciencia (SAF2009-08367), Comunidad de Madrid (CCG10-UAM/BIO-5289),
FISS (PI10/00072), and a grant from by Pfizer (NY, USA), Spanish Ministry of
Economy and Competitiveness (MINECO) CTQ2011-23562. These grants were
used to provide consumables and animals required. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of
the manuscript. AF received funding from the European Union Seventh
Framework Programme [FP7/2007-2013] under grant agreement nº 26486
Targeting metabolic disturbance in the diabetic heart
No full textDiabetic cardiomyopathy is defined as ventricular dysfunction initiated by alterations in cardiac energy substrates in
the absence of coronary artery disease and hypertension. In addition to the demonstrated burden of cardiovascular
events associated with diabetes, diabetic cardiomyopathy partly explains why diabetic patients are subject to
a greater risk of heart failure and a worse outcome after myocardial ischemia. The raising prevalence and
accumulating costs of cardiovascular disease in diabetic patients underscore the deficiencies of tertiary prevention
and call for a shift in medical treatment. It is becoming increasingly clearer that the effective prevention and
treatment of diabetic cardiomyopathy require measures to regulate the metabolic derangement occurring in the
heart rather than merely restoring suitable systemic parameters. Recent research has provided deeper insight into
the metabolic etiology of diabetic cardiomyopathy and numerous heart-specific targets that may substitute or
reinforce current strategies. From both experimental and translational perspectives, in this review we first discuss
the progress made with conventional therapies, and then focus on the need for prospective metabolic targets that
may avert myocardial vulnerability and functional decline in next-generation diabetic careThis work was supported by national grants from Ministerio de Educación y
Ciencia (SAF2009-08367) and Comunidad de Madrid (CCG10-UAM/BIO-5289)
Correction: Sitagliptin Reduces Cardiac Apoptosis, Hypertrophy and Fibrosis Primarily by Insulin-Dependent Mechanisms in Experimental type-II Diabetes. Potential Roles of GLP-1 Isoforms
No full textCorrection: Sitagliptin Reduces Cardiac Apoptosis, Hypertrophy and Fibrosis Primarily by Insulin-Dependent Mechanisms in Experimental type-II Diabetes. Potential Roles of GLP-1 Isoforms.
No full textSitagliptin and metformin reduced T2DM-associated cell-death and fibrosis in the heart.
No full text<p>(<b>a</b>) By TUNEL, detection of apoptotic cells in the myocardium (see arrows) and heart vessel (see arrowheads). At the bottom, a typical striated-like pattern immunostaining of vinculin (see arrows). (<b>b</b>) Caspase-3 expression in the hearts. (<b>c</b>) Masson staining for wistar, GK and GK-treated hearts showing ECM accumulation (green-blue staining) (n=10, each group). (<b>d</b>) ECM protein [pro-type-I collagen and fibronectin (FN)] levels, and pro-fibrotic mRNA expression (TGFß<sub>1</sub> and CTGF) (n=10, each group). *p<0.05 and **p<0.01 vs. wistar. †p<0.05 and ††p<0.01 vs. GK rats.</p
GLP-1 reduced pro-fibrotic molecules in HF- or HG-stimulated cardiomyocytes.
No full text<p>(<b>a</b>) GLP1R expression in the GK model (left) (n=5, each group), and HL-1 stimulated cardiomyocytes (right). A representative QPCR-amplification plot of each rat or stimulated cell is also showed. (<b>b</b>) Intracellular (by WB and IF) and (<b>c</b>) secreted levels of fibronectin (FN) in GLP-1-pre-treated cardiomyocytes exposed to HF (0.25 mM) or HG (33 mM). (<b>d</b>) Pro-fibrotic expression (TGFß<sub>1</sub> and CTGF) in stimulated cardiomyocytes. *p<0.05 and **p<0.01 vs. control. †p<0.05 and ††p<0.01 vs. HF or HG.</p
Sitagliptin improved glucose intolerance in GK
No full text<p><b>rats</b>. Plasma (<b>a</b>) GLP-1, (<b>b</b>) insulin and (<b>c</b>) glucose were evaluated in the rats before (fasting) and 15-min/60-min after glucose loading (n=10, each group). The G-black arrow indicates glucose-overload. *p<0.05 and **p<0.01 vs. wistar. †p<0.05 and ††p<0.01 vs. GK rats. §p<0.05 and §§p<0.01 vs. fasting state.</p
