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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(9): 765-771, 2020 Sep 12.
Artigo em Chinês | MEDLINE | ID: mdl-32894910

RESUMO

Objective: To explore the protective effect of human adipose-derived mesenchymal stem cells (AD-MSCs) and liraglutide on lipopolysaccharide (LPS) -induced acute lung injury (ALI) . Methods: AD-MSCs were cultured in vitro and randomly divided into 3 groups: control group, LPS group (30 mg/L) , and LPS (30 mg/L) +liraglutide (10 nM) group. MTT assay was used to detect the proliferation of AD-MSCs at 6, 24, 48 and 72 h. Annexin V-FITC / PI double staining flow cytometry was used to detect the apoptosis of the cells. Western blot was used to detect the expression of apoptotic proteins cleaved caspase-3, Bax and Bcl-2 at 72 h in vitro. For the in vivo experiment, 60 male SPF BALB/c mice were randomly divided into 5 groups: control group, ALI group, ALI+AD-MSCs group, ALI+Liraglutide group, and ALI+AD-MSCs+Lraglutide group. The mice were sacrificed on day 2 and day 7 after LPS treatment. HE staining was used to examine the pathological changes of the lungs of mice, and the scores of lung injury were measured. The lung tissues of mice were examined by immunohistochemistry, and the expression of the marker protein Nanog of mesenchymal stem cells was observed. BALF was collected, and the number of BALF neutrophils was counted by Rayleigh Giemsa staining. The wet/dry specific gravity of mouse lung tissue was recorded. Results: The apoptosis of AD-MSCs stimulated by LPS was significantly higher than that of the control group (P<0.05) , and the proliferation of AD-MSCs at 6, 24, 48 and 72 h was significantly lower than that of the control group (all P<0.05) . The addition of Liraglutide reduced the apoptosis of AD-MSCs (P<0.05) , and promoted the proliferation of AD-MSC at 6, 24, 48 and 72 h. Compared with the control group, in the 2 d and 7 d model groups, the lung injury pathology of ALI group had lung injury, increased number of neutrophils in BALF (65.63±1.34 vs 1.74±0.17, 51.67±1.35 vs 1.55±0.13) ×10(4)/ml (all P<0.05) , and increased W/D of lung tissues. The expression level of Nanog protein was low in the 7 d model group. Compared with the ALI group, in 2 d and 7 d model groups, the ALI+AD-MSCs group, the ALI+liraglutide group, and the ALI+AD-MSCs+liraglutide group showed reduced lung injury pathology, and the number of neutrophils was decreased, (37.04±1.23, 29.17±0.68) ×10(4) / ml (all P<0.05) in the ALI+AD -MSCs group, (39.58±1.67, 35.42±0.25) ×10(4) / ml in the ALI+Liraglutide group (all P<0.05) and (28.54±0.37, 21.46±0.89) ×10(4)/ml (all P<0.05) in the ALI+AD-MSCs+Liraglutide group. Lung tissue W/D in the ALI+AD-MSCs group, ALI+Liraglutide group and ALI+AD-MSCs+Liraglutide group showed the same trend. Nanog protein expression increased in the 7 d model group. Conclusions: AD-MSCs play a protective role in acute lung injury in mice under the synergistic effect of liraglutide.


Assuntos
Lesão Pulmonar Aguda , Células-Tronco Mesenquimais , Animais , Lipopolissacarídeos , Liraglutida , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos BALB C
2.
Medicine (Baltimore) ; 99(35): e21939, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871938

RESUMO

RATIONALE: Maturity-onset diabetes of the young type 5 (MODY 5) is a form of monogenic diabetes that is often accompanied by pancreatic dysfunction. To date, no cases of MODY 5 treated with glucagon-like peptide-1 receptor agonist (GLP-1RA) have been reported. We present the first case of MODY 5 treated with GLP-1RA. PATIENT CONCERNS: A 17-year-old woman, with a history of being operated for congenital ileal atresia at birth, was admitted to our hospital due to hyperglycemia. She had been clinically diagnosed with type 1 diabetes 1 month prior, and administered 14 units of insulin glargine 300 U/mL per day. DIAGNOSIS: She had hypopotassemia, hypomagnesaemia, pancreatic body, and tail defects, multiple renal cysts, and a family history of diabetes, and urogenital anomaly. Genetic testing revealed heterozygous deletion of hepatocyte nuclear transcription factor-1 beta, leading to the diagnosis of MODY 5. INTERVENTIONS: The patient was treated with multiple daily insulin injections for 9 days (22 units/d) before administration of GLP-1RA, and then liraglutide was initiated. OUTCOMES: Liraglutide treatment (0.6 mg/d) alone maintained the patient's glycated hemoglobin level below 7.0% for at least 12 months after discharge. A higher dose, 0.9 mg/d, of liraglutide was not tolerated by the patient due to nausea. Serum levels of C-peptide immunoreactivity were 1.15 ng/mL and 1.91 ng/mL, respectively, after 6 and 12 months of liraglutide therapy. LESSONS: GLP-1RA might be effective at regulating glucose metabolism by utilizing residual pancreatic endocrine function in patients with MODY 5. Imaging and genetic screening were helpful in the diagnosis of MODY 5.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Doenças Renais Císticas/tratamento farmacológico , Liraglutida/uso terapêutico , Adolescente , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Esmalte Dentário/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Feminino , Humanos , Hipoglicemiantes/farmacologia , Doenças Renais Císticas/diagnóstico por imagem , Liraglutida/farmacologia , Pâncreas/diagnóstico por imagem
3.
Med Sci Monit ; 26: e922210, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32238798

RESUMO

BACKGROUND The aim of this study was to explore the potential therapeutic targets and pathways of liraglutide against type 2 diabetes mellitus (T2DM) in streptozotocin-induced diabetic rats based on lncRNA sequencing. MATERIAL AND METHODS Male Wistar rats were randomly divided into 3 groups: the control group (n=10), the T2DM model group (high-sugar and high-fat diet, and streptozotocin-induced, n=11), and the liraglutide group (model plus liraglutide, n=10). After 8 weeks of drug treatment, lncRNA sequencing was used to identify the lncRNA therapeutic targets and their related protein-coding genes of liraglutide against T2DM, which were further studied by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to determine the major biological processes and pathways involved in the action of liraglutide treatment. Lastly, several lncRNA targets were randomly detected based on quantitative real-time polymerase chain reaction (QRT-PCR) to verify the accuracy of sequencing results. RESULTS A total of 104 lncRNA targets of liraglutide against T2DM were screened, with 27 upregulated and 77 downregulated, including NONRATT030354.2, MSTRG.1456.6, and NONRATT011758.2. The major biological processes involved were glucose and lipid metabolism and amino acid metabolism. Liraglutide had a therapeutic effect in T2DM, mainly through the Wnt, PPAR, amino acid metabolism signaling, mTOR, and lipid metabolism-related pathways. CONCLUSIONS In this study, we screened 104 lncRNA therapeutic targets and several signaling pathways (Wnt, PPAR, amino acid metabolism signaling pathway, mTOR, and lipid metabolism-related pathways) of liraglutide against T2DM based on lncRNA sequencing.


Assuntos
Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Masculino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos , Ratos Wistar
4.
Life Sci ; 252: 117648, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275937

RESUMO

AIMS: This study was conducted to determine the relationship between mesencephalic astrocyte-derived neurotrophic factor (MANF), autophagy and endoplasmic reticulum (ER) stress, and whether liraglutide (LRG) can protect ß cells, promote autophagy and alleviate ER stress by regulating MANF expression. MAIN METHODS: Human serum samples were collected from healthy controls (NC), simple hyperlipidemia (HLD), and newly diagnosed type 2 diabetes (T2D). The MANF levels were detected using ELISA. In vitro, after the mouse islet MIN6 cells were treated with glucose (GLU), palmitate (PA), thapsigargin (TG), LRG, and chloroquine (CQ), cell proliferation was detected using cell counting kit-8 (CCK-8), apoptosis-related protein cleaved caspase 3 (C-cas-3), ER stress, and autophagy-related proteins were detected by Western blotting, MANF, insulin, and C-cas-3 proteins were detected via immunofluorescence. Subcellular structures and autophagosomes were examined using electron microscopy. KEY FINDINGS: Compared with the NC group, the MANF levels in the HLD and T2D groups increased significantly. After ER stress induced by GLU, PA, and TG, cell viability decreased, while MANF, c-cas3, ERS, and autophagy-related proteins increased, which was related to the concentration of GLU, PA, and TG. Compared with the BSA group, the number of mitochondria and autophagosomes in the PA group increased and the mitochondria were damaged. In the PA and TG plus CQ groups, the effect was further exaggerated. But after co-treatment with LRG, the effects of GLU, PA, and TG were attenuated. SIGNIFICANCE: LRG protects islet ß cells from ER stress by upregulating MANF to promote autophagy turnover.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Liraglutida/farmacologia , Fatores de Crescimento Neural/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/metabolismo , Camundongos , Regulação para Cima/efeitos dos fármacos
5.
N Engl J Med ; 382(22): 2117-2128, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32233338

RESUMO

BACKGROUND: Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity. METHODS: In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56. RESULTS: A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment. CONCLUSIONS: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).


Assuntos
Estilo de Vida Saudável , Incretinas/uso terapêutico , Liraglutida/uso terapêutico , Obesidade Pediátrica/tratamento farmacológico , Adolescente , Glicemia/análise , Índice de Massa Corporal , Criança , Terapia Combinada , Método Duplo-Cego , Feminino , Gastroenteropatias/induzido quimicamente , Hemoglobina A Glicada/análise , Humanos , Incretinas/efeitos adversos , Injeções Subcutâneas , Liraglutida/efeitos adversos , Masculino , Obesidade Pediátrica/sangue , Obesidade Pediátrica/terapia
6.
Nutr Metab Cardiovasc Dis ; 30(4): 616-624, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32127340

RESUMO

BACKGROUND AND AIMS: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes. METHODS AND RESULTS: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911). CONCLUSION: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss. TRIAL REGISTRY NUMBER: NCT01761318.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Liraglutida/uso terapêutico , Perda de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
7.
Metabolism ; 106: 154190, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109448

RESUMO

INTRODUCTION AND AIM: Real-word data on the head-to-head comparisons among glucagon-like peptide-1 receptor agonists (GLP-1RA) are scant. Therefore, we aimed to compare the effectiveness of dulaglutide versus liraglutide and exenatide once weekly (exeOW) in type 2 diabetic (T2D) patients under routine care. METHODS: This was a retrospective, multicenter, real-world study on patients with T2D (aged 18-80) initiating a GLP-1RA between 2010 and 2018 at specialist outpatient clinics. We compared the effectiveness of dulaglutide versus liraglutide and exeOW on the changes in HbA1c (primary outcome), body weight, blood pressure and fasting glucose (secondary outcomes). Average follow-up was 5.9 months. Channelling biases were addressed with propensity score matching or multivariable adjustment. Meta-analyses of observational studies, covering the same comparisons, are also presented. RESULTS: 849, 1371 and 198 patients were included in the dulaglutide, liraglutide and exeOW groups, respectively. The reduction of HbA1c was greater with dulaglutide than with liraglutide (-0.24 ±â€¯0.08%; p = 0.003), and was confirmed in the meta-analysis of observational studies. In our study, dulaglutide showed similar effectiveness compared to exeOW. When these results were pooled with other observational studies, dulaglutide showed a greater reduction of HbA1c (-0.19%; p = 0.003) and body weight (-0.8 kg; p = 0.007). CONCLUSIONS: In a real-world scenario, dulaglutide reduced HbA1c more than liraglutide. Conversely, we found similar effect of dulaglutide and exeOW, with statistical differences arising solely when results were meta-analysed with those from other observational studies. Lack of up-titration for liraglutide and higher discontinuation rate for exeOW likely influenced the estimated treatment difference.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Liraglutida/administração & dosagem , Estudos Observacionais como Assunto/estatística & dados numéricos , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Esquema de Medicação , Quimioterapia Combinada , Exenatida/efeitos adversos , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
8.
Obesity (Silver Spring) ; 28(3): 529-536, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32090517

RESUMO

OBJECTIVE: Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight-loss medication. The present multisite study provides the first evaluation, in primary care, of the effect of the Centers for Medicare and Medicaid Services-based IBT benefit, delivered alone (with placebo) or in combination with liraglutide 3.0 mg. METHODS: The Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes (SCALE) IBT was a 56-week, randomized, double-blind, placebo-controlled, multicenter trial in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140) as an adjunct to IBT. RESULTS: At week 56, mean weight loss with liraglutide 3.0 mg plus IBT was 7.5% and 4.0% with placebo combined with IBT (estimated treatment difference [95% CI]-3.4% [-5.3% to -1.6%], P = 0.0003). Significantly more individuals on liraglutide 3.0 mg than placebo achieved ≥ 5% weight loss (61.5% vs. 38.8%; odds ratio [OR] 2.5% [1.5% to 4.1%], P = 0.0003), > 10% weight loss (30.5% vs. 19.8%; OR 1.8% [1.0% to 3.1%], P = 0.0469), and > 15% weight loss (18.1% vs. 8.9%; OR 2.3% [1.1% to 4.7%], P = 0.0311). Liraglutide 3.0 mg in combination with IBT was well tolerated, with no new safety signals identified. CONCLUSIONS: In a primary care setting, Centers for Medicare and Medicaid Services-based IBT produced clinically meaningful weight loss at 56 weeks, enhanced by the addition of liraglutide 3.0 mg.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Terapia Comportamental/métodos , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Método Duplo-Cego , Feminino , Humanos , Liraglutida/farmacologia , Masculino , Pessoa de Meia-Idade , Obesidade/psicologia , Resultado do Tratamento , Estados Unidos
9.
Cardiovasc Diabetol ; 19(1): 24, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093680

RESUMO

BACKGROUND: Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl). METHODS: Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting. RESULTS: We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1ß, TGF-ß1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably. CONCLUSIONS: In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.


Assuntos
Doença da Artéria Coronariana/prevenção & controle , Circulação Coronária/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Resistência à Insulina , Liraglutida/farmacologia , Microcirculação/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Zucker , Cloreto de Sódio na Dieta , Remodelação Ventricular/efeitos dos fármacos
10.
Biochem Biophys Res Commun ; 523(3): 666-671, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31948746

RESUMO

Liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist and incretin mimetic used for the treatment of Type 2 diabetes mellitus. It has also been shown to have a beneficial role in the cardiovascular system. Here, we investigated the mechanism by which liraglutide promotes angiogenesis using human umbilical vein endothelial cells (HUVECs). HUVECs were treated with various concentrations of liraglutide, and assessed by wound healing assay and tube formation assay as measures of angiogenesis. We found that liraglutide at 10 and 100 nmol/L greatly promoted the angiogenic ability of HUVECs. Next, we examined the JAK2/STAT3 signaling pathway and found that liraglutide treatment led to JAK2/STAT3 activation and significant increase in the angiogenic mediator expressions, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and endothelial nitric oxide synthase (eNOS) in HUVECs. Treatment with JAK2 inhibitor, AG490, in HUVECs successfully reduced the observed effects of liraglutide. We conclude that liraglutide promotes the angiogenic ability of HUVECs by activating the JAK2/STAT3 signaling pathway and upregulating its downstream factors, VEGF, bFGF and eNOS. Thus, liraglutide may provide ischemic relief for diabetic patients with cardiovascular diseases in addition to glycemic control.


Assuntos
Indutores da Angiogênese/farmacologia , Janus Quinase 2/metabolismo , Liraglutida/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipoglicemiantes/farmacologia
14.
J Bone Miner Metab ; 38(1): 117-125, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31471646

RESUMO

Pathogenic mutations in the melanocortin-4 receptor (MC4R) are associated with obesity, increased linear growth, and higher bone mass in children, and rodent studies have indicated an effect of the MC4R on bone turnover. Furthermore, GLP-1 receptor agonists (GLP-1 RAs) may influence bone metabolism. However, these associations have not been assessed in adults with pathogenic MC4R mutations. Thus, we wished to assess the impact of the MC4R on bone mass and metabolism. Secondly, we wished to investigate the impact of the GLP-1 RA liraglutide on bone mass in adults with pathogenic MC4R mutations. 17 patients with obesity-causing MC4R mutations (BMI: 35.5 ± 7.6) and 35 matched control participants with common obesity (BMI: 34.3 ± 7.1) underwent a DEXA scan for assessment of bone mineral density (BMD), bone mineral apparent density [BMAD = (BMD/√(bone area)], and bone turnover markers (BTMs). Individuals with a BMI above 28 (14 MC4R mutation carriers and 28 matched control participants) underwent 16 weeks treatment with liraglutide 3.0 mg. The MC4R group had higher BMD [mean difference: 0.065 g/m2 (- 0.008 to 0.138), p = 0.03], but BMAD and BTMS were not different compared to the control group. In response to liraglutide, BMAD increased in the control group, compared to no change in the MC4R group [mean group difference: 0.0007 (0.0001-0.001), p = 0.04]. In conclusion, BMD is increased in MC4R causal obesity compared to common obesity, but when corrected for body size (BMAD), bone mass was not increased, and no evidence of an influence of the MC4R on bone metabolism in adults was found. Liraglutide treatment did not change bone metabolism in MC4R causal obesity, but increased bone mass as measured by BMAD in common obesity.


Assuntos
Estatura/genética , Osso e Ossos/patologia , Mutação/genética , Receptor Tipo 4 de Melanocortina/genética , Absorciometria de Fóton , Adulto , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Liraglutida/farmacologia , Masculino , Tamanho do Órgão/efeitos dos fármacos
15.
Arterioscler Thromb Vasc Biol ; 40(1): 145-158, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31747801

RESUMO

OBJECTIVE: Cardiovascular outcome trials demonstrated that GLP-1 (glucagon-like peptide-1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus. Whether GLP-1 analogs reduce the risk for atherosclerosis independent of glycemic control is challenging to elucidate as the GLP-1R (GLP-1 receptor) is expressed on different cell types, including endothelial and immune cells. Approach and Results: Here, we reveal the cardio- and vasoprotective mechanism of the GLP-1 analog liraglutide at the cellular level in a murine, nondiabetic model of arterial hypertension. Wild-type (C57BL/6J), global (Glp1r-/-), as well as endothelial (Glp1rflox/floxxCdh5cre) and myeloid cell-specific knockout mice (Glp1rflox/floxxLysMcre) of the GLP-1R were studied, and arterial hypertension was induced by angiotensin II. Liraglutide treatment normalized blood pressure, cardiac hypertrophy, vascular fibrosis, endothelial dysfunction, oxidative stress, and vascular inflammation in a GLP-1R-dependent manner. Mechanistically, liraglutide reduced leukocyte rolling on the endothelium and infiltration of myeloid Ly6G-Ly6C+ and Ly6G+Ly6C+ cells into the vascular wall. As a consequence, liraglutide prevented vascular oxidative stress, reduced S-glutathionylation as a marker of eNOS (endothelial NO synthase) uncoupling, and increased NO bioavailability. Importantly, all of these beneficial cardiovascular effects of liraglutide persisted in myeloid cell GLP-1R-deficient (Glp1rflox/floxxLysMcre) mice but were abolished in global (Glp1r-/-) and endothelial cell-specific (Glp1rflox/floxxCdh5cre) GLP-1R knockout mice. CONCLUSIONS: GLP-1R activation attenuates cardiovascular complications of arterial hypertension by reduction of vascular inflammation through selective actions requiring the endothelial but not the myeloid cell GLP-1R.


Assuntos
Aterosclerose/genética , Pressão Sanguínea/efeitos dos fármacos , Células Endoteliais/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipertensão/genética , Liraglutida/farmacologia , RNA/genética , Animais , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/biossíntese , Hipertensão/complicações , Hipertensão/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Am J Physiol Heart Circ Physiol ; 318(1): H72-H77, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729903

RESUMO

Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic perturbations of nitric oxide function, reflective of generalized endothelial dysfunction. Therapies that target the nitric oxide pathway have shown promise in both clinical and preclinical studies of preeclampsia. The glucagon-like peptide 1 agonists have been shown to increase nitric oxide and lower blood pressure in patients with diabetes, in part, through activation of nitric oxide synthase (NOS). Therefore, we hypothesized that a direct acting glucagon-like peptide 1 receptor agonist would improve stigmata of the preeclampsia syndrome. Using the reduced uterine perfusion pressure rat model, we found that treatment with liraglutide significantly lowered blood pressure, improved renal function, and upregulated NOS3 protein expression in the mesenteric arterial bed. However, there were adverse effects on pup growth that were likely related to diminished food intake in the dams. Collectively, these data support the premise that the use of drugs that improve NOS abundance, including the glucagon-like peptide 1 agonists, is a rational therapeutic approach to the treatment of preeclampsia, but suggest cautious and careful study of their safety before potential clinical use in humans.NEW & NOTEWORTHY Drugs that target the glucagon-like peptide-1 pathway such as liraglutide are already used clinically, and it has been shown to promote endothelial nitric oxide synthase (NOS3) expression. We demonstrate that liraglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, lowers blood pressure, improves renal function, and upregulates NOS3 in a rat model of placental ischemia. These data suggest that drugs that target the nitric oxide system, including GLP-1R agonists, are a potential therapeutic option for preeclampsia.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Isquemia/tratamento farmacológico , Liraglutida/farmacologia , Placenta/irrigação sanguínea , Pré-Eclâmpsia/prevenção & controle , Animais , Animais Recém-Nascidos , Anti-Hipertensivos/toxicidade , Regulação do Apetite/efeitos dos fármacos , Peso ao Nascer/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Isquemia/complicações , Isquemia/metabolismo , Isquemia/fisiopatologia , Liraglutida/toxicidade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos , Fluxo Sanguíneo Regional , Transdução de Sinais
17.
Metabolism ; 103: 154044, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31812628

RESUMO

BACKGROUND: Skeletal muscle atrophy is characterized by muscle wasting with partial or complete functional loss. Skeletal muscle atrophy severely affects the quality of life and currently, there is no available therapy except for spinal muscular atrophy. OBJECTIVE: Drug repositioning is a promising strategy that reduces cost and time due to prior availability of safety and toxicity details. Here we investigated myogenic and anti-atrophy effects of glucagon-like peptide-1 (GLP-1) analog liraglutide. METHODS: We used several in vitro atrophy models in C2C12 cells and in vivo models in Sprague Dawley rats to study Liraglutide's efficacy. Western blotting was used to assess cAMP-dependent signaling pathways specifically activated by liraglutide. Therapeutic efficacy of liraglutide was investigated by histological analysis of transverse muscle sections followed by morphometry. Myogenic capacity was investigated by immunoblotting for myogenic factors. RESULTS: Liraglutide induced myogenesis in C2C12 myoblasts through GLP-1 receptor via a cAMP-dependent complex network of signaling events involving protein kinase A, phosphoinositide 3-kinase/protein kinase B, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. Liraglutide imparted protection against freeze injury, denervation, and dexamethasone -induced skeletal muscle atrophy and improved muscular function in all these models. In a therapeutic model, liraglutide restored myofibrillar architecture in ovariectomy-induced atrophy. Anti-atrophy actions of liraglutide involved suppression of atrogene expression and enhancement in expression of myogenic factors. CONCLUSION: Liraglutide imparted protection and restored myofibrillar architecture in diverse models of muscle atrophy. Given its potent anti-atrophy, and recently reported osteoanabolic effects, we propose liraglutide's clinical evaluation in skeletal muscle atrophy and musculoskeletal disorders associated with diverse pathologies.


Assuntos
Liraglutida/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Animais , Células Cultivadas , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/uso terapêutico , Masculino , Desenvolvimento Muscular/efeitos dos fármacos , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/fisiologia , Ratos , Ratos Sprague-Dawley , Roedores
18.
J Biochem Mol Toxicol ; 34(1): e22415, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31682045

RESUMO

The aim of this study was to assess the therapeutic potential of oxytocin and liraglutide (LIR), a GLP-1 analogue, in a rat model of vincristine-induced neuropathy. Rats were injected with vincristine (VCR) at a dose of 4 mg/kg twice a week for 5 weeks. The VCR-administered rats were divided into three groups and received saline, oxytocin, or liraglutide simultaneously with VCR. After the treatment period, electrophysiological, biochemical, histological, and immunohistochemical investigations were performed. Electromyography (EMG) recordings demonstrated significant alterations in the VCR + saline group (p < .001). Also, motor performance was decreased in the VCR + saline group (p < .05). Histologically, the axonal diameter was decreased in all groups. VCR + saline group showed significantly increased lipid peroxidation and decreased nerve growth factor (NGF) expression. However, the administration of oxytocin and liraglutide significantly prevented the EMG alterations, lipid peroxidation, and reduction in neuronal NGF expression. On the basis of these findings, oxytocin and liraglutide may be considered as potential agents for the prevention of VCR-induced neuropathy.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Liraglutida/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Ocitocina/uso terapêutico , Vincristina/toxicidade , Animais , Liraglutida/administração & dosagem , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Ocitocina/administração & dosagem , Ratos , Ratos Sprague-Dawley
19.
Endocr Pract ; 26(2): 235-240, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31682516

RESUMO

Objective: Liraglutide is a glucagon-like peptide 1 receptor agonist which acts through peripheral and central receptor pathways affecting food intake. Preliminary identification of responder patients represents a crucial point to reduce an inappropriate exposure to the drug and the health expenditure. The primary endpoint of our study was to identify predictors of liraglutide efficacy in the short term follow-up. The secondary endpoint was to evaluate the treatment efficacy stratified by the underlying psychiatric disorder. Methods: We evaluated a cohort of 100 patients (77 females, 23 males, mean body mass index 38.6 ± 3.2 kg/m2) who were evaluated at baseline, and after 1, 3, and 6 months of treatment. Liraglutide efficacy was defined by a weight loss ≥5% of initial weight. Sociodemographic/metabolic parameters, food intake, smoking habit, and physical activity were correlated with liraglutide efficacy. Results: There was a significant weight loss after 1 month of therapy, as well as after 3 and 6 months when compared to the baseline (P<.0001; 27%, 45%, and 57% of patients showed a weight loss ≥5%, respectively). No difference was found in weight loss between the 3 groups of patients (with binge eating, with/without psychiatric disorders). The weight loss at 1 month was the only predictor of a positive response to the treatment. Conclusion: Our results confirm the efficacy of liraglutide even at a lower dose than conventional. The early response to the drug seems to be a good predictor of long-term efficacy and it might be useful in clinical practice to identify patients in whom liraglutide may induce a significant weight loss. Abbreviations: BMI = body mass index; EMA = European Medicine Agency; FDA = Food and Drug Administration; GLP-1 RA = glucagon-like peptide 1 receptor agonist.


Assuntos
Perda de Peso , Peso Corporal , Feminino , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes , Liraglutida , Masculino , Obesidade
20.
Am J Pathol ; 190(2): 400-411, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31759969

RESUMO

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r-/- mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r-/- mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r-/- mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell-dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Ativação Linfocitária/imunologia , Nefrite/prevenção & controle , Linfócitos T/imunologia , Animais , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite/imunologia , Nefrite/metabolismo , Nefrite/patologia , Linfócitos T/efeitos dos fármacos
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