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1.
Cochrane Database Syst Rev ; 6: CD012906, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501595

RESUMO

BACKGROUND: Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES: To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS: We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS: We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS: There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adulto , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/uso terapêutico , Metformina/efeitos adversos , Infarto do Miocárdio/epidemiologia , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/epidemiologia , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
2.
Am J Physiol Renal Physiol ; 318(6): F1409-F1417, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390511

RESUMO

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.


Assuntos
Arteríolas/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Rim/irrigação sanguínea , Pré-Hipertensão/metabolismo , Artéria Renal/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Modelos Animais de Doenças , Feminino , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pré-Hipertensão/genética , Pré-Hipertensão/fisiopatologia , Ratos Endogâmicos SHR , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia
3.
Acta Diabetol ; 57(10): 1129-1144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32300876

RESUMO

AIMS: The effects of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors/DPP-4I) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) on cognition in patients with type 2 diabetes mellitus (T2DM) remain controversial. We aimed to explore this clinical issue through a systematic review and meta-analysis. METHODS: PubMed, EMBASE and the Cochrane Library were searched, and data were expressed as mean difference (MD) or hazard ratio (HR)/odds ratio (OR) with a 95% confidence interval (CI). Heterogeneity was assessed using the Chi-squared test and the I2 statistic. The study was registered with PROSPERO (ID: CRD42019138777). RESULTS: Eleven studies (n = 304,258 T2DM patients) were included in our review. In the DPP-4I group, six studies were enrolled to estimate ΔMini-Mental State Examination (MMSE) scores from baseline to the final evaluations after DPP-4I treatment, which showed no statistical difference (MD 0.20; 95% CI - 0.75 to 1.15, p = 0.68). ΔMMSE scores in the DPP-4I group and the other antidiabetic groups were compared, revealing no statistical difference (MD 0.57; 95% CI - 0.05 to 1.19, p = 0.07). Two cohort studies were pooled to determine the HRs for dementia, showing a lower risk of dementia after DPP-4I treatment (HR 0.52; 95% CI 0.29-0.93, p = 0.03). In the GLP-1 analogs group, two studies were included, one of which revealed a downward trend in the risk of dementia after GLP-1 analog treatment, while the other revealed no significant difference after incretins treatment. CONCLUSIONS: Currently there is not enough irrefutable evidence to support the hypothesis of positive effects of incretins on cognition. Further clinical studies need to be performed.


Assuntos
Cognição/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Adulto , Cognição/fisiologia , Diabetes Mellitus Tipo 2/psicologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Incretinas/uso terapêutico
5.
Biochim Biophys Acta Proteins Proteom ; 1868(7): 140426, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32272193

RESUMO

Lipotoxicity, an important factor in the pathogenesis of diabetes, leads to defective ß-cell proliferation and increased apoptosis. Glucagon-like peptide-1 (GLP-1) analogs, which are used to treat type 2 diabetes, reduce endoplasmic reticulum stress and inflammation in pancreatic ß-cells and improve their survival. However, their effects on the heat shock response (HSR) have not been elucidated yet. We investigated whether the GLP-1 analog exendin-4 exerts its protective effect by modulating the HSR and mitogen-activated protein kinases (MAPKs) in BTC-6 mouse pancreatic cells under palmitic acid (PA) stress. Expression patterns were analyzed using mass spectrometry, Western blotting, and qRT-PCR in the presence of 250 or 400 µM PA and 100 nM exendin-4. Additionally, we measured MAPK expression and phosphorylation using qRT-PCR and Western blotting, respectively. Upregulation of heat shock protein (HSP), notably HSP72, in the presence of PA, was attenuated by exendin-4. Despite the absence of global effects on the HSR system, exendin-4 attenuated the expression of other non-classical HSPs (GRP94, DNAJA1, and DNAJB6) in the presence of PA. Regarding MAPKs, only extracellular signal-regulated kinase (ERK) phosphorylation was highly increased by exendin-4 in both the presence and absence of PA. Furthermore, exendin-4 significantly alleviated PA-induced cell death, which was further confirmed with proteomics analysis where key cellular functions, including cellular growth, assembly, and organization, were improved by exendin-4 treatment. Thus, our results expand the protective role of GLP-1 analogs to include other cellular mechanisms involved in restoring normal ß-cell homeostasis.


Assuntos
Exenatida/metabolismo , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Proteínas de Choque Térmico HSP72/metabolismo , Células Secretoras de Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Exenatida/farmacologia , Proteínas de Choque Térmico HSP40 , Glicoproteínas de Membrana , Camundongos , Chaperonas Moleculares , Fosforilação , Substâncias Protetoras/farmacologia , Mapas de Interação de Proteínas , Regulação para Cima
6.
Arterioscler Thromb Vasc Biol ; 40(3): e65-e77, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31893947

RESUMO

OBJECTIVE: In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4-/-), but not of GLP-1-receptors (Glp1r-/-), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced upon ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role. CONCLUSIONS: Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets.


Assuntos
Plaquetas/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fibrinolíticos/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Linagliptina/farmacologia , Fosfato de Sitagliptina/farmacologia , Trombose/prevenção & controle , Animais , Plaquetas/metabolismo , Dipeptidil Peptidase 4/genética , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Transdução de Sinais , Trombose/enzimologia , Trombose/genética
7.
Biomed Chromatogr ; 34(2): e4729, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31656040

RESUMO

FIM protein, which consists of 155 amino acids, was developed as a novel GLP-1 analog to reduce blood glucose, and pharmacodynamic results showed that it had a certain effect when used in treating Alzheimer's disease. The molecular weight of FIM is 16,304 Da. In theory, the concentration of FIM in biological samples should be determined by the ligand binding assay method or indirectly quantified using LC-MS/MS instrumentation. However, the above methods are complex and time-consuming. In this study, we successfully developed a simpler LC-MS/MS method for directly quantifying the intact FIM protein in monkey plasma for the first time. The chromatographic separation of FIM was achieved using an InertSustain Bio C18 column with a mobile phase of acetonitrile containing 0.1% formic acid (A)-water containing 0.1% formic acid (B) at a flow rate of 0.3 ml/min. Good linearity was observed in the concentration range of 5-500 ng/ml (r2 > 0.99). The intra- and inter-day precisions (expressed as relative standard deviation, RSD) of FIM were 2.30-12.8 and 7.30-13.2%, respectively. The intra- and inter-day accuracies (expressed as a relative error, RE) were -12.7-6.55 and - 10.1-0.892%, respectively. This method was successfully applied for a pharmacokinetic study of the FIM protein in four monkeys after subcutaneous administration.


Assuntos
Proteínas Sanguíneas/análise , Proteínas Sanguíneas/farmacocinética , Cromatografia Líquida/métodos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Animais , Proteínas Sanguíneas/química , Limite de Detecção , Modelos Lineares , Macaca fascicularis , Reprodutibilidade dos Testes
8.
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
9.
JCI Insight ; 5(2)2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31877117

RESUMO

Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective, and frataxin-inducing effects of glucagon-like peptide-1 (GLP-1) analogs in in vivo and in vitro models and in patients with Friedreich ataxia. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic ß cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in ß cells and brain and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress, and improved mitochondrial function in Friedreich ataxia patients' induced pluripotent stem cell-derived ß cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.


Assuntos
Exenatida/farmacologia , Ataxia de Friedreich/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismo , Mitocôndrias/metabolismo , Adolescente , Adulto , Idoso , Animais , Encéfalo/patologia , Cerebelo/patologia , Modelos Animais de Doenças , Exenatida/uso terapêutico , Feminino , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Gânglios Espinais/patologia , Técnicas de Introdução de Genes , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ferro/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Expansão das Repetições de Trinucleotídeos , Adulto Jovem
10.
Mol Cell Endocrinol ; 499: 110584, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539596

RESUMO

Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala2]palmitoyl-lamprey GLP-1 and [D-Ala2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal ß-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet ß-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.


Assuntos
Glicemia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Incretinas/administração & dosagem , Ilhotas Pancreáticas/metabolismo , Lampreias/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Proteínas de Peixes/química , Peptídeo 1 Semelhante ao Glucagon/química , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Incretinas/química , Incretinas/farmacologia , Insulina/sangue , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Camundongos , Receptores de Glucagon/metabolismo
11.
Presse Med ; 48(12): 1489-1495, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757735

RESUMO

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Citoproteção/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Seleção de Pacientes , Preparações Farmacêuticas/classificação , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico
13.
J Diabetes Res ; 2019: 1534365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396537

RESUMO

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia. Methods: We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia. Results: Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.46), liraglutide (OR 1.08, 95% CI 0.91-1.27; p = 0.38), exenatide (OR 1.00, 95% CI 0.86-1.16; p = 1.00), semaglutide (OR 0.89, 95% CI 0.35-2.22; p = 0.80), or albiglutide (OR 1.07, 95% CI 0.23-4.88; p = 0.93). A subanalysis of trials lasting longer than 3 years also showed no increase in the neoplasia risk with GLP-1 receptor agonist use (OR 1.03, 95% CI 0.92-1.15; p = 0.60). Between-trial statistical heterogeneity was low for all comparisons. Conclusion: GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Neoplasias/epidemiologia , Exenatida/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Incidência , Liraglutida/uso terapêutico , Neoplasias/induzido quimicamente , Fatores de Risco
14.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261624

RESUMO

Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor Agonists (GLP-1R) and sodium glucose cotransporter-2 inhibitors are suggested as the first line towards fighting all DM, CVD and ESRD. However, the benefits of GLP-1R in organ transplantation recipients remain very limited. No clinical trials have been designed for this particular population. GLP-1R, a gastrointestinal hormone of the incretin family, possesses antidiabetic, antihypertensive, anti-inflammatory, anti-apoptotic and immunomodulatory actions. There are few drug-drug interactions, with delayed gastric emptying being the major concern. The trough level of tacrolimus may not be significant but should still be closely monitored. There are some reasons which support GLP-1R in recipients seeking glycemic control. Post-transplant DM is due to an impaired ß-cell function and glucose-induced glucagon suppression during hyperglycemia, which can be reversed by GLP-1R. GLP-1R infusion tends to relieve immunosuppressant related toxicity. Until now, in some cases, glycemic control and body weight reduction can be anticipated with GLP-1R. Additional renal benefits have also been reported. Side effects of hypoglycemia and gastrointestinal discomfort were rarely reported. In conclusion, GLP-1R could be implemented for recipients while closely monitoring their tacrolimus levels and any potential side effects. Any added benefits, in addition to sugar level control, still require more well-designed studies to prove their existence.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Transplante de Rim/efeitos adversos , Síndrome Metabólica/tratamento farmacológico , Diabetes Mellitus/etiologia , Nefropatias Diabéticas/cirurgia , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem
15.
Aliment Pharmacol Ther ; 50(2): 193-203, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31246368

RESUMO

BACKGROUND: Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. AIM: To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. METHODS: Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. RESULTS: Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. CONCLUSIONS: Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/farmacologia , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/metabolismo , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Fígado/enzimologia , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/complicações , Obesidade/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Programas de Redução de Peso , Adulto Jovem
16.
Chem Biol Interact ; 310: 108688, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173752

RESUMO

Glucagon-like peptide 1 (GLP-1) has neuroprotective properties in Alzheimer's disease (AD). In this study, our aim is to explore the neuroprotective effects of liraglutide, a GLP-1 analogue, on AD-like neurodegeneration induced by H2O2 in human neuroblastoma SH-SY5Y cells. Cytotoxicity was determined by MTT assay and lactate dehydrogenase level was monitored by LDH assay. The level of lipid peroxidation and cell apoptosis rate were measured by malondialdehyde (MDA) assay and Annexin V-FITC/propidium iodide (PI) staining. Western blotting was used to assess the expression of Bcl-2, Bax, caspase-3, tau and the Akt/GSK-3ß. Liraglutide pre-treatment enhanced cell viability with reduced cytotoxicity, lipid peroxidationand and apoptosis. In addition, pre-treatment of liraglutide displayed that increased the expression of the pro-survival Bcl-2 and reduced pro-apoptotic Bax with ameliorated the hyperphosphorylation of tau and Akt/GSK-3ß signaling pathway in H2O2 stressed SH-SY5Y cells. These finding provided evidences that liraglutide protected the H2O2 induced AD-like neurodegeneration through improving Akt/GSK-3ß signaling pathway. These results suggest that liraglutide may have potential values for the treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Liraglutida/uso terapêutico , Neuroblastoma/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo , Linhagem Celular Tumoral , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Neuroblastoma/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/etiologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
17.
Rev Med Suisse ; 15(653): 1117-1123, 2019 May 29.
Artigo em Francês | MEDLINE | ID: mdl-31148423

RESUMO

GLP-1 analogues are a well-established treatment for type 2 diabetes. They act by improving glycemic control through several mechanisms. They also have the advantage of inducing weight loss without the risk of associated hypoglycemia. This class of molecules has also shown a benefit in cardiovascular events such as cardiovascular mortality, stroke and myocardial infarction, and albuminuria. These favorable effects place them, like SGLT-2 inhibitors, as a second option in the case of unsatisfactory glycemic control after metformin and dietary and lifestyle measures. This article provides an overview of the current knowledge of GLP-1 analogue therapy in patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes , Metformina , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico
18.
Diabetologia ; 62(9): 1701-1711, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31203378

RESUMO

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues. METHODS: Trial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 µg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals (N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells. RESULTS: Study 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups (n = 21 per group, p < 0.001), with the microvascular responses similar across groups (p ≥ 0.389). Study 2 results: liraglutide response (stabilised response and total response) was not influenced by pretreatment with exendin-(9,39) (70 nmol/l) (N = 15, one dataset excluded) (p ≥ 0.609). Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020). CONCLUSIONS/INTERPRETATION: Liraglutide and exenatide increased skin microvascular perfusion in individuals with and without well-controlled diabetes, potentially mediated, at least in part, by NO. TRIAL REGISTRATION: ClinicalTrials.gov NCT01677104. FUNDING: This work was supported by Diabetes UK (grant numbers: 09/0003955 and 12/0004600 [RW and JM Collins Legacy, Funded Studentship]).


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Exenatida/administração & dosagem , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Modelos Lineares , Liraglutida/administração & dosagem , Masculino , Microcirculação/efeitos dos fármacos , Pessoa de Meia-Idade
19.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040160

RESUMO

Currently there is no effective therapy available for cognitive impairments in Down syndrome (DS), one of the most prevalent forms of intellectual disability in humans associated with the chromosomes 21 trisomy. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that maintains glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36) lacks insulinotropic effects and has a low binding affinity for GLP-1 receptors; thus, GLP-1 (9-36) has historically been identified as an inactive metabolite. Conversely, recent work has demonstrated interesting physiological properties of GLP-1 (9-36) such as cardioprotection and neuroprotection. We have previously shown that GLP-1 (9-36) administration enhances neuronal plasticity in young WT mice and ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Here, we report that systemic administration of GLP-1 (9-36) in Ts65Dn DS model mice of either sex resulted in decreased mitochondrial oxidative stress in hippocampus and improved dendritic spine morphology, increase of mature spines and reduction of immature spines. Importantly, these molecular alterations translated into functional changes in that long-term potentiation failure and cognitive impairments in TsDn65 DS model mice were rescued with GLP-1 (9-36) treatment. We also show that chronic GLP-1 (9-36) treatment did not alter glucose tolerance in either WT or DS model mice. Our findings suggest that GLP-1 (9-36) treatment may have therapeutic potential for DS and other neurodegenerative diseases associated with increased neuronal oxidative stress.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Espinhas Dendríticas/efeitos dos fármacos , Síndrome de Down/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Nootrópicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Teste de Tolerância a Glucose , Masculino , Camundongos , Camundongos Transgênicos , Nootrópicos/administração & dosagem
20.
Diabetes Res Clin Pract ; 152: 125-134, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004676

RESUMO

AIMS: Compare the efficacy and safety of albiglutide from a ready-to-use, single-dose, auto-injector system with the lyophilized product in patients with type 2 diabetes mellitus (T2DM). METHODS: In this phase 3 study, 308 patients between 18 and 80 years with T2DM and experiencing inadequate glycemic control on their current regimen of diet/exercise alone or in combination with metformin were randomized 1:1 to weekly injections for 26 weeks with an active albiglutide auto-injector and placebo lyophilized dual-chamber cartridge (DCC) pen injector (n = 154) or active albiglutide lyophilized DCC pen injector and placebo liquid auto-injector (n = 154). Participants received liquid or lyophilized albiglutide 30 mg for 4 weeks, and then 50 mg for the remaining 22 weeks. Change in HbA1c and fasting plasma glucose (FPG), pharmacokinetics, and safety were assessed. RESULTS: In the albiglutide liquid and lyophilized drug product groups, 55.6% (85/153) and 45.5% of patients (70/154) had a baseline HbA1c ≥ 8.0%, respectively. The model-adjusted least squares (LS) mean change in HbA1c from baseline at week 26 was -1.1% (95% CI: -1.3, -1.0) and -1.2% (95% CI: -1.3, -1.0; noninferiority P = 0.0002) in the albiglutide liquid and lyophilized product groups, respectively. Similarly, the model-adjusted LS mean change in FPG from baseline at week 26 in the albiglutide liquid and lyophilized product groups was -2.2 (95% CI: -2.6, -1.8) mmol/L and -1.9 (95% CI: -2.3, -1.5) mmol/L, respectively. No new safety concerns were identified. CONCLUSION: Change from baseline in HbA1c for albiglutide liquid was noninferior to lyophilized drug product in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Composição de Medicamentos , Feminino , Liofilização , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Soluções , Resultado do Tratamento , Adulto Jovem
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