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2.
Postgrad Med ; 131(8): 555-565, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31580737

RESUMO

Type 2 diabetes (T2D) has a complex pathophysiology composed of multiple underlying defects that lead to impaired glucose homeostasis and the development of macrovascular and microvascular complications. Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) both provide effective glycemic control and have been shown to reduce cardiovascular (CV) events in patients with T2D and a high CV risk or established CV disease. Because these agents have complementary mechanisms of action, they are able to act on multiple defects of T2D when used in combination. This review discusses the rationale for and potential benefits of SGLT-2i plus GLP-1RA combination therapy in patients with T2D. A search of the PubMed database was conducted for studies and reviews describing the combined use of SGLT-2is and GLP-1RAs, with a specific focus on identifying clinical studies of combination therapy in patients with T2D. In clinical studies, glycated hemoglobin (A1c) was significantly reduced over 28-52 weeks with SGLT-2i plus GLP-1RA therapy versus the individual agents or baseline. Several CV risk factors, including body weight, blood pressure, and lipid parameters, were also improved. SGLT-2i plus GLP-1RA therapy was generally well tolerated, with a low risk of hypoglycemia and no unexpected findings. Taken together with results from large CV outcomes trials of SGLT-2is and GLP-1RAs, combination therapy with these agents potentially provides effective durable glycemic control and CV benefits due to their complementary actions on the defects of T2D.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicemia , Pressão Sanguínea , Peso Corporal , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Quimioterapia Combinada , Hemoglobina A Glicada , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Lipídeos/sangue , Guias de Prática Clínica como Assunto , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
3.
Endocrinology ; 160(12): 2787-2799, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593246

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperandrogenismo/complicações , Liraglutida/uso terapêutico , Síndrome Metabólica/prevenção & controle , Síndrome do Ovário Policístico/complicações , Animais , Pressão Sanguínea/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Resistência à Insulina , Leptina/sangue , Lipídeos/sangue , Liraglutida/farmacologia , Síndrome Metabólica/etiologia , Pós-Menopausa , Distribuição Aleatória , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos
4.
Medicine (Baltimore) ; 98(36): e17081, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490412

RESUMO

OBJECTIVE: The purpose of this study was to assess the efficacy and hypoglycemic risk of sitagliptin versus that of GLP-1 receptor agonists in the management of obese/overweight patients with T2DM. METHODS: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched; randomized controlled trials comparing the efficacy of sitagliptin versus that of GLP-1 receptor agonists in obese/overweight patients with T2DM were included. The mean BMI of participants for each study was ≥30 kg/m. We conducted a meta-analysis according to the methods specified in the Cochrane Handbook for Systematic Reviews of Interventions. RevMan 5.1 software was used to perform the meta-analysis. The Cochrane Q test and I statistics were used to estimate the heterogeneity among studies. The results are expressed as the mean difference (MD) or risk ratio (RR) with 95% confidence intervals. RESULTS: A total of 8 eligible studies were included in our meta-analysis. Compared with GLP-1 receptor agonists, sitagliptin was less effective at reducing HbA1c (0.42 [0.27, 0.56]), FPG (0.78 [0.36, 1.19]), PPG (2.61 [1.35, 3.87]), and body weight (1.42 [0.71, 2.14]). Conversely, there were no significant differences in SBP reduction (0.38 [-1.14, 1.89]), DBP reduction (-0.30 [-1.00, 0.39]), and hypoglycemic risk (1.09 [0.50, 2.35]). CONCLUSION: For obese/overweight patients, sitagliptin may exert a less potent effect on HbA1C, FPG, PPG, and weight reduction than GLP-1 receptor agonists, but these drugs had a similar efficacy in reducing blood pressure; furthermore, there was no significant difference in hypoglycemic risk.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Fosfato de Sitagliptina/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/farmacologia , Fosfato de Sitagliptina/farmacologia
5.
Life Sci ; 234: 116776, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425698

RESUMO

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Animais , Diabetes Mellitus/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Estresse Oxidativo/efeitos dos fármacos
6.
Sheng Li Xue Bao ; 71(4): 514-526, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31440748

RESUMO

Glucagon-like peptide-1 (GLP-1) expression is shared by both intestinal cells and neurons of brainstem, which plays anorexigenic role on food intake. However, the exact source of physiological GLP-1 influencing food intake and pertinent mechanism of GLP-1 receptor agonists (GLP-1RA) remain unelucidated. In this study, the immediate early gene product c-Fos was chosen as the specific antigen for immunohistochemistry to show the certain areas of central nervous system (CNS) activation by the GLP-1RA. Thirty normal SD rats were randomly assigned to 3 groups, which were single intraperitoneally injected with Liraglutide (200 µg/kg), Exenatide (10 µg/kg) and saline, respectively. After injection, the amount of food intake and acute glycemic variation were assessed for comparison. The results showed that acute pharmacological dosage of GLP-1RA (Liraglutide or Exenatide) could significantly influence food intake. However, glycemic change indicated that the anorexic effect was dissociated with change in blood glucose in normal rats. Moreover, c-Fos was expressed significantly higher in major critical nuclei related to food intake in GLP-1RA groups when compared with the control group, and its expression was also found in spinal cord. The results suggested that acute administration of pharmacological doses of GLP-1 influences CNS via circulation and vagal pathways, especially on the arcuate nucleus (ARC) and the nucleus of solitary tract (NTS), and GLP-1 modulates autonomic nervous activities.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Liraglutida/farmacologia , Animais , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
7.
Rev Med Suisse ; 15(659): 1436-1441, 2019 Aug 21.
Artigo em Francês | MEDLINE | ID: mdl-31436058

RESUMO

Some sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their ability to reduce major cardiovascular events in patients with type 2 diabetes at high cardiovascular risk. Furthermore, SGLT2is reduce the risk of hospitalization for heart failure and the progression of renal disease. The 2018 ADA-EASD consensus gave the preference to either SGLT2is or GLP-1 RAs to prevent these complications. Underlying protective mechanisms are complex, differ between the two pharmacological classes and are potentially complementary, thus providing a rationale for a combination in patients at very high risk. Some studies already showed positive complementary effects on glucose control, body weight and arterial blood pressure, but not on cardiovascular and/or renal outcomes yet.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Inibidores do Transportador 2 de Sódio-Glicose , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
8.
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
9.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443356

RESUMO

The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/biossíntese , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos
10.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330984

RESUMO

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR agonists remains controversial. Recent studies suggest that simultaneous activation of GLP-1R and GIPR with a single peptide provides superior glycemic control with fewer adverse effects than activation of GLP-1R alone. We investigated the signaling properties of a recently reported dual-incretin receptor agonist (P18). GLP-1R, GIPR, and the closely related glucagon receptor (GCGR) were expressed in HEK-293 cells. Activation of adenylate cyclase via Gαs was monitored using a luciferase-linked reporter gene (CRE-Luc) assay. Arrestin recruitment was monitored using a bioluminescence resonance energy transfer (BRET) assay. GLP-1, GIP, and glucagon displayed exquisite selectivity for their receptors in the CRE-Luc assay. P18 activated GLP-1R with similar potency to GLP-1 and GIPR with higher potency than GIP. Interestingly, P18 was less effective than GLP-1 at recruiting arrestin to GLP-1R and was inactive at GCGR. These data suggest that P18 can act as both a dual-incretin receptor agonist, and as a G protein-biased agonist at GLP-1R.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucagon/metabolismo , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Glucagon/metabolismo , Sequência de Aminoácidos , Arrestina/metabolismo , Arrestina/farmacologia , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Peptídeos/química , Peptídeos/farmacologia , Receptores de Glucagon/antagonistas & inibidores
11.
Medicine (Baltimore) ; 98(28): e16428, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305464

RESUMO

CONTEXT: Alarin has been reported to be relative to food intake and an increase in body weight. However, to date, no report has demonstrated the relationship between circulating alarin and diabetes in humans. OBJECTIVE: The objective of this study is to gain insight into the possible role of alarin in humans. DESIGN AND METHODS: 164 patients with newly diagnosed type 2 diabetes mellitus (nT2DM), 112 IGT and 134 healthy subjects were recruited for this study. In an interventional study, 29 nT2DM patients were treated by a weekly GLP-1RA for 6 months. Plasma alarin concentrations were measured by ELISA. RESULTS: Circulating alarin concentrations were significantly higher in both IGT and nT2DM subjects than in healthy individuals (0.40 ±â€Š0.14 and 0.54 ±â€Š0.24 vs 0.37 ±â€Š0.10 µg/L, P < .05 or P < .01), whereas in T2DM patients, circulating alarin levels were higher than in IGT subjects. Circulating alarin positively correlated with FBG, HbA1c, HOMA-IR, AUCglucose and TNFα (P < .05 or P < .01). Multivariate logistic regression revealed that circulating alarin levels were correlated with IGT and T2DM. GLP-1RA treatment for 6 months increased circulating alarin levels in T2DM patients (from 0.34 ±â€Š0.10 for baseline, to 0.39 ±â€Š0.14 for 12 weeks, and finally to 0.38 ±â€Š0.15 µg/L for 24 weeks; vs. pre-treatment P < .05). CONCLUSIONS: These data suggest that alarin might be involved in the pathogenesis of T2DM in humans. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OCS-13003185 (18/03/2013 ).


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo Semelhante a Galanina/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos Transversais , Citocinas/sangue , Método Duplo-Cego , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Clin Drug Investig ; 39(8): 805-819, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317516

RESUMO

Glucagon-like peptide-1 receptor analogues/agonists (GLP-1RAs) are well established as effective adjuncts to lifestyle modification in the treatment of type 2 diabetes (T2D) as monotherapy or in combination with oral glucose-lowering drugs ± insulin. The six subcutaneous GLP-1RA formulations (i.e. twice-daily exenatide, once-daily liraglutide and lixisenatide, and once-weekly dulaglutide, exenatide and semaglutide) currently available in the EU and USA have many similarities, but also some unique features and properties. By stimulating GLP-1 receptors, GLP-1RAs increase insulin secretion and suppress glucagon release in a glucose-dependent manner, thereby improving clinical and patient-reported outcomes related to glycaemic control and weight. They also have been shown to reduce, or at least not increase, the risk of major cardiovascular outcomes. GLP-1RAs are generally well tolerated, with gastrointestinal and injection-site reactions being the most troublesome drug-related adverse events, and are associated with a very low intrinsic risk of hypoglycaemia. Treatment with GLP-1RAs should be customized to meet the clinical needs and personal preferences of the individual.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Administração Oral , Glicemia/efeitos dos fármacos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas
13.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336911

RESUMO

Mitochondrial dysfunction is associated with cardiovascular diseases and diabetes. Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, and the abnormal proliferation, apoptosis and migration of pulmonary arterial smooth muscle cells (PASMCs). The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, has been shown to prevent pulmonary hypertension in monocrotaline-exposed rats. The aim of this study was to investigate the effect of liraglutide on autophagy, mitochondrial stress and apoptosis induced by platelet-derived growth factor BB (PDGF-BB). PASMCs were exposed to PDGF-BB, and changes in mitochondrial morphology, fusion-associated protein markers, and reactive oxygen species (ROS) production were examined. Autophagy was assessed according to the expressions of microtubule-associated protein light chain 3 (LC3)-II, LC3 puncta and Beclin-1. Western blot analysis was used to assess apoptosis, mitochondrial stress and autophagy markers. Liraglutide significantly inhibited PDGF-BB proliferation, migration and motility in PASMCs. PDGF-BB-induced ROS production was mitigated by liraglutide. Liraglutide increased the expression of α-smooth muscle actin (α-SMA) and decreased the expression of p-Yes-associated protein (p-YAP), inhibited autophagy-related protein (Atg)-5, Atg-7, Beclin-1 and the formation of LC3-ß and mitochondrial fusion protein dynamin-related (Drp)1. Therefore, liraglutide can mitigate the proliferation of PASMCs via inhibiting cellular Drp1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) pathways and Atg-5/Atg-7/Beclin-1/LC3ß-dependent pathways of autophagy in PAH.


Assuntos
Autofagia/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , /metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Becaplermina/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Liraglutida/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Modelos Biológicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
14.
Medicina (Kaunas) ; 55(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159279

RESUMO

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin-angiotensin-aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Rim/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Humanos , Rim/fisiopatologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico
15.
Artif Cells Nanomed Biotechnol ; 47(1): 2325-2332, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31174433

RESUMO

Increased free fatty acids (FFA) are one of the risk factors for type 2 diabetes. FFA also contribute to endothelial dysfunction in both the prediabetes and diabetes conditions. Therefore, FFA are an important link between diabetes and endothelial dysfunction. In therapeutic application, GLP-1 receptor agonists have been implemented to lower blood glucose in diabetes. Here, we investigate the role of the common clinically used GLP-1 receptor agonist lixisenatide in endothelial cells. We demonstrate that lixisenatide could protect endothelial cells from high FFA-induced toxicity and cell death. Lixisenatide also suppresses FFA-caused cellular ROS generation and production of the lipid oxidation byproduct 4-HNE. Lixisenatide inhibits FFA-triggered production of TNF-α, IL-6, VCAM-1 and ICAM-1. The presence of lixisenatide in co-culture experiments suppresses adhesion of monocytes to endothelial cells. Moreover, lixisenatide ameliorates FFA-induced decreased eNOS phosphorylation and NO reduction. We also demonstrate that lixisenatide inhibits FFA-induced IκBα activation, nuclear p65 translocation and NF-κB activation. This evidence indicates that lixisenatide suppresses activation of the NF-κB pathway in endothelial cells. Collectively, our findings suggest that lixisenatide might have therapeutic potential to modulate diabetes-associated vascular complications.


Assuntos
Citoproteção/efeitos dos fármacos , Ácidos Graxos não Esterificados/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/farmacologia , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/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 , Inflamação/prevenção & controle , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos
16.
Diabetes Res Clin Pract ; 154: 101-115, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31238059

RESUMO

We provided an updated systematic review with meta-analysis of randomized controlled trials (RCTs) assessing the metabolic effects of combination therapy of insulin and GLP-1RA (combo) in comparison with other injectable therapy. We searched PubMed, Cochrane Register of Controlled Trials, Scholar, and ClinicalTrials.gov for RCTs evaluating changes in HbA1c (primary outcome), proportion of patients at HbA1c target <7%, hypoglycaemia, and weight change (secondary end-points). We included 36 RCTs involving 14,636 patients. Compared with comparator therapies (overall analysis), the combo led to a significant HbA1c reduction (=-0.49%, 95% CI -0.61 to -0.38%, P < 0.001), more patients at HbA1c target [relative risk, (RR) = 1.77, 95% CI, 1.56, 2.01, P < 0.001], similar hypoglycaemic events (RR = 1.03, 95% CI, 0.88, 1.19, P = 0.728), and reduction in body weight (-2.5 Kg, 95% CI -3.1 to -1.8 kg, P < 0.001), with high heterogeneity in each analysis. The quality of the evidence was low for three of the considered outcomes. Compared with intensified insulin regimens (basal-plus/basal-bolus) the combo produced similar glycemic control with reduction of both hypoglycaemia, and body weight. Combination therapy of GLP-1RA and insulin could represent a valuable treatment strategy to improve glycemic control in the management of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Quimioterapia Combinada , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
N Engl J Med ; 381(9): 841-851, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31185157

RESUMO

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Idoso , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Risco
18.
Drugs ; 79(11): 1187-1197, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243696

RESUMO

Obesity, type 2 diabetes, and the numerous associated metabolic co-morbidities are growing global threats to public health. Despite recent progress in pharmacotherapies for metabolic diseases, the current treatment options have limited efficacy and provide mostly symptomatic relief with little or no impact on disease reversal. Thus, improved therapies are urgently needed. As a result, the scientific community has increasingly invested in leveraging new pathophysiological insights into more efficacious pharmacotherapies for metabolic complications. A heightened understanding of the large, interindividual variation in responsiveness to certain metabolic medicines combined with advances in engineering multi-agonist candidates are important steps towards this goal. Additionally, the emerging pharmacological concept of peptide-mediated targeting of small molecules for tissue-specific delivery holds promise for more powerful treatment solutions in the future. In this review, we summarize recent advances in medicinal chemistry and molecular pharmacology that have enabled the engineering of several, novel, poly-agonist drug candidates for treatment of metabolic diseases, and we discuss the recent results from clinical trials assessing the efficacy and safety of glucagon-like peptide (GLP)-1/glucagon and GLP-1/GIP co-agonists.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/metabolismo , Doenças Metabólicas/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Glucagon/agonistas , Animais , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Terapia de Alvo Molecular , Medicina de Precisão , Receptores de Glucagon/metabolismo
19.
Expert Rev Cardiovasc Ther ; 17(5): 377-387, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31055989

RESUMO

Introduction: The GLP-1 receptor agonist (GLP-1 RA) liraglutide has a half-life of approximately 13 h and is suitable for subcutaneous administration once daily. The use of liraglutide in people with type 2 diabetes has become popular because of the efficacy and durability in relation to glycemic control in combination with weight loss in most patients. Areas covered: PubMed searches were completed using the terms 'GLP-1 receptor agonist', 'Liraglutide', 'Liraglutide and CVD', 'Liraglutide and CVD risk factors'. The reference list of articles subsequently identified was searched and articles of interest were selected. Expert commentary: Liraglutide has been found superior to oral antidiabetic drugs and other GLP-1 RAs with greater reductions in both HbA1c and weight except when compared with semaglutide. Liraglutide has beneficial effects on blood pressure, weight, postprandial lipids, low-grade inflammation and on the myocardium. In the cardiovascular endpoint trial LEADER liraglutide reduced the composite endpoint of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke as well as cardiovascular and total mortality but had no effect on heart failure. Liraglutide reduces the progression of diabetic kidney disease. In the recent 2018 consensus report from EASD/ADA liraglutide is recommended to patients with established cardiovascular diseases after metformin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Fatores de Risco
20.
Drug Res (Stuttg) ; 69(9): 479-486, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31083740

RESUMO

BACKGROUND: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for treatment of type 2 diabetes (T2DM) in the United States, the European Union, and Japan. In our previous work, we designed and characterized a novel GLP-1 RA, SKL-18287. This RA consists of only natural L-amino acids, and is believed to exist in an oligomer form in systemic circulation. This unique feature may allow high biological stability and a long-lasting glucose lowering effect in T2DM treatment. In the present study, we investigated the pharmacokinetic properties of SKL-18287 in rats, monkeys, and mini-pigs. Tissue distributions of radioactivity were also studied in rats after subcutaneous administration of [3H]-SKL-18287. METHODS: Plasma concentrations of SKL-18287 were measured by LC-MS/MS after intravenous and subcutaneous administration of SKL-18287 in rats, monkeys, and mini-pigs. Pharmacokinetic parameters were then calculated and compared among these animal species. Tissue concentrations of radioactivity were determined by liquid scintillation counting following sample combustion, after subcutaneous administration of [3H]-SKL-18287 to rats. RESULTS: SKL-18287 showed an extended half-life of over 5 h, with good subcutaneous bioavailability, in all animal species. Prediction of the pharmacokinetic profiles of SKL-18287 in humans using an animal scale-up approach revealed an SKL-18287 half-life of 14.8 h. The radioactivity concentration in the pancreas, a target tissue of GLP-1RA, was relatively higher than in other tissues, until 12 h after [3H]-SKL-18287 administration. CONCLUSION: SKL-18287 might be sufficient to maintain an effective concentration for a once-daily treatment for T2DM, and is a unique GLP-1 RA with a pancreas-selective feature.


Assuntos
Preparações de Ação Retardada/farmacocinética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Animais , Disponibilidade Biológica , Preparações de Ação Retardada/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Meia-Vida , Haplorrinos , Humanos , Japão , Ratos , Suínos , Porco Miniatura
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