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1.
Rev Med Liege ; 75(1): 60-66, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31920046

RESUMO

The shift to injection therapy, after failure of oral antidiabetic agents, is often considered as a difficult step by both the patient with type 2 diabetes and the physician, a situation that may lead to clinical inertia. Schematically, two options may be considered, either starting insulin therapy with a preference for basal insulin analogues, or adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA). Each option has its advantages and disadvantages, which opens the road to personalized medicine. Nevertheless, the preference is increasingly given to GLP-1 AR, yet this solution is more limited by reimbursement conditions. A combination of the two approaches is also possible, with the recent commercialisation of fixed-ratio specialities combining a basal insulin analogue and a GLP-1 RA. This clinical case offers the opportunity to discuss all these different therapeutic options in a patient with poorly controlled type 2 diabetes despite a combination of oral antidiabetic agents, taking also into account the current conditions for reimbursement in Belgium.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Administração Oral , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem
4.
Mol Immunol ; 116: 73-79, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31630078

RESUMO

Atherosclerosis is a common comorbidity of type II diabetes and a leading cause of death worldwide. The presence of oxidized low-density lipoprotein (ox-LDL) drives atherogenesis by inducing oxidative stress, mitochondrial dysfunction, expression of proinflammatory cytokines and chemokines including interleukin (IL)-1ß, IL-6, and monocyte chemoattractant protein 1 (MCP-1), adhesion molecules including vascular cellular adhesion molecule 1 (VCAM-1) and E-selectin, and downregulating expression of the Krüppel-like factor 2 (KLF2) transcription factor. Importantly, ox-LDL induced the attachment of THP-1 monocytes to endothelial cells. In the present study, we demonstrate for the first time that the specific glucagon-like peptide 1 receptor (GLP-1R) agonist dulaglutide may prevent these atherosclerotic effects of ox-LDL by preventing suppression of KLF2 by p53 protein in human aortic endothelial cells. KLF2 has been shown to play a major role in protecting vascular endothelial cells from damage induced by ox-LDL and oscillatory shear, and therefore, therapies capable of mediating KLF2 signaling may be an attractive treatment option for preventing the development and progression of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/farmacologia , Lipoproteínas LDL/metabolismo , Monócitos/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Aterosclerose/metabolismo , Adesão Celular , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Monócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
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
8.
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
9.
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
10.
Rev Med Liege ; 74(9): 488-494, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31486321

RESUMO

Semaglutide (Ozempic®) is a new once-weekly agonist of glucagon-like peptide-1 receptors (GLP-1 AR) indicated in the treatment of type 2 diabetes (T2D). Phase III clinical trials of the SUSTAIN programme demonstrated both the efficacy and safety of semaglutide in patients with T2D treated by diet and exercise, oral antidiabetic agents or even insulin. Direct and indirect comparative clinical trials showed that semaglutide (subcutaneous 0.5 or 1.0 mg once weekly) exerts a better glucose-lowering activity and a greater weight loss than other GLP-1 AR. Presented as prefilled pens for subcutaneous injection, semaglutide is currently reimbursed in Belgium after failure of antidiabetic therapy including metformin (HbA1c superior to 7,5 % or 58 mmol/mol) in T2D patients with body mass index ? 30 kg/m².


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Hipoglicemiantes , Bélgica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico
11.
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
12.
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
13.
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
14.
J Biochem Mol Toxicol ; 33(10): e22388, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468622

RESUMO

The aim of the study is to clarify the effect of ghrelin treatment on the messenger RNA (mRNA) expression of the cannabinoid receptor 1 (Cnr1/CB1) and glucagon-like peptide 1 receptor (Glp1r/GLP-1R) as well as microRNAs (miR)-122 and miR-33a in the liver of rats with type 2 diabetes mellitus (T2DM). Adult Sprague-Dawley rats were divided into three groups: control (n = 7), T2DM (n = 7), and treatment (n = 7). Control animals received tap water. T2DM was induced by feeding 10% fructose in drinking water for 2 weeks followed by a single injection of streptozotocin (40 mg/kg, intraperitoneally [IP]). In the treatment group, diabetic rats were injected ghrelin (25 µg/kg, IP) for 14 days. Serum lipid profiles were evaluated, and mRNA expression levels of Cnr1 and Glp1r in the liver were detected using quantitative real-time polymerase chain reaction (RT-qPCR). In addition, miR-122 and miR-33a levels were measured using RT-qPCR. Serum triglycerides, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol significantly increased in the T2DM group compared with control rats but ghrelin treatment showed no effect on serum lipid levels. The mRNA expression levels of Cnr1 and Glp1r decreased in the T2DM group compared with the control group. These reductions were significantly increased in the T2DM group treated with ghrelin. Furthermore, the increase in miR-33a expression level was reduced in the treatment group compared to rats with T2DM. Our findings suggested that ghrelin treatment may alter the mRNA expression levels of CB1 and GLP-1R in the liver of rats with T2DM. The mRNA levels of Cnr1 and Glp1r may inversely correlate with the expression level of miR-33a but not miR-122.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grelina/administração & dosagem , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Fígado/metabolismo , MicroRNAs/genética , RNA Mensageiro/genética , Receptor CB1 de Canabinoide/genética , Animais , Ratos , Ratos Sprague-Dawley
15.
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
16.
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
17.
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
18.
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
19.
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
20.
Mol Med Rep ; 20(3): 2276-2284, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257516

RESUMO

Glucagon­like peptide­1 (GLP­1) and its receptor (GLP­1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a non­invasive method for monitoring GLP­1R expression. In the present study, a fluorine­18­labeled aluminum fluoride exendin­4 analog [18F­AlF conjugated with 1,4,7­triazacyclononanetriacetic acid (NOTA)­maleimide (MAL)­Cys40­exendin­4] was synthesized and evaluated in a rat MI/R model for GLP­1R imaging. NOTA­MAL­Cys40­exendin­4 was synthesized by coupling Cys40­exendin­4 with NOTA­MAL. NOTA­MAL­Cys40­exendin­4 was then conjugated with 18F­AlF to obtain 18F­AlF­NOTA­MAL­Cys40­exendin­4. The yield of 18F­AlF­NOTA­MAL­Cys40­exendin­4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP­1R and an appropriate signal­to­noise ratio. At 8 h post­MI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) post­MI/R compared with 8 h post­MI/R, but still remained higher compared with sham­operated groups (0.06±0.012 %ID/g; n=6). Pre­injected unlabeled exendin­4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, 18F­AlF­NOTA­MAL­Cys40­exendin­4 demonstrated favorable characteristics for GLP­1R imaging following MI/R. PET imaging using 18F­AlF­NOTA­MAL­Cys40­exendin­4 in rodent hearts after MI/R revealed a dynamic pattern of GLP­1R upregulation.


Assuntos
Exenatida/química , Radioisótopos de Flúor/química , Receptor do Peptídeo Semelhante ao Glucagon 1/análise , Coração/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Animais , Exenatida/síntese química , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Masculino , Maleimidas/síntese química , Maleimidas/química , Tomografia por Emissão de Pósitrons/métodos , Ratos Sprague-Dawley
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