RESUMEN
Berberine (BBR) is a principal component of Rhizoma coptidis known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it's believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM.
Asunto(s)
Berberina , Diabetes Mellitus Tipo 2 , Enfermedades Mitocondriales , Ratones , Animales , Berberina/farmacología , Berberina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Glucosa , Obesidad/metabolismo , Estrés Oxidativo , Enfermedades Mitocondriales/tratamiento farmacológicoRESUMEN
Dipeptidyl peptidase IV (DPP-IV) is an enzyme responsible for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1). DPP-IV plays a significant role in regulating blood glucose levels by modulating the activity of GLP-1. In the context of diabetes, DPP-IV inhibitors effectively block the activity of DPP-IV, hence mitigating the degradation of GLP-1. This, in turn, leads to an extension of GLP-1's duration of action, prolongs gastric emptying, enhances insulin sensitivity, and ultimately results in the reduction of blood glucose levels. Nonetheless, reported adverse events of DPP-IV inhibitors on T2DM patients make it essential to understand the activity and mechanism of these drugs, particularly viewed from the perspective of finding the effective and safe add-on medicinal plants, to be implemented in clinical practice. This review is intended to bring forth a thorough overview of plants that work by reducing DPP-IV activity, from computational technique, enzymatic study, animal experiments, and studies in humans. The articles were searched on PubMed using "Plants", "DPP-IV", "DPP-IV inhibitor", "GLP-1", "Type 2 diabetes", "diabetes", "in silico", "in vitro", "in vivo", "studies in human", "clinical study" as the query words, and filtered for ten years of publication period. Eighteen plants showed inhibition against DPP-IV as proven by in silico, in vitro, and in vivo studies; however, only ten plants were reported for efficacy in clinical studies. Several plant-based DPP-IV inhibitors, eg, Allium sativum, Morus Alba, Curcuma longa, Pterocarpus marsupium, and Taraxacum officinale, have established their functional role in inhibiting DPP-IV and have proven their effectiveness through studies in humans earning them a prominent place in therapeutic discovery.
Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Plantas Medicinales , Animales , Humanos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Dipeptidil Peptidasa 4/metabolismo , Glucemia/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/uso terapéuticoRESUMEN
BACKGROUND: Obesity is a multifaceted disease characterized by an abnormal accumulation of adipose tissue. Growing evidence has proposed microbiota-derived metabolites as a potential factor in the pathophysiology of obesity and related metabolic conditions over the last decade. As one of the essential metabolites, butyrate affects several host cellular mechanisms related to appetite sensations and weight control. However, the effects of butyrate on obesity in humans have yet to be studied. Thus, the present study was aimed to evaluate the effects of sodium butyrate (SB) supplementation on the expression levels of peroxisome proliferator activated-receptor (PPAR) gamma coactivator-1α (PGC-1α), PPARα and uncoupling protein 1 (UCP1) genes, serum level of glucagon-like peptide (GLP1), and metabolic parameters, as well as anthropometric indices in obese individuals on a weight loss diet. METHODS: This triple-blind randomized controlled trial (RCT) will include 50 eligible obese subjects aged between 18 and 60 years. Participants will be randomly assigned into two groups: 8 weeks of SB (600 mg/day) + hypo-caloric diet or placebo (600 mg/day) + hypo-caloric diet. At weeks 0 and 8, distinct objectives will be pursued: (1) PGC-1α, PPARα, and UCP1 genes expression will be evaluated by real-time polymerase chain reaction; (2) biochemical parameters will be assayed using enzymatic methods; and (3) insulin and GLP1 serum level will be assessed by enzyme-linked immunosorbent assay kit. DISCUSSION: New evidence from this trial may help fill the knowledge gap in this realm and facilitate multi-center clinical trials with a substantially larger sample size. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT20190303042905N2 . Registered on 31 January 2021.
Asunto(s)
Dieta Reductora , PPAR alfa , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR alfa/uso terapéutico , Ácido Butírico/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , Proteína Desacopladora 1/genética , Factores de Transcripción , Obesidad/diagnóstico , Obesidad/tratamiento farmacológico , Obesidad/genética , Suplementos Dietéticos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
INTRODUCTION: There is no conclusive evidence comparing the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists to the other guidelines recommended pharmacotherapy for nonalcoholic fatty liver disease (NAFLD). Therefore, we aim to compare the effects of GLP-1 receptor agonists, pioglitazone and vitamin E in patients with NAFLD. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Library up to 11 April 2022. Randomized clinical trials (RCTs) comparing GLP-1 receptor agonists, pioglitazone and vitamin E against placebo or other active controls in patients with NAFLD were included. RESULTS: Nine RCTs including 1482 patients proved eligible. GLP-1 receptor agonists ranked first in steatosis, ballooning necrosis, γ-glutamyl transferase, body weight, body mass index, and triglycerides. Administration of GLP-1 receptor agonists, as compared with placebo, was associated with improvement in liver histology [steatosis (OR = 4.11, 95% CI: 2.83, 5.96), ballooning necrosis (OR = 3.07, 95% CI: 2.14, 4.41), lobular inflammation (OR = 1.86, 95% CI: 1.29, 2.68), fibrosis (OR = 1.52, 95% CI: 1.06, 2.20)]. CONCLUSIONS: GLP-1 receptor agonists were as effective as pioglitazone and vitamin E for liver histology among patients with NAFLD. GLP-1 receptor agonists might be considered as an alternative or complementary treatment in the future clinical practice. [Figure: see text].
Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/uso terapéutico , Hipoglucemiantes/efectos adversos , Necrosis/tratamiento farmacológico , Metaanálisis en Red , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Pioglitazona/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Vitamina E/efectos adversos , Proyectos PilotoRESUMEN
BACKGROUND: Acarbose is one of the optimal drugs for patients with the first diagnosis of type 2 diabetes mellitus (T2DM). But what kind of emerging patients has the best therapeutic response to acarbose therapy has never been reported. To this end, we investigated predictors of acarbose therapeutic efficacy in newly diagnosed T2DM patients in China. METHODS: A total of 346 T2DM patients received acarbose monotherapy for 48 weeks as part of participating in the Study of Acarbose in Newly Diagnosed Patients with T2DM in China (MARCH study) from November 2008 to June 2011. Change in glycated hemoglobin (ΔHbA1c) served as a dependent variable while different baseline variables including sex, age, disease duration, weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), HbA1c, fasting plasma glucose (FPG), 2-h postprandial blood glucose (2 h PG), fasting insulin (FINS), 2-h postprandial insulin (2 h INS), early insulin secretion index (IGI), homeostasis model assessment of insulin resistance index (HOMA-IR), homeostasis model assessment of beta cell function (HOMA-B), area under the curve (AUC) of glucagon, insulin and GLP-1 were assessed as independent predictors. Step-wise multiple linear regression was employed for statistical analysis. RESULTS: The results suggested that independent predictors of ΔHbA1c at 12 weeks included baseline body weight (ß = - 0.012, P = 0.006), DBP (ß = 0.010, P = 0.047), FPG (ß = 0.111, P = 0.005) and 2 h PG (ß = 0.042, P = 0.043). Independent predictors of ΔHbA1c at 24 weeks included disease duration (ß = 0.040, P = 0.019) and FPG (ß = 0.117, P = 0.001). Finally, independent predictor of ΔHbA1c at 48 weeks was disease duration (ß = 0.038, P = 0.046). CONCLUSIONS: Acarbose may be more effective in newly diagnosed T2DM patients with low FPG, low 2 h PG and obesity. The earlier T2DM is diagnosed and continuously treated with acarbose, the better the response to therapy.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Insulinas , Humanos , Acarbosa/uso terapéutico , Hemoglobina Glucada/análisis , Glucemia/análisis , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucagón/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , China , Insulinas/uso terapéutico , Insulina/uso terapéuticoRESUMEN
Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aß plaques as well as the insoluble and soluble forms of Aß40 and Aß42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18 F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Inhibidores de la Dipeptidil-Peptidasa IV , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/farmacología , Animales , Encéfalo , Cognición , Disfunción Cognitiva/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Modelos Animales de Enfermedad , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Glucosa/metabolismo , Hipocampo , Ratones , Ratones TransgénicosRESUMEN
Monoacylglycerol O-acyltransferase 2 (MGAT2) is one of the key enzymes responsible for triglyceride (TG) re-synthesis in the small intestine. We have previously demonstrated that pharmacological inhibition of MGAT2 has beneficial effects on obesity and metabolic disorders in mice. Here, we further investigate the effects of MGAT2 inhibition on (a) fat-induced gut peptide release and fat intake in normal mice and (b) metabolic disorders in high-fat diet (HFD)-fed ob/ob mice, a model of severe obesity and type 2 diabetes mellitus, using an orally bioavailable MGAT2 inhibitor Compound B (CpdB). CpdB inhibited elevation of plasma TG in mice challenged with an oil-supplemented liquid meal. Oil challenge stimulated the secretion of two gut anorectic hormones (peptide tyrosine-tyrosine and glucagon-like peptide-1) into the bloodstream, and these responses were augmented in mice pretreated with CpdB. In a two-choice test using an HFD and a low-fat diet, CpdB selectively inhibited intake of the HFD in normal mice. Administration of CpdB to HFD-fed ob/ob mice for 5 weeks suppressed food intake and body weight gain and inhibited elevation of glycated hemoglobin. These results indicate that pharmacological MGAT2 inhibition modulates fat-induced gut peptide release and fat intake in normal mice and improves obesity and diabetes in HFD-fed ob/ob mice and thus may have potential for development into a treatment of obesity and its related metabolic diseases.
Asunto(s)
Aciltransferasas/genética , Aciltransferasas/metabolismo , Obesidad/metabolismo , Aciltransferasas/antagonistas & inhibidores , Animales , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/metabolismo , Dipéptidos/farmacología , Dipéptidos/uso terapéutico , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Metabolismo Energético , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/genética , Obesidad/fisiopatología , Triglicéridos/metabolismo , Aumento de PesoRESUMEN
La diabetes mellitus tipo 1 (DM1), es una enfermedad crónica caracterizada por la deficiencia de insulina debido a la pérdida de células ß pancreáticas, las alteraciones hormonales en la DM 1 no se limitan a la deficiencia de insulina; existiendo también secreción inadecuadada de glucagón en el período postprandial. Aunque el control glucémico con terapias intensivas con insulina ha reducido la incidencia de complicaciones microvascular y macrovasculares. La mayoría de las personas con DM1 tienen un control glucémico subóptimo; Por lo tanto, el uso de farmacoterapia adyuvante para mejorar el control ha sido de interés clínico. El uso de estos nuevos medicamentos brindaría la oportunidad de imitar más de cerca la fisiología pancreática normal, y contrarrestar otros mecanismos fisiopatológicos diferentes a Insulinopenia; contribuyendo a lograr un mejor control metabólico y expectativa de vida.
Type 1 diabetes mellitus (T1DM), is a chronic disease characterized by insulin deficiency due to the loss of pancreatic ß cells, the hormonal alterations in T1DM are not limited to insulin deficiency; there is also a deregulated glucagon secretion in the postprandial period. Although glycemic control with intensive therapies with insulin has reduced the incidence of microvascular and macrovascular complications, most people with T1DM1 glycemic control; therefore, the use of adjuvant pharmacotherapy to improve control has been of clinical interest. The use of these new drugs would offer the opportunity to imitate more closely the normal pancreatic physiology, and to counteract other physiopathological mechanisms different from insulinopenia; contributing to achieve better metabolic control and life expectancy.
Asunto(s)
Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Quimioterapia Adyuvante , Péptido 1 Similar al Glucagón/uso terapéutico , Transportador 2 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Metformina/uso terapéuticoRESUMEN
Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (â¼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)-deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (â¼5-30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (â¼300-400 pmol/L), drastically reducing glucose in Gipr null and Leprdb/db mice in a GLP-1 receptor-dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Drogas en Investigación/uso terapéutico , Péptido 1 Similar al Glucagón/análogos & derivados , Modelos Biológicos , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Drogas en Investigación/administración & dosificación , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/uso terapéutico , Hiperglucemia/prevención & control , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Prueba de Estudio Conceptual , Receptores Acoplados a Proteínas G/metabolismo , Receptores de la Hormona Gastrointestinal/genética , Receptores de la Hormona Gastrointestinal/metabolismo , Fosfato de Sitagliptina/uso terapéuticoRESUMEN
Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.
Asunto(s)
Dexametasona/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , Glucocorticoides/uso terapéutico , Incretinas/uso terapéutico , Inflamación/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Animales , Peso Corporal/efectos de los fármacos , Dexametasona/análogos & derivados , Metabolismo Energético/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Glucocorticoides/química , Glucosa/metabolismo , Células HEK293 , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Incretinas/química , Inflamación/complicaciones , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/complicaciones , Obesidad/metabolismoRESUMEN
Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential 'antioxidant' activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Práctica Clínica Basada en la Evidencia , Exenatida , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Péptidos/farmacología , Péptidos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Ponzoñas/farmacología , Ponzoñas/uso terapéuticoRESUMEN
The safety and effectiveness of islet transplantation has been proven through world-wide trials. However, acute and chronic islet loss has hindered the ultimate objective of becoming a widely used treatment option for type 1 diabetes. A large islet loss is attributed, in part, to the liver being a less-than-optimal site for transplantation. Over half of the transplanted islets are destroyed shortly after transplantation due to direct exposure to blood and non-specific inflammation. Successfully engrafted islets are continuously exposed to the liver micro-environment, a unique immune system, low oxygen tension, toxins and high glucose, which is toxic to islets, leading to premature islet dysfunction/death. Investigations have continued to search for alternate sites to transplant islets that provide a better environment for prolonged function and survival. This article gathers courses and conditions that lead to islet loss, from organ procurement through islet transplantation, with special emphasis on hypoxia, oxidative stress, and antigen non-specific inflammation, and reviews strategies using pharmacological agents that have shown effectiveness in protecting islets, including a new treatment approach utilizing siRNA. Pharmacological agents that support islet survival and promote ß-cell proliferation are also included. Treatment of donor pancreata and/or islets with these agents should increase the effectiveness of islets transplanted into extrahepatic sites. Furthermore, the development of methods designed to release these agents over an extended period, will further increase their efficacy. This requires the combined efforts of both islet transplant biologists and bioengineers.
Asunto(s)
Trasplante de Islotes Pancreáticos/métodos , Hígado/cirugía , Trasplante Heterotópico/métodos , Inductores de la Angiogénesis/farmacología , Inductores de la Angiogénesis/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Hipoxia de la Célula/efectos de los fármacos , Microambiente Celular , Evaluación Preclínica de Medicamentos , Técnicas de Silenciamiento del Gen , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Glucosa/metabolismo , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Islotes Pancreáticos/efectos de los fármacos , Hígado/citología , Hígado/inmunología , Hígado/metabolismo , Ratones , Especificidad de Órganos , Estrés Oxidativo/efectos de los fármacos , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Inhibidores Tisulares de Metaloproteinasas/farmacología , Inhibidores Tisulares de Metaloproteinasas/uso terapéutico , Obtención de Tejidos y Órganos/métodosRESUMEN
INTRODUCTION: The glucagon-like peptide-1 (GLP-1) mimetics are an established therapeutic option for patients with type 2 diabetes. However, the properties of the GLP-1 mimetics go beyond the strict metabolic control of the patients with diabetes. The neuroprotective effects of GLP-1 have been shown in recent studies opening new areas of research in neurodegenerative diseases such as Alzheimer's disease (AD), among others. AIM. Systematic review including experimental studies and human clinical trials demonstrating the neuroprotective properties of GLP-1 mimetics in AD. DEVELOPMENT: The experimental studies that have been conducted in rodent models of AD have demonstrated the neuroprotective properties of GLP-1 in the central nervous system reducing beta-amyloid plaques, the oxidative stress and the inflammatory brain response. Clinical trials in patients with cognitive impairment and AD testing the effects of GLP-1 analogs have recently started. CONCLUSION: The GLP-1 analogs have neuroprotective properties. Considering that type 2 diabetes is a risk factor for cognitive impairment and dementia, the benefits of GLP-1 mimetics on cognition must be considered. Likewise, the GLP-1 mimetics represent a promising treatment for neurodegenerative diseases such as AD.
TITLE: Analogos del glucagon-like peptide-1 (GLP-1): una nueva estrategia de tratamiento para la enfermedad de Alzheimer?Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptido 1 Similar al Glucagón/agonistas , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Animales , Barrera Hematoencefálica , Química Encefálica , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Evaluación Preclínica de Medicamentos , Exenatida , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Incretinas/fisiología , Resistencia a la Insulina , Liraglutida , Modelos Neurológicos , Fármacos Neuroprotectores/farmacología , Péptidos/farmacología , Péptidos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Glucagón/efectos de los fármacos , Receptores de Glucagón/fisiología , Factores de Riesgo , Ponzoñas/farmacología , Ponzoñas/uso terapéuticoRESUMEN
This article highlights important prescribing information for new drugs approved by the FDA over the last year. These include albiglutide, apremilast, dapagliflozin, insulin human inhalation powder, riociguat, timothy grass pollen allergen extract, umeclidinium and vilanterol inhalation powder, and vorapaxar.
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Aprobación de Drogas , United States Food and Drug Administration , Alérgenos/uso terapéutico , Compuestos de Bencidrilo/uso terapéutico , Alcoholes Bencílicos/uso terapéutico , Clorobencenos/uso terapéutico , Inhaladores de Polvo Seco , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/uso terapéutico , Glucósidos/uso terapéutico , Humanos , Insulina/uso terapéutico , Lactonas/uso terapéutico , Enfermeras Practicantes , Phleum , Extractos Vegetales/uso terapéutico , Polen , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Quinuclidinas/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Estados UnidosRESUMEN
AIMS: Examine the association between weight loss and adherence with glycaemic goal attainment in patients with inadequately controlled T2DM. MATERIALS AND METHODS: Patients ≥ 18 years with T2DM from a US integrated health system starting a new class of diabetes medication between 11/1/10 and 4/30/11 (index date) with baseline HbA1c ≥ 7.0% were included in this cohort study. Target HbA1c and weight change were defined at 6-months as HbA1c < 7.0% and ≥ 3% loss in body weight. Patient-reported medication adherence was assessed per the Medication Adherence Reporting Scale. Structural equation modelling was used to describe simultaneous associations between adherence, weight loss and HbA1c goal attainment. RESULTS: Inclusion criteria were met by 477 patients; mean (SD) age 59.1 (11.6) years; 50.9% were female; 30.4% were treatment naïve; baseline HbA1c 8.6% (1.6); weight 102.0 kg (23.0). Most patients (67.9%) reported being adherent to the index diabetes medication. At 6 months mean weight change was -1.3 (5.1) kg (p = 0.39); 28.1% had weight loss of ≥ 3%. Mean HbA1c change was -1.2% (1.8) (p< 0.001); 42.8% attained HbA1c goal. Adherent patients (OR 1.70; p = 0.02) and diabetes therapies that lead to weight loss (metformin, GLP-1) were associated with weight loss ≥ 3% (OR 2.96; p< 0.001). Weight loss (OR 3.60; p < 0.001) and adherence (OR 1.59; p < 0.001) were associated with HbA1c goal attainment. CONCLUSIONS: Weight loss ≥ 3% and medication adherence were associated with HbA1c goal attainment in T2DM; weight loss was a stronger predictor of goal attainment than medication adherence in this study population. It is important to consider weight-effect properties, in addition to patient-centric adherence counselling, when prescribing diabetes therapy.
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Diabetes Mellitus Tipo 2/dietoterapia , Índice Glucémico , Pérdida de Peso , Adulto , Anciano , Peso Corporal , Estudios de Cohortes , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/rehabilitación , Femenino , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
AIM: To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07. METHOD: A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment. RESULTS: HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. CONCLUSION: The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes.
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Glucemia/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Péptido 1 Similar al Glucagón/uso terapéutico , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/uso terapéutico , Animales , Cumarinas/farmacología , Diabetes Mellitus/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Exenatida , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Hipoglucemiantes/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Péptidos/farmacología , Receptores de Glucagón/metabolismo , Ponzoñas/farmacologíaRESUMEN
GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.
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Tejido Adiposo Pardo/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/farmacología , Hipotálamo/efectos de los fármacos , Proteínas Quinasas/metabolismo , Termogénesis/efectos de los fármacos , Quinasas de la Proteína-Quinasa Activada por el AMP , Tejido Adiposo Pardo/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Exenatida , Femenino , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Hipotálamo/metabolismo , Liraglutida , Masculino , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Persona de Mediana Edad , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Ratas , Ponzoñas/farmacología , Ponzoñas/uso terapéutico , Adulto JovenRESUMEN
We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an â¼15% body weight loss, upon which they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an â¼18% greater weight loss as compared with PEG-GLP-1/glucagon alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes.
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Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/uso terapéutico , Leptina/agonistas , Obesidad/tratamiento farmacológico , Receptores de Glucagón/agonistas , Animales , Dieta Alta en Grasa , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Glucagón/agonistas , Glucagón/uso terapéutico , Leptina/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Polietilenglicoles/uso terapéutico , Pérdida de PesoRESUMEN
In the current context of limited economic and health resources, efficiency of drug treatments is of paramount importance, and their clinical effects and related direct costs should therefore be analyzed. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM) which, in addition to its normoglycemic effects, induces a significant improvement in body weight and several cardiovascular risk factors. The aim of this narrative review is to summarize the available evidence about the effects of liraglutide upon cardiovascular risk factors and how these improve its cost-effectiveness profile. Despite the relatively higher cost of liraglutide as compared to other alternative therapies, liraglutide has been shown to be cost-effective when clinical indicators and total costs associated to T2DM management are analyzed.
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Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Hipoglucemiantes/economía , Hipoglucemiantes/uso terapéutico , Análisis Costo-Beneficio , Péptido 1 Similar al Glucagón/economía , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Liraglutida , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: The efficacy and safety of glucagon-like peptide (GLP)-1 receptor agonists for weight loss in adult patients without diabetes is reviewed. SUMMARY: GLP-1 receptor agonists have been associated with significant weight loss in patients with diabetes, raising the question of whether these agents could be used for weight loss in patients without diabetes. The mechanism by which GLP-1 receptor agonists induce weight loss is believed to be related to multiple actions involving the brain and gastrointestinal tract, with the primary action related to an increase in satiety. Trials examining the effects of GLP-1 receptor agonists for weight loss have compared exenatide, liraglutide, and orlistat. Of the studies completed to date, the majority of patients have been enrolled in trials involving liraglutide. Based on the reviewed literature, both exenatide 10 µg twice daily and liraglutide in dosages of up to 3 mg daily resulted in significant weight loss in patients without diabetes. A decrease in the proportion of patients with prediabetes was also found in studies of liraglutide. Nausea and vomiting were the most frequently reported adverse events in patients from these studies. Symptomatic hypoglycemia was reported in only one study with liraglutide in patients without diabetes and was not objectively confirmed by laboratory data. A higher frequency of psychiatric disorders, specifically insomnia, was reported by patients taking high doses of liraglutide. CONCLUSION: GLP-1 receptor agonists offer a reasonable alternative for nondiabetic patients not able to achieve weight-loss goals with lifestyle modifications alone.