RESUMEN
AIM: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. MATERIALS AND METHODS: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. RESULTS: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). CONCLUSIONS: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.
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Glucemia , Estudios Cruzados , Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Hiperglucemia , Hipoglucemiantes , Humanos , Femenino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Persona de Mediana Edad , Péptido 1 Similar al Glucagón/administración & dosificación , Masculino , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Método Doble Ciego , Anciano , Inyecciones Subcutáneas , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Infusiones Intravenosas , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Glucagón/administración & dosificación , Glucagón/sangre , Péptido C/sangreRESUMEN
Glucagon-like peptide-1-based medicines have weight loss-independent actions.
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Sistema Cardiovascular , Péptido 1 Similar al Glucagón , Agonistas Receptor de Péptidos Similares al Glucagón , Péptidos Similares al Glucagón , Pérdida de Peso , Humanos , Sistema Cardiovascular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al Glucagón/administración & dosificación , Agonistas Receptor de Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/farmacología , Liraglutida/administración & dosificación , Liraglutida/farmacología , Isquemia Miocárdica/prevención & control , Isquemia Miocárdica/terapia , Pérdida de Peso/efectos de los fármacos , AnimalesRESUMEN
BACKGROUND: No meta-analysis has holistically analyzed and summarized the therapeutic efficacy and safety of albiglutide in type 2 diabetes (T2D). This meta-analysis addresses this knowledge gap. METHODS: Randomized controlled trials involving patients with T2D receiving albiglutide in the intervention arm and either a placebo or an active comparator in the control arm were searched through electronic databases. The primary outcome was the change from baseline (CFB) in glycated hemoglobin (HbA1c); secondary outcomes included CFB in fasting plasma glucose, body weight, and adverse events (AE). RESULTS: From 443 initially screened articles, data from 12 randomized controlled trials involving 6423 subjects were analyzed. Albiglutide, at both doses, outperformed placebo in terms of HbA1c reductions (for albiglutide 30 mg: mean differences -1.04%, 95% confidence interval [CI] [-1.37--0.72], Pâ <â .00001, I2â =â 89%; and for albiglutide 50 mg: mean differences -1.10%, 95% CI [-1.45--0.75], Pâ <â .00001, I2â =â 90%). Higher proportions of subjects achieved HbA1câ <â 7% in the albiglutide arm than in placebo (for albiglutide 30 mg: odds ratio 6.26, 95% CI [2.50-15.70], Pâ <â .0001, I2â =â 82%; and for albiglutide 50 mg: odds ratio 5.57, 95% CI [2.25-13.80], Pâ =â .0002, I2â =â 84%). Albiglutide had glycemic efficacy comparable to other glucose-lowering drugs. CFB in body weight was similar with albiglutide and placebo. AE profile, including gastrointestinal AE, was identical with albiglutide and placebo, except for higher drug-related AE and injection-site reaction with albiglutide. CONCLUSION: Albiglutide provides reassuring data on good glycemic efficacy, tolerability, and safety over an extended period of clinical use in patients with T2D. Albiglutide 30 mg has comparable efficacy and safety profiles to albiglutide 50 mg.
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Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Resultado del TratamientoRESUMEN
AIM: To evaluate gastric emptying (GE) and the glycaemic response to a 75-g oral glucose load in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12-15 months after insulin pump therapy. MATERIALS AND METHODS: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75-g glucose drink containing 150 mg 13C-acetate, to determine the gastric half-emptying time, and underwent assessment of plasma glucose and serum insulin, C-peptide and glucagon-like peptide-1 (GLP-1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re-assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12-15 months, GE was re-measured in 14 of the T2D participants. RESULTS: At baseline, participants with T2D exhibited substantially augmented fasting and post-glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP-1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP-1 secretion was attenuated, fasting and post-glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12-15 months of follow-up. CONCLUSIONS: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short-term insulin pump therapy. The effect on GE is maintained for at least 12 months.
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Glucemia , Diabetes Mellitus Tipo 2 , Vaciamiento Gástrico , Hipoglucemiantes , Sistemas de Infusión de Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Masculino , Femenino , Persona de Mediana Edad , Vaciamiento Gástrico/efectos de los fármacos , Glucemia/análisis , Glucemia/metabolismo , Insulina/administración & dosificación , Hipoglucemiantes/administración & dosificación , China , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Adulto , Pueblo Asiatico , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido C/sangre , Secreción de Insulina/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Pueblos del Este de AsiaRESUMEN
Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2-7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1-65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6-89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63-0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit.NEW & NOTEWORTHY If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp.
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Arginina , Péptido C , Diabetes Mellitus Tipo 1 , Alimentos Formulados , Péptido 1 Similar al Glucagón , Glucosa , Islotes Pancreáticos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arginina/administración & dosificación , Arginina/farmacología , Glucemia/metabolismo , Péptido C/sangre , Péptido C/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/administración & dosificación , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Hiperglucemia/metabolismo , Insulina/metabolismo , Insulina/administración & dosificación , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/fisiología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/efectos de los fármacosRESUMEN
It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7-36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/administración & dosificación , Péptido 1 Similar al Glucagón/administración & dosificación , Hipoglucemiantes/administración & dosificación , Incretinas/administración & dosificación , Secreción de Insulina/efectos de los fármacos , Metformina/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada/métodos , Femenino , Polipéptido Inhibidor Gástrico/sangre , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa/métodos , Humanos , Hipoglucemiantes/sangre , Incretinas/sangre , Insulina/sangre , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Fosfato de Sitagliptina/sangre , Resultado del TratamientoRESUMEN
Glucagon-like peptide (GLP)-1 and GLP-2, proglucagon-derived brain-gut peptides, function as anorexigenic neuropeptides in mammals. We previously showed that central administration of GLP-1 and GLP-2 potently suppressed food intake in chicks. GLP-1 and GLP-2 specifically activate their receptors GLP-1 receptor (GLP1R) and GLP-2 receptor (GLP2R), respectively in chickens. In adult chickens, GLP1R and GLP2R are expressed in different brain regions. These findings raise the hypothesis that both GLP-1 and GLP-2 function as anorexigenic peptides in the chicken brain but the mechanisms underlying the anorexigenic effects are different between them. In the present study, we compared several aspects of GLP-1 and GLP-2 in chicks. GLP1R mRNA levels in the brain stem and optic lobes were significantly higher than in other parts of the brain, whereas GLP2R mRNA was densely expressed in the telencephalon. Intracerebroventricular administration of either GLP-1 or GLP-2 significantly reduced the mRNA levels of corticotrophin releasing factor and AMP-kinase (AMPK) α1. The mRNA level of proopiomelanocortin was significantly increased, and those of AMPKα2 and GLP2R were significantly decreased by GLP-2, whereas the mRNA level of pyruvate dehydrogenase kinase 4 was significantly increased, and that of GLP1R was significantly decreased by GLP-1. Intracerebroventricular administration of either GLP-1 or GLP-2 induced sleep-like behavior in chicks. Our findings suggest that the anorexigenic peptides GLP-1 and GLP-2 induce similar behavioral changes in chicks, but the mechanism may differ between them.
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Apetito/efectos de los fármacos , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 2 Similar al Glucagón/administración & dosificación , Hipotálamo/efectos de los fármacos , Sueño/efectos de los fármacos , Animales , Apetito/fisiología , Pollos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 2 Similar al Glucagón/metabolismo , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Sueño/fisiologíaRESUMEN
CONTEXT: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery. OBJECTIVE: To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). DESIGN AND SETTING: Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. PATIENTS AND INTERVENTIONS: Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. MAIN OUTCOME MEASURES: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention. RESULTS: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. CONCLUSIONS: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.
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Restricción Calórica/estadística & datos numéricos , Diabetes Mellitus Tipo 2/terapia , Derivación Gástrica/estadística & datos numéricos , Hormonas Gastrointestinales/administración & dosificación , Obesidad Mórbida/terapia , Adulto , Anciano , Glucemia/análisis , Restricción Calórica/métodos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/orina , Quimioterapia Combinada/métodos , Femenino , Derivación Gástrica/métodos , Péptido 1 Similar al Glucagón/administración & dosificación , Humanos , Infusiones Subcutáneas , Masculino , Metabolómica/estadística & datos numéricos , Persona de Mediana Edad , Obesidad Mórbida/sangre , Obesidad Mórbida/metabolismo , Obesidad Mórbida/orina , Oxintomodulina/administración & dosificación , Péptido YY/administración & dosificación , Método Simple Ciego , Resultado del Tratamiento , Pérdida de Peso , Adulto JovenRESUMEN
Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novel Xenopus GLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its short in vivo half-life. Starting from xGLP/GCG-13, dual Cys mutation was performed, followed by covalent side-chain stapling and serum albumin binder incorporation, resulting in a stabilized secondary structure, enhanced agonist potency at GLP-1R and GCGR, and improved stability. The lead peptide 2c (stapled xGLP/GCG-13 analogue with a palmitic acid albumin binder) exhibits balanced GLP-1R and GCGR activations and potent, long-lasting effects on in vivo glucose control. 2c was further explored pharmacologically in diet-induced obesity and db/db rodent models. Chronic administration of 2c potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, increased energy expenditure, and normalized lipid metabolism and adiposity in relevant animal models. These results indicated that 2c has potential for development as a novel antidiabetic and/or antiobesity drug. Furthermore, we propose that the incorporation of a proper serum protein-binding motif into a di-Cys staple is an effective method for improving the stabilities and bioactivities of peptides. This approach is likely applicable to other therapeutic peptides, such as glucose-dependent insulin-tropic peptide receptor (GIPR) and GLP-1R dual agonists or GLP-1R/GCGR/GIPR triagonists.
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Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/administración & dosificación , Receptor del Péptido 1 Similar al Glucagón/agonistas , Obesidad/tratamiento farmacológico , Péptidos/administración & dosificación , Receptores de Glucagón/agonistas , Animales , Células CHO , Cricetulus , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Obesidad/etiología , Obesidad/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/metabolismo , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacos , XenopusRESUMEN
RATIONALE: Dumping syndrome is a frequent and potentially severe complication after gastric surgery. Beinaglutide, a recombinant human glucagon-like peptide-1 (GLP-1) which shares 100% homology with human GLP-1(7-36), has never been reported in the treatment of dumping syndrome before. PATIENT CONCERNS: The patient had undergone distal gastrectomy for gastric signet ring cell carcinoma 16âmonths ago. He presented with symptoms of paroxysmal palpitation, sweating, and dizziness for 4 months. DIAGNOSIS: He was diagnosed with late dumping syndrome. INTERVENTIONS AND OUTCOMES: The patient was treated with dietary changes and acarbose for 4 months before admitted to our hospital. The treatment with dietary changes and acarbose did not prevent postprandial hyperinsulinemia and hypoglycemia according to the 75âg oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) on admission.Therefore, the patient was treated with beinaglutide 0.1âmg before breakfast and lunch instead of acarbose. After the treatment of beinaglutide for 1 month, OGTT showed a reduction in postprandial hyperinsulinemia compared with before starting treatment, and the time in the range of 3.9 to 10âmmol/L became 100% in CGM. No side effect was observed in this patient during beinaglutide treatment. LESSONS: These findings suggest that beinaglutide may be effective for treating post-gastrectomy late dumping syndrome.
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Síndrome de Vaciamiento Rápido/tratamiento farmacológico , Gastrectomía/efectos adversos , Péptido 1 Similar al Glucagón/administración & dosificación , Hiperinsulinismo/tratamiento farmacológico , Hipoglucemia/tratamiento farmacológico , Fragmentos de Péptidos/administración & dosificación , Glucemia/análisis , Carcinoma de Células en Anillo de Sello/cirugía , Síndrome de Vaciamiento Rápido/sangre , Síndrome de Vaciamiento Rápido/diagnóstico , Síndrome de Vaciamiento Rápido/etiología , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/etiología , Hipoglucemia/sangre , Hipoglucemia/diagnóstico , Hipoglucemia/etiología , Masculino , Persona de Mediana Edad , Periodo Posprandial , Proteínas Recombinantes/administración & dosificación , Neoplasias Gástricas/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. METHODS: We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time-Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). RESULTS: There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G - 0.23 s (0.27) versus group GT - 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: - 20.83 mmHg s (24.54 vs. - 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine - 2.0 ng/ml (- 117.1, 14.8) versus - 0.5 ng/ml (- 19.6, 9.4); p = 0.60. CONCLUSION: The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. TRIAL REGISTRATION: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.
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Adenosina/metabolismo , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/efectos de los fármacos , Péptido 1 Similar al Glucagón/administración & dosificación , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificación , Anciano , Anciano de 80 o más Años , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/metabolismo , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores Purinérgicos P1/administración & dosificación , Transducción de Señal , Teofilina/administración & dosificaciónRESUMEN
The glucagon-like peptide-1 (GLP-1) was shown to have neuroprotective effects in Alzheimer's disease (AD). However, the underlying mechanism remains elusive. Astrocytic mitochondrial abnormalities have been revealed to constitute important pathologies. In the present study, we investigated the role of astrocytic mitochondria in the neuroprotective effect of GLP-1 in AD. To this end, 6-month-old 5 × FAD mice were subcutaneously treated with liraglutide, a GLP-1 analogue (25 nmol/kg/qd) for 8 weeks. Liraglutide ameliorated mitochondrial dysfunction and prevented neuronal loss with activation of the cyclic adenosine 3',5'-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway in the brain of 5 × FAD mice. Next, we exposed astrocytes to ß-amyloid (Aß) in vitro and treated them with GLP-1. By activating the cAMP/PKA pathway, GLP-1 increased the phosphorylation of DRP-1 at the s637 site and mitigated mitochondrial fragmentation in Aß-treated astrocytes. GLP-1 further improved the Aß-induced energy failure, mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (MMP) collapse, and cell toxicity in astrocytes. Moreover, GLP-1 also promoted the neuronal supportive ability of Aß-treated astrocytes via the cAMP/PKA pathway. This study revealed a new mechanism behind the neuroprotective effect of GLP-1 in AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Péptido 1 Similar al Glucagón/análogos & derivados , Mitocondrias/metabolismo , Neuronas/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Péptido 1 Similar al Glucagón/administración & dosificación , Hipoglucemiantes/administración & dosificación , Liraglutida/administración & dosificación , Ratones , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
The repurposing of drugs developed to treat type 2 diabetes for the treatment of Parkinson's disease (PD) was encouraged by the beneficial effect exerted by the glucagon-like peptide 1 (GLP-1) analogue exenatide in a phase 2 clinical trial. The effects of GLP-1 analogues have been investigated extensively using rodent toxin models of PD. However, many of the toxin-based models used lack robust α-synuclein (α-syn) pathology, akin to the Lewy bodies and neurites seen in PD. One prior study has reported a protective effect of a GLP-1 analogue on midbrain dopamine neurons following injection of α-syn preformed fibrils (PFF) into the striatum. Here, we used olfactory bulb injections of PFF as a model of prodromal PD and monitored the effect of a long-acting GLP-1 analogue on the propagation of α-syn pathology in the olfactory system. Thirteen weeks after PFF injection, mice treated with long-acting the GLP-1 analogue had a significant increase in pathological α-syn in brain regions connected to the olfactory bulb, accompanied by signs of microglia activation. Our results suggest that the nature of the neuronal insult and intrinsic properties of the targeted neuronal population markedly influence the effect of GLP-1 analogues.
Asunto(s)
Péptido 1 Similar al Glucagón/análogos & derivados , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Síntomas Prodrómicos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidad , Animales , Modelos Animales de Enfermedad , Femenino , Péptido 1 Similar al Glucagón/administración & dosificación , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos C57BL , alfa-Sinucleína/administración & dosificaciónRESUMEN
Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250).
Asunto(s)
Afecto/efectos de los fármacos , Emociones/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/administración & dosificación , Hiperfagia/tratamiento farmacológico , Estrés Psicológico/tratamiento farmacológico , Afecto/fisiología , Animales , Fármacos Antiobesidad/administración & dosificación , Eje Cerebro-Intestino/efectos de los fármacos , Eje Cerebro-Intestino/fisiología , Ensayos Clínicos Fase III como Asunto/métodos , Emociones/fisiología , Exenatida/administración & dosificación , Humanos , Hiperfagia/metabolismo , Hiperfagia/psicología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/psicología , Estrés Psicológico/metabolismo , Estrés Psicológico/psicologíaRESUMEN
The postweaning fast of northern elephant seal pups is characterized by a lipid-dependent metabolism and associated with a decrease in plasma glucagon-like peptide-1 (GLP-1), insulin, and glucose and increased gluconeogenesis (GNG) and ketogenesis. We have also demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of GNG, ketogenesis, and glycolysis. To assess the effects of GLP-1 on metabolism using primary carbon metabolite profiles in late-fasted seal pups, we dose-dependently infused late-fasted seals with low (LDG; 10 pM/kg; n = 3) or high (HDG; 100 pM/kg; n = 4) GLP-1 immediately following a glucose bolus (0.5 g/kg), using glucose without GLP-1 as control (n = 5). Infusions were performed in similarly aged animals 6-8 wk into their postweaning fast. The plasma metabolome was measured from samples collected at five time points just prior to and during the infusions, and network maps constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased key tricarboxylic acid (TCA) cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate (P < 0.05) suggesting that elevated levels of GLP-1 promote glycolysis and suppress GNG and ketogenesis, which collectively increase glucose clearance. These GLP-1-mediated effects on cellular metabolism help to explain why plasma GLP-1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose during the late-fasting period.
Asunto(s)
Glucemia/efectos de los fármacos , Ciclo del Ácido Cítrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/administración & dosificación , Gluconeogénesis/efectos de los fármacos , Cuerpos Cetónicos/metabolismo , Phocidae/metabolismo , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Ayuno/sangre , Infusiones Intravenosas , Masculino , Metaboloma , Metabolómica , Phocidae/sangre , Factores de Tiempo , DesteteRESUMEN
AIMS: To develop an oral delivery system of glucagon-like peptide 1 (GLP-1) (28-36) for treating type-2 diabetes, B.S-GLP-1(28-36), a recombinant Bacillus subtilis spores transformed with a plasmid vector encoding five consecutive GLP-1 (28-36) nonapeptides with an enterokinase site was constructed. METHODS AND RESULTS: GLP-1(28-36) nonapeptide was successfully expressed on the surface of B. subtilis spores and validated by Western blot and immunofluorescence. The therapeutic effect of oral administration of B.S-GLP-1(28-36) spores was evaluated in type 2 diabetic model mice. The efficacy of recombinant spores was examined for a period of 13 weeks after oral administration in diabetic mice. At the end of the sixth week, diabetic mice with oral administration of BS-GLP-1(28-36) spores showed decreased blood glucose levels from 2·4 × 10- 2 mol l-1 to 1·7 × 10- 2 mol l-1 . By the ninth week, the mean fasting blood glucose level in the experimental group was significantly lower than that in the control group 30 min after injection of pyruvate. At the end of the 10th week of oral administration, the blood glucose of the experimental group was significantly lower than that of the control group after intraperitoneal injection of glucose. By the 12th week, fasting blood glucose level and fasting insulin level were measured in all mice, the results showed that the recombinant spores increased the insulin sensitivity of mice. CONCLUSIONS: The results of pathological observation showed that the recombinant spores also had a certain protective effect on the liver and islets of mice, and the content of GLP-1(28-36) in the pancreas of the experimental group was increased. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study revealed that GLP-1(28-36) nonapeptides can reduce blood glucose and play an important role in the treatment of type 2 diabetes.
Asunto(s)
Bacillus subtilis/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/metabolismo , Incretinas/administración & dosificación , Administración Oral , Animales , Bacillus subtilis/genética , Glucemia/efectos de los fármacos , Técnicas de Visualización de Superficie Celular , Diabetes Mellitus Experimental , Péptido 1 Similar al Glucagón/genética , Insulina/sangre , Masculino , Ratones , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Esporas Bacterianas/genética , Esporas Bacterianas/metabolismo , Resultado del TratamientoRESUMEN
Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym SG ), which is estimated by modeling of glucose and insulin data after an intravenous glucose administration, and accounts for ≈70% of glucose disposal. This review summarizes studies on SG , mainly in humans and rodents with focus on results achieved in model experiments in mice. In humans, SG is reduced in type 2 diabetes, in obesity, in liver cirrhosis and in some elderly populations. In model experiments in mice, SG is independent from glucose levels, but increases when insulin secretion is stimulated, such as after administration of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. SG is reduced in insulin resistance induced by high-fat feeding and by exogenous administration of glucagon. Glucose-dependent (insulin-independent) glucose disposal is therefore important for glucose elimination, and it is also well regulated. It might be of pathophysiological relevance for the development of type 2 diabetes, in particular during insulin resistance, and might also be a target for glucose-reducing therapy. Measuring SG is essentially important when carrying out metabolic studies to understand glucose homeostasis.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/administración & dosificación , Glucosa/metabolismo , Administración Intravenosa , Adulto , Anciano , Animales , Transporte Biológico , Modelos Animales de Enfermedad , Femenino , Polipéptido Inhibidor Gástrico/administración & dosificación , Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/administración & dosificación , Homeostasis/efectos de los fármacos , Humanos , Incretinas/administración & dosificación , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina/efectos de los fármacos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
BACKGROUND AND AIMS: The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. METHODS: We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the ß-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. RESULTS: a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100â¯pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. CONCLUSION: We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/administración & dosificación , Péptido 1 Similar al Glucagón/administración & dosificación , Incretinas/administración & dosificación , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Polipéptido Inhibidor Gástrico/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , Prueba de Tolerancia a la Glucosa , Humanos , Incretinas/uso terapéutico , Células Secretoras de Insulina/metabolismo , Modelos TeóricosRESUMEN
In this study, we investigated the effects of feeding a moderate- or high-energy close-up diet to close-up cows on response of newborn calves to intravenously (i.v.) injected glucagon-like peptide 1 (GLP-1). Newborn Holstein heifer calves (n = 37) from cows fed with a moderate-energy [M, 1.54 Mcal/kg of dry matter (DM) NEl; 14% starch; n = 17] or high-energy (H, 1.63 Mcal/kg of DM NEl; 26% starch; n = 20) diet in the last 28 d prepartum were assigned to one of two treatment groups, which were i.v. injected with saline (MC and HC, n = 9 and 10, respectively) or GLP-1 solution at 1.0 µg/kg BW (MG and HG, n = 8 and 10, respectively) immediately after milk replacer (MR; 26% CP, 16% fat) feeding. Blood samples were obtained through a jugular vein catheter at -10, 0, 10, 20, 30, 40, 50, 60, 90, and 120 min relative to MR feeding at 2, 10, and 20 d after birth, and plasma glucose, insulin, and GLP-1 concentrations were measured. Plasma GLP-1 concentration tended to increase starting from 30 min after MR feeding in the MC relative to the HC group at 10 (0.77 ng/mL vs 0.69 ng/mL for MC and HC, respectively; P = 0.10) and 20 d after birth (0.47 ng/mL vs 0.35 ng/mL for MC and HC, respectively; P = 0.07). Plasma glucose and insulin concentrations after MR feeding did not differ between MC and HC groups at 2 and 20 d after birth but were higher (P < 0.05) in MC (158 mg/dL and 3.64 ng/mL for glucose and insulin, respectively) than in HC (143 mg/dL and 2.46 ng/mL for glucose and insulin, respectively) calves at 10 d after birth. The elevation in plasma glucose concentration after MR feeding was suppressed by direct glucose-lowering action of i.v. injected GLP-1 at 2, 10, and 20 d after birth in M and H calves; this direct glucose-lowering action by GLP-1 was greater (P < 0.05) for H than for M calves at 20 d after birth. These results indicate that feeding a high-energy close-up diet to cows affects glucose status in their female offspring via suppression of postprandial plasma concentrations of GLP-1 and insulin as well as the alteration in the glucose-lowering action of GLP-1 after feeding depending on the day after birth.
Asunto(s)
Alimentación Animal/análisis , Dieta/veterinaria , Ingestión de Energía , Péptido 1 Similar al Glucagón/farmacología , Fenómenos Fisiologicos de la Nutrición Prenatal , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Animales Recién Nacidos , Glucemia , Bovinos , Femenino , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/sangre , Insulina/sangre , Sustitutos de la Leche , EmbarazoRESUMEN
GLP-1 receptor agonists are used for the treatment of type 2 diabetes but they may reduce appetite and cause nausea and emesis. We investigated if GLP-1 (7-36) amide can modulate glucose homoeostasis, emesis and feeding via an exendin (9-39)-sensitive mechanism in Suncus murinus. The effect of GLP-1 (7-36) amide on glucose homeostasis was examined using an intraperitoneal glucose tolerance test. In conscious fasted animals, food and water consumption and behavior were measured for 1 h following drug administration. c-Fos expression in the brain was measured using immunohistochemistry. GLP-1 (7-36) amide reduced blood glucose levels dose-dependently. Exendin (9-39) did not modify blood glucose levels but suppressed the glucose-lowering effect of GLP-1 (7-36) amide. GLP-1 (7-36) amide inhibited food and water intake, induced emesis and elevated c-Fos expression in the brainstem and hypothalamic nuclei in the brain. Exendin (9-39) antagonised the inhibition of food and water intake and emesis induced by GLP-1 (7-36) amide and the effects on c-Fos expression in the hypothalamus and brainstem, excepting for the bed nucleus of the stria terminalis. These data suggest that the action of GLP-1 (7-36) amide to modulate blood glucose, suppress food and water intake and induce emesis involve GLP-1 receptors in the hypothalamus and brainstem.