RESUMEN
Background: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice. Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1ß, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1ß were measured using Western blotting. Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1ß levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1ß, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway. Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NFκB signaling pathway in PCOS mice.
Asunto(s)
Agonistas Receptor de Péptidos Similares al Glucagón , Péptidos Similares al Glucagón , Inflamación , Síndrome del Ovario Poliquístico , Transducción de Señal , Animales , Femenino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Modelos Animales de Enfermedad , Péptidos Similares al Glucagón/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Ovario/efectos de los fármacos , Ovario/patología , Ovario/metabolismo , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismo , Agonistas Receptor de Péptidos Similares al Glucagón/farmacologíaRESUMEN
BACKGROUND: The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans. METHODS: In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests. FINDINGS: 24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred. INTERPRETATION: In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters. FUNDING: Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.
Asunto(s)
Estudios Cruzados , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Fragmentos Fc de Inmunoglobulinas , Proteínas Recombinantes de Fusión , Humanos , Masculino , Fragmentos Fc de Inmunoglobulinas/farmacología , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Adulto , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Persona de Mediana Edad , Adulto Joven , Método Doble Ciego , Adolescente , Testosterona/análogos & derivados , Hormona Luteinizante/sangreRESUMEN
BACKGROUND: Older adults with type 2 diabetes mellitus (T2DM) or prediabetes are at increased risk of adverse changes in body composition, physical function, and aging-related biomarkers compared to those with normal glucose tolerance. Semaglutide is a glucagon-like peptide 1 receptor agonist that has been approved for T2DM and chronic weight management. Although semaglutide is effective for weight loss and T2DM management, its effects on lean body mass, physical function, and biomarkers of aging are understudied in older adults. OBJECTIVE: This study aims to compare the effects of lifestyle counseling with and that without semaglutide on body composition, physical function, and biomarkers of aging in older adults. METHODS: This is an open-label randomized controlled trial. A total of 20 adults (aged 65 years and older) with elevated BMI (27-40 kg/m2) and prediabetes or well-controlled T2DM (hemoglobin A1c 5.7%-7.5%) are recruited, stratified by sex, and randomized 1:1 to one of 2 groups (semaglutide plus lifestyle counseling vs lifestyle counseling alone) and followed up for 5 months. Those in the semaglutide group are titrated to 1 mg weekly, as tolerated, for 12 weeks. Lifestyle counseling is given by registered dietitians and based on the Diabetes Prevention Program Lifestyle Change Program. Our primary outcomes include changes in lean mass, physical function, and biomarkers of aging. Body composition is measured by dual-energy x-ray absorptiometry and includes total fat mass and lean mass. Physical function is measured by 6-minute walk distance, grip strength, and short physical performance battery. Biomarkers of aging are measured in blood, skeletal muscle, and abdominal adipose tissue to include C-reactive protein, interleukin-6, tumor necrosis factors α, and ß galactosidase staining. RESULTS: The study was funded in December 2021 with a projected data collection period from spring 2023 through summer 2024. CONCLUSIONS: Despite the elevated risk of adverse changes in body composition, physical function, and biomarkers of aging among older adults with glucose intolerance and elevated adiposity, the benefits and risks of commonly prescribed antihyperglycemic or weight loss medications such as semaglutide are understudied. This study aims to fill this knowledge gap to inform clinicians about the potential for additional clinically meaningful, nonglycemic effects of semaglutide. TRIAL REGISTRATION: ClinicalTrials.gov NCT05786521; https://clinicaltrials.gov/study/NCT05786521. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/62667.
Asunto(s)
Biomarcadores , Composición Corporal , Diabetes Mellitus Tipo 2 , Péptidos Similares al Glucagón , Resistencia a la Insulina , Sobrepeso , Humanos , Composición Corporal/efectos de los fármacos , Anciano , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Masculino , Biomarcadores/sangre , Femenino , Sobrepeso/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Envejecimiento/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/sangre , Rendimiento Físico FuncionalRESUMEN
In addition to optimal glycemic control and management of other factors aggravating the pathology (hypertension, dyslipidemia, -obesity), the cornerstone of treatment of diabetic kidney disease (DKD) includes blockers of the renin-angiotensin system, sodium-glucose cotransporter 2 inhibitors or nonsteroidal antagonists of the mineralocorticoid receptor (finerenone). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended in the treatment of high-risk patients with type 2 diabetes (T2DM) to reduce cardiovascular (CV) risk. Data from CV studies indicate a nephroprotective effect of certain GLP-1 RAs in T2DM patients with DKD. The FLOW study published in May 2024, analyzing the impact of semaglutide vs placebo on renal events as primary outcome, confirms this renal protection of GLP-1 RAs.
Outre le contrôle glycémique et la prise en charge d'autres facteurs d'aggravation de la pathologie, la pierre angulaire du traitement de la maladie rénale diabétique (MRD) comprend les bloqueurs du système rénine-angiotensine, les inhibiteurs du cotransporteur sodium-glucose de type 2 ou encore la finérénone (antagoniste de l'aldostérone). Les agonistes du récepteur du glucagon-like peptide-1 (ARGLP-1) sont recommandés dans le traitement des patients avec un diabète de type 2 (DT2) à haut risque afin de réduire le risque cardiovasculaire (CV). Les données provenant des études CV indiquent un effet néphroprotecteur de certains ARGLP-1 chez les patients DT2 avec MRD. L'étude FLOW, publiée fin mai 2024 et analysant l'impact du sémaglutide sur les événements rénaux comme critère principal, confirme cette protection rénale des ARGLP-1.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Receptor del Péptido 1 Similar al Glucagón , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Nefropatías Diabéticas/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Enfermedades Cardiovasculares/prevención & control , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
The STEP-HFpEF DM trial1 showed that semaglutide improved body weight, systemic inflammation, and heart failure symptoms in people with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes. By addressing both metabolic and cardiovascular risk, semaglutide is a promising therapeutic option for HFpEF in addition to SGLT2i.
Asunto(s)
Diabetes Mellitus Tipo 2 , Péptidos Similares al Glucagón , Insuficiencia Cardíaca , Obesidad , Volumen Sistólico , Humanos , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/efectos de los fármacos , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
The availability of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as liraglutide and semaglutide, and a GLP-1 and glucose dependent insulinotropic polypeptide coagonist (tirzepatide) represents a paradigm shift in the management of both type 2 diabetes and obesity. There is now considerable attention, including in the public media, on the effect of both long-acting and short-acting GLP-1RAs to delay gastric emptying. Although slowed gastric emptying is integral to reducing post-prandial blood glucose responses in type 2 diabetes, marked slowing of gastric emptying might also increase the propensity for longer intragastric retention of food, with a consequent increased risk of aspiration at the time of surgery or upper gastrointestinal endoscopy. This Personal View summarises current knowledge of the effects of GLP-1 and GLP-1RAs on gastrointestinal physiology, particularly gastric emptying, and discusses the implications for the development of sound pre-operative or pre-procedural guidelines. The development of pre-procedural guidelines is currently compromised by the poor evidence base, particularly in relation to the effect of long-acting GLP-1RAs on gastric emptying. We suggest pre-procedural management pathways for individuals on GLP-1RA-based therapy and discuss priorities for future research.
Asunto(s)
Diabetes Mellitus Tipo 2 , Vaciamiento Gástrico , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Hipoglucemiantes , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Vaciamiento Gástrico/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Obesidad/tratamiento farmacológico , Liraglutida/uso terapéutico , Liraglutida/farmacología , Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al GlucagónAsunto(s)
Tejido Adiposo , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Agonistas Receptor de Péptidos Similares al Glucagón , Péptidos Similares al Glucagón , Pericardio , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tejido Adiposo/efectos de los fármacos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Progresión de la Enfermedad , Tejido Adiposo Epicárdico , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Pericardio/efectos de los fármacos , Agonistas Receptor de Péptidos Similares al Glucagón/farmacología , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéuticoRESUMEN
Previously, no randomized controlled trials investigated the renoprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) as the primary endpoint in patients with diabetes and chronic kidney disease. In the FLOW trial, Perkovic et al. showed that once-weekly semaglutide reduced kidney failure, kidney-related death, and cardiovascular death by 24% as compared with placebo in patients with type 2 diabetes at high risk of renal progression.1.
Asunto(s)
Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Insuficiencia Renal Crónica/tratamiento farmacológico , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/administración & dosificación , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Nefropatías Diabéticas/tratamiento farmacológicoRESUMEN
Obesity is a well-known risk factor for testicular function; however, dulaglutide's effect on the testis in obesity has received little attention. Currently, clinicians prescribe the antidiabetic drug dulaglutide only off-label for weight management in non-diabetics. Investigating the impact of this novel compound on obesity is critical for determining whether it has any disruptive effects on testicular cells. We used a well-known animal model of high-fat diet-induced obesity in this investigation, and testicular dysfunction was determined by sperm DNA damage, spermatocyte chromosomal abnormalities, and spermiogram analysis. Following a 12-week high-fat diet challenge, mice were randomly assigned to dulaglutide (0.6â¯mg/kg/day) or saline treatments for five weeks. Testes and sperm cells were collected 24â¯h after the last dulaglutide injection. Untreated obese mice had a lower testes/body weight ratio, more sperm DNA damage, diakinesis-metaphase I chromosomal abnormalities, a lower sperm count/motility, more cell morphological defects, and an altered testicular redox balance. In obese mice, dulaglutide injection efficiently restored all disturbed parameters to their control levels. Dulaglutide injection into healthy mice exhibited no significant harmful effects at the applied regimen. As a result, we infer that dulaglutide therapy might bring obese men additional benefits by recovering testicular dysfunction induced by obesity.
Asunto(s)
Dieta Alta en Grasa , Modelos Animales de Enfermedad , Péptidos Similares al Glucagón , Fragmentos Fc de Inmunoglobulinas , Obesidad , Proteínas Recombinantes de Fusión , Testículo , Animales , Masculino , Fragmentos Fc de Inmunoglobulinas/farmacología , Obesidad/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Ratones , Proteínas Recombinantes de Fusión/farmacología , Testículo/efectos de los fármacos , Testículo/patología , Testículo/metabolismo , Daño del ADN/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Hipoglucemiantes/farmacología , Motilidad Espermática/efectos de los fármacos , Ratones Endogámicos C57BL , Aberraciones Cromosómicas/efectos de los fármacos , Enfermedades Testiculares/tratamiento farmacológicoRESUMEN
Objective: This study aims to investigate the effects of semaglutide on gut microbiota, cognitive function, and inflammation in obese mice. Method: Twenty-four C57BL/6J male mice were randomly assigned to three groups: a normal-chow diet group (NCD, n = 8), high-fat diet group (HFD, n = 8), and HFD+semaglutide group (Sema, n = 8). The mice were fed a HFD to establish an animal model of obesity and then administered with semaglutide or saline for 12 weeks. Cognitive function was assessed using the Morris water maze test. Serum pro-inflammatory cytokines were measured. 16S rRNA gene sequencing technology was used to explore gut microbiota characteristics in obese mice. Result: Obese mice showed significant cognitive impairment and inflammation. Semaglutide improved cognitive function and attenuated inflammation induced by a HFD diet. The abundance of gut microbiota was significantly changed in the HFD group, including decreased Akkermansia, Muribaculaceae, Coriobacteriaceae_UCG_002, Clostridia_UCG_014 and increased Romboutsia, Dubosiella, Enterorhabdus. Whereas semaglutide could dramatically reverse the relative abundance of these gut microbiota. Correlation analysis suggested that cognitive function was positively correlated with Muribaculaceae and Clostridia_UCG_014, and negatively associated with Romboutsia and Dubosiella. Romboutsia was positively correlated with TNFα, IL-6 and IL-1ß. While Clostridia_UCG_014 was negatively related to TNFα, IL-6 and IL-1ß. Conclusions: For the first time semaglutide displayed different regulatory effects on HFD-induced gut microbiota dysbiosis. Semaglutide could regulate the structure and composition of gut microbiota associated with cognitive function and inflammation. Thus, affecting gut microbiota might be a potential mechanism of semaglutide in attenuating cognitive function and inflammation.
Asunto(s)
Cognición , Dieta Alta en Grasa , Microbioma Gastrointestinal , Péptidos Similares al Glucagón , Inflamación , Ratones Endogámicos C57BL , Obesidad , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Péptidos Similares al Glucagón/farmacología , Ratones , Masculino , Obesidad/microbiología , Obesidad/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Cognición/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Ratones Obesos , Modelos Animales de Enfermedad , Citocinas/metabolismo , Citocinas/sangre , Disfunción Cognitiva/tratamiento farmacológicoAsunto(s)
Enfermedades Cardiovasculares , Aprobación de Drogas , Péptidos Similares al Glucagón , Hipoglucemiantes , Humanos , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Enfermedades Cardiovasculares/prevención & control , Reino Unido , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.
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Reparación del ADN , Péptidos Similares al Glucagón , Animales , Masculino , Péptidos Similares al Glucagón/farmacología , Reparación del ADN/efectos de los fármacos , Ratones , Modelos Animales de Enfermedad , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Expresión Génica/efectos de los fármacos , Hipoglucemiantes/farmacología , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Conducta Animal/efectos de los fármacosRESUMEN
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide (Ozempic®), have emerged as effective treatments for diabetes and weight management. However, recent evidence indicates that GLP-1R signalling influences various tissues, including the immune system. Notably, GLP-1 has a short half-life (< 5â¯minutes) and exists in the picomolar range, while GLP-1RAs like semaglutide have extended half-lives of several days and are administered at supraphysiological doses. This review explores the potential impact of these medications on vaccine efficacy. We examine evidence suggesting that GLP-1RAs may attenuate vaccine responses through direct effects on immune cells and modulation of other tissues. Additionally, we discuss how GLP-1R signalling may create a tolerogenic environment, potentially reducing vaccine immunogenicity. Given the widespread use of GLP-1RAs, it is crucial to understand their impact on immune responses and the translational implications for vaccination outcomes.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Animales , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Vacunas/uso terapéutico , Vacunas/inmunología , Transducción de Señal/efectos de los fármacos , Vacunación , Péptido 1 Similar al Glucagón/inmunología , Péptido 1 Similar al Glucagón/uso terapéuticoRESUMEN
Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.
Asunto(s)
Daño del ADN , Metilación de ADN , Reparación del ADN , Dieta Alta en Grasa , Péptidos Similares al Glucagón , Fragmentos Fc de Inmunoglobulinas , Oxidación-Reducción , Proteínas Recombinantes de Fusión , Animales , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Metilación de ADN/efectos de los fármacos , Fragmentos Fc de Inmunoglobulinas/farmacología , Daño del ADN/efectos de los fármacos , Ratones , Reparación del ADN/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Proteínas Recombinantes de Fusión/farmacología , Masculino , Oxidación-Reducción/efectos de los fármacos , Inflamación/metabolismo , Inflamación/genética , Estrés Oxidativo/efectos de los fármacos , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/genética , Regulación de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Glucagon-like peptide-1-based medicines have weight loss-independent actions.
Asunto(s)
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
Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1ß and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.
Asunto(s)
Ansiedad , Eje Cerebro-Intestino , Disfunción Cognitiva , Depresión , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Péptidos Similares al Glucagón , Ratones Endogámicos C57BL , Animales , Péptidos Similares al Glucagón/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Diabetes Mellitus Tipo 2/metabolismo , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Depresión/tratamiento farmacológico , Depresión/psicología , Depresión/metabolismo , Masculino , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Ansiedad/etiología , Microbioma Gastrointestinal/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Antidepresivos/farmacología , Antidepresivos/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Very-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes (T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes. METHODS: Thirty individuals with T2D (age 18-75 years, BMI 27-50 kg m-2) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR. RESULTS: Significantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p < 0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p < 0.01). CONCLUSION: VLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management.
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Glucemia , Restricción Calórica , Diabetes Mellitus Tipo 2 , Péptidos Similares al Glucagón , Hemoglobina Glucada , Hipoglucemiantes , Pérdida de Peso , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/dietoterapia , Persona de Mediana Edad , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/farmacología , Masculino , Femenino , Adulto , Anciano , Restricción Calórica/métodos , Proyectos Piloto , Pérdida de Peso/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Adolescente , Adulto Joven , Composición Corporal/efectos de los fármacos , Insulina/sangre , Resistencia a la Insulina , Prueba de Tolerancia a la Glucosa , Terapia CombinadaRESUMEN
Melanocortin 4 receptor (MC4R) mutations are the commonest cause of monogenic obesity through dysregulation of neuronal pathways in the hypothalamus and prefrontal cortex that regulate hunger and satiety. MC4R also regulates neuropathic pain pathways via JNK signaling after nerve injury. We show evidence of corneal small fiber degeneration in 2 siblings carrying a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene. Both children were treated with once weekly semaglutide for 6 months with no change in weight, and only a minor improvement in HbA1c and lipid profile. However, there was evidence of nerve regeneration with an increase in corneal nerve fiber density (CNFD) [child A (13.9%), child B (14.7%)], corneal nerve branch density (CNBD) [child A (110.2%), child B (58.7%)] and corneal nerve fiber length (CNFL) [child A (21.5%), child B (44.0%)].
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Regeneración Nerviosa , Receptor de Melanocortina Tipo 4 , Humanos , Receptor de Melanocortina Tipo 4/genética , Masculino , Femenino , Niño , Regeneración Nerviosa/efectos de los fármacos , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patología , Mutación , Obesidad/tratamiento farmacológico , Obesidad/genética , Córnea/efectos de los fármacos , Córnea/inervación , Córnea/patología , Obesidad Infantil/tratamiento farmacológico , AdolescenteRESUMEN
ABSTRACT: With the increase in use of GLP-1 receptor agonists such as semaglutide (Ozempic, Wegovy, Rybelsus) in the population, nuclear medicine physicians should be aware of the possibility of nondiagnostic FDG PET scans due to these medications, which work partly by increasing insulin secretion. We demonstrate a case where a patient's use of such a medication presumptively led to muscular and myocardial uptake, complicating scan interpretation considerably. Clinicians should be aware of the presence of these drugs and their potential effect on biodistribution in FDG PET. Further study is needed to best understand the effects of these medications on FDG biodistribution.
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Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Humanos , Fluorodesoxiglucosa F18/farmacocinética , Insulina , Péptidos Similares al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón , Masculino , Persona de Mediana Edad , FemeninoRESUMEN
Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.