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1.
Rev Assoc Med Bras (1992) ; 69(1): 112-118, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36629649

RESUMEN

OBJECTIVE: Pathological destruction of insulin signaling molecules such as insulin receptor substrate, especially due to the increase in suppressors of cytokine signaling molecules, has been demonstrated in experimental diabetes. The contribution of suppressors of cytokine signaling proteins to the development of insulin resistance and the effects of antidiabetic drugs and exercise on suppressors of cytokine signaling proteins are not clearly known. METHODS: A total of 48 Wistar albino adult male rats were divided into six groups: control group, obese group with diabetes, obese diabetic rats treated with metformin, obese diabetic rats treated with pioglitazone, obese diabetic rats treated with exenatide, and obese diabetic rats with applied exercise program. Immunohistochemical staining was performed in both the liver and adipose tissue. RESULTS: There was a statistically significant decrease in suppressors of cytokine signaling-1, a decrease in suppressors of cytokine signaling-3, an increase in insulin receptor substrate-1, and a decrease in immunohistochemical staining in the obese group treated with metformin and exenatide compared to the obese group without treatment in the liver tissue (p<0.05). A statistically significant decrease in immunohistochemical staining of suppressors of cytokine signaling-1 and suppressors of cytokine signaling-3 was found in the obese group receiving exercise therapy compared to the obese group without treatment in visceral adipose tissue (p<0.05). Likewise, no significant immunohistochemistry staining was seen in diabetic obese groups. CONCLUSION: Metformin or exenatide treatment could prevent the degradation of insulin receptor substrate-1 protein by reducing the effect of suppressors of cytokine signaling-1 and suppressors of cytokine signaling-3 proteins, especially in the liver tissue. In addition, exercise can play a role as a complementary therapy by reducing suppressors of cytokine signaling-1 and suppressors of cytokine signaling-3 proteins in visceral adipose tissue.


Asunto(s)
Diabetes Mellitus Experimental , Resistencia a la Insulina , Metformina , Animales , Humanos , Masculino , Ratas , Citocinas/metabolismo , Exenatida/metabolismo , Terapia por Ejercicio , Hipoglucemiantes , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Obesidad/metabolismo , Ratas Wistar , Proteínas Supresoras de la Señalización de Citocinas/metabolismo
2.
Pharmacol Rep ; 71(2): 338-346, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30831439

RESUMEN

BACKGROUND: In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex - brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions. METHODS: Adult male PS rats were subjected to acute stress and/or received orally glucose. Levels of hormones and their receptors were assayed with ELISA method. In vitro studies were performed on mHypoA-2/12 hypothalamic cell line, stably transfected with CRH promoter coupled with luciferase. RESULTS: PS has reduced GLP-1 and GLP-1R levels, attenuated glucose-induced increase in insulin concentration and increased the amount of phosphorylated IR in the hypothalamus of animals subjected to additional stress stimuli, and also decreased the GLP-1R level in the hippocampus. In vitro studies demonstrated that insulin is capable of increasing CRH promoter activity in the condition of stimulation of the cAMP/PKA pathway in the applied cellular model. CONCLUSION: Prenatal stress may act as a preconditioning factor, affecting the concentrations of hormones such as insulin and GLP-1 in the hypothalamus in response to adverse stimuli. The decreased GLP-1R level in the hippocampus could be linked with the disturbances in neuronal plasticity.


Asunto(s)
Depresión/fisiopatología , Péptido 1 Similar al Glucagón/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Animales , Línea Celular , Hormona Liberadora de Corticotropina/genética , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Exenatida/metabolismo , Femenino , Glucosa/metabolismo , Masculino , Ratones , Plasticidad Neuronal/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Regiones Promotoras Genéticas/genética , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/fisiopatología
3.
Mol Metab ; 11: 33-46, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29650350

RESUMEN

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. METHODS: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. RESULTS: GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. CONCLUSIONS: Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Adiposidad , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipotálamo/metabolismo , Termogénesis , Animales , Exenatida/metabolismo , Neuronas GABAérgicas/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genética , Resistencia a la Insulina , Lipogénesis , Masculino , Neuropéptido Y/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteína Desacopladora 1/metabolismo
4.
J Control Release ; 277: 165-172, 2018 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-29574041

RESUMEN

BACKGROUND: The aim of the study was to develop an oral self-emulsifying drug delivery system (SEDDS) for exenatide and to evaluate its in vivo efficacy. METHODS: Exenatide was lipidised via hydrophobic ion pairing with sodium docusate (DOC) and incorporated in SEDDS consisting of 35% Cremophor EL, 25% Labrafil 1944, 30% Capmul-PG 8 and 10% propylene glycol. Exenatide/DOC was characterized in terms of lipophilicity evaluating the octanol/water phase distribution (logP). Exenatide/DOC SEDDS were characterized via droplet size analysis, drug release characteristics (log DSEDDS/release medium determination) and mucus permeation studies. Furthermore, the impact of orally administered exenatide/DOC SEDDS on blood glucose level was investigated in vivo on healthy male Sprague-Dawley rats. RESULTS: Hydrophobic ion pairing in a molar ratio of 1:4 (exenatide:DOC) increased the effective logP of exenatide from -1.1 to 2.1. SEDDS with a payload of 1% exenatide/DOC had a mean droplet size of 45.87 ±â€¯2.9 nm and a Log DSEDDS/release medium of 1.9 ±â€¯0.05. Permeation experiments revealed 2.7-fold improved mucus diffusion for exenatide/DOC SEDDS compared to exenatide in solution. Orally administered exenatide/DOC SEDDS showed a relative bioavailability (versus s.c.) of 14.62% ±â€¯3.07% and caused a significant (p < .05) 20.6% decrease in AUC values of blood glucose levels. CONCLUSION: According to these results, hydrophobic ion pairing in combination with SEDDS represents a promising tool for oral peptide delivery.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Emulsionantes/metabolismo , Exenatida/metabolismo , Administración Oral , Animales , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Emulsionantes/administración & dosificación , Exenatida/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley
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