RESUMO
BACKGROUND/AIMS: Autonomic nervous system imbalance is associated with metabolic diseases, including diabetes. Glibenclamide is an antidiabetic drug that acts by stimulating insulin secretion from pancreatic beta cells and is widely used in the treatment of type 2 diabetes. Since there is scarce data concerning autonomic nervous system activity and diabetes, the aim of this work was to test whether glibenclamide can improve autonomic nervous system activity and muscarinic acetylcholine receptor function in pre-diabetic obese male rats. METHODS: Pre-diabetes was induced by treatment with monosodium L-glutamate in neonatal rats. The monosodium L-glutamate group was treated with glibenclamide (2 mg/kg body weight /day) from weaning to 100 days of age, and the control group was treated with water. Body weight, food intake, Lee index, fasting glucose, insulin levels, homeostasis model assessment of insulin resistance, omeostasis model assessment of ß-cell function, and fat tissue accumulation were measured. The vagus and sympathetic nerve electrical activity were recorded. Insulin secretion was measured in isolated islets challenged with glucose, acetylcholine, and the selective muscarinic acetylcholine receptor antagonists by radioimmunoassay technique. RESULTS: Glibenclamide treatment prevented the onset of obesity and diminished the retroperitoneal (18%) and epididymal (25%) fat pad tissues. In addition, the glibenclamide treatment also reduced the parasympathetic activity by 28% and glycemia by 20% in monosodium L-glutamate-treated rats. The insulinotropic effect and unaltered cholinergic actions in islets from monosodium L-glutamate groups were increased. CONCLUSION: Early glibenclamide treatment prevents monosodium L-glutamate-induced obesity onset by balancing autonomic nervous system activity.
Assuntos
Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/metabolismo , Estado Pré-Diabético/tratamento farmacológico , Nervo Vago/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Insulina/sangue , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Obesidade/fisiopatologia , Estado Pré-Diabético/induzido quimicamente , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/fisiopatologia , Ratos , Ratos Wistar , Glutamato de Sódio , Nervo Vago/fisiopatologiaRESUMO
Neuroendocrine dysfunctions such as the hyperactivity of the vagus nerve and hypothalamus-pituitary-adrenal (HPA) axis greatly contribute to obesity and hyperinsulinemia; however, little is known about these dysfunctions in the pancreatic ß-cells of obese individuals. We used a hypothalamic-obesity model obtained by neonatal treatment with monosodium l-glutamate (MSG) to induce obesity. To assess the role of the HPA axis and vagal tonus in the genesis of hypercorticosteronemia and hyperinsulinemia in an adult MSG-obese rat model, bilateral adrenalectomy (ADX) and subdiaphragmatic vagotomy (VAG) alone or combined surgeries (ADX-VAG) were performed. To study glucose-induced insulin secretion (GIIS) and the cholinergic insulinotropic process, pancreatic islets were incubated with different glucose concentrations with or without oxotremorine-M, a selective agonist of the M3 muscarinic acetylcholine receptor (M3AChR) subtype. Protein expression of M3AChR in pancreatic islets, corticosteronemia, and vagus nerve activity was also evaluated. Surgeries reduced 80% of the body weight gain. Fasting glucose and insulin were reduced both by ADX and ADX-VAG, whereas VAG was only associated with hyperglycemia. The serum insulin post-glucose stimulation was lower in all animals that underwent an operation. Vagal activity was decreased by 50% in ADX rats. In the highest glucose concentration, both surgeries reduced GIIS by 50%, whereas ADX-VAG decreased by 70%. Additionally, M3AChR activity was recovered by the individual surgeries. M3AChR protein expression was reduced by ADX. Both the adrenal gland and vagus nerve contribute to the hyperinsulinemia in the MSG model, although adrenal is more crucial as it appears to modulate parasympathetic activity and M3AChR expression in obesity.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiopatologia , Insulina/metabolismo , Obesidade/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Nervo Vago/fisiopatologia , Animais , Glucose/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Obesidade/induzido quimicamente , Obesidade/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Wistar , Glutamato de Sódio , Nervo Vago/metabolismoRESUMO
It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Metformina/farmacologia , Neoplasias/patologia , Animais , Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Feminino , Xenoenxertos , Masculino , Metformina/administração & dosagem , Neoplasias/tratamento farmacológico , RatosRESUMO
NEW FINDINGS: What is the central question of this study? Different nerve contributes periods of life are known for their differential sensitivity to interventions, and increased parasympathetic activity affects the development and maintenance of obesity. Thus, we evaluated the involvement of the vagus nerve by performing a vagotomy in young or adult rats that were offered an obesogenic high-fat diet. What is the main finding and its importance? Although the accumulation of adipose tissue decreased in both younger and older groups, the younger rats showed a greater response to the effects of vagotomy in general. In addition to the important role of the parasympathetic activity, we suggest that the vagus nerve contributes to the condition of obesity. Obesity has become a global problem, and this condition develops primarily because of an imbalance between energy intake and expenditure. The high complexity involved in the regulation of energy metabolism results from several factors besides endocrine factors. It has been suggested that obesity could be caused by an imbalance in the autonomous nervous system, which could lead to a condition of high parasympathetic activity in counterpart to low sympathetic tonus. High-fat (HF) diets have been used to induce obesity in experimental animals, and their use in animals leads to insulin resistance, hyperinsulinaemia and high parasympathetic activity, among other disorders. The aim of this work was to evaluate the effects of a vagotomy performed at the initiation of a HF diet at two different stages of life, weaning and adulthood. The vagotomy reduced parasympathetic activity (-32 and -51% in normal fat-fed rats and -43 and -55% in HF diet-fed rats; P < 0.05) and fat depots (-17 and -33%, only in HF diet-fed rats; P < 0.05). High-fat diet-fed rats exhibited fasting hyperinsulinaemia (fivefold higher in young rats and threefold higher in older rats; P < 0.05); however, vagotomy corrected it in younger rats only, and a similar effect was also observed during the glucose tolerance test. The insulin resistance exhibited by the HF diet-fed groups was not altered in the vagotomized rats. We suggest that the vagus nerve, in addition to the important role of parasympathetic activity, contributes to the condition of obesity, and that non-vagal pathways may be involved along with the imbalanced autonomic nervous system.
Assuntos
Dieta Hiperlipídica , Síndrome Metabólica/etiologia , Obesidade/etiologia , Nervo Vago/fisiopatologia , Adiposidade , Fatores Etários , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Modelos Animais de Doenças , Insulina/sangue , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/fisiopatologia , Síndrome Metabólica/prevenção & controle , Obesidade/sangue , Obesidade/fisiopatologia , Obesidade/prevenção & controle , Ratos Wistar , Fatores de Tempo , Vagotomia , Nervo Vago/cirurgia , Desmame , Aumento de PesoRESUMO
BACKGROUND/AIMS: Impaired pancreatic beta cell function and insulin secretion/action are a link between obesity and type 2 diabetes, which are worldwide public health burdens. We aimed to characterize the muscarinic acetylcholine receptor (mAChR) M1-M4 subtypes in isolated pancreatic islets from pre-diabetic obese rats that had been treated neonatally with monosodium L-glutamate (MSG). METHODS: At 90 days of age, both the MSG and the control groups underwent biometric and biochemical evaluation. Anti-muscarinic drugs were used to study mAChR function either in vivo or in vitro. RESULTS: The results demonstrated that atropine treatment reduced insulin secretion in the MSG-treated and control groups, whereas treatment with an M2mAChR-selective antagonist increased secretion. Moreover, the insulinostatic effect of an M3mAChR-selective antagonist was significantly higher in the MSG-treated group. M1mAChR and M3mAChR expression was increased in the MSG-obese group by 55% and 73%, respectively. In contrast, M2mAChR expression decreased by 25% in the MSG group, whereas M4mAChR expression was unchanged. CONCLUSIONS: Functional changes in and altered content of the mAChR (M1-M4) subtypes are pivotal to the demand for high pancreatic beta cell insulin secretion in MSG-obese rats, which is directly associated with vagal hyperactivity and peripheral insulin resistance.
Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Obesidade/metabolismo , Receptores Muscarínicos/metabolismo , Glutamato de Sódio/farmacologia , Animais , Glicemia/análise , Teste de Tolerância a Glucose , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Obesidade/patologia , Ratos , Ratos Wistar , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/metabolismo , Receptor Muscarínico M4/metabolismo , Receptores Muscarínicos/químicaRESUMO
Nutrition and lifestyle, particularly over-nutrition and lack of exercise, promote the progression and pathogenesis of obesity and metabolic diseases. Nutrition is likely the most important environmental factor that modulates the expression of genes involved in metabolic pathways and a variety of phenotypes associated with obesity and diabetes. During pregnancy, diet is a major factor that influences the organ developmental plasticity of the foetus. Experimental evidence shows that nutritional factors, including energy, fatty acids, protein, micronutrients, and folate, affect various aspects of metabolic programming. Different epigenetic mechanisms that are elicited by bioactive factors in early critical developmental ages affect the susceptibility to several diseases in adulthood. The beneficial effects promoted by exercise training are well recognised, and physical exercise may be considered one of the more prominent non-pharmacological tools that can be used to attenuate metabolic programming and to consequently ameliorate the illness provoked by metabolic diseases and reduce the prevalence of obesity, type 2 diabetes, and cardiovascular diseases. Literature on the different outcomes of unbalanced diets and the beneficial effects of some bioactive molecules during gestation and lactation on the metabolic health of offspring, as well as the potential mechanisms underlying these effects, was reviewed. The importance of the combined effects of functional nutrition and exercise as reprogramming tools of metabolic programming is discussed in depth. Finally, this review provides recommendations to healthcare providers that may aid in the control of early programming in an attempt to optimise the health of the mother and child.
Assuntos
Medicina Baseada em Evidências , Hiperfagia/fisiopatologia , Comportamento Materno , Fenômenos Fisiológicos da Nutrição Materna , Troca Materno-Fetal , Síndrome Metabólica/etiologia , Comportamento Sedentário , Animais , Desenvolvimento Infantil , Suscetibilidade a Doenças , Epigênese Genética , Exercício Físico , Feminino , Desenvolvimento Fetal , Humanos , Hiperfagia/dietoterapia , Hiperfagia/metabolismo , Lactente , Recém-Nascido , Lactação/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/prevenção & controle , Atividade Motora , GravidezRESUMO
Impaired pancreatic ß-cell function, as observed in the cases of early nutrition disturbance, is a major hallmark of metabolic diseases arising in adulthood. In the present study, we aimed to investigate the function/composition of the muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3, in the pancreatic islets of adult offspring of rats that were protein malnourished during lactation. Neonates were nursed by mothers that were fed either a low-protein (4 %, LP) or a normal-protein (23 %, NP) diet. Adult rats were pre-treated with anti-muscarinic drugs and subjected to the glucose tolerance test; the function and protein expression levels of M2mAChR and M3mAChR were determined. The LP rats were lean and hypoinsulinaemic. The selective M2mAChR antagonist methoctramine increased insulinaemia by 31 % in the NP rats and 155 % in the LP rats, and insulin secretion was increased by 32 % in the islets of the NP rats and 88 % in those of the LP rats. The selective M3mAChR antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide decreased insulinaemia by 63 % in the NP rats and 40 % in the LP rats and reduced insulin release by 41 % in the islets of the NP rats and 28 % in those of the LP rats. The protein expression levels of M2mAChR and M3mAChR were 57 % higher and 53 % lower, respectively, in the islets of the LP rats than in those of the NP rats. The expression and functional compositions of M2mAChR and M3mAChR were altered in the islets of the LP rats, as a result of metabolic programming caused by the protein-restricted diet, which might be another possible effect involved in the weak insulin secretion ability of the islets of the programmed adult rats.