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Metformin is an antidiabetic drug used for the treatment of diabetes and metabolic diseases. Imbalance in the autonomic nervous system (ANS) is associated with metabolic diseases. This study aimed to test whether metformin could improve ANS function in obese rats. Obesity was induced by neonatal treatment with monosodium L-glutamate (MSG). During 21-100 days of age, MSG-rats were treated with metformin 250 mg/kg body weight/day or saline solution. Rats were euthanized to evaluate biometric and biochemical parameters. ANS electrical activity was recorded and analyzed. Metformin normalized the hypervagal response in MSG-rats. Glucose-stimulated insulin secretion in isolated pancreatic islets increased in MSG-rats, while the cholinergic response decreased. Metformin treatment normalized the cholinergic response, which involved mostly the M3 muscarinic acetylcholine receptor (M3 mAChR) in pancreatic beta-cells. Protein expression of M3 mAChRs increased in MSG-obesity rats, while metformin treatment decreased the protein expression by 25%. In conclusion, chronic metformin treatment was effective in normalizing ANS activity and alleviating obesity in MSG-rats.
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Sistema Nervioso Autónomo/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Obesidad/tratamiento farmacológico , Acetilcolina/farmacología , Animales , Glucosa/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Neostigmina/farmacología , Obesidad/inducido químicamente , Obesidad/metabolismo , Obesidad/fisiopatología , Ratas Wistar , Receptor Muscarínico M3/metabolismo , Glutamato de Sodio , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiologíaRESUMEN
Currently, metabolic disorders are one of the major health problems worldwide, which have been shown to be related to perinatal nutritional insults, and the autonomic nervous system and endocrine pancreas are pivotal targets of the malprogramming of metabolic function. We aimed to assess glucose-insulin homeostasis and the involvement of cholinergic responsiveness (vagus nerve activity and insulinotropic muscarinic response) in pancreatic islet capacity to secrete insulin in weaned rat offspring whose mothers were undernourished in the first 2 weeks of the suckling phase. At delivery, dams were fed a low-protein (4% protein, LP group) or a normal-protein diet (20.5% protein, NP group) during the first 2 weeks of the suckling period. Litter size was adjusted to six pups per mother, and rats were weaned at 21 days old. Weaned LP rats presented a lean phenotype (P < 0.01); hypoglycaemia, hypoinsulinaemia and hypoleptinaemia (P < 0.05); and normal corticosteronaemia (P > 0.05). In addition, milk insulin levels in mothers of the LP rats were twofold higher than those of mothers of the NP rats (P < 0.001). Regarding glucose-insulin homeostasis, weaned LP rats were glucose-intolerant (P < 0.01) and displayed impaired pancreatic islet insulinotropic function (P < 0.05). The M3 subtype of the muscarinic acetylcholine receptor (M3mAChR) from weaned LP rats was less responsive, and the superior vagus nerve electrical activity was reduced by 30% (P < 0.01). A low-protein diet in the suckling period malprogrammes the vagus nerve to low tonus and impairs muscarinic response in the pancreatic ß-cells of weaned rats, which are imprinted to secrete inadequate insulin amounts from an early age.
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Diabetes Mellitus Tipo 2/fisiopatología , Islotes Pancreáticos/embriología , Desnutrición/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Animales , Glucemia/análisis , Células Cultivadas , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Dieta con Restricción de Proteínas/efectos adversos , Femenino , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Células Secretoras de Insulina , Islotes Pancreáticos/inervación , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/fisiopatología , Lactancia/fisiología , Masculino , Desnutrición/etiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Cultivo Primario de Células , Ratas , Ratas Wistar , Nervio Vago/fisiopatología , DesteteRESUMEN
We examined the long-term effects of protein restriction during puberty on the function of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in male rats. Male Wistar rats from the age of 30 to 60 days were fed a low-protein diet (4%, LP). A normal-protein diet (20.5%) was reintroduced to rats from the age of 60 to 120 days. Control rats were fed a normal-protein diet throughout life (NP). Rats of 60 or 120 days old were killed. Food consumption, body weight, visceral fat deposits, lipid profile, glycemia, insulinemia, corticosteronemia, adrenocorticotropic hormone (ACTH), testosteronemia and leptinemia were evaluated. Glucose-insulin homeostasis, pancreatic-islet insulinotropic response, testosterone production and hypothalamic protein expression of the androgen receptor (AR), glucocorticoid receptor (GR) and leptin signaling pathway were also determined. LP rats were hypophagic, leaner, hypoglycemic, hypoinsulinemic and hypoleptinemic at the age of 60 days (P < 0.05). These rats exhibited hyperactivity of the HPA axis, hypoactivity of the HPG axis and a weak insulinotropic response (P < 0.01). LP rats at the age of 120 days were hyperphagic and exhibited higher visceral fat accumulation, hyperleptinemia and dyslipidemia; lower blood ACTH, testosterone and testosterone release; and reduced hypothalamic expression of AR, GR and SOCS3, with a higher pSTAT3/STAT3 ratio (P < 0.05). Glucose-insulin homeostasis was disrupted and associated with hyperglycemia, hyperinsulinemia and increased insulinotropic response of the pancreatic islets. The cholinergic and glucose pancreatic-islet responses were small in 60-day-old LP rats but increased in 120-day-old LP rats. The hyperactivity of the HPA axis and the suppression of the HPG axis caused by protein restriction at puberty contributed to energy and metabolic disorders as long-term consequences.
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Dieta con Restricción de Proteínas/efectos adversos , Metabolismo Energético , Maduración Sexual , Testosterona/metabolismo , Animales , Células Cultivadas , Proteínas en la Dieta/farmacología , Metabolismo Energético/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Wistar , Maduración Sexual/efectos de los fármacosRESUMEN
PURPOSE: Environmental and nutritional disorders during perinatal period cause metabolic dysfunction in the progeny and impair human health. Advanced glycation end products (AGEs) are primarily produced during metabolism of excess blood glucose, which is observed in diabetes. Methylglyoxal (MG) is a precursor for the generation of endogenous AGEs, which disturbs the metabolism. This work aimed to investigate whether the maternal MG treatment during lactation programs the progeny to metabolic dysfunction later in life. METHODS: Female Wistar rats were divided into two groups: control group (C) treated with saline and MG group treated with MG (60 mg/kg/day) by gavage throughout the lactation period. Both mothers and offspring were fed a standard chow. At weaning, breast milk composition was analyzed and mothers euthanized for blood and tissue sample collections. At 90 days of age, offspring were submitted to glucose tolerance test (ivGTT) and euthanized for blood and tissue samples collection. RESULTS: MG mothers showed increase in glucose and fructosamine levels; however, they showed low insulin levels and failure in ß-cell function (p < 0.05). MG mothers also showed dyslipidemia (p < 0.05). Moreover, breast milk had elevated levels of glucose, triglycerides, cholesterol and fructosamine and low insulin (p < 0.05). Interestingly, MG offspring had increased body weight and adipose tissue at adulthood, and they also showed glucose intolerance and failure in ß-cell function (p < 0.05). Besides, MG offspring showed dyslipidemia (p < 0.05) increasing cardiovascular diseases risk. CONCLUSIONS: Maternal MG treatment negatively affects the male rat offspring, leading to type 2 diabetes and dyslipidemia in later life, possibly by changes in breast milk composition.
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Diabetes Mellitus Tipo 2/inducido químicamente , Dislipidemias/inducido químicamente , Contaminantes Ambientales/toxicidad , Lactancia/efectos de los fármacos , Exposición Materna/efectos adversos , Obesidad/inducido químicamente , Piruvaldehído/toxicidad , Adiposidad/efectos de los fármacos , Administración Oral , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dislipidemias/sangre , Dislipidemias/metabolismo , Dislipidemias/patología , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/análisis , Femenino , Insulina/análisis , Insulina/sangre , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Lactancia/metabolismo , Masculino , Leche/química , Obesidad/sangre , Obesidad/metabolismo , Obesidad/patología , Embarazo , Piruvaldehído/administración & dosificación , Piruvaldehído/análisis , Distribución Aleatoria , Ratas Sprague-Dawley , Toxicocinética , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: The sulphonylurea glibenclamide (Gli) is widely used in the treatment of type 2 diabetes. In addition to its antidiabetic effects, low incidences of certain types of cancer have been observed in Gli-treated diabetic patients. However, the mechanisms underlying this observation remain unclear. The aim of the present work was to evaluate whether obese adult rats that were chronically treated with an antidiabetic drug, glibenclamide, exhibit resistance to rodent breast carcinoma growth. METHODS: Neonatal rats were treated with monosodium L-glutamate (MSG) to induce prediabetes. Control and MSG groups were treated with Gli (2 mg/kg body weight/day) from weaning to 100 days old. After Gli treatment, the control and MSG rats were grafted with Walker-256 tumour cells. After 14 days, grafted rats were euthanized, and tumour weight as well as glucose homeostasis were evaluated. RESULTS: Treatment with Gli normalized tissue insulin sensitivity and glucose tolerance, suppressed fasting hyperinsulinaemia, reduced fat tissue accretion in MSG rats, and attenuated tumour growth by 27% in control and MSG rats. CONCLUSIONS: Gli treatment also resulted in a large reduction in the number of PCNA-positive tumour cells. Although treatment did improve the metabolism of pre-diabetic MSG-rats, tumour growth inhibition may be a more direct effect of glibenclamide.
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Proliferación Celular/efectos de los fármacos , Gliburida/farmacología , Estado Prediabético/prevención & control , Animales , Caquexia/etiología , Línea Celular Tumoral , Glucosa/metabolismo , Gliburida/uso terapéutico , Hiperinsulinismo/prevención & control , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inmunohistoquímica , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/patología , Estado Prediabético/etiología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Wistar , Glutamato de Sodio/toxicidadRESUMEN
Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long-term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F2) (CTLF2), MSG-treated second generation (F2) (MSGF2), which suckled from their CTL and MSG biological dams, respectively, or CTLF2-CR, control offspring suckled by MSG dams and MSGF2-CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG-induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases.
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Modelos Animales de Enfermedad , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/prevención & control , Efectos Tardíos de la Exposición Prenatal , Adiposidad , Animales , Animales Recién Nacidos , Femenino , Desarrollo Fetal , Aromatizantes/administración & dosificación , Aromatizantes/efectos adversos , Aditivos Alimentarios/administración & dosificación , Aditivos Alimentarios/efectos adversos , Inyecciones Subcutáneas , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Masculino , Obesidad/etiología , Obesidad/metabolismo , Embarazo , Ratas Wistar , Glutamato de Sodio/administración & dosificación , Glutamato de Sodio/efectos adversos , Técnicas de Cultivo de Tejidos , Aumento de PesoRESUMEN
Essential polyunsaturated fatty acids (PUFAs) prevent cardiometabolic diseases. We aimed to study whether a diet supplemented with a mixture of n-6/n-3 PUFAs, during perinatal life, attenuates outcomes of long-term metabolic dysfunction in prediabetic and obese mice. Seventy-day-old virgin female mice were mated. From the conception day, dams were fed a diet supplemented with sunflower oil and flaxseed powder (containing an n-6/n-3 PUFAs ratio of 1.2 : 1.0) throughout pregnancy and lactation, while control dams received a commercial diet. Newborn mice were treated with monosodium L-glutamate (MSG, 4 mg g-1 body weight per day) for the first 5 days of age. A batch of weaned pups was sacrificed to quantify the brain and pancreas total lipids; another batch were fed a commercial diet until 90 days of age, where glucose homeostasis and glucose-induced insulin secretion (GIIS) as well as retroperitoneal fat and Lee index were assessed. MSG-treated mice developed obesity, glucose intolerance, insulin resistance, pancreatic islet dysfunction, and higher fat stores. Maternal flaxseed diet-supplementation decreased n-6/n-3 PUFAs ratio in the brain and pancreas and blocked glucose intolerance, insulin resistance, GIIS impairment, and obesity development. The n-6/n-3 essential PUFAs in a ratio of 1.2 : 1.0 supplemented in maternal diet during pregnancy and lactation prevent metabolic dysfunction in MSG-obesity model.
RESUMEN
PURPOSE: The long-term effects of the development of chronic metabolic diseases such as type 2 diabetes and obesity have been associated with nutritional insults in critical life stages. In this study, we evaluated the effect of a low-protein diet on metabolism in mid-adulthood male rats. METHODS: At 90 days of age, Wistar male rats were fed a low-protein diet (4.0 %, LP group) for 30 days, whereas control rats were fed a normal-protein diet (20.5 %, NP group) throughout their lifetimes. To allow for dietary rehabilitation, from 120 to 180 days of age, the LP rats were fed a normal-protein diet. Then, we measured body composition, fat stores, glucose-insulin homeostasis and pancreatic islet function. RESULTS: At 120 days of age, just after low-protein diet treatment, the LP rats displayed a strong lean phenotype, hypoinsulinemia, as assessed under fasting and glucose tolerance test conditions, as well as weak pancreatic islet insulinotropic response to glucose and acetylcholine (p < 0.01). At 180 days of age, after poor-protein diet rehabilitation, the LP rats displayed a slight lean phenotype (p < 0.05), which was associated with a high body weight gain (p < 0.001). Additionally, fat pad accumulation, glycemia and insulinemia, as well as the pancreatic islet insulinotropic response, were not significantly different between the LP and NP rats (p > 0.05). CONCLUSIONS: Taken together, the present data suggest that the effects of dietary restriction as a stressor in adulthood are reversible with dietary rehabilitation, indicating that adulthood is not a sensitive or critical time window for metabolic programming.
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Dieta con Restricción de Proteínas/efectos adversos , Síndrome Metabólico/metabolismo , Desnutrición Proteico-Calórica/metabolismo , Acetilcolina/metabolismo , Animales , Glucemia/metabolismo , Composición Corporal , Peso Corporal , Proteínas en la Dieta/administración & dosificación , Prueba de Tolerancia a la Glucosa , Homeostasis , Insulina/sangre , Islotes Pancreáticos/metabolismo , Masculino , Fenotipo , Ratas , Ratas Wistar , Aumento de PesoRESUMEN
INTRODUCTION: A sedentary lifestyle and high-fat feeding are risk factors for cardiometabolic disorders. This study determined whether moderate exercise training prevents the cardiometabolic changes induced by a high-fat diet (HFD). MATERIALS AND METHODS: Sixty-day-old rats were subjected to moderate exercise three times a week for 30 days. After that, trained rats received a HFD (EXE-HFD) or a commercial normal diet (EXE-NFD) for 30 more days. Sedentary animals also received the diets (SED-HFD and SED-NFD). Food intake and body weight were measured weekly. After 120 days of life, analyses were performed. Data were analysed with two-way ANOVA and the Tukey post-test. RESULTS: Body weight gain induced by HFD was attenuated in trained animals. HFD reduced food intake by approximately 30% and increased body fat stores by approximately 75%. Exercise attenuated 80% of the increase in fat pads and increased 24% of soleus muscle mass in NFD animals. HFD induced a hyper-response to glucose injection, and exercise attenuated this response by 50%. Blood pressure was increased by HFD, and the beneficial effect of exercise in reducing blood pressure was inhibited by HFD. HFD increased vagal activity by 65% in SED-HFD compared with SED-NFD rats, and exercise blocked this increase. HFD reduced sympathetic activity and inhibited the beneficial effect of exercise on ameliorating sympathetic activity. CONCLUSION: Four weeks of moderate exercise at low frequency was able to prevent the metabolic changes induced by a HFD but not the deleterious effects of diet on the cardiovascular system.
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Dieta Alta en Grasa/efectos adversos , Enfermedades Metabólicas/prevención & control , Condicionamiento Físico Animal , Animales , Glucemia/metabolismo , Presión Sanguínea , Composición Corporal , Peso Corporal , Grasas de la Dieta/administración & dosificación , Ingestión de Energía , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Masculino , Síndrome Metabólico/prevención & control , Músculo Esquelético/fisiología , Obesidad/prevención & control , Ratas , Ratas Wistar , Conducta Sedentaria , Aumento de PesoRESUMEN
BACKGROUND/AIMS: The objective of the current work was to test the effect of metformin on the tumor growth in rats with metabolic syndrome. METHODS: We obtained pre-diabetic hyperinsulinemic rats by neonatal treatment with monosodium L-glutamate (MSG), which were chronically treated every day, from weaning to 100 day old, with dose of metformin (250 mg/kg body weight). After the end of metformin treatment, the control and MSG rats, treated or untreated with metformin, were grafted with Walker 256 carcinoma cells. Tumor weight was evaluated 14 days after cancer cell inoculation. The blood insulin, glucose levels and glucose-induced insulin secretion were evaluated. RESULTS: Chronic metformin treatment improved the glycemic homeostasis in pre-diabetic MSG-rats, glucose intolerance, tissue insulin resistance, hyperinsulinemia and decreased the fat tissue accretion. Meanwhile, the metformin treatment did not interfere with the glucose insulinotropic effect on isolated pancreatic islets. Chronic treatment with metformin was able to decrease the Walker 256 tumor weight by 37% in control and MSG rats. The data demonstrated that the anticancer effect of metformin is not related to its role in correcting metabolism imbalances, such as hyperinsulinemia. However, in morphological assay to apoptosis, metformin treatment increased programmed cell death. CONCLUSION: Metformin may have a direct effect on cancer growth, and it may programs the rat organism to attenuate the growth of Walker 256 carcinoma.
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Carcinoma 256 de Walker/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Metformina/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Glucemia , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/patología , Hipoglucemiantes/administración & dosificación , Insulina/metabolismo , Resistencia a la Insulina/genética , Islotes Pancreáticos/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Ratas , Glutamato de Sodio/toxicidadRESUMEN
BACKGROUND: Postnatal early overfeeding and physical inactivity are serious risk factors for obesity. Physical activity enhances energy expenditure and consumes fat stocks, thereby decreasing body weight (bw). This study aimed to examine whether low-intensity and moderate exercise training in different post-weaning stages of life is capable of modulating the autonomic nervous system (ANS) activity and inhibiting perinatal overfeeding-induced obesity in rats. METHODS: The obesity-promoting regimen was begun two days after birth when the litter size was adjusted to 3 pups (small litter, SL) or to 9 pups (normal litter, NL). The rats were organized into exercised groups as follows: from weaning until 90-day-old, from weaning until 50-day-old, or from 60- until 90-days-old. All experimental procedures were performed just one day after the exercise training protocol. RESULTS: The SL-no-exercised (SL-N-EXE) group exhibited excess weight and increased fat accumulation. We also observed fasting hyperglycemia and glucose intolerance in these rats. In addition, the SL-N-EXE group exhibited an increase in the vagus nerve firing rate, whereas the firing of the greater splanchnic nerve was not altered. Independent of the timing of exercise and the age of the rats, exercise training was able to significantly blocks obesity onset in the SL rats; even SL animals whose exercise training was stopped at the end of puberty, exhibited resistance to obesity progression. Fasting glycemia was maintained normal in all SL rats that underwent the exercise training, independent of the period. These results demonstrate that moderate exercise, regardless of the time of onset, is capable on improve the vagus nerves imbalanced tonus and blocks the onset of early overfeeding-induced obesity. CONCLUSIONS: Low-intensity and moderate exercise training can promote the maintenance of glucose homeostasis, reduces the large fat pad stores associated to improvement of the ANS activity in adult rats that were obesity-programmed by early overfeeding.
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Monosodium glutamate-obese rats are glucose intolerant and insulin resistant. Their pancreatic islets secrete more insulin at increasing glucose concentrations, despite the possible imbalance in the autonomic nervous system of these rats. Here, we investigate the involvement of the cholinergic/protein kinase (PK)-C and PKA pathways in MSG ß-cell function. Male newborn Wistar rats received a subcutaneous injection of MSG (4 g/kg body weight (BW)) or hyperosmotic saline solution during the first 5 days of life. At 90 days of life, plasma parameters, islet static insulin secretion and protein expression were analyzed. Monosodium glutamate rats presented lower body weight and decreased nasoanal length, but had higher body fat depots, glucose intolerance, hyperinsulinemia and hypertrigliceridemia. Their pancreatic islets secreted more insulin in the presence of increasing glucose concentrations with no modifications in the islet-protein content of the glucose-sensing proteins: the glucose transporter (GLUT)-2 and glycokinase. However, MSG islets presented a lower secretory capacity at 40 mM K(+) (P < 0.05). The MSG group also released less insulin in response to 100 µM carbachol, 10 µM forskolin and 1 mM 3-isobutyl-1-methyl-xantine (P < 0.05, P < 0.0001 and P < 0.01). These effects may be associated with a the decrease of 46 % in the acetylcholine muscarinic type 3 (M3) receptor, and a reduction of 64 % in PKCα and 36 % in PKAα protein expressions in MSG islets. Our data suggest that MSG islets, whilst showing a compensatory increase in glucose-induced insulin release, demonstrate decreased islet M3/PKC and adenylate cyclase/PKA activation, possibly predisposing these prediabetic rodents to the early development of ß-cell dysfunction.
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Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Islotes Pancreáticos/metabolismo , Obesidad/metabolismo , Proteína Quinasa C/metabolismo , Receptor Muscarínico M3/metabolismo , Transducción de Señal , Animales , Glucemia , Modelos Animales de Enfermedad , Quinasas del Centro Germinal , Glucosa/metabolismo , Transportador de Glucosa de Tipo 2/metabolismo , Insulina/metabolismo , Secreción de Insulina , Masculino , Obesidad/inducido químicamente , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Glutamato de Sodio/administración & dosificación , Glutamato de Sodio/efectos adversosRESUMEN
The goal of the present study was to investigate changes on glucose homoeostasis and of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) signalling in pancreatic islets from MSG-obese mice submitted to or not submitted to swim training. Swim training of 90-day-old MSG mice was used to evaluate whether signalling pathways of the IR and IRS-1 in islets are involved with the insulin resistance and glucose intolerance observed in this obese animal model. The results showed that IR tyrosine phosphorylation (pIR) was reduced by 42 % in MSG-obese mice (MSG, 6.7 ± 0.2 arbitrary units (a.u.); control, 11.5 ± 0.4 a.u.); on the other hand, exercise training increased pIR by 76 % in MSG mice without affecting control mice (MSG, 11.8 ± 0.3; control, 12.8 ± 0.2 a.u.). Although the treatment with MSG increased IRS-1 tyrosine phosphorylation (pIRS-1) by 96 % (MSG, 17.02 ± 0.6; control, 8.7 ± 0.2 a.u.), exercise training also increased it in both groups (control, 13.6 ± 0.1; MSG, 22.2 ± 1.1 a.u.). Current research shows that the practice of swim training increases the tyrosine phosphorylation of IRS-1 which can modulate the effect caused by obesity in insulin receptors.
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Islotes Pancreáticos/metabolismo , Obesidad/metabolismo , Condicionamiento Físico Animal/fisiología , Receptor de Insulina/metabolismo , Natación/fisiología , Animales , Glucemia/metabolismo , Glucosa/farmacología , Insulina/metabolismo , Resistencia a la Insulina , Islotes Pancreáticos/efectos de los fármacos , Masculino , Ratones , Obesidad/inducido químicamente , Fosforilación/efectos de los fármacos , Glutamato de SodioRESUMEN
Similar to gestation/lactation, puberty is also a critical phase in which neuronal connections are still being produced and during which metabolic changes may occur if nutrition is disturbed. In the present study we aimed to determine whether peripubertal protein restriction induces metabolic programming. Thirty-day-old male rats were fed either a low protein (LP group) diet (4% w/w protein) or a normal protein (NP group) diet (23%) until 60 days of age, when they received the NP diet until they were 120 days old. Body weight (BW), food intake, fat tissue accumulation, glucose tolerance, and insulin secretion were evaluated. The nerve electrical activity was recorded to evaluate autonomous nervous system (ANS) function. Adolescent LP rats presented hypophagia and lower BW gain during the LP diet treatment (P<0.001). However, the food intake and BW gain by the LP rats were increased (P<0.001) after the NP diet was resumed. The LP rats presented mild hyperglycemia, hyperinsulinemia, severe hyperleptinemia upon fasting, peripheral insulin resistance and increased fat tissue accumulation and vagus nerve activity (P<0.05). Glucose-induced insulin secretion was greater in the LP islets than in the NP islets; however, the cholinergic response was decreased (P<0.05). Compared with the islets from the NP rats, the LP islets showed changes in the activity of muscarinic receptors (P<0.05); in addition, the inhibition of glucose-induced insulin secretion by epinephrine was attenuated (P<0.001). Protein restriction during adolescence caused high-fat tissue accumulation in adult rats. Islet dysfunction could be related to an ANS imbalance.
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Dieta con Restricción de Proteínas/efectos adversos , Islotes Pancreáticos/metabolismo , Pubertad/metabolismo , Animales , Peso Corporal/fisiología , Ingestión de Alimentos/fisiología , Glucosa/farmacología , Hiperglucemia/metabolismo , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Masculino , RatasRESUMEN
Pancreatic islets from adult rats whose mothers were protein restricted during lactation undersecrete insulin. The current work analyzes whether this secretory dysfunction can be improved when the pancreatic islets are grafted into hyperglycemic diabetic rats. Two groups of rats were used: the adult offspring from dams that received a low protein diet (4%) during the initial 2/3 of lactation (LP) and, as a control, the adult offspring from dams that consumed a normal protein diet (23%) during the entire period of lactation (NP). Islets from NP- and LP-rats were transplanted into diabetic recipient rats, which were generated by streptozotocin treatment. The islets were transplanted via the portal vein under anesthesia. The fed blood glucose levels were monitored during the 4 days post-transplantation. Transplanted islets from LP-rats (T LP) decreased the fed glucose levels of diabetic rats 34% (21.37 ± 0.24 mM, p<0.05); however, the levels still remained 2-fold higher than those of the sham-operated controls (6.88 ± 0.39 mM, p<0.05). Grafts with NP-islets (T NP) produced the same effect as the LP-islets in diabetic rats. The high fasting blood glucose levels of diabetic rats were improved by the transplantations. Islet grafts from both rat groups recovered 50% of the retroperitoneal fat mass of the diabetic rats (0.55 ± 0.08 g/100 g of body weight for T NP and 0.56 ± 0.07 g/100 g of body weight for T LP, p<0.05). Because pancreatic islets from both the NP- and LP-rats were able to regulate fasting blood glucose concentrations in hyperglycemic rats, we propose that the altered function of pancreatic islets from LP-rats is not permanent.