RESUMO
Bisphenol-A (BPA) is an endocrine disruptor associated with higher risk of insulin resistance, type 2 diabetes, and cardiovascular diseases especially in susceptible populations. Because malnutrition is a nutritional disorder associated with high cardiovascular risk, we sought to compare the effects of short-term BPA exposure on cardiovascular parameters of healthy and protein-malnourished mice. Postweaned male mice were fed a normo- (control) or low-protein (LP) diet for 8 weeks and then exposed or not to BPA (50 µg kg-1 day-1) for the last 9 days. Systolic blood pressure was higher in BPA or LP groups compared with the control group. However, diastolic blood pressure was enhanced by BPA only in malnourished mice. Left ventricle (LV) end diastolic pressure (EDP), collagen deposition, and CTGF mRNA expression were higher in the control or malnourished mice exposed to BPA than in the respective nonexposed groups. Nevertheless, mice fed LP diet exposed to BPA exhibited higher angiotensinogen and cardiac TGF-ß1 mRNA expression than mice treated with LP or BPA alone. Wall:lumen ratio and cross-sectional area of intramyocardial arteries were higher either in the LP or BPA group compared with the control mice. Taken together, our data suggest that short-term BPA exposure results in LV diastolic dysfunction and fibrosis, and intramyocardial arteries inward remodeling, besides potentiate protein malnutrition-induced hypertension and cardiovascular risk.
RESUMO
Taurine (Tau) regulates ß-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release. Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in ß-cells and Ca(2+) oscillations were increased in α-cells. Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group. In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and ß-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating ß-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes.
Assuntos
Suplementos Nutricionais , Glucagon/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Taurina/administração & dosagem , Taurina/metabolismo , Animais , Glicemia/metabolismo , Cálcio/metabolismo , Homeostase/efeitos dos fármacos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Taurina/sangueRESUMO
Glucocorticoid (GC)-based therapies can cause insulin resistance (IR), glucose intolerance, hyperglycemia and, occasionally, overt diabetes. Understanding the mechanisms behind these metabolic disorders could improve the management of glucose homeostasis in patients undergoing GC treatment. For this purpose, adult rats were treated with a daily injection of dexamethasone (1 mg/kg b.w., i.p.) (DEX) or saline as a control for 5 consecutive days. The DEX rats developed IR, augmented glycemia, hyperinsulinemia and hyperglucagonemia. Treatment of the DEX rats with a glucagon receptor antagonist normalized their blood glucose level. The characteristic inhibitory effect of glucose on glucagon secretion was impaired in the islets of the DEX rats, while no direct effects were found on α-cells in islets that were incubated with DEX in vitro. A higher proportion of docked secretory granules was found in the DEX α-cells as well as a trend towards increased α-cell mass. Additionally, insulin secretion in the presence of glucagon was augmented in the islets of the DEX rats, which was most likely due to their higher glucagon receptor content. We also found that the enzyme 11ßHSD-1, which participates in GC metabolism, contributed to the insulin hypersecretion in the DEX rats under basal glucose conditions. Altogether, we showed that GC treatment induces hyperglucagonemia, which contributes to an imbalance in glucose homeostasis and compensatory ß-cell hypersecretion. This hyperglucagonemia may result from altered α-cell function and, likely, α-cell mass. Additionally, blockage of the glucagon receptor seems to be effective in preventing the elevation in blood glucose levels induced by GC administration.
Assuntos
Glicemia/efeitos dos fármacos , Dexametasona/efeitos adversos , Células Secretoras de Glucagon/fisiologia , Glucocorticoides/efeitos adversos , Homeostase/efeitos dos fármacos , Hiperinsulinismo/induzido quimicamente , Insulina/metabolismo , Animais , Glicemia/metabolismo , Células Cultivadas , Dexametasona/administração & dosagem , Esquema de Medicação , Células Secretoras de Glucagon/efeitos dos fármacos , Células Secretoras de Glucagon/patologia , Glucocorticoides/administração & dosagem , Hiperinsulinismo/sangue , Injeções Intraperitoneais , Resistência à Insulina , Secreção de Insulina , Masculino , Ratos , Ratos WistarRESUMO
Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor ß subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr(308) residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor ß subunit.In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. Thus, our findings support the notion that BPA can be considered a risk factor for the development of type 2 diabetes.