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Batista T.M.,University of Campinas | Batista T.M.,Instituto Nacional Of Ciencia E Tecnologia Of Obesidade E Diabetes | Alonso-Magdalena P.,University Miguel Hernandez | Alonso-Magdalena P.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | And 11 more authors.
PLoS ONE | Year: 2012

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 β 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 β 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. © 2012 Batista et al. Source

Soriano S.,University Miguel Hernandez | Gonzalez A.,University Miguel Hernandez | Marroqui L.,University Miguel Hernandez | Tuduri E.,University Miguel Hernandez | And 13 more authors.
Endocrinology | Year: 2010

The mechanism by which protein malnutrition impairs glucose-stimulated insulin secretion in the pancreatic β-cell is not completely known but may be related to alterations in the signaling events involved in insulin release. Here, we aimed to study the stimulus-secretion coupling of β-cells from mice fed with low-protein (LP) diet or normal-protein (NP) diet for 8wkafter weaning. Patch-clamp measurements in isolated cells showed that β-cells from LP mice had a resting membrane potential thatwasmorehyperpolarized than controls. Additionally, depolarizationandgeneration of action potentials in response to stimulatory glucose concentrations were also impaired in β-cells of LP mice. All these alterations in the LP group were most likely attributed to higher ATP-dependent K+ (KATP) channel activity in resting conditions and lower efficiency of glucose to induce the closure of these channels. Moreover, a Western blot analysis revealed higher protein levels of the sulphonylurea receptor of the KATP channel in islets of LP mice. Because β-cell Ca2+ signals depend on electrical activity, intracellular Ca2+ oscillations were measured by fluorescence microscopy in intact islets, indicating a lower response to glucose in the LP group. Finally, cell-to-cell synchrony of Ca2+ signals was analyzed by confocal microscopy. Islets from LP mice exhibited a decreased level of coupling among β-cells, which was probably due to the low expression levels of connexin 36. Therefore, low-protein diet leads to several alterations in the stimulus-secretion coupling of pancreatic β-cells that might explain the diminished insulin secretion in response to glucose in this malnutrition state. Copyright © 2010 by The Endocrine Society. Source

Vieira E.,University Miguel Hernandez | Vieira E.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Marroqui L.,University Miguel Hernandez | Marroqui L.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | And 12 more authors.
Endocrinology | Year: 2012

Disturbances of circadian rhythms have been associated with obesity and type 2 diabetes. The nuclear receptor Rev-erbα was suggested to link circadian rhythms and metabolism in peripheral tissues. The aim of the present study was to dissect the role of this clock gene in the pancreatic β-cell function and to analyze whether its expression is modulated by leptin and diet-induced obesity. To address the function of Rev-erbα, we used small interfering RNA in mouse islet cells and in MIN-6 cells. Cell proliferation was measured by bromodeoxyuridine incorporation, apoptosis by the terminal deoxynucleotidyl transferase dUTP nick end labeling technique, insulin secretion by RIA, and gene expression by RT-PCR. Pancreatic islets were isolated at different zeitgeber times 0, 6, and 12 after 6 wk of high-fat diet treatment, and then gene expression and insulin secretion were determined. Rev-erbα down-regulation by small interfering RNA treatment in islet cells and MIN-6 cells impaired glucose-induced insulin secretion, decreased the expression of key lipogenic genes, and inhibited β-cell proliferation. In vivo and in vitro leptin treatment increased Rev-erbα expression in isolated islets through a MAPK pathway. High-fat diet treatment disrupted the circadian Rev-erbα gene expression profile along with insulin secretion, indicating an important role of this clock gene in β-cell function. These results indicate that the clock gene Rev-erbα plays multiple functions in the pancreatic β-cell. Although the increase in Rev-erbα expressionmaypromote β-cell adaptation in different metabolic situations, its deregulation may lead to altered β-cell function. Copyright © 2012 by The Endocrine Society. Source

Marroqui L.,University Miguel Hernandez | Marroqui L.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Batista T.M.,University of Campinas | Batista T.M.,Instituto Nacional Of Ciencia E Tecnologia Of Obesidade E Diabetes | And 15 more authors.
Endocrinology | Year: 2012

Chronic malnutrition leads to multiple changes in β-cell function and peripheral insulin actions to adapt glucose homeostasis to these restricted conditions. However, despite glucose homeostasis also depends on glucagon effects, the role of α-cells in malnutrition is largely unknown. Here, we studied α-cell function and hepatic glucagon signaling in mice fed with low-protein (LP) or normal-protein diet for 8 wk after weaning. Using confocal microscopy, we found that inhibition of Ca 2+signaling by glucose was impaired in α-cells of LP mice. Consistent with these findings, the ability of glucose to inhibit glucagon release in isolated islets was also diminished in LP mice. This altered secretion was not related with changes in either glucagon gene expression or glucagon content. A morphometric analysis showed that α-cell mass was significantly increased in malnourished animals, aspect that was probably related with their enhanced plasma glucagon levels. When we analyzed the hepatic function, we observed that the phosphorylation of protein kinase A and cAMP response-binding element protein in response to fasting or exogenous glucagon was impaired in LP mice. Additionally, the up-regulated gene expression in response to fasting observed in the hepatic glucagon receptor as well as several key hepatic enzymes, such as peroxisome proliferator-activated receptor γ, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase, was altered in malnourished animals. Finally, liver glycogen mobilization in response to fasting and the ability of exogenous glucagon to raise plasma glucose levels were lower in LP mice. Therefore, chronic protein malnutrition leads to several alterations in both the α-cell function and hepatic glucagon signaling. Copyright © 2012 by The Endocrine Society. Source

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