Aumento da secreção e redução do clearance de insulina contribuem para a hiperinsulinemia compensatória em ratos e camundongos tratados com glicocorticoide

Orientadores: Antonio Carlos Boschiero, Alex RafachoTese (doutorado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: Os glicocorticoides (GC) são amplamente utilizados devido aos seus efeitos anti-inflamatórios. Porém, o tratamento com GC pode induzir efeitos deletérios sobre a homeostase glicêmica como a resistência à insulina (RI), intolerância à glicose e, dependendo do tempo e dose, pode levar a instalação do Diabetes mellitus tipo 2 (DM2). Neste sentido, ratos têm sido vastamente utilizados como modelo animal para elucidar as compensações pancreáticas envolvidas na hiperinsulinemia induzida por GC e, poucos estudos enfocando os efeitos do tratamento com GC foram realizados em camundongos. Além disso, não é completamente elucidado se a hiperinsulinemia compensatória induzida pelo tratamento com GC esta associada com alteração do clearance de insulina. Assim, nossos objetivos foram avaliar se: as compensações do pâncreas endócrino em resposta ao tratamento com GC são similares entre camundongos e ratos e, identificar possíveis mecanismos que as expliquem; e se a hiperinsulinemia compensatória induzida pelo tratamento com GC em camundongos e ratos esta associada com alterações do clearance de insulina e a expressão da proteína insuling degrading enzyme (IDE) no fígado. Para isto, camundongos Swiss e ratos Wistar machos foram tratados com o glicocorticoide sintético dexametasona (1 mg/kg p.c.; 5 dias consecutivos). O tratamento com GC induziu RI, hiperinsulinemia e dislipidemia em ambas as espécies, embora mais pronunciado em ratos, que também apresentaram intolerância à glicose e hiperglicemia no jejum. Ambas as espécies tratadas com GC apresentaram incremento da secreção de insulina ex vivo estimulada com glicose, massa e proliferação de células ?, que foram associados com aumento da sinalização da via Ir-?/AKT/mTOR e redução da via AMPK/ACC/AS160 em ilhotas isoladas. O clearance de insulina reduziu em camundongos e ratos tratados com GC, o que foi associado com redução da expressão de IDE no fígado. Desta forma, nossos resultados indicam que camundongos são menos sensíveis aos efeitos deletérios do tratamento com GC sobre a homeostase glicêmica, quando comparado com ratos. Ainda, camundongos e ratos apresentam compensações pancreáticas semelhantes (incremento da função e massa de células ?) em resposta ao tratamento com GC, que foi associado com aumento da sinalização da via canônica de insulina e redução da via não canônica em ilhotas isoladas. Além disso, a redução do clearance de insulina foi, ao menos em parte, devido a redução da expressão de IDE no fígado, o que contribuiu para a hiperinsulinemia compensatória em ambas as espécies tratadas com GC. Em conclusão, estes resultados corroboram a hipótese de que fármacos que inibam a expressão ou atividade da IDE no fígado podem ser uma intervenção anti-diabetogênica que auxilie na manutenção da homeostase glicêmica sem sobrecarregar as células ?Abstract: Glucocorticoids (GCs) are widely used as anti-inflammatory agent, but they may induce adverse metabolic effects such as insulin resistance (IR), glucose intolerance, and occasionally, diabetes mellitus type 2. Healthy rats have been used as animal models to elucidate the islet compensatory mechanisms involved in these metabolic disturbances, and only a few studies, which have focused on the in vivo effects of GCs, have been conducted in mice models. Yet, whether the reduced insulin clearance also contributes to the compensatory hyperinsulinemia in GC-treated rodents is not fully understood. Here, we aimed to elucidate whether mice and rats share the pancreatic compensations that result in response to dexamethasone (DEX) treatment and also to identify the possible mechanisms that can explain its effects. Yet, we investigated whether the hyperinsulinemia induced by GC treatment in mice and rats is associated with altered hepatic insulin degrading enzyme (IDE) expression and insulin clearance. For this, male Swiss mice and Wistar rats were treated with the synthetic GC dexamethasone (1 mg/kg b.w.; 5 days). DEX treatment induced IR, hyperinsulinemia and dyslipidemia in both species (there was a higher magnitude in rats), but treatment had a greater effect in rats that had glucose intolerance and increased basal blood glucose compared to the control group. Ex vivo insulin secretion at different glucose concentrations was higher in both groups of DEX-treated rodents compared to their controls. Mice and rats showed a significant increase in ?-cell mass due to increased ?-cell proliferation, which was associated with upregulation of the Ir-?/AKT/mTOR and downregulation of AMPK/ACC/AS160 signaling. Insulin clearance reduced in GC-treated mice and rats, which were associated with reduced hepatic IDE expression. Thus, mice are less vulnerable than rats to the deleterious effect of GCs on glucose homeostasis. In addition, rats and mice share common islet compensations (increased ?-cell function and mass) in response to GC treatment, which were associated with increased canonical and decreased non-canonical insulin signaling. Farther, the reduced insulin clearance in GC-treated rodents was, at least in part, due to reduced hepatic IDE expression, which contributed to the compensatory hyperinsulinemia. These findings corroborate the idea that pharmacological interventions that inhibit hepatic IDE may be an alternative anti-diabetic agent that helps to maintain glucose homeostasis due to hyperinsulinemia instead of hypoglycemic agent, which increase the overload in the ?-cells and may lead to ?-cell failure and DM2DoutoradoFisiologiaDoutor em Biologia Funcional e Molecula

research article

During embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types are specified from populations of multipotent precursor cells. Molecular mechanisms that enable both robust cell-type proportioning despite variable initial conditions in the precursor cells, and the re-establishment of these proportions upon perturbations in a developing tissue remain to be characterized. Here, we report that the differentiation of robust proportions of epiblast-like and primitive endoderm-like cells in mouse embryonic stem cell cultures emerges at the population level through cell-cell communication via a short-range fibroblast growth factor 4 (FGF4) signal. We characterize the molecular and dynamical properties of the communication mechanism and show how it controls both robust cell-type proportioning from a wide range of experimentally controlled initial conditions, as well as the autonomous re-establishment of these proportions following the isolation of one cell type. The generation and maintenance of reproducible proportions of discrete cell types is a new function for FGF signaling that might operate in a range of developing tissues

Evaluation of mechanical properties of composite of pinhão with polyrethane derived from castor oil.

Polymer matrix composites reinforced with pine nut shell that can be used in various application such as aerospace industry, automotive industry, electronics, and construction industry. The polyurethane derived from castor oil is a matrix that can be used to fabricate green composites, because it is derived from renewable resource, biodegradable and solvent free. The Paraná pine nut is a sub product of Paraná pine, cheap and there is a plenty of it because is a food residue. The aim of this study was to produce Paraná pine nut composites with polyurethane derived from castor oil. These composites were obtained by hot-pressing method. The mechanical proprieties were analyzed using three-point flexion test, density test and swelling test. The results indicate that these materials have mechanical resistance to be used as wooden partition panels

Augmented β-cell function and mass in glucocorticoid-treated rodents are associated with increased islet ir-β /AKT/mTOR and decreased AMPK/ACC and AS160 signaling

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOGlucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented β-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented β-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase2014114FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçã

Análise das propriedades físicas do compósito de serragem e poliuretano derivado de óleo de mamona.

Com o avanço tecnológico surgiu a necessidade de se obter materiais com diferentes propriedades, resultando no desenvolvimento de compósitos. O Medium Density Fiberboard, MDF, possui grande aplicação tanto na indústria moveleira e na construção civil. O grande problema do MDF é o adesivo usado para a aglutinação das fibras, pois é uma substância tóxica ao ser humano e possui grande impacto ambiental. Logo, percebe-se a necessidade de substituição dessa resina. O adesivo de poliuretano derivado do óleo de mamona é um material biodegradável, de fonte renovável e não possui compósitos orgânicos voláteis em sua composição. Foram analisadas as propriedades físicas de compósitos de serragem com o adesivo de poliuretano derivado do óleo de mamona nas proporções de 30, 40 e 50% de resina. O ensaio de absorção indicou valores próximos ao adesivo de poliuretano, o ensaio de inchamento indicou que quanto maior a quantidade de resina, menor será a absorção de água e o ensaio de ângulo de contato demonstrou que este material é hidrofóbico

Adaptive Evolution in the Glucose Transporter 4 Gene Slc2a4 in Old World Fruit Bats (Family: Pteropodidae)

Frugivorous and nectarivorous bats are able to ingest large quantities of sugar in a short time span while avoiding the potentially adverse side-effects of elevated blood glucose. The glucose transporter 4 protein (GLUT4) encoded by the Slc2a4 gene plays a critical role in transmembrane skeletal muscle glucose uptake and thus glucose homeostasis. To test whether the Slc2a4 gene has undergone adaptive evolution in bats with carbohydrate-rich diets in relation to their insect-eating sister taxa, we sequenced the coding region of the Slc2a4 gene in a number of bat species, including four Old World fruit bats (Pteropodidae) and three New World fruit bats (Phyllostomidae). Our molecular evolutionary analyses revealed evidence that Slc2a4 has undergone a change in selection pressure in Old World fruit bats with 11 amino acid substitutions detected on the ancestral branch, whereas, no positive selection was detected in the New World fruit bats. We noted that in the former group, amino acid replacements were biased towards either Serine or Isoleucine, and, of the 11 changes, six were specific to Old World fruit bats (A133S, A164S, V377F, V386I, V441I and G459S). Our study presents preliminary evidence that the Slc2a4 gene has undergone adaptive changes in Old World fruit bats in relation to their ability to meet the demands of a high sugar diet

Preparation and characterization of pinhão husk and polyurethane derived from castor oil green composite

Polymeric composites reinforced with natural fibers are denominated green composites. Polymers comes from petroleum source, a non-biodegradable material and has volatile organic compounds, VOC, in its composition. Organic solvent are toxics and pollute the environment. The Polyurethane derived from castor oil is polymer produced from renewable sources, biodegradable material and there are no VOC in its composition. Araucária pine nut shell is a residue from its Araucaria pine seed. The aim of this work is to develop and characterize composites of pine nut shell with polyurethane derived from castor oil. The fiber was chemically characterized, thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). PU was characterized by flexural strength, FTIR and TGA and composites was characterizes by density test, water absorption and swelling in thickness, flexural strength, FTIR, TGA. SEM evaluated the fracture surface and X-ray and vertical density profile verified the composites homogeneity. 35%PU composites presented flexural strength of 51,55 MPa, density of 1018 kg/m³, 7,95% of 24h water absorption and 5,36% of 24h swelling in thickness of. The material exhibits properties suitable for use in furniture and handicrafts.Compósitos verdes são caracterizados por possuir matriz polimérica e reforço derivado de fontes naturais. Polímeros derivados do petróleo não são biodegradáveis e possuem solventes orgânicos na sua composição. Solventes orgânicos são tóxicos e poluentes. A poliuretana derivada do óleo de mamona é derivada de fonte renovável, biodegradável e não possui solventes orgânicos em sua composição. A casca de pinhão é um resíduo do pinhão, semente do pinheiro de Paraná. O objetivo desse trabalho é desenvolver e caracterizar o compósito de casca de pinhão com PU derivada do óleo de mamona. A fibra foi caracterizada quimicamente, por FTIR, TGA e MEV. A PU foi caracterizada por ensaio de resistência à flexão, FTIR e TGA e os compósitos, por testes de densidade, absorção de água, inchamento em espessura, resistência à flexão de três pontos, FTIR e TGA. A superfície da fratura foi avaliada por MEV e a homogeneidade dos compósitos por perfil de densidade e raios-X. O compósito de 35%PU apresentou resistência à flexão de 51,55 MPa, densidade de 1018 kg/m³, absorção de água em 24 horas de 7,95% e inchamento em espessura em 24 horas de 5,36%. O material apresenta propriedades mecânicas apropriadas para uso em mobiliário e artesanato