Avaliação dos mecanismos moleculares envolvidos na instalação da resistência periférica à insulina em camundongos portadores de caquexia tumoral
Carregando...
Data
2016-02-25
Autores
Malmonge, Levy [UNESP]
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
A insulina é o hormônio produzido pelas células beta das ilhotas pancreáticas, responsável pela captação da glicose pelos tecidos periféricos. A glicose é o principal estimulante para a secreção deste hormônio e é também o substrato energético mais utilizado pelas células para produção de energia ou armazenamento na forma de glicogênio. A insulina atinge os tecidos-alvo e se liga a um receptor de superfície da membrana plasmática, ativando uma cascata de fosforilação envolvendo as proteínas IRS1, PI-3 cinase, AKT e GLUT4. Qualquer defeito nesta sequência resulta em uma menor captação da glicose e uma maior secreção de insulina, estabelecendo um quadro chamado resistência periférica à insulina, frequente em pacientes portadores de malignidades que apresentam também uma síndrome conhecida como caquexia, caracterizada pela perda de peso, de tecido adiposo, atrofia muscular e anorexia. Esse conjunto de fatores é resultado da tentativa do organismo de produzir energia em grande escala para suprir o hospedeiro e seu tumor. Trabalhos anteriores em nosso laboratório já haviam descrito que a secreção de insulina por ilhotas de camundongos portadores de tumor solido de Ehrlich, apóes 14 dias de inoculação, apresentava-se diminuída, enquanto a sensibilidade periférica tanto à insulina quanto à glicose se mostraram aumentadas, portanto, o presente trabalho teve como objetivo avaliar a via de sinalização de insulina em tecido muscular, hepático e adiposo de camundongos caquéticos portadores do tumor sólido de Ehrlich 14 dias após inoculação. Foram analisadas as expressões gênicas por RT-qPCR e expressão protéica por Western Blotting das proteínas da via de sinalização da insulina, como IR, IRS1, PI3-K e AKT. Em uma análise geral do quadro sistêmico dos camundongos, estes apresentaram alterações metabólicas condizentes com o quadro de caquexia já estabelecido, como perda de peso, esplenomegalia, diminuição de colesterol, de glicogênios hepático e muscular e aumento de triglicerídeos plasmáticos. No tecido hepático, proteínas-chave na regulação da via - IR e AKT – apresentaram niveis proteicos aumentadas, enquanto no tecido muscular a proteína IRS1 em sua forma inativa, juntamente com AKT, estavam diminuídas. O tecido adiposo apresentou aumento na expressão gênica de algumas proteínas, mas não apresentou alteração na expressão proteica das mesmas. Portanto, o mesmo organismo apresenta orgãos com maior sensibilidade à insulina, como o tecido hepático e outros com resistencia à insulina, como o tecido muscular, mostrando uma resposta tecido-especifica à ação da insulina.
Insulin is the hormone produced by the β cells of the pancreatic islets, responsible for the absorption of glucose by peripheral tissues. Glucose is the major stimulant for the secretion of this hormone and is also the main substrate used by the cells for energy production or storage as glycogen. After the stimulus, insulin arrives at the target tissues and binds to its receptor at the surface of the cell membrane, activating a cascade of proteins phosphorylation such as IRS1, PI-3 kinase, AKT and GLUT4. Any defect in this sequence results in a lower glucose uptake and increased insulin secretion, resulting in a situation called insulin resistance, often seen in patients with malignancies and intimately linked with a syndrome called cachexia characterized by loss of weight and fat mass, muscle wasting and anorexia. These factors are the result of an attempt of the body to produce energy on a large scale to supply the host and his tumor because tumor cells absorb nutrients faster than normal cells. This study aimed to investigate the insulin signaling pathway in muscle, liver and fat tissue of solid Ehrlich carcinoma-bearing mice after 14 days of inoculation. At this time, previous studies of our laboratory had already described that the secretion of insulin showed significant decrease, while the peripheral sensitivity, for both insulin and glucose was increased. From this, we analyzed the gene expression by RT-PCR and protein expression by Western Blotting of the insulin signaling pathway proteins such as IR, IRS1, PI3-K and AKT. In a general analysis, the animals showed metabolic abnormalities consistent with cachexia already established, such as weight loss, splenomegaly, decreased cholesterol, liver and muscle glycogen and increased plasma triglycerides. In liver, IR and AKT, key proteins in the pathway regulation, were increased, while in muscle IRS1 protein in its inactive form, along with AKT were decreased. The fat tissue showed no alterations in protein expression, but showed a increased expression of genes for some proteins of the pathway. These data allow us to conclude that the sensitivity shown in ipITT it is a tissue-specific response, that is, while there is greater sensitivity to insulin in the liver, muscle appears to be resistant to the hormone.
Insulin is the hormone produced by the β cells of the pancreatic islets, responsible for the absorption of glucose by peripheral tissues. Glucose is the major stimulant for the secretion of this hormone and is also the main substrate used by the cells for energy production or storage as glycogen. After the stimulus, insulin arrives at the target tissues and binds to its receptor at the surface of the cell membrane, activating a cascade of proteins phosphorylation such as IRS1, PI-3 kinase, AKT and GLUT4. Any defect in this sequence results in a lower glucose uptake and increased insulin secretion, resulting in a situation called insulin resistance, often seen in patients with malignancies and intimately linked with a syndrome called cachexia characterized by loss of weight and fat mass, muscle wasting and anorexia. These factors are the result of an attempt of the body to produce energy on a large scale to supply the host and his tumor because tumor cells absorb nutrients faster than normal cells. This study aimed to investigate the insulin signaling pathway in muscle, liver and fat tissue of solid Ehrlich carcinoma-bearing mice after 14 days of inoculation. At this time, previous studies of our laboratory had already described that the secretion of insulin showed significant decrease, while the peripheral sensitivity, for both insulin and glucose was increased. From this, we analyzed the gene expression by RT-PCR and protein expression by Western Blotting of the insulin signaling pathway proteins such as IR, IRS1, PI3-K and AKT. In a general analysis, the animals showed metabolic abnormalities consistent with cachexia already established, such as weight loss, splenomegaly, decreased cholesterol, liver and muscle glycogen and increased plasma triglycerides. In liver, IR and AKT, key proteins in the pathway regulation, were increased, while in muscle IRS1 protein in its inactive form, along with AKT were decreased. The fat tissue showed no alterations in protein expression, but showed a increased expression of genes for some proteins of the pathway. These data allow us to conclude that the sensitivity shown in ipITT it is a tissue-specific response, that is, while there is greater sensitivity to insulin in the liver, muscle appears to be resistant to the hormone.
Descrição
Palavras-chave
Metabolismo de glicose, Sensibilidade à insulina, Tumor de Ehrlich, Ehrlich tumor, Glucose metabolism, Insulin sensitivity