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Doctoral Thesis
DOI
10.11606/T.42.2016.tde-10112016-112543
Document
Author
Full name
Rodolfo Gonzalez Camargo
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2016
Supervisor
Committee
Seelaender, Marilia Cerqueira Leite (President)
Câmara, Niels Olsen Saraiva
Colquhoun, Alison
Neuschäfer-rube, Frank
Puschel, Gerhard Paul
Schulz, Tim Julius
Title in Portuguese
Resistência à insulina na caquexia associada ao câncer e na síndrome metabólica: papel dos macrófagos ativados pela insulina e do miRNA-21-5p.
Keywords in Portuguese
Caquexia
Fígado
Inflamação
Insulina
Macrófagos
MicroRNAs
Resistência à insulina
Síndrome metabólica
Abstract in Portuguese
A Caquexia associada ao câncer (CC) e a Síndrome Metabólica (MetS) apresentam características comuns como inflamação e resistência à insulina. Na MetS, a resistência à insulina é compensada pela hiperinsulinemia, que pode contribuir para a resistência à insulina através do aumento da inflamação, em particular, no fígado, onde a concentração de insulina é mais elevada. Esta hipótese foi testada neste estudo. Células da linhagem humanas U937 foram diferenciadas em macrófagos e expostas à insulina, LPS e PGE2. A insulina induziu a expressão gênica de IL-1β e IL-8 e potencializou a indução provocada por LPS, além de aumentar a indução de IL-1β provocada por PGE2 e atenuar a inibição de TNF-α causada por PGE2. Sobrenadantes de macrófagos tratados com insulina reduziram em hepatócitos a indução da glucoquinase dependente de insulina. Isso foi causado por citocinas contidas nos sobrenadantes, que ativaram ERK 1/2 e STAT3, resultando na fosforilação inibitória do substrato do receptor da insulina e a indução de SOCS3, respectivamente. MicroRNAs são protagonistas em doenças inflamatórias. Pacientes caquéticos exibiram níveis circulantes elevados dos mediadores pró-inflamatórios IL-6 e IL-8 e reduzidos do microRNA-21-5p em relação à pacientes não-caquéticos; a expressão do microRNA-21-5p correlaciona-se negativamente com níveis de IL-6. Isto indica que a hiperinsulinemia e a expressão do microRNA-21-5p diminuída podem contribuir para a inflamação e a resistência à insulina.
Title in English
Insulin resistance in cancer cachexia and metabolic syndrome: role of insulin activated macrophages and miRNA-21-5p.
Keywords in English
Cachexia
Inflammation
Insulin
Insulin resistance
Liver
Macrophages
Metabolic syndrome
MicroRNAs
Abstract in English
Cancer Cachexia (CC) and Metabolic Syndrome (MetS) share common issues as inflammation and insulin resistance. In MetS insulin resistance is compensated by hyperinsulinemia, which might contribute to insulin resistance by enhancing inflammation in particular in liver where insulin concentration is higher. This hypothesis was tested in this study. Cells of the human cell line U937 were differentiated into macrophages and exposed to insulin, LPS and PGE2. Insulin induced the gene expression of pro-inflammatory mediators like IL-1β and IL-8 and enhanced the induction provoked by LPS. Insulin enhanced the induction of IL-1β by PGE2 and attenuated the inhibition of TNFα by PGE2. Supernatants of insulin-treated macrophages reduced insulin-dependent glucokinase induction in hepatocytes. This insulin resistance was caused by cytokines contained in the supernatants, which activated ERK1/2 and STAT3, resulting in inhibitory phosphorylation of insulin receptor substrate and induction of SOCS3, respectively. MicroRNAs are active players in inflammatory disorders. In cachectic cancer patients circulating levels of the pro-inflammatory mediators IL-6 and IL-8 were higher and microRNA-21-5p lower than in non-cachectic patients; microRNA-21-5p negatively correlated with IL-6. This indicates that hyperinsulinemia and diminished microRNA-21-5p expression might contribute to inflammation and insulin resistance.
 
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Publishing Date
2016-11-10
 
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