Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated ...inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.
Hyperglycemia and insulin resistance have been associated with a worse outcome in sepsis. Although tight glycemic control through insulin therapy has been shown to reduce morbidity and mortality ...rates, the effect of intensive insulin therapy in patients with severe sepsis is controversial because of the increased risk of serious adverse events related to hypoglycemia. Recently, knowledge about diacerhein, an anthraquinone drug with powerful antiinflammatory properties, revealed that this drug improves insulin sensitivity, mediated by the reversal of chronic subclinical inflammation. The aim of the present study was to evaluate whether the antiinflammatory effects of diacerhein after onset of sepsis-induced glycemic alterations is beneficial and whether the survival rate is prolonged in this situation.
Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Blood glucose and inflammatory cytokine levels were assessed 24 hours after CLP. The effect of diacerhein on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle, and adipose tissue.
Here we demonstrated that diacerhein treatment improves survival during peritoneal-induced sepsis and inhibits sepsis-induced insulin resistance by improving insulin signaling via increased insulin-receptor substrate-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. Diacerhein also decreases the activation of endoplasmic reticulum stress signaling that involves upregulation of proinflammatory pathways, such as the I kappa B kinase and c-Jun NH2-terminal kinase, which blunts insulin-induced insulin signaling in liver, muscle, and adipose tissue. Additionally, our data show that this drug promoted downregulation of proinflammatory signaling cascades that culminate in transcription of immunomodulatory factors such interleukin (IL)-1β, IL-6, and tumor necrosis factor-α.
This study demonstrated that diacerhein treatment increases survival and attenuates the inflammatory response with a significant effect on insulin sensitivity. On the basis of efficacy and safety profile, diacerhein represents a novel antiinflammatory therapy for management of insulin resistance in sepsis and a potential approach for future clinical trials.
Abstract Objective Recent data show that iNOS has an essential role in ER stress in obesity. However, whether iNOS is sufficient to account for obesity-induced ER stress and Unfolded Protein Response ...(UPR) has not yet been investigated. In the present study, we used iNOS knockout mice to investigate whether high-fat diet (HFD) can still induce residual ER stress-associated insulin resistance. Methods For this purpose, we used the intraperitoneal glucose tolerance test (GTT), euglycemic-hyperinsulinemic clamp, western blotting and qPCR in liver, muscle, and adipose tissue of iNOS KO and control mice on HFD. Results The results of the present study demonstrated that, in HFD fed mice, iNOS-induced alteration in insulin signaling is an essential mechanism of insulin resistance in muscle, suggesting that iNOS may represent an important target that could be blocked in order to improve insulin sensitivity in this tissue. However, in liver and adipose tissue, the insulin resistance induced by HFD was only partially dependent on iNOS, and, even in the presence of genetic or pharmacological blockade of iNOS, a clear ER stress associated with altered insulin signaling remained evident in these tissues. When this ER stress was blocked pharmacologically, insulin signaling was improved, and a complete recovery of glucose tolerance was achieved. Conclusions Taken together, these results reinforce the tissue-specific regulation of insulin signaling in obesity, with iNOS being sufficient to account for insulin resistance in muscle, but in liver and adipose tissue ER stress and insulin resistance can be induced by both iNOS-dependent and iNOS-independent mechanisms.
The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in ...parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult.
Orientador: Mário José Abdalla Saad
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Previous issue date: 2012
Resumo: Na sepse o sistema imune torna-se hiperativo, levando a excessiva produção de mediadores pró-inflamatórios. Tanto componentes bacterianos, como o LPS, quanto citocinas pro-inflamatórias resultantes da resposta imune, podem ativar mecanismos intracelulares associados à resistência à insulina, como a via IKK'beta'/NF'capa'B e a via da JNK. Hiperglicemia e resistência à insulina ocorrem durante a sepse, como consequência dos efeitos metabólicos da excessiva produção de mediadores pró-inflamatórios. Sabe-se que a resistência à insulina pode agravar ainda mais o quadro da sepse, todavia a manutenção da normoglicemia com a insulinoterapia reduz os índices de morbidade e mortalidade. Por esta razão, o objetivo do presente estudo foi investigar o efeito de fármacos (atorvastatina e diacereína) sobre a sobrevivência, sinalização inflamatória e, paralelamente, a sua ação sobre a via de sinalização da insulina em ratos com sepse induzida por peritonite. Nossos dados demonstram que os tratamentos com atorvastatina e diacereína aumentam a sobrevida, com um efeito benéfico sobre a sensibilidade à insulina, melhorando a sinalização da insulina dos animais sépticos. Ademais, os tratamentos reduziram a ativação de JNK e IKK e consequente expressão de citocinas pró-inflamatórias, e em paralelo reduziram estresse do retículo endoplasmático induzido pela sepse. Com isso, podemos sugerir que a restauração da sinalização da insulina demonstrada pela reativação da via PI3K/Akt induzida pelos tratamentos, desempenhou um papel fundamental no aumento da sobrevida na sepse. Neste contexto, acreditamos que a melhora na via de sinalização da insulina, induzida pelos tratamentos com atorvastatina e diacereína, em paralelo com uma atenuação da inflamação nos tecidos, pode ajudar a predizer a eficácia destes tratamentos na sepse
Abstract: During the onset of sepsis, the inflammatory system becomes hyperactive, and the persistent activating stimuli induce cells to produce excessive amounts of cytokines and mediators that lead to tissue damage. Both bacterial components and proinflammatory cytokines can directly activate pro-inflammatory pathways as IKK'beta'/NF'kappa'B and JNK that seem to be associated to disruption on insulin signaling. Hyperglycemia and insulin resistance occur during sepsis, as a consequence of the metabolic effects of stress hormone and cytokine production. Studies indicate that insulin resistance may aggravate sepsis. Furthermore, it was demonstrated that the maintenance of normoglycemia with insulin therapy reduces morbidity and mortality rates in sepsis. The aim of the present study was to investigate the effect of drugs (atorvastatin and diacerhein) on survival, inflammatory signaling and insulin signaling pathway in rat model of CLP-induced sepsis. Our data demonstrate that atorvastatin and diacerhein treatment improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity. Sepsis induced an increase in JNK and IKK/NF-'kappa'B activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin and diacerhein reversed all these alterations in parallel with a decrease sepsis-induced endoplasmic stress reticulum and circulating levels proinflammatory cytokines. The improvement insulin signaling pathway through PI3K/Akt induced by treatments with atorvastatin and diacerhein, in parallel with a decrease in tissue inflammation, may play a central role in regulation of insulin signaling and survival in sepsis insult
Doutorado
Clinica Medica
Doutor em Ciências Médicas
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