Abstract
BackgroundSepsis is one of the leading causes of death among hospitalized patients. At the onset of this condition, there is an over-production of pro-inflammatory mediators that contribute to organ failure and death. The excess production of pro-inflammatory mediators also impairs insulin signaling, which may be a pathophysiological tissue marker of proinflammatory cytokine action before organ failure. Statins and diacerein have pleiotropic effects, such as the blockage of inflammatory signaling pathways, suggesting that these drugs may be an attractive therapeutic or prophylactic strategy against sepsis. The aim of the present study was to investigate whether a statin or diacerein can improve insulin signaling, disease tolerance and survival in sepsis by inhibiting inflammatory pathways.MethodsWe investigated the effect of these drugs on survival, tissue insulin signaling and inflammatory pathways in the liver and muscle of rats with sepsis induced by cecal ligation and puncture (CLP).ResultsThe results showed that administration of medications, with anti-inflammatory ability, to septic animals increased survival and improved disease tolerance and insulin resistance in the liver and muscle. The treatment also attenuated ER stress, NF-κB, JNK activation and restored glucose-6-phosphatase (G6Pase) levels in the liver.ConclusionsOur results indicate that atorvastatin and diacerein treatment can modulate inflammatory pathways and, in parallel, attenuate insulin resistance in sepsis. Since these two drugs have safety profiles and minimal side effects, we suggest that these drugs may be alternative therapies for the prevention or therapies for the treatment of insulin resistance in sepsis, which could potentially reduce mortality in patients with sepsis.
Highlights
Sepsis is one of the leading causes of death among hospitalized patients
Atorvastatin and Diacerein improve survival in septic rats To test the hypothesis that these two drugs with antiinflammatory activity can decrease sepsis mortality, we monitored the survival in septic and sham-operated animals
The results showed a significant improvement in the survival curves after atorvastatin (P < 0.0001) or diacerein (P < 0.0001) treatment in septic animals (Fig. 1a), when compared to septic animals that received a placebo
Summary
Sepsis is one of the leading causes of death among hospitalized patients. At the onset of this condition, there is an over-production of pro-inflammatory mediators that contribute to organ failure and death. The excess production of pro-inflammatory mediators impairs insulin signaling, which may be a pathophysiological tissue marker of proinflammatory cytokine action before organ failure. The excess production of pro-inflammatory mediators results in a significant pro-inflammatory state, which in turn reduces insulin sensitivity [4,5,6,7,8,9,10]. The molecular mechanism by which insulin resistance is induced is through serine phosphorylation of the insulin receptor substrate 1 (IRS-1), impairing insulin action This insulin resistance, in the liver and muscle, characterized by a down-regulation of insulin signaling may unveil the overreaction at the tissue level, and may be used to predict the effectiveness of treatment
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