Diacerhein attenuates the inflammatory response and improves survival in a model of severe sepsis.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kelly L
KL
Calisto
Angélica C
AC
Camacho
Francine C
FC
Mittestainer
Bruno M
BM
Carvalho
Dioze
D
Guadagnini
José B
JB
Carvalheira
Mario J
MJ
Saad
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D007249:Inflammation / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology*; D015398:Signal Transduction
D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; C025292:diacerein