title: Atorvastatin improves survival in septic rats: effect on tissue inflammatory pathway and on insulin signaling.
abstract: 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.
authors.affiliation: Department of Internal Medicine, FCM, State University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Kelly Lima
authors.initials: KL
authors.lastname: Calisto
authors.forename: Bruno de Melo
authors.initials: Bde M
authors.lastname: Carvalho
authors.forename: Eduardo Rochete
authors.initials: ER
authors.lastname: Ropelle
authors.forename: Francine Cappa
authors.initials: FC
authors.lastname: Mittestainer
authors.forename: Angélica Costa Aranha
authors.initials: AC
authors.lastname: Camacho
authors.forename: Dioze
authors.initials: D
authors.lastname: Guadagnini
authors.forename: José Barreto Campelo
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Mario José Abdalla
authors.initials: MJ
authors.lastname: Saad
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D005947:Glucose / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D015850:Interleukin-6; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D005947:Glucose