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. 2018 May 9:15:8.
doi: 10.1186/s12950-018-0184-9. eCollection 2018.

Atorvastatin and diacerein reduce insulin resistance and increase disease tolerance in rats with sepsis

K L C da Silva  1 , A P Camacho  1 , F C Mittestainer  1 , B M Carvalho  2 , A Santos  1   3 , D Guadagnini  1 , A G Oliveira  4 , M J A Saad  1   3
Affiliations

Atorvastatin and diacerein reduce insulin resistance and increase disease tolerance in rats with sepsis

K L C da Silva et al. J Inflamm (Lond). .

Abstract

Background: 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 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.

Methods: We 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).

Results: The 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.

Conclusions: Our 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.

Keywords: Diacerein; Insulin resistance; Sepsis; Statin.

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Conflict of interest statement

All animal protocols of this study were approved by the Animal Care and Use Committee at State University of Campinas (CEUA/UNICAMP 1267-1), and they are by international guidelines for the care and use of experimental animals.Availability of data and material: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Effect Atorvastatin and Diacerein survival in CLP sepsis model. Male Wistars rats, 8 weeks old, received saline (Sham/Sal, n  =  20), (Sepsis/Sal, n  =  20) or atorvastatin 10 mg/kg (Sepsis/Ator, n  =  20), or diacerein 100 mg/kg (Sepsis/Diac n  =  20) 3 h after surgery and once a day following CLP. Survival of the rats was monitored at intervals of 4 h for 1-week, than every 12 h until day 15. The overall difference in survival rate between the groups with and without atorvastatin was significant (P < 0.0001). The overall difference in survival rate between the groups with and without diacerein was significant (P < 0.0001) (a). Fasting blood glucose (b). Glucose disappearance rate (c). Serum levels of IL-6 (d) and TNF-α (e). Data are presented as means ± SEM of six rats per group (except for survival curve). *P < 0.05 (Sepsis saline vs. all others groups)
Fig. 2
Fig. 2
Effects of Atorvastatin and Diacerein treatment on insulin signaling in the CLP rat. Insulin-induced protein expression of Akt serine phosphorylation with Atorvatatin or Diacerein treatment (a-d upper panels). a- Atorvastatin/Liver; b- Atorvastatin/Muscle; c- Diacerein /Liver and d- Diacerein/Muscle. In this case, blots quantification were normalized with total AKT protein expression (a-d, lower panels). The amount of protein loaded was 30 μg. Data are presented as means +/− SEM from 6 rats per group. *P < 0.05 (Sepsis/Sal vs. all others groups). IB, immunoblotting; p, phosphorylated
Fig. 3
Fig. 3
NFkB activation in nuclear fractions. NFκB activation in nuclear fractions of liver (a) and muscle (b) of sham and septic rats were given saline or atorvastatin or diacerein . Data are presented as means ± SEM from 6 rats per group. *P < 0.05 (Sepsis/Sal vs. all others groups). C: Sham/Saline; Sal: Saline: Ator: Atorvastatin; Diac: Diacerein
Fig. 4
Fig. 4
Atorvastatin or diacerein attenuate JNK and IRS phosphorylation in liver and muscle of septic animals. Phosphorylation of JNK in liver (a-b), muscle (c-d) after Atorvatatin or Diacerein treatment of sham and septic rats. Total protein expression of JNK. Serine 307 Phosphorylation of IRS1 in liver (a-b), muscle (c-d) after Atorvatatin or Diacerein treatment of septic rats. Total protein expression of IRS-1. The amount of protein loaded was 30 μg. Data are presented as means ± SEM from 6 rats per group. *P < 0.05 (Sepsis/Sal vs. all others groups). IB, immunoblot; C: Sham/Saline; Sal: Saline: Ator: Atorvastatin; Diac: Diacerein; ShT: Sham treatment
Fig. 5
Fig. 5
Effects of Atorvastatin or Diacerein administration on the expression of gene PERK and IRE1 in septic rats. Determination of IRE1 and PERK mRNA expression by qPCR in the liver (a-b) and muscles (c-d) after Atorvatatin or Diacerein treatment of septic rats. Data are presented as means ± SEM from 6 rats per group. *P < 0.05 (Sepsis/Sal vs. all others groups). C: Sham/Saline; Sal: Saline: Ator: Atorvastatin; Diac: Diacerein
Fig. 6
Fig. 6
Atorvastatin (a) and diacerein (b) restore G6Pase in liver of septic animals. Protein expression of G6Pase in the liver after Atorvatatin or Diacerein treatment of sham and septic rats. The amount of protein loaded was 60 μg. Data are presented as means ± SEM from 6 rats per group. *P < 0.05 (Sepsis/Sal vs. all others groups). IB, immunoblot; C: Sham/Saline; Ator: Atorvastatin; Diac: Diacerein, ShT: Sham treatment
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