Linagliptin Attenuates the Cardiac Dysfunction Associated With Experimental Sepsis in Mice With Pre-existing Type 2 Diabetes by Inhibiting NF-κB.

Abstract

The mortality rate of patients who develop sepsis-related cardiac dysfunction is high. Many disease conditions (e.g., diabetes) increase the susceptibility to infections and subsequently sepsis. Activation of the NF-κB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is still highly controversial. We here hypothesized that type 2 diabetes (T2DM) augments the cardiac (organ) dysfunction associated with sepsis, and that inhibition of the NF-κB pathway with linagliptin attenuates the cardiac (organ) dysfunction in mice with T2DM/sepsis. To investigate this, 10-week old male C57BL/6 mice were randomized to receive normal chow or high fat diet (HFD), 60% of calories derived from fat). After 12 weeks, mice were subjected to sham surgery or cecal ligation and puncture (CLP) for 24 h. At 1 hour after surgery, mice were treated with linagliptin (10 mg/kg, i.v.), IKK-16 (1 mg/kg, i.v.), or vehicle (2% DMSO, 3 ml/kg, i.v.). Mice also received analgesia, fluids and antibiotics at 6 and 18 h after surgery. Mice that received HFD showed a significant increase in body weight, impairment in glucose tolerance, reduction in ejection fraction (%EF), and increase in alanine aminotransferase (ALT). Mice on HFD subjected to CLP showed further reduction in %EF, increase in ALT, developed acute kidney dysfunction and lung injury. They also showed significant increase in NF-κB pathway, iNOS expression, and serum inflammatory cytokines compared to sham surgery group. Treatment of HFD-CLP mice with linagliptin or IKK-16 resulted in significant reductions in (i) cardiac, liver, kidney, and lung injury associated with CLP-sepsis, (ii) NF-κB activation and iNOS expression in the heart, and (iii) serum inflammatory cytokine levels compared to HFD-CLP mice treated with vehicle. Our data show that pre-existing type 2 diabetes phenotype worsens the organ dysfunction/injury associated with CLP-sepsis in mice. Most notably, inhibition of NF-κB reduces the organ dysfunction/injury associated with sepsis in mice with pre-existing T2DM.

• Authors: Sura Al Zoubi, Jianmin Chen, Catherine Murphy, Lukas Martin, Fausto Chiazza, Debora Collotta, Muhammad M Yaqoob, Massimo Collino, Christoph Thiemermann
• Journal: Frontiers in immunology (Front Immunol) Vol. 9 Pg. 2996 ( 2018) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 30619349 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IkK-16 compound
• NF-kappa B
• Piperidines
• Pyrrolidines
• Linagliptin

Topics

• Animals
• Cecum (microbiology)
• Diabetes Mellitus, Type 2 (complications, drug therapy, etiology, immunology)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Heart Diseases (immunology)
• Humans
• Linagliptin (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors, immunology, metabolism)
• Piperidines (pharmacology, therapeutic use)
• Pyrrolidines (pharmacology, therapeutic use)
• Sepsis (complications, etiology, immunology)
• Signal Transduction (drug effects, immunology)