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.

Highlights

  • Sepsis is a dysregulated body response to infection that results in life-threatening organ dysfunction [1]

  • A “two-hit” model of pre-existing type 2 diabetes mellitus (T2DM) followed by a mild Cecal Ligation and Puncture (CLP) surgery was used to study (a) the effect of pre-existing T2DM on the cardiac dysfunction associated with sepsis and (b) to test novel therapeutic interventions aimed at reducing cardiac dysfunction in T2DM/sepsis mice

  • To confirm the potential key role of the activation of NF-κB in the pathophysiology of septic cardiomyopathy in animals with T2DM, we investigated the effect of NF-κB pathway inhibition using a selective IKK inhibitor (IKK-16) on cardiac dysfunction associated with sepsis

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Summary

Introduction

Sepsis is a dysregulated body response to infection that results in life-threatening organ dysfunction [1]. All patients with septic shock, develop sepsisrelated cardiovascular dysfunction [2, 3], which is a key driver of in-hospital mortality in these patients [4]. Both the incidence of sepsis and sepsis-related mortality increase with age due to the presence of significant comorbidities including chronic kidney disease and type 2 diabetes in the elderly [5]. This study was undertaken to investigate the effects of pre-existing type 2 diabetes mellitus (T2DM) caused by high fat diet (HFD) on cardiac dysfunction in mice with sepsis

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Conclusion

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