Inhibition of NF-κB Pathway with IKK-16 or Linagliptin Attenuates the Cardiac Dysfunction Associated with Polymicrobial Sepsis in Mice with Preexisting Type 2 Diabetes Mellitus (T2DM)

Introduction: Patients with diabetes are more susceptible to infections and sepsis. Activation of nuclear factor-κB (NF-κB) plays a substantial role in the pathophysiology of sepsis and diabetes. Here we investigate i) the effect of preexisting type 2 diabetes mellitus on cardiac dysfunction associated with sepsis and ii) whether inhibition of NF-κB using IKK-16 or linagliptin attenuates cardiac dysfunction in mice with sepsis and diabetes.

Methods: Ten-week old male C57BL/6 mice received high fat (HFD) or chow diet for 12 weeks, and were then subjected to caecal ligation and puncture (CLP) or sham surgery for 24 hours. At 1 hour after CLP, mice received IKK-16, linagliptin, or vehicle.

Results: Administration of HFD resulted in a significant impairment in glucose tolerance and a small, but significant, reduction in ejection fraction. Immunoblot analysis of hearts tissue showed that HFD caused significant NF-κB pathway activation and expression of inducible nitric oxide synthase (iNOS). Mice on HFD subjected to CLP showed further (i) decline in EF, (ii) increase in NF-κB pathway activation, (iii) increase in iNOS expression, (iv) an increase in serum ALT, and (v) a significant renal dysfunction. Treatment of HFD-CLP mice with IKK-16 or linagliptin resulted in significant reduction of the CLP-induced i) cardiac dysfunction, ii) NF-κB pathway activation, and iii) iNOS expression when compared to mice treated with vehicle.

Conclusion: Our results show that HFD results in inflammation and cardiac dysfunction. Moreover, a preexisting diabetic phenotype worsened the cardiac dysfunction associated with CLP-sepsis. Most notably, inhibition of NF-κB reduced the cardiac dysfunction caused by sepsis in animals with preexisting T2DM.