Diabetes and the cardiac dysfunction caused by experimental sepsis

Abstract

Sepsis is the leading cause of death in ICU patients. Patients with sepsis may develop sepsis-related cardiac dysfunction. The presence of this cardiac dysfunction can increase the mortality rate from 40% to 70%. Diabetes is a chronic disease that manifests as an elevation in blood glucose. Patients with diabetes are more susceptible to, and at increasing risk of developing, infections and subsequently sepsis. Activation of the NF-ĸB 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 highly controversial and it is still unclear whether pre-existing T2DM augments the cardiac dysfunction associated with sepsis and whether activation of NF-ĸB drives the cardiac dysfunction in T2DM/sepsis patients. In this thesis, I have first developed two models of high fat diet (HFD)-induced diabetes and diabetic cardiomyopathy in mice. Then, I developed two models of sepsis associated cardiac dysfunction using lipopolysaccharide (LPS) or caecumligation and puncture (CLP) in diabetic mice. I have demonstrated that mice with pre-existing T2DM exhibit a significantly greater cardiac (organ) dysfunction after challenge with either (low dose) LPS or mild CLP surgery. The exacerbated cardiac dysfunction was accompanied by an increase in NF-ĸB activation and reduction in Akt phosphorylation in the heart and an increase in the serum levels of proinflammatory cytokines. The increase in cardiac dysfunction, as well as the increase in the activation of NF-ĸB, caused by sepsis in animals with T2DM was largely attenuated by treatment with a selective IĸB kinase inhibitor (IKK-16) or a DPP-4 inhibitor (linagliptin). Thus, excessive activation of NF-ĸB in animals with diabetes/sepsis drives the observed excessive cardiac dysfunction, and that inhibition of NF-ĸB may be a useful target to treat the excessive inflammation and sepsis associated cardiac (organ) dysfunction in patients with T2DM and sepsis.