Diabetes and the cardiac dysfunction caused by experimental sepsis
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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.
Authors
Al Zoubi, Sura Yahia YosefCollections
- Theses [4125]