PB1426 - Studies of Streptozotocin-Induced Hyperglycemia on the Host Response to Sepsis

Background: Hyperglycemia is a common complication in the intensive care unit and is associated with increased morbidity and mortality. The causes of hyperglycemia during critical illness include pre-existing conditions (e.g., diabetes mellitus) as well as the host response to severe stress (e.g., sepsis, trauma). Individuals with hyperglycemia also carry an additional risk of developing sepsis, a dysregulated host response to infection associated with a prothrombotic state. However, the precise mechanisms by which hyperglycemia modulates host response to sepsis remains unclear. The objective of this project is to investigate the host response to infection in hyperglycemic and normoglycemic mice.

Aims: Investigate time-dependent changes in markers of coagulation, anticoagulation, inflammation, and the formation of neutrophil extracellular traps (NETs) in a streptozotocin (STZ)-induced model of hyperglycemia in mice.

Methods: 5-week-old C57Bl/6 mice from both sexes were administer 10 rounds of STZ to induced hyperglycemic (blood glucose >15mmol/L). At 11-12 weeks of age the mice are given an IP injection of rat fecal slurry (0.6mg/g) to induce sepsis. The mice were monitored for 48h and euthanized at the humane or study endpoint. Additionally, ELISAs on collected plasma were performed to measure coagulation, anticoagulation, inflammation, and NET formation.

Results: The 48h survival was similar in male and female hyperglycemic mice. There is a significant decrease in endogenous protein C in hyperglycemic mice that died during sepsis. Levels of IL-6, TAT, cfDNA, and MPO were not significantly different between hyperglycemic and normoglycemic mice. We also observed that acquired hypoglycemia in normoglycemic mice (defined as < 3.1 mM) may be a useful predictor of poor outcomes in sepsis.

Conclusion(s): Our data suggests that exposure to sepsis in a hyperglycemic state impairs endogenous anticoagulation mediated by protein C. An acquired deficiency of protein C may contribute to a prothrombotic state associated with hyperglycemia in sepsis.

Funding:
Canadian Institute of Health Research
CanVECTOR