Time-Dependent Metabolic Response in Sepsis Severity: The Influence of Glucose in the Disease Outcome

Abstract

Sepsis is a syndrome caused by a dysregulated host response to pathogens, representing the leading cause of death from infection. Various murine models of sepsis have shown a time-dependent response based on the time of induction. Mice stimulated with high doses of bacterial lipopolysaccharide (LPS) at the end of the day exhibit a higher mortality rate (~80%) compared with those inoculated in the middle of the night (~30%). In this work, we assessed the differences in serum proteins of septic mice during the day and night. Through this proteomic study, we found significant variations in metabolic pathways, including glucose metabolism, which were associated with a better prognosis. Therefore, we studied the glucose response to LPS during the day and night. In this context, we found an early peak of LPS-induced glucose exclusively at the time of worse prognosis. We also observed a hypoglycemic response to LPS, which was independent of the time of sepsis induction. Finally, we performed a set of metabolic manipulations to study how hyperglycemia influences sepsis severity in mice. We observed that suppressing the glucose peak during the day, through metformin administration, reduced sepsis severity. In contrast, nocturnal glucose administration with LPS was rapidly metabolized and also decreased sepsis severity. In conclusion, sepsis severity may be influenced by the metabolic state at the time of the stimulus. Metabolic rhythms could lead to differences in early glucose management, affecting the outcome of this pathology.