Insulin sensitivity during sepsis induced by peritoneal contamination and infection in transgenic SIRT1-overexpressing mice

Sepsis is a severe complication of infection linked to high mortality by organ failure such as septic cardiomyopathy. As a result of inflammation, insulin resistance can be found during sepsis. Restoring insulin sensitivity is also known to improve sepsis outcome and organ dysfunction. Sepsis models which were already used to investigate sepsis-associated insulin resistance have known methodical limitation. The use of injection-based peritoneal contamination and infection (PCI) offers an improvement in standardization and comparability. However, sepsis-associated insulin resistance has not been investigated during a PCI-induced sepsis. The objective of this study was to measure insulin resistance and insulin-mediated glucose uptake (IMGU) during a PCI-induced sepsis. A PCI-induced sepsis was then used to identify influences of SIRT1, a NAD-dependent sirtuin enzyme, on a sepsis-associated insulin resistance. SIRT1 is known to improve insulin sensitivity in healthy mice. Growing evidence suggests that SIRT1 can affect sepsis progression and septic cardiomyopathy. However, there are no studies investigating whether SIRT1-overexpression could improve insulin sensitivity and insulin-mediated glucose uptake during sepsis. Sepsis was induced by PCI in wildtype (WT) and SIRT1-overexpressing mice. Morphometrical parameters such as plasma glucose levels and body temperature were evaluated before and during sepsis. Insulin and glucose tolerance tests were used to compare the baseline insulin sensitivity of WT and SIRT1-overexpressing mice without sepsis. The hyperinsulinemic-euglycemic clamp was used to measure insulin sensitivity during sepsis after 6 h, 24 h and 72 h from induction. By injecting radioactive labeled 2[14C]desoxyglucose intravenously, tissue and organ specific glucose uptake was estimated. Protein abundance of SIRT1, GLUT4 and PGC1α and phosphorylation of insulin receptor (IR) and protein kinase B (Akt) were assessed performing western blot analyses.