Insulin Attenuates the Systemic Inflammatory Response in Endotoxemic Rats

Abstract

Insulin decreases the mortality and prevents the incidence of infection and sepsis in critically ill patients. The molecular and cellular mechanisms by which insulin improves survival have not been defined. The purpose of the present study was to determine the effect of insulin on the inflammatory reaction during endotoxemia. Endotoxemic rats were randomly divided into two groups to receive either saline or insulin. The effects of insulin on hepatic signal transcription factor mRNA expression, proinflammatory and antiinflammatory cytokine mRNA and protein concentration were determined. Insulin administration did not change glucose or electrolyte levels, but significantly decreased proinflammatory signal transcription factors [CCAAT/enhancer-binding protein-beta, signal transducer and activator of transcription-3 and-5, RANTES (regulated on activation, normal T cell expressed and secreted)] and cytokine expression in the liver and serum levels of IL-1beta, IL-6, macrophage inflammatory factor, and TNFalpha. Insulin administration further decreased high mobility group 1 protein in the serum compared with controls. In addition, insulin increased antiinflammatory cytokine expression in the liver; serum levels of IL-2, IL-4, and IL-10; and hepatic suppressor of cytokine signaling-3 mRNA expression. Insulin modulates the inflammatory response by decreasing the proinflammatory and increasing the antiinflammatory cascade. Because glucose and electrolyte levels did not differ between insulin-treated patients and controls, we hypothesize that the effects are direct antiinflammatory mechanisms of insulin, rather than indirect, through modulation of glucose or electrolyte metabolism.

Insulin Decreases Inflammatory Signal Transcription Factor Expression in Primary Human Liver Cells after LPS Challenge

“…There is evidence that insulin per se acts as an anti-inflammatory molecule (9,17-23), but there is also evidence that insulin acts through modulation of glucose levels (24)(25)(26)(27)(28)(29)(30). In a burn and endotoxemic rodent model, we found that insulin administration decreased proinflammatory and increased antiinflammatory mediators associated with improved hepatic function and structure (20,21,23,31). In severely burned patients, insulin improves the inflammatory response and attenuates the acutephase response (22).…”

Insulin Resistance as Estimated by Homeostasis Model Assessment Predicts Incident Symptomatic Cardiovascular Disease in Caucasian Subjects From the General Population

“…Nontraditional risk factors might represent further links (or intermediate phenotypes) between insulin resistance and CVD. Accordingly, in vitro and in vivo data suggest that insulin reduces platelet aggregation (10) and fibrinogen synthesis (12), possesses antiinflammatory and antioxidant properties (13,14), and favorably influences the endothelial function and the physiology of the vascular wall (11,15,16). If we assume that insulin resistance is not confined to glucose metabolism but encompasses many, if not all, biological effects of the hormone, these effects of insulin would be blunted in insulin-resistant states.…”

The Involvement of Cholesterol in Sepsis and Tolerance to Lipopolysaccharide Highlighted by the Transcriptome Analysis of Zebrafish (Danio rerio)

“…This is consistent with reports in mammals because insulin regulates the inflammatory response either directly or indirectly. [65][66][67][68][69][70][71][72] As in the case of the lethal LPS treatment, the lipid metabolism-related genes were affected: the low-density lipoprotein receptor (LDLR) was the most up-modulated gene at 4 dpf. Because LPS can be bound by triglyceride-rich lipoproteins (TRL) that may be internalized through the LDLR pathway, the internalization of lipoprotein bound endotoxin (TRL-LPS) could attenuate the systemic inflammatory response.…”