Euglycaemic hyperinsulinaemia augments the cytokine and endocrine responses to endotoxin in man

Type II diabetes is associated with biochemical evidence of low-grade inflammation and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans we administered 20U/kg E Coli lipopolysaccharide (LPS) or saline (control) to 14 subjects, during a euglycaemic hyperinsulinaemic clamp (n=6) or an infusion of sterile healthy saline (n=8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6) tumor necrosis factor-α ( TNF-α) and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-α production by glucose, insulin or leptin at physiologically relevant concentrations. Hyperinsulinaemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.