Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans

Abstract

Type 2 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 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp (n = 6) or an infusion of sterile 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-alpha (TNF-alpha), 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-alpha production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.

Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-α, and FFAs to low-dose endotoxemia in humans

“…The neutrophil number increased, peaking at 180 min, whereas the lymphocytes decreased in accord with previous studies (23,52). The dose of endotoxin in the present study was 0.2 ng/kg, which is ϳ10 times lower than that used in other studies (14,42,45). The advantage of using this lower dose is that the subjects do not develop any symptoms during the studies.…”

Insulin stimulates interleukin-6 and tumor necrosis factor-α gene expression in human subcutaneous adipose tissue

“…The effect on mortality was achieved mainly by a reduction in late deaths (after 5 days of admission) due to a septic focus (1). In addition, a euglycemic hyperinsulinemic clamp (compared with saline infusion) in volunteers who had received an endotoxin dose at 2 ng/kg induced an increase in the IL-6 response to endotoxin (23). Thus the latter study, in accord with data presented here, demonstrates an effect of insulin on circulating levels of IL-6, although the use of supraphysiological concentrations of insulin on adipose tissue IL-6 production in the present study cannot easily be extrapolated into a clinical state of hyperinsulinemia, such as in insulin resistance.…”

Subcutaneous adipose tissue exerts proinflammatory cytokines after minimal trauma in humans

“…Recent data from in vivo studies in humans applying hyperinsulinemic euglycemic clamp studies have produced evidence that cytokine release (IL-6 and TNF-␣) could be influenced by insulin (14,26). To further elucidate insulin's role in modulating acute inflammation at the level of cytokines, our secondary objective was to investigate the effect of locally administered insulin on the proinflammatory cytokine response in subcutaneous adipose tissue.…”