Acute Hyperinsulinemia Restrains Endotoxin-induced Systemic Inflammatory Response

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Abstract
Background: Intensive insulin therapy in critically ill patients reduces morbidity and mortality. The current study elucidates whether acute hyperinsulinemia per se could attenuate the systemic cytokine response and improve neutrophil function during endotoxin (lipopolysaccharide)-induced systemic inflammation in a porcine model. Methods: Pigs were anesthetized, mechanically ventilated, randomized into four groups, and followed for 570 min: group 1 (anesthesia solely, n = 10), group 2 (hyperinsulinemic euglycemic clamp [HEC], n = 9), group 3 (lipopolysaccharide, n = 10), group 4 (lipopolysaccharide-HEC, n = 9). Groups 3 and 4 were given a 180-min infusion of lipopolysaccharide (total, 10 microg/kg). Groups 2 and 4 were clamped (p-glucose: 5 mM/l, insulin 0.6 mU.kg(-1).min(-1)) throughout the study period. Changes in pulmonary and hemodynamic function, circulating cytokines, free fatty acids, glucagon, and neutrophil chemotaxis were monitored. Results: Tumor necrosis factor alpha and interleukin 6 were significantly reduced in the lipopolysaccharide-HEC group compared with the lipopolysaccharide group (both P = 0.04). In the lipopolysaccharide-HEC group, the glucagon response was diminished compared with the lipopolysaccharide group (P < 0.05). Serum free fatty acid concentrations were decreased in animals exposed to HEC. Animals receiving lipopolysaccharide showed an increase in pulmonary pressure (P < 0.001), but otherwise, there were no major changes in pulmonary or hemodynamic function. Neutrophil function was impaired after lipopolysaccharide administration. Conclusion: Hyperinsulinemia concomitant with normoglycemia reduces plasma concentrations of tumor necrosis factor alpha and the catabolic hormone glucagon in lipopolysaccharide-induced systemic inflammation in pigs. The finding strongly supports the role of insulin as an antiinflammatory hormone. Whether the effect to some extent operates via a reduced free fatty acid concentration is unsettled.