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Am J Physiol Endocrinol Metab (January 13, 2004). doi:10.1152/ajpendo.00468.2003
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Submitted on October 16, 2003
Accepted on January 6, 2004

Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha and free fatty acids to low-dose endotoxemia in humans

Rikke Krogh-Madsen1, Kirsten Moller1, Flemming Dela2, Gitte Kronborg1, Sune Jauffred1, and Bente Klarlund Pedersen3*

1 Department of Infectious Diseases, University Hospital Rigshospitalet, Copenhagen, Denmark
2 Copenhagen Muscle Research Centre, The Panum Institue, Copenhagen, Denmark; Department of Medical Physiology, The Panum Institute, Copenhagen, Denmark
3 Department of Infectious Diseases, University Hospital Rigshospitalet, Copenhagen, Denmark; Copenhagen Muscle Research Centre, The Panum Institue, Copenhagen, Denmark

* To whom correspondence should be addressed. E-mail: bkp{at}rh.dk.

Introduction: Insulin therapy to maintain euglycemia increases survival in critically ill patients. To explore possible mechanisms of action, we investigated the effect of endotoxin on circulating cytokines, free fatty acids (FFA), and leukocytes, during manipulated plasma glucose and insulin concentrations. Methods: Ten volunteers underwent three trials each receiving an intravenous bolus of endotoxin (0.2 ng/kg) during normoglycemia (Trial A, control), during a hyperglycemic clamp at 15mM (Trial B) and during a hyperinsulinemic euglycemic clamp (Trial C). Results: Endotoxin induced an increase in neutrophil and a decrease in lymphocyte counts and an increase in serum levels of tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), as well as FFA. There was no difference in the TNF response between the three trials; the IL-6 levels were increased during the late phase of Trials B and C, compared to Trial A. The endotoxin-induced elevation in FFA in Trial A was suppressed during Trial B and C. Clamping (Trial B and C) caused a reduction in lymphocyte count, which persisted after endotoxin injection. Conclusion: Low-dose endotoxemia triggers a subclinical inflammatory response and an elevation in FFA. The finding that high insulin serum concentrations induce a more prolonged increase in the anti-inflammatory cytokine IL-6 and suppress the levels of FFA suggests that insulin treatment of patients with sepsis may exert beneficial effects by inducing anti-inflammation and protection against FFA toxicity and inhibit FFA induced insulin resistance.




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