title: Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans.
abstract: 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. 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 15 mM (trial B), and during a hyperinsulinemic euglycemic clamp (trial C). Endotoxin induced an increase in neutrophil count, a decrease in lymphocyte count, and an increase in serum levels of TNF-alpha, IL-6, and 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 with trial A. The endotoxin-induced elevation in FFA in trial A was suppressed during trials B and C. Clamping (trials B and C) caused a reduction in lymphocyte count that persisted after endotoxin injection. We conclude that 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 thereby inhibit FFA-induced insulin resistance.
authors.affiliation: Professor of Internal Medicine, Dept. of Infectious Diseases 7641, Univ. Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. bkp@rh.dk
authors.forename: Rikke
authors.initials: R
authors.lastname: Krogh-Madsen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Møller
authors.forename: Flemming
authors.initials: F
authors.lastname: Dela
authors.forename: Gitte
authors.initials: G
authors.lastname: Kronborg
authors.forename: Sune
authors.initials: S
authors.lastname: Jauffred
authors.forename: Bente Klarlund
authors.initials: BK
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000097:blood*; D006946:Hyperinsulinism / Q000097:blood*; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D007958:Leukocyte Count; D008297:Male; D012016:Reference Values; D044967:Serum / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha