title: Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans.
abstract: Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU.min(-1).kg(-1)), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.
authors.affiliation: Rigshospitalet, Section 7641, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. krogh-madsen@inflammation-metabolism.dk
authors.forename: Rikke
authors.initials: R
authors.lastname: Krogh-Madsen
authors.forename: Peter
authors.initials: P
authors.lastname: Plomgaard
authors.forename: Kirsten
authors.initials: K
authors.lastname: Møller
authors.forename: Bettina
authors.initials: B
authors.lastname: Mittendorfer
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D001707:Biopsy, Needle; D001786:Blood Glucose / Q000378:metabolism; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D015309:Glucose Clamp Technique; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020382:Interleukin-18; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1; D006854:Hydrocortisone