title: Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown.
  
  
  METHODS
  We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated.
  
  
  RESULTS
  TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged.
  
  
  CONCLUSIONS
  In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect.
authors.affiliation: Centre of Inflammation and Metabolism and CMRC, Section 7641 Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Signe Tellerup
authors.initials: ST
authors.lastname: Nielsen
authors.forename: Louise
authors.initials: L
authors.lastname: Lehrskov-Schmidt
authors.forename: Rikke
authors.initials: R
authors.lastname: Krogh-Madsen
authors.forename: Thomas P J
authors.initials: TP
authors.lastname: Solomon
authors.forename: Lars
authors.initials: L
authors.lastname: Lehrskov-Schmidt
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.forename: Kirsten
authors.initials: K
authors.lastname: Møller
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D016207:Cytokines / Q000097:blood; D005951:Glucose Tolerance Test; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D054795:Incretins / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D016207:Cytokines; D054795:Incretins; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D006854:Hydrocortisone
keywords: glucose; incretins; insulin resistance; systemic inflammation; tumour necrosis factor-alpha