title: The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown.
  
  
  OBJECTIVE
  The objective of the study was to determine whether the infusion of TNF-α at high physiological levels impairs GLP-1's effects on glucose metabolism.
  
  
  METHODS
  This was a randomized, controlled, cross-over trial.
  
  
  METHODS
  The study was conducted at a hospital clinical research laboratory.
  
  
  METHODS
  Twelve healthy males (aged 24 ± 3 y; body mass index 22.9 ± 1.3 kg/m(2)).
  
  
  METHODS
  After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m(2) · h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg · min) began. From t = 4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg · min. Plasma glucose was clamped at 5 mmol/L throughout via a variable rate 20% dextrose infusion. Trials were 7-14 days apart.
  
  
  METHODS
  Endogenous glucose production (EGP) was measured by the [6,6-(2)H2]glucose isotope tracer dilution method.
  
  
  RESULTS
  GLP-1 infusion suppressed plasma glucagon (P < .01), elevated plasma insulin, and C-peptide (P < .01) and suppressed EGP (P < .001) during the saline infusion. In contrast, the infusion of TNF-α increased plasma TNF-α and IL-6, elevated body temperature, and blunted the GLP-1-induced suppression of EGP during high-dose GLP-1 infusion (all P < .05, TNF-α vs saline). However, TNF-α infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P < .001).
  
  
  CONCLUSIONS
  TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.
authors: Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (Lo.L.-S., La.L.-S., S.T.N., K.M., T.P.J.S.), Department of Infectious Diseases, Rigshospitalet, Novo Nordisk Foundation Centre for Basic Metabolic Research and Department of Biomedical Sciences (J.J.H.), Faculty of Health Sciences, Neurointensive Care Unit (K.M.), Department of Neuroanesthesiology, Rigshospitalet, Faculty of Health Sciences, and Department of Biomedical Sciences (P.J.S.), Panum Institute, University of Copenhagen, Copenhagen 2200, Denmark.
authors: Louise
authors: L
authors: Lehrskov-Schmidt
authors: Lars
authors: L
authors: Lehrskov-Schmidt
authors: Signe T
authors: ST
authors: Nielsen
authors: Jens J
authors: JJ
authors: Holst
authors: Kirsten
authors: K
authors: Møller
authors: Thomas P J
authors: TP
authors: Solomon
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C508600:IL6 protein, human; C517652:hemoglobin A1c protein, human