title: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress.
abstract: BACKGROUND
  Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-alpha, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione.
  
  
  RESULTS
  Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-alpha, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-alpha levels higher (P<0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P<0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P<0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses.
  
  
  CONCLUSIONS
  Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.
authors.affiliation: Department of Geriatric and Metabolic Diseases, Second University of Naples, Italy.
authors.forename: Katherine
authors.initials: K
authors.lastname: Esposito
authors.forename: Francesco
authors.initials: F
authors.lastname: Nappo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Marfella
authors.forename: Giovanni
authors.initials: G
authors.lastname: Giugliano
authors.forename: Francesco
authors.initials: F
authors.lastname: Giugliano
authors.forename: Myriam
authors.initials: M
authors.lastname: Ciotola
authors.forename: Lisa
authors.initials: L
authors.lastname: Quagliaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Ceriello
authors.forename: Dario
authors.initials: D
authors.lastname: Giugliano
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis*; D016207:Cytokines / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D005951:Glucose Tolerance Test; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008297:Male; D018384:Oxidative Stress; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D016207:Cytokines; D020382:Interleukin-18; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione