Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress

Circulation. 2002 Oct 15;106(16):2067-72. doi: 10.1161/


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.

Methods and 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.

MeSH terms

  • Adult
  • Antioxidants / pharmacology
  • Blood Glucose / analysis*
  • Cytokines / blood*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / immunology*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Glucose Intolerance / blood
  • Glucose Intolerance / immunology*
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test
  • Glutathione / pharmacology
  • Humans
  • Inflammation / blood
  • Interleukin-18 / blood
  • Interleukin-6 / blood
  • Kinetics
  • Male
  • Oxidative Stress*
  • Tumor Necrosis Factor-alpha


  • Antioxidants
  • Blood Glucose
  • Cytokines
  • Interleukin-18
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Glutathione