Human pancreatic islet beta-cell destruction by cytokines involves oxygen free radicals and aldehyde production

J Clin Endocrinol Metab. 1996 Sep;81(9):3197-202. doi: 10.1210/jcem.81.9.8784069.


Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokine-induced islet beta-cell destruction may be mediated by reactive oxygen intermediates. To determine the possible roles of oxygen free radicals and nitric oxide (NO) as mediators of islet beta-cell destruction, we studied the relationships among cytokine-induced beta-cell destruction, production of malondialdehyde (MDA; an end product of lipid peroxidation), and production of nitrite (the stable end product of NO). The cytokine combination of interleukin-1 beta (50 U/mL), tumor necrosis factor-alpha (10(3) U/mL), and interferon-gamma (10(3) U/mL) induced significant increases in MDA and nitrite and significant decreases in insulin and DNA in islets after 60-h incubation. A novel antioxidant (lazaroid U78518E) significantly inhibited both a strong oxidant. t-butylhydroperoxide, and the combination of cytokines from inducing MDA production, but not from increasing nitrite production in the islets. Also, the lazaroid antioxidant significantly reversed the cytokine-induced decreases in insulin and DNA contents of the islet cultures. In contrast, L-NG-monomethyl arginine, an inhibitor of NO synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in MDA and decreases in insulin and DNA in the islet cultures. In addition, the addition of MDA to the islets produced a dose-dependent decrease in their insulin and DNA contents, and this was only partially prevented by the lazaroid antioxidant. These results suggest that cytokines may be toxic to human islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and aldehyde production in the islets, and that MDA is one of the cytotoxic mediators of cytokine-induced beta-cell destruction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism*
  • Antioxidants / pharmacology
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Autoimmune Diseases / immunology*
  • Cytokines / immunology*
  • DNA / metabolism
  • Diabetes Mellitus, Type 1 / immunology*
  • Enzyme Inhibitors / pharmacology
  • Ethylamines / pharmacology
  • Free Radicals
  • Humans
  • Insulin / metabolism
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / immunology*
  • Malondialdehyde / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • omega-N-Methylarginine


  • Aldehydes
  • Antioxidants
  • Cytokines
  • Enzyme Inhibitors
  • Ethylamines
  • Free Radicals
  • Insulin
  • Interleukin-1
  • Piperazines
  • Pyridines
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • U 78518F
  • omega-N-Methylarginine
  • Nitric Oxide
  • Malondialdehyde
  • Interferon-gamma
  • DNA
  • Arginine
  • Nitric Oxide Synthase