Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis

Endocrinology. 2004 Nov;145(11):5305-12. doi: 10.1210/en.2004-0392. Epub 2004 Aug 12.


The pathogenesis of diabetes associated with hemochromatosis is not known. We therefore examined glucose homeostasis and beta-cell function in mouse models of hemochromatosis. Mice with targeted deletion of the hemochromatosis gene (Hfe(-/-)) on the 129/Sv genetic background exhibited a 72% increase in iron content in the islets of Langerhans compared with wild-type controls. Insulin content was decreased in Hfe(-/-) mice by 35%/pancreas and 25%/islet. Comparable decreases were seen in the mRNA levels of beta-cell-specific markers, ins1, ins2, and glucose transporter 2. By 6-8 months, islets from Hfe(-/-) mice were 45% smaller, associated with increased staining for activated caspase 3 and terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling. Islets from Hfe(-/-) mice were also desensitized to glucose, with half-maximal stimulation of insulin secretion seen at 16.7 +/- 0.9 mm glucose in perifused islets from Hfe(-/-) mice compared with 13.1 +/- 0.6 mm glucose in wild-type animals. Carbonyl protein modification, a marker for oxidative stress, was increased by 58% in Hfe(-/-) islets. Despite decreased islet size, Hfe(-/-) mice exhibited enhanced glucose tolerance. Fasting serum insulin levels were comparable between Hfe(-/-) and Hfe(+/+) mice, but were 48% lower in the Hfe(-/-) mice 30 min after challenge. Similar results were seen in mice carrying an Hfe mutation analogous to the common human mutation (C282Y) and in mice fed excess dietary iron. Hfe(-/-)mice on the C57BL6 background exhibited decreased glucose tolerance at 10-12 months due to an inability to increase insulin levels as they aged. We conclude that iron excess results in beta-cell oxidant stress and decreased insulin secretory capacity secondary to beta-cell apoptosis and desensitization of glucose-induced insulin secretion. This abnormality alone, however, is insufficient to cause diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Apoptosis / physiology*
  • Disease Models, Animal
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / physiopathology
  • Hemochromatosis / metabolism*
  • Hemochromatosis / physiopathology
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Iron / metabolism
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / metabolism*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidation-Reduction
  • Oxidative Stress / physiology


  • Hemochromatosis Protein
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Insulin
  • Membrane Proteins
  • Iron