Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis.
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.
Cooksey
Robert C
RC
Division of Endocrinology, University of Utah School of Medicine, 30 North 2030 East, Salt Lake City, Utah 84132. donald.mcclain@hsc.utah.edu.
Jouihan
Hani A
HA
Ajioka
Richard S
RS
Hazel
Mark W
MW
Jones
Deborah L
DL
Kushner
James P
JP
McClain
Donald A
DA
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D006432:Hemochromatosis / Q000378:metabolism* / Q000503:physiopathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007501:Iron / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology
D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D008565:Membrane Proteins; D007501:Iron