Molecular mechanisms of pancreatic beta-cell destruction in autoimmune diabetes: potential targets for preventive therapy.
Mononuclear cell infiltration into the islets of the pancreas (insulitis) is characteristic of autoimmune diabetes. T lymphocytes are the predominant subpopulation seen in insulitis, and are involved in the autoimmune process. Insulin-producing beta cells are thought to be destroyed by cytotoxic T cells, cytokines or nitric oxide, and beta-cell death occurs, at least partly, via apoptosis. Beta-cell death induced by cytokines is inhibited by Bcl-2, suggesting its potential as a tool for gene therapy. The Fas/Fas-ligand system plays a critical role in inducing insulitis and overt diabetes in nonobese diabetic (NOD) mice, a model of autoimmune diabetes. T-cell receptor gene usage in infiltrating T cells is not restricted in NOD mice, but there are some observations indicating relative restriction in human IDDM patients. Preventive strategies might be developed by focusing on these molecules involved in beta-cell destruction. The establishment of screening techniques for detecting prediabetic patients is also necessary to allow successful intervention.
Iwahashi
H
H
Second Department of Internal Medicine, Osaka University Medical School, Japan. iwahashi@imed2.med.osaka-u.ac.jp
Itoh
N
N
Yamagata
K
K
Imagawa
A
A
Nakajima
H
H
Tomita
K
K
Moriwaki
M
M
Waguri
M
M
Yamamoto
K
K
Miyagawa
J
J
Namba
M
M
Hanafusa
T
T
Matsuzawa
Y
Y
D000818:Animals; D015551:Autoimmunity; D016923:Cell Death; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000517:prevention & control; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D054353:Perforin