Diabetes-prone biobreeding (BB) rats often develop lymphocytic thyroiditis. Intraperitoneal administration of silica to young BB rats (40-days-old) nearly completely prevented the development of lymphocytic thyroiditis as well as insulitis. Since silica is known to be toxic to macrophages, these data suggest that the presentation of autoantigen(s) on the specific target cells such as thyroid and pancreatic B cells by antigen-presenting cells (e.g., macrophages) would be the initial step in the development of organ-specific autoimmune diseases in diabetes-prone BB rats.
In NOD mice, 50-70% of females and 10-20% of males develop diabetes, although almost all the animals show insulitis. To see if environmental insults could induce diabetes in subjects with pre-clinical anti-Beta cell autoimmunity, non-diabetic NOD mice were selected and injected with a sub-diabetogenic dose of streptozotocin at 6 or 20 weeks of age. The streptozotocin failed to induce diabetes in 16 male and 16 female NOD mice within 4 weeks when they were injected at the age of 6 weeks. In contrast, 6 of 16 male and 10 of 16 female NOD mice developed diabetes within 4 weeks when they were injected at the age of 20 weeks. In untreated age-matched control NOD mice, none of the male and only 2 of 16 female mice became diabetic during the same 4 week period. On histotogic examination, the degree of insulitis in streptozotocin-treated NOD mice (at the age of 24 weeks) was not significantly dif-ferent from that of untreated control NOD mice. However, the streptozotocin-treated animals showed significantly lower pancreatic insulin content than the control mice. These results show that an anti-Beta cell autoimmune process in NOD mice has a predisposing effect on the induction of diabetes by a sub-diabetogenic dose of streptozotocin, and suggest that the precipitation of clinical diabetes by some environmental insults in subjects with pre-existing pre-clinical autoimmune Beta-cell destruction may be one mechanism of disease presentation in human Type 1 (insulin-dependent) diabetes.
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