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 histologic examination, the degree of insulitis in streptozotocin-treated NOD mice (at the age of 24 weeks) was not significantly different 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.