Young NOD mice show increased diabetes sensitivity to low doses of streptozotocin

In type 1 diabetes, environmentally induced early-limited beta cell damage may pre-empt the subsequent immune-mediated beta cell destruction. Low doses of streptozotocin (Stz), given early to diabetesprone mice, may cause limited beta cell destruction during the early phase and precipitate diabetes. Here, we aimed to see if young NOD mice are more diabetes-sensitive to various multiple low doses of Stz than nondiabetes-prone mice. We also determined the molecular pathology of islets following administration of the diabetogen. Female NOD and CD-1 mice received 5 daily doses of Stz at day 21 (20, 30, and 40 mg/kg body weight; 18 mice per group) or diluent, and diabetes was monitored. Pancreas were studied histochemically and immunohistochemically at various time points after Stz administration. Following administration of Stz, NOD mice showed a much earlier onset and increased diabetes rate, at all three doses, than CD-1 mice. By day 80, the final diabetes rates following the 40,30, and 20 mg dose in NOD mice were 95%, 85%, and 33%, respectively, compared with 33%, 28%, and 5.5%, respectively, in CD-1 mice. However, following the 20 mg dose, only 2 of the 12 remaining NOD mice developed the disease between 90 and 250 days compared with 19 of 24 NOD mice that did not receive Stz at day 21. Stz-administered NOD and CD-I mice showed an initial loss of beta cells, with redistribution of islet endocrine cells, early macrophage infiltration, and increasing insulitis.