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 diabetes-prone 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 non-diabetes-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-1 mice showed an initial loss of beta cells, with redistribution of islet endocrine cells, early macrophage infiltration, and increasing insulitis.
Reddy
Shiva
S
School of Biological Sciences, University of Auckland, Auckland, New Zealand. s.reddy@auckland.ac.nz
Chang
Mike
M
Robinson
Elizabeth
E
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006651:Histocytochemistry; D007150:Immunohistochemistry; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
D007328:Insulin; D013311:Streptozocin; D005934:Glucagon