Early manifestations in multiple-low-dose streptozotocin-induced diabetes in mice

Objective: Administration of multiple low doses of streptozotocin (mld-SZ) to mice results in the development of autoimmune diabetes. Hyperglycemia does not develop until a few days after the last injection. In this study, we explored immune-related alterations found in the very early stages of this diabetic syndrome and the capacity of mononuclear spleen cells (MSs) from mld-SZ mice to impair insulin secretion. Methods: Mice injected with mld-SZ were used as an animal model of type 1 diabetes. MSs were isolated from control and mld-SZ mice at days 4, 6, 9, 12, and 16 after the first injection of the diabetogenic drug. MSs were transferred to normal syngeneic recipients or were cocultured with dispersed rat islet cells as an in vitro insulin secretion study. Results: MSs from mld-SZ mice were able to diminish insulin secretion when transferred to normal syngeneic recipients and presented anti-beta-cell immune aggression when cocultured with dispersed rat islet cells as early as day 4 after mld-SZ administration. This capacity persisted throughout the experimental period. As early as 6 days after mld-SZ, islets showed insulitis followed by cell death with progressive severity. Hyperglycemia and diminished insulin secretion from perifused pancreatic islets only appeared at day 9 after mld-SZ. Conclusions: This study suggests that transferred or cocultured MSs from mld-SZ mice exert a functional immune aggression against beta cells at a very early stage, before donor mice develop impaired insulin secretion and hyperglycemia.