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Published on: November 29, 2024
Early manifestations in multiple-low-dose streptozotocin-induced diabetes in mice
Liliana M Karabatas1, Claudia Pastorale, Lidia Fabiano de Bruno
1Centro de Investigaciones Endocrinológicas, CONICET, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
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.
Insights
Mononuclear spleen cells from mice treated with multiple low doses of streptozotocin (mld-SZ) show early immune aggression against beta cells. This immune attack occurs before the onset of hyperglycemia or impaired insulin secretion in type 1 diabetes models.
Area of Science:
- Immunology
- Endocrinology
- Diabetes Research
Background:
- Autoimmune diabetes development in mice involves multiple low doses of streptozotocin (mld-SZ).
- Hyperglycemia typically manifests days after the final mld-SZ injection.
- Early immune alterations preceding hyperglycemia are not well understood.
Purpose of the Study:
- To investigate early immune changes in mld-SZ-induced autoimmune diabetes.
- To assess the capacity of mononuclear spleen cells (MSs) from mld-SZ mice to affect insulin secretion.
Main Methods:
- Mice were administered mld-SZ to model type 1 diabetes.
- MSs were isolated at various time points post-mld-SZ injection.
- MSs were transferred to recipients or co-cultured with rat islet cells for functional assays.
Main Results:
- MSs from mld-SZ mice exhibited anti-beta-cell immune aggression as early as day 4.
- This immune aggression led to diminished insulin secretion upon transfer or co-culture.
- Insulitis and beta-cell death were observed by day 6, preceding hyperglycemia (day 9).
Conclusions:
- MSs from mld-SZ mice exert functional immune aggression against beta cells early in the disease process.
- Immune attack on beta cells precedes detectable hyperglycemia and impaired insulin secretion.
- This highlights early immune mechanisms in the pathogenesis of autoimmune diabetes.
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