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Methods to Assess Beta Cell Death Mediated by Cytotoxic T Lymphocytes
Published on: June 16, 2011
Assessment of antipsychotic-induced cytotoxic effects on isolated CD1 mouse pancreatic beta cells
Huda A Al Doghaither1, Ekramy Mahmoud Elmorsy2,3
1Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Objectives:
The study aims to assess apoptosis, oxidative stress, and inflammation as underlying diabetogenic mechanisms in isolated CD1 mouse beta-pancreatic cells of some prescribed Antipsychotics (APs).
Methods:
Three types of APs were tested in different concentrations (0.1, 1, 10, and 100 μM) on adult male CD1 mice. The cytotoxicity of the tested APs was determined using different assays including MTT and Lactate Dehydrogenase (LDH) assays. Oxidative stress was assessed by and measuring Reactive oxygen species (ROS) production, lipid peroxidation, and antioxidant enzyme activities. Moreover, the effect on the inflammatory cascade was also investigated.
Results:
The tested APs were cytotoxic to beta cells and showed patterns dependent on both concentration and exposure, with a parallel reduction in glucose-stimulated insulin secretion of the treated cells. The APs also showed induction of oxidative stress in the treated cells by significantly increasing the ROS, lipid peroxidation, and NRf2 gene expression, together with decreased antioxidant enzyme activities. Moreover, APs showed significant increases in cytokines levels to their estimated IC50 levels. The activities of caspases 3, 8, and 9 were also significantly increased in all treated samples at their IC50s and at 10 μM concentrations of all tested APs. However, the glutathione and inhibitors of caspase-3, IL-6, and TNF-α significantly improved GSIS and the viability of the AP-treated cells.
Conclusion:
The results suggest a significant role for apoptosis, oxidative stress, and inflammation, in the diabetogenic effect of APs, expected role of antioxidants and anti-inflammatory drugs as therapeutics for improving the outcome in cases of long-term prescribed APs.
Insights
Antipsychotics (APs) induce diabetes by causing beta-cell apoptosis, oxidative stress, and inflammation. Antioxidants and anti-inflammatory drugs may mitigate these diabetogenic effects in patients on long-term AP treatment.
Area of Science:
- Endocrinology
- Pharmacology
- Cell Biology
Background:
- Antipsychotics (APs) are widely prescribed but can induce diabetes.
- The underlying mechanisms of AP-induced diabetes are not fully understood.
- Beta-pancreatic cells are crucial for glucose homeostasis and are potential targets of AP toxicity.
Purpose of the Study:
- To investigate apoptosis, oxidative stress, and inflammation as mechanisms of AP-induced diabetogenesis.
- To assess the effects of different AP concentrations on beta-pancreatic cell function.
- To explore potential therapeutic interventions for AP-induced diabetes.
Main Methods:
- Primary beta-pancreatic cells from adult male CD1 mice were exposed to three APs at varying concentrations (0.1–100 μM).
- Cytotoxicity was evaluated using MTT and lactate dehydrogenase assays.
- Oxidative stress markers (ROS, lipid peroxidation, antioxidant enzymes) and inflammatory markers (cytokines) were measured.
- Caspase activities and glucose-stimulated insulin secretion (GSIS) were assessed.
Main Results:
- APs demonstrated dose-dependent cytotoxicity to beta cells, reducing GSIS.
- Significant induction of oxidative stress was observed, with increased ROS and lipid peroxidation, and decreased antioxidant enzyme activity.
- Inflammatory markers, including cytokines IL-6 and TNF-α, were elevated.
- Caspase 3, 8, and 9 activities increased, indicating apoptosis.
- Glutathione and caspase-3, IL-6, and TNF-α inhibitors improved cell viability and GSIS.
Conclusions:
- Apoptosis, oxidative stress, and inflammation are key mechanisms contributing to the diabetogenic effects of APs.
- Antioxidant and anti-inflammatory strategies show promise for managing AP-induced diabetes.
- These findings support the use of adjunct therapies to mitigate long-term risks associated with AP prescriptions.
