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Alterations in pancreatic islet function produced by carcinogenic nitrosamines in the Syrian hamster
1Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Canada.
Abstract:
Exposure of hamsters to 5 daily doses of 20 mg/kg N-nitrosobis(2-oxopropyl)amine (BOP) or 76 mg/kg N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), resulted in reduced insulin secretion in freshly isolated pancreatic islets. These treatments also reduced plasma insulin and glucose levels, and were hepatotoxic. The inhibition of insulin secretion, however, was transient. Islets isolated from treated hamsters that were then placed in culture secreted elevated levels of insulin for many months. When cultured islets were directly exposed to the nitrosamines for 3 days, there was also a transient reduction of insulin secretion that was subsequently normalized after removal of the nitrosamine from the medium. These results show that BOP and HPOP modify beta-cell function both directly, and possibly indirectly, via damage to the liver. Furthermore, the lack of immediate inhibition of insulin secretion when islets were incubated in the presence of BOP or HPOP as well as glucose, suggests that the nitrosamines do not bind to the glucose receptor.
Insights
N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) exposure temporarily impairs hamster insulin secretion and causes liver damage. However, pancreatic islet function recovers in culture, indicating a transient effect.
Area of Science:
- Toxicology
- Endocrinology
- Cell Biology
Background:
- N-nitrosobis(2-oxopropyl)amine) (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) are chemical compounds with known toxic effects.
- Pancreatic beta-cells are responsible for insulin secretion, a critical process in glucose homeostasis.
Purpose of the Study:
- To investigate the effects of BOP and HPOP exposure on pancreatic islet function and insulin secretion in hamsters.
- To determine if the observed effects on insulin secretion are transient or permanent.
- To explore the potential mechanisms underlying the impact of these nitrosamines on beta-cell function.
Main Methods:
- Hamsters were administered daily doses of BOP or HPOP.
- Insulin secretion was measured in freshly isolated pancreatic islets and in cultured islets.
- Plasma insulin and glucose levels were monitored.
- Hepatotoxicity was assessed.
- Direct exposure of cultured islets to nitrosamines was performed.
Main Results:
- BOP and HPOP treatments led to reduced insulin secretion in freshly isolated islets and lower plasma insulin and glucose levels.
- These treatments also caused hepatotoxicity.
- The inhibition of insulin secretion was transient; cultured islets showed normalized or elevated insulin secretion over time.
- Direct exposure of cultured islets to nitrosamines resulted in a temporary decrease in insulin secretion, which recovered after removal of the compounds.
- Nitrosamines did not immediately inhibit insulin secretion in the presence of glucose, suggesting they do not bind to the glucose receptor.
Conclusions:
- BOP and HPOP transiently impair pancreatic beta-cell function, affecting insulin secretion both directly and potentially indirectly through liver damage.
- The reversibility of insulin secretion inhibition in cultured islets suggests a dynamic interaction between nitrosamines and beta-cells.
- The findings indicate that the mechanism of action of these nitrosamines does not involve direct binding to the glucose receptor on beta-cells.