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Structural beta-cell changes and transient hyperglycemia in mice treated with compounds inducing inhibited citric
L Boquist1, S Boquist, I Ericsson
1Institute of Pathology, University of Umeå, Sweden.
Abstract:
An initial transient hyperglycemia was seen in mice injected with asparagine, fluoroacetate, hydroxylamine, or malonate plus methionine, whereas an initial triphasic blood glucose response and a transient "secondary" hyperglycemia were exhibited in those injected with hydroxylamine plus arsenite, and a delayed hypoglycemia was observed in those treated with fluoroacetate or arsenite. The glucose-induced insulin secretion was significantly decreased in isolated pancreatic islets incubated with hydroxylamine plus arsenite. Light and electron microscopy, pyroantimonate technique, and X-ray microanalysis disclosed mitochondrial damage, degeneration, and necrosis among the beta-cells in the islets of mice injected with hydroxylamine plus arsenite. Glycogen depletion and microvesicular fatty change were seen in the liver of mice treated with fluoroacetate, arsenite, or hydroxylamine plus arsenite. These observations support the view that inhibition of the activity of citric acid cycle enzymes and associated reactions in the beta-cells play a role in the induction of diabetic features.
Insights
Certain chemical exposures in mice caused significant blood glucose fluctuations and impaired insulin secretion. These effects were linked to mitochondrial damage in pancreatic beta-cells and liver changes, suggesting a role for citric acid cycle inhibition in diabetes.
Area of Science:
- Biochemistry
- Toxicology
- Endocrinology
Background:
- Metabolic disturbances, including hyperglycemia and hypoglycemia, can arise from various chemical exposures.
- Pancreatic beta-cells are crucial for glucose homeostasis, and their dysfunction can lead to diabetes.
- The citric acid cycle is a central metabolic pathway essential for cellular energy production.
Purpose of the Study:
- To investigate the effects of specific chemical agents on glucose metabolism and pancreatic beta-cell function in mice.
- To elucidate the cellular mechanisms underlying chemically induced diabetic features.
Main Methods:
- Administration of various chemicals (e.g., asparagine, fluoroacetate, hydroxylamine, malonate, methionine, arsenite) to mice.
- Monitoring of blood glucose levels and insulin secretion.
- Histopathological examination of pancreatic islets and liver using light and electron microscopy, pyroantimonate technique, and X-ray microanalysis.
Main Results:
- Transient hyperglycemia was observed with several agents; hydroxylamine plus arsenite induced a triphasic response and secondary hyperglycemia.
- Fluoroacetate or arsenite caused delayed hypoglycemia.
- Hydroxylamine plus arsenite significantly decreased glucose-induced insulin secretion and induced mitochondrial damage, degeneration, and necrosis in pancreatic beta-cells.
- Fluoroacetate, arsenite, or hydroxylamine plus arsenite led to glycogen depletion and microvesicular fatty change in the liver.
Conclusions:
- Inhibition of citric acid cycle enzyme activity in pancreatic beta-cells contributes to the development of diabetic features.
- Chemical-induced mitochondrial damage in beta-cells and liver alterations are key pathological events.
- These findings provide insights into the mechanisms of chemically induced diabetes.