Mouse islets {not used for respiration), kidneys and liver were studied in early and manifest alloxan diabetes, and in genetic diabetes. In these organs the mito~hondrial aconitase activity was lower, state 3 respiration with citrate or pyruvate plus malate (but not with succinate) was decreased, and the concentration of citrate was increased, compared with non-diabetic control mice. The alterations suggest a role of lowered activity of mitochondrial aconitase in alloxan diabetes, and probably also in genetic diabetes.
Aconitase
Considerable variations were found in the in vitro effect of alloxan on mouse liver enzymes associated with the citric acid cycle. The following approximative alloxan concentrations induced 50% inhibition of enzyme activity: 10m6 M for aconitase, lo-' M for NAD-linked isocitrate dehydrogenase, glutamate dehydrogenase, a-ketoglutarate dehydrogenase, succinyl-CoA synthetase and fumarase, and 10m3 M for citrate synthase and NADP-linked isocitrate dehydrogenase. Pyruvate dehydrogenase, succinate dehydrogenase and malate dehydrogenase were not inhibited by 10m3 M alloxan. The inhibition of aconitase was competitive both when using mouse liver and purified porcine heart enzyme. The K, values for the purified enzyme in the presence of 5 PM alloxan were 0.22 PM with citrate, 4.0 PM with cis-aconitate and 0.62 PM with isocitrate as substrate. The high sensitivity of aconitase for inhibition by alloxan probably plays a prominent role for the toxic effects of alloxan.
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.
The activity of succinyl‐CoA synthetase from mouse liver and kidney was inhibited by streptozotocin in vitro. Streptozotocin behaved essentially as a non‐competitive inhibitor, and the following kinetic values were obtained (in the presence of 10 nM streptozotocin): apparent K
m 1.7 mM, apparent K
i 10 nM, and k
cat 440 nkat·kg−1. Compared with non‐diabetic control mice, the succinyl‐CoA synthetase activity was significantly decreased in the islets and kidneys of mice with early (1 h) and manifest (≧ 2 days) streptozotocin diabetes, whereas the activity in the liver was not significantly altered. Inhibited succinyl‐CoA synthetase activity is believed to play a prominent role in the cellular effects of streptozotocin.
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