Alloxan derivatives as a tool for the elucidation of the mechanism of the diabetogenic action of alloxan

Lenzen, Sigurd; Tiedge, Markus; Jörns, Anne; Munday, Rex

doi:10.1007/978-1-4612-4112-6_8

Cited by 41 publications

(38 citation statements)

References 13 publications

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“…In 1838, Wöhler and Liebig [1] synthesised a pyrimidine derivative, which they later called alloxan [2,3]. In 1943, alloxan became of interest in diabetes research when Dunn and McLetchie reported that it could induce diabetes in animals [4] as a result of the specific necrosis of the pancreatic beta cells [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent 'alloxan diabetes'. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.

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Section: Introductionmentioning

confidence: 99%

“…Again, this insulinopenia syndrome, called 'streptozotocin diabetes' [13], is caused by the specific necrosis of the pancreatic beta cells and streptozotocin has been the agent of choice for the induction of diabetes mellitus in animals ever since [3,16].…”

Section: Introductionmentioning

confidence: 99%

The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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“…9 Kidney/tubular necrosis due to the toxic effects of the higher doses of aldrugloxan has been suggestive as a cause of animal loss. 10 It has been reported that alloxan rapidly and selectively accumulated in the pancreatic beta cells. 11,12 and induced DNA strand breaks in isolated rat pancreatic islets.…”

Section: Introductionmentioning

confidence: 99%

Evaluation and Optimization of Effective-dose of Alloxan for Inducing Type-2 Diabetes Mellitus in Long Evans Rat

Rahman¹,

Yasmin²,

Rahman³

et al. 2017

IJPER

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Background:The optimal effective and safe dose of alloxan for inducing stable diabetes in rats has been long arguable. Lower doses can result in auto-reversion from diabetogenic state to normal state. On the other hand, higher doses cause toxicity and loss of experimental animals since it completely destroys the insulin-producing pancreatic β cells. Therefore, determination of effective as well as safe dose of alloxan to induce stable diabetes in experimental Long Evan rats is crucial for investigating on diabetes. Objective: To determine effective and safe dose of alloxan for inducing a stable diabetes mellitus in Long Evans Rats to facilitate availability of diabetic rats for studying on diabetes. Methods: Healthy adult Long Evans rats (80-156 g) were divided into eight groups and each group contains six rats. One group treated as a nondiabetic control (C) while the other seven groups (Group-2 to Group-8) were used as experimental diabetic groups. Different doses of alloxan (80, 100, 120, 130, 140, 150 and 160 mg/kg body weight) were injected through intraperitoneal routes in overnight fasting group-2 to group-8 rats respectively. Blood glucose levels were monitored before and after administering alloaxan dose (for 7 consecutive weeks) by using a blood glucose meter and test strips. Results: In the case of non-diabetic rats, the normal blood glucose levels were found between 7.75 to 10.8 mmol/L. On the other hand, a slow gradual increment of blood glucose levels were measured among the rats (group-2, group-3 and group-4) treated with low doses of alloxan (80, 100 and 120 mg/kg BW) until 5 weeks. However, the increased blood glucose levels were reverted back to its normal by the following two weeks. Group-5 and Group-6 rats treated with alloxan doses of 130 mg/kg and 140 mg/kg respectively stably increased blood glucose levels during the experimental periods. While rats in group-7 and group-8 (treated with 150 and 160 mg/kg BW) were expired by the experimental period might be due to severe alloxan toxicity. Group-6 rats treated with 140 mg/kg alloxan were more preferable because the diabetic level is much more stable and significant than group-5. Conclusion: The optimum effective dose of alloxan was found to be 140 mg/kg BW for induction of stable diabetes in Long Evan rats.

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“…In addition since STZ is an NO donor it also acts as a producer of reactive oxygen species (ROS) [26,27]. At high doses the diabetogenic potential of STZ is explained by its capacity to selectively destroy insulin-producing beta cells [28]. At variance, at low dose STZ induces minor damage to beta cell that, however, promotes a secondary T-cell-mediated autoimmune response ultimately leading to overt IDDM [29].…”

Section: Introductionmentioning

confidence: 99%