Alloxan: history and mechanism of action

Lenzen, Sigurd; Panten, U.

doi:10.1007/bf02341500

Cited by 207 publications

(139 citation statements)

References 71 publications

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“…Alloxan and streptozotocin cause a selective destruction of insulin-producing cells by overproduction of reactive oxygen and nitrogen intermediates [51,52,63]. Up to now there are no data on their influence on peroxiredoxin expression.…”

Section: Discussionmentioning

confidence: 99%

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

et al. 2002

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Aims/hypothesis. Insulin-producing beta cells are destroyed by oxidative and nitrosative stress during the pathogenesis of Type I (insulin-dependent) diabetes mellitus. These cells are more sensitive than others due to their deficiency of well known antioxidant enzymes like superoxide dismutase, glutathione peroxidase and catalase. However the peroxiredoxins discovered in the past decade form a large family of highly conserved thioredoxin-dependent peroxide reductases, which are present in most tissues. We investigated whether peroxiredoxins I and II are present in pancreatic beta cells and if they are inducible by oxidative and nitrosative stress. Methods. To detect these enzymes in insulin-producing beta cells we used semiquantitative RT-PCR, western blots and immunohistochemistry. The expression of peroxiredoxins I and II was analysed after treatment with cytokines, hydrogen peroxide, alloxan or streptozotocin in the rat insulinoma cells INS-1 using RT-PCR and western blots. Results. We show that peroxiredoxins I and II are present in the cytoplasm of pancreatic islet cells as well as in insulinoma cell lines βTC6-F7 and INS-1. Peroxiredoxins I and II were up-regulated by all stress agents used. Conclusion/interpretation. Beta cells, undersupplied with well characterized antioxidant enzymes, possess an additional antioxidant system which is inducible by oxidative as well as nitrosative stress. [Diabetologia (2002) 45:867-876]

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Section: Discussionmentioning

confidence: 99%

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

et al. 2002

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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%

“…After decades of research a unifying explanation for the selective toxicity of these two most prominent diabetogenic agents [2,[17][18][19][20][21][22] can be provided. Since an understanding of the chemical reactivity of these compounds is crucial for understanding their diabetogenicity, this review will provide an integrated view of their chemical properties and biological effects.…”

Section: Introductionmentioning

confidence: 99%

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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“…This is usually achieved with beta cell toxic agents, such as streptozotocin or alloxan [13,14]. However, streptozotocin and alloxan are not neutral with regards to their effects on the immune system and have been reported to have deleterious effects on host immunity [15].…”

Section: Introductionmentioning

confidence: 99%

“…However, streptozotocin and alloxan are not neutral with regards to their effects on the immune system and have been reported to have deleterious effects on host immunity [15]. These agents also have detrimental effects on multiple other organs, including the kidney, the preferred site for islet and beta stem and progenitor cell transplantation [14,16,17]. Moreover, streptozotocin is highly genotoxic, leading to the production of DNA strand breaks.…”

Section: Introductionmentioning

confidence: 99%

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

et al. 2008

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Aims/hypothesis To develop and validate a new immunodeficient mouse strain that spontaneously develops a nonautoimmune hyperglycaemia to serve as a diabetic host for human islets and human beta stem and progenitor cells without the need for induction of hyperglycaemia by toxic chemicals with their associated side effects. Methods We generated and characterised a new strain of immunodeficient spontaneously hyperglycaemic mice, the NOD-Rag1 null Prf1 null Ins2 Akita strain and compared this strain with the NOD-scid Il2rγ null (also known as Il2rg) immunodeficient strain rendered hyperglycaemic by administration of a single dose of streptozotocin. Hyperglycaemic mice were transplanted with human islets ranging from 1,000 to 4,000 islet equivalents (IEQ) and were monitored for normalisation of blood glucose levels. Results NOD-Rag1 null Prf1 null Ins2 Akita mice developed spontaneous hyperglycaemia, similar to Ins2 Akita -harbouring strains of immunocompetent mice. Histological examination of islets in the host pancreas validated the spontaneous loss of beta cell mass in the absence of mononuclear cell infiltration. Human islets transplanted into spontaneously diabetic NOD-Rag1 null Prf1 null Ins2 Akita and chemically diabetic NOD-scid Il2rγ null mice resulted in a return to euglycaemia that occurred with transplantation of similar beta cell masses. Conclusions/interpretation The NOD-Rag1 null Prf1 null Ins2 Akita mouse is the first immunodeficient, spontaneously hyperglycaemic mouse strain described that is based on the Ins2 Akita mutation. This strain is suitable as hosts for human islet and human beta stem and progenitor cell transplantation in the absence of the need for pharmacological induction of diabetes. This strain of mice also has low levels of innate immunity and can be engrafted with a human immune system for the study of human islet allograft rejection.

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Alloxan: history and mechanism of action

Cited by 207 publications

References 71 publications

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

The mechanisms of alloxan- and streptozotocin-induced diabetes

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

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