The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas.

By T. Szkudelski. Physiological Research, 2001

3,470 citations recorded by the source corpus.

Alloxan and streptozotocin are widely used to induce experimental diabetes in animals. The mechanism of their action in B cells of the pancreas has been intensively investigated and now is quite well understood. The cytotoxic action of both these diabetogenic agents is mediated by reactive oxygen species, however, the source of their generation is different in the case of alloxan and streptozotocin. Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals. These radicals undergo dismutation to hydrogen peroxide. Thereafter highly reactive hydroxyl radicals are formed by the Fenton reaction. The action of reactive oxygen species with a simultaneous massive increase in cytosolic calcium concentration causes rapid destruction of B cells. Streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA. DNA damage induces activation of poly ADP-ribosylation, a process that is more important for the diabetogenicity of streptozotocin than DNA damage itself. Poly ADP-ribosylation leads to depletion of cellular NAD+ and ATP. Enhanced ATP dephosphorylation after streptozotocin treatment supplies a substrate for xanthine oxidase resulting in the formation of superoxide radicals. Consequently, hydrogen peroxide and hydroxyl radicals are also generated. Furthermore, streptozotocin liberates toxic amounts of nitric oxide that inhibits aconitase activity and participates in DNA damage. As a result of the streptozotocin action, B cells undergo the destruction by necrosis.

Subfields: Cell Biology, Endocrinology, Diabetes and Metabolism, Surgery

View Paper: https://www.semanticscholar.org/paper/6e3290d931b7156d9a352f97ea168246e5ec0eed

How researchers see this paper

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In Cell Biology

1. Ming Zhang
2. A. King
3. Zhi-Gang Xu
4. Li Chen
5. Jing Li
6. Xiaodan Lv
7. S. Lenzen

In Endocrinology, Diabetes and Metabolism

1. Ming Zhang
2. A. King
3. Zhi-Gang Xu
4. Li Chen
5. Jing Li
6. Xiaodan Lv
7. S. Lenzen

In Surgery

1. Ming Zhang
2. A. King
3. Zhi-Gang Xu
4. Li Chen
5. Jing Li
6. Xiaodan Lv
7. S. Lenzen

Citations in the corpus

• The mechanisms of alloxan- and streptozotocin-induced diabetes (2008, background): “After decades of research a unifying explanation for the selective toxicity of these two most prominent diabetogenic agents [2, 17–22] can be provided.”
• The Characterization of High-Fat Diet and Multiple Low-Dose Streptozotocin Induced Type 2 Diabetes Rat Model (2009, positive): “At the same time, streptozotocin (STZ) is widely used to reproducibly induce both insulin-dependent and noninsulindependent diabetes mellitus presently by inducing β cell death through alkylation of DNA [8].”
• Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. (2003, background): “Chemicals with antioxidant properties and free radical scavengers in particular prevent autopoly (ADP-ribosyl)-ation of PARP and by stabilizing Reg gene transcriptional complex, result in the regeneration of b-cells and protect pancreatic islets against cytotoxic effects of STZ or alloxan (Szkudelsk”
• The use of animal models in diabetes research (2012, background): “Alloxan is reduced to dialuric acid and then re-oxidized back to alloxan, creating a redox cycle for the generation of superoxide radicals that undergo dismutation to form hydrogen peroxide and thereafter highly reactive hydroxyl radicals that cause fragmentation of beta cell DNA (Szkudelski, 2001).”