Streptozotocin, but not alloxan, induces DNA repair synthesis in mouse pancreatic islets in vitro

Sandler, Stellan; Swenne, Ingemar

doi:10.1007/bf00282526

Cited by 75 publications

(39 citation statements)

References 25 publications

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“…In the attempt to repair DNA, poly(ADP-ribose) polymerase (PARP) is overstimulated. This diminishes cellular NAD + , and subsequently ATP, stores [82,[85][86][87]. The depletion of the cellular energy stores ultimately results in beta cell necrosis.…”

Section: Beta Cell Toxicity Of Streptozotocinmentioning

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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Section: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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“…In pancreatic islets the activity of this enzyme increases upon exposure to streptozotocin, leading to cytotoxic cellular NAD depletion [5,6] coupled to increased DNA repair synthesis [7,8]. The B-cytotoxic effects of streptozotocin can be counteracted by inhibitors of poly(ADP-ribose) synthetase such as nicotinamide and 3-aminobenzamide [5,6,9,10].…”

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confidence: 99%

Long-term effects of exposure of pancreatic islets to nicotinamide in vitro on DNA synthesis, metabolism and B-cell function

Sandler

Andersson

1986

Diabetologia

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Using 3H-thymidine labeling techniques, we found that rates of DNA synthesis in islet cells doubled when mouse pancreatic islets were cultured for 1 week with 10 mmol/l nicotinamide, a potent poly(ADP-ribose) synthetase inhibitor. Culture with nicotinamide partially inhibited glucose-stimulated insulin release, whereas the islet insulin content and rate of (pro)insulin biosynthesis remained unchanged. Long-term exposure to nicotinamide decreased glucose oxidation and ATP content in the islets. The findings support the view that poly(ADP-ribose)synthetase inhibitors stimulate islet cell replication, but may be accompanied by significant inhibitory effects on islet cell function.

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“…peróxido de hidrógeno y aniones superóxidos). Sandler y Swenne (1983), describieron que el daño sobre el ADN inducido por la STZ activa mecanismos de reparación (29), como PARP (poli ADP-ribosa polimerasa) (30). Esta enzima cataliza la ADP-ribosilación usando NAD+ como sustrato.…”

Section: Discussionunclassified

Obtención De Un Modelo Múrido De Diabetes Inducida Por Estreptozotocina Útil en La Evaluación Farmacodinámica De La Insulina Regular

Valencia

Zuluaga²,

Jaramillo³

et al. 2017

Vitae

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RESUMENAntecedentes: Existen múltiples modelos animales de diabetes, pero todavía no se ha validado uno útil para determinar la farmacodinamia de medicamentos. Objetivos. Usar el modelo de inducción de diabetes mediante estreptozotocina equilibrada en ratones no emparentados, para determinar de forma precisa y reproducible la farmacodinamia de insulina regular. Métodos. En ratones machos no emparentados de aproximadamente 37 g, se inyectó una dosis intraperitoneal de 150 mg/kg de una solución equilibrada de estreptozotocina. La glucemia (mg/dL) se midió a los 0, 7, 9, 14, 16, 17 y 18 días post-inducción. Una vez los ratones alcanzaron glucemias >300 mg/dL, se determinó la eficacia hipoglucemiante de insulina regular en tres experimentos independientes. El rango de dosis fue 0,25 UI/kg a 4 UI/kg. Una ecuación de decaimiento exponencial de dos parámetros se ajustó a los datos. Resultados. Al día 18, el modelo tuvo una efectividad del 80% para producir diabetes (glucemia 446 ± 59 mg/dL), con mortalidad de sólo 2%. El coeficiente de variación intra e interexperimento fue ≤13%. Los parámetros farmacodinámicos de insulina fueron indistinguibles después de tres experimentos (P=0,32). La magnitud del efecto máximo fue -374 ± 30,7 mg/dL y la dosis efectiva 50 fue 1,34 ± 0,2 UI/kg. Conclusión. El modelo de diabetes inducida por estreptozotocina equilibrada permitió determinar de manera reproducible la farmacodinamia de la insulina regular.Palabras clave: Diabetes Inducida por Estreptozotocina, Estreptozotocina, Insulina, Modelos Animales de Enfermedad, Farmacología. ABSTRACTBACKGROUND. There are multiple animal models of diabetes, but still no one has been validated useful to determine the pharmacodynamics of drugs. Objectives: To use the streptozotocin-induced model of diabetes in outbred mice, to reliably determine the pharmacodynamics of regular insulin. Methods. Outbred mice weighing 37 g in average, were injected by intraperitoneal route with 150 mg/ kg of an equilibrated solution of streptozotocin. Blood glucose (mg/dL) was measured at 0,7,9,14,16,17

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Streptozotocin, but not alloxan, induces DNA repair synthesis in mouse pancreatic islets in vitro

Cited by 75 publications

References 25 publications

The mechanisms of alloxan- and streptozotocin-induced diabetes

The mechanisms of alloxan- and streptozotocin-induced diabetes

Long-term effects of exposure of pancreatic islets to nicotinamide in vitro on DNA synthesis, metabolism and B-cell function

Obtención De Un Modelo Múrido De Diabetes Inducida Por Estreptozotocina Útil en La Evaluación Farmacodinámica De La Insulina Regular

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