Comparison of inhibition of glucose-stimulated insulin secretion in rat islets of Langerhans by Streptozotocin and methyl and ethyl nitrosoureas and methanesulphonates

Delaney, Carol A.; Dunger, A; Matteo, Mauro Di; Cunningham, James M.; Green, M. H. L.; Green, I. C.

doi:10.1016/0006-2952(95)02102-7

Cited by 57 publications

(40 citation statements)

References 30 publications

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“…The role of alkylation in beta cell damage has also been examined by the use of ethylating agents, which are less toxic than their methylating counterparts, on account of O 6 -ethylguanine being less toxic than O 6 -methylguanine [91]. [77,91] has been taken as support for the notion that in insulinproducing cells, as in other cell types, the mechanism of toxic action is due to alkylation, with methylation of DNA bases being more toxic than ethylation [22,81].…”

Section: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

“…[77,91] has been taken as support for the notion that in insulinproducing cells, as in other cell types, the mechanism of toxic action is due to alkylation, with methylation of DNA bases being more toxic than ethylation [22,81]. An alternative hypothesis proposes that part of the diabetogenic effect of streptozotocin may relate not to its alkylating ability but to its potential to act as an intracellular nitric oxide (NO) donor [92].…”

Section: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

“…In fact, streptozotocin has been shown to increase the activity of guanylyl cyclase and the formation of cGMP, which are characteristic effects of NO. However, the alkylating agent methyl methanesulphonate is the most toxic compound, though unlike MNU, it is not a NO donor [91], indicating that NO is not an indispensable prerequisite for the toxic action of the family of alkylating agents that streptozotocin belongs to.…”

Section: Beta Cell Toxicity Of Streptozotocinmentioning

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: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

Section: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

Section: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

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The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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“…Streptozotocin is a specific -cell toxin and can be used to induce diabetes chemically in rats and mice. Streptozotocin is taken up by the -cells through the glucose transporter, Glut-2 (Schnedl et al 1994, Elsner et al 2000, where it decomposes intracellularly, causing DNA damage directly, by alkylation (Delaney et al 1995, Elsner et al 2000, and indirectly, via generation of nitric oxide (NO) (Turk et al 1993), resulting in -cell death by necrosis (Like et al 1978). There are two streptozotocin-induced animal models of diabetes: administration of a single high dose of streptozotocin (SHDS) induces diabetes by directly destroying the -cells, and administration of multiple low-dose streptozotocin (MLDS) induces diabetes progressively via an immune cell response directed towards the -cells.…”

Section: Introductionmentioning

confidence: 99%

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Mabley¹,

Haskó²,

Liaudet³

et al. 2002

Journal of Endocrinology

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Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic -cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NF B. Inhibition of the entire NF B family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NF B subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NF B subunit, p50, in the development of IDDM, mice with gene disruption for NF B (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NF B (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NF B (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NF B (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

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“…Diabetes mellitus, as a complex and heterogenic metabolic syndrome, is characterized by extensive disturbances in different metabolic pathways, with special respect to carbohydrate metabolism [9] and cell vulnerability [10], most obviously because of the down-regulated heat shock proteins (HSP) synthesis [11][12][13]. Concerning carbohydrate metabolism, it is well known that diabetes mellitus impairs the normal capacity of the liver to synthesize glycogen [14,15], causes suppression of hepatic glycolysis through decreased hexokinase, glucokinase and phosphofructokinase activity) [15,16], increases the activity of gluconeogenic enzymes, i.e.…”

Section: Introductionmentioning

confidence: 99%

Prior heat stress induces moderation of diabetic alterations in glycogen metabolism of rats

Miova

Dinevska-Ќovkarovska

Djimrevska³

et al. 2013

Open Life Sciences

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Adaptation to one environmental stressor sometimes provides protection against additional, more intensive type of stress, a phenomenon called cross-tolerance. We aimed to estimate theprotection provided by acute heat stress (AHS) over carbohydrate disturbances in streptozotocin-diabetic rats. We investigated changes in activity of some hepatic glycolitic and gluconeogenic enzymes, and concentration of some substrates in control and diabetic animals exposed to AHS (41±0.5°C / 1 h), with 1 h and 24 h recovery at room temperature before sacrifice or induction of streptozotocin (STZ)-diabetes, respectively. AHS with 1 h-recovery before sacrifice resulted in intensive glycogenolysis, directed to endogenous glucose production and further utilization of glucose by peripheral tissues, while 24 h recovery resulted in a slight tendency towards normalization of metabolic disturbances caused by AHS. Experimental diabetes caused a significant decrease of substrates and glycolytic enzymes, but an increase of gluconeogenic enzymes. In diabetic animals previously exposed to AHS we measured a less intensive decrease of liver glycogen and glucose-6-phosphate concentration and hexokinase activity, as well as less intensive increase of liver glucose concentration, glucose-6-phosphatase and fructose-1,6-bisphosphatase activity compared to control diabetic animals that had been maintained at room temperature. Prior AHS provided some protection over diabetes-induced alterations in carbohydrate-related parameters (see graphical apstract), indicating a possible development of cross-tolerance phenomenon between the two stressors, AHS and STZ-diabetes.

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Comparison of inhibition of glucose-stimulated insulin secretion in rat islets of Langerhans by Streptozotocin and methyl and ethyl nitrosoureas and methanesulphonates

Cited by 57 publications

References 30 publications

The mechanisms of alloxan- and streptozotocin-induced diabetes

The mechanisms of alloxan- and streptozotocin-induced diabetes

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Prior heat stress induces moderation of diabetic alterations in glycogen metabolism of rats

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