Streptozotocin and alloxan induce DNA strand breaks and poly(ADP–ribose) synthetase in pancreatic islets

Yamamoto, Hiroshi; Uchigata, Yasuko; Okamoto, Hiroshi

doi:10.1038/294284a0

Cited by 485 publications

(292 citation statements)

References 30 publications

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“…However, the effect of gliclazide on leukostasis shown in this study is not attributable to this principal mechanism of action of the agent, because the pancreas of STZ-induced diabetic rats is severely damaged and does not respond to any sulphonylurea agent [31] as is shown by the unchanged blood glucose concentrations of the three groups of STZ-diabetic rats after treatment with gliclazide or glibenclamide.…”

Section: Discussionmentioning

confidence: 60%

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Kinoshita¹,

Kakehashi²,

Inoda

et al. 2002

Diabetologia

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Aims/hypothesis. Early stage leukocyte entrapment in the retinal microcirculation (retinal leukostasis) is considered to be one of the important pathogenetic events in diabetic retinopathy. Gliclazide, a sulphonylurea, was reported to reduce leukocyte adhesion to endothelial cells in hyperglycaemia in vitro, thus suggesting possible selective efficacy of this sulphonylurea in preventing leukostasis in diabetic patients. This study evaluated the effectiveness and selectivity of gliclazide treatment on retinal leukostasis of diabetic rats in vivo. Methods. Streptozotocin (STZ) (65 mg/kg)-induced diabetic rats were divided into three groups (n = 8 each): an untreated diabetic group, a gliclazide-treated diabetic group, and a glibenclamide-treated diabetic group. Gliclazide or glibenclamide was administered orally during a 3-week period. Non-diabetic rats were used as a control (n = 8). Retinal leukostasis was quantitatively evaluated in vivo by acridine orange leukocyte fluorography using a scanning laser ophthalmoscope.Results. The number of leukocytes trapped in the area around the optic disc in the untreated diabetic group (36.9 ± 5.1 cells) increased significantly compared with the non-diabetic control group (21.9 ± 2.9 cells; p = 0.0007). The number of leukocytes trapped in the gliclazide-treated diabetic group (23.5 ± 4.0 cells) decreased significantly compared with untreated diabetic group (p = 0.0008). In contrast, no reduction of retinal leukostasis was found in the glibenclamide-treated diabetic group (37.8 ± 5.8 cells; p = 0.7923). Conclusion/interpretation. This suggests that gliclazide could directly improve abnormalities in the retinal microcirculation independent of blood glucose control and possibly have selective therapeutic benefits in preventing early, critical events in diabetic retinopathy compared with other sulphonylurea drugs. [Diabetologia (2002) 45:735-739] Keywords Gliclazide, sulphonylurea, diabetic retinopathy, retinal leukostasis, acridine orange leukocyte fluorography, scanning laser ophthalmoscope. Diabetic retinopathy is a leading cause of adult vision loss and blindness and early-stage, preventive strategies are important research areas. Leukocyte adhesion to the diabetic retinal vasculature is presumed to be the critical early event in the pathogenesis of diabetic retinopathy [1,2,3], resulting in a breakdown in the blood-retinal barrier and in capillary nonperfusion [1,4,5,6,7,8,9,10,11,12]. In a rat model of diabetic retinopathy, investigators demonstrated retinal capillary occlusion by neutrophils and monocytes in histologic sections and found that areas of endothelial cell damage, capillary loss, and leukocyte extravasation existed adjacent to the static leukocytes [1]. In another post mortem study of human subjects, increased numbers of neutrophils were observed in the choroid and retina of patients with diabetes [2].

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Section: Discussionmentioning

confidence: 60%

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Kinoshita¹,

Kakehashi²,

Inoda

et al. 2002

Diabetologia

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“…The transfer of the methyl group from streptozotocin to the DNA molecule causes damage, which along a defined chain of events [84], results in the fragmentation of the DNA [85]. Protein glycosylation may be an additional damaging factor [41].…”

Section: Beta Cell Toxicity Of Streptozotocinmentioning

confidence: 99%

“…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%

“…Even before the negative effects of mitochondrial DNA and protein alkylation and glycosylation become evident, streptozotocin-induced depletion of NAD + may result in the inhibition of insulin biosynthesis and secretion [82,85,94]. Later, inhibition of glucose-induced and amino acidinduced insulin secretion [97] as a result of mitochondrial enzyme dysfunction [98] and damage to the mitochondrial genome [99] become apparent.…”

Section: Inhibition Of Insulin Secretion By 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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“…DNA strand breaks seem to be responsible for the diabetes mellitus induced by alloxan. 10,11) Nonetheless, the cell death associated with DNA strand breaks by alloxan has not been indicated necrosis or apoptosis. To our knowledge, the results described herein are the first to demonstrate that alloxan induces apoptotic cell death, and this finding suggests the possibility that the character of islet DNA strand breaks induced by alloxan injected in vivo may be the form of DNA ladder.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and Mitochondrial Damage in INS-1 Cells Treated with Alloxan.

Sakurai

Katoh

Someno

et al. 2001

Biological & Pharmaceutical Bulletin

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A variety of mechanisms have been identified as responsible for the onset of diabetes mellitus. Alloxan shows a selective cytotoxicity on pancreatic b-cells and thus causes insulin-dependent (type I) diabetes mellitus. Although the mechanism of alloxan cytotoxicity is not yet clearly understood, several researchers 1,2) demonstrated that the diabetogenic action was initiated by the generation of reactive oxygen species (ROS). Alloxan is a mild oxidant and is easily reduced to alloxan radicals (A· Ϫ ) by GSH or ascorbic acid. 3) Our previous study 4) demonstrated that A· Ϫ can directly reduce O 2 and ferric ions to superoxide anion radical (O 2 · Ϫ ) and ferrous ions, respectively. The extreme and indiscriminate reactivity of ROS could easily explain the killing of b-cells by alloxan. In support of this hypothesis alloxan diabetes is prevented by HO · scavengers, 5-7) superoxide dismutase (SOD) 2) and vitamin E. 8) In addition, on the basis of in vivo and in vitro studies using rats and isolated islet cells, respectively, it was proposed that the process of alloxan toxicity involved the generation of HO · by which the DNA strands break of pancreatic islets is attacked to produce. 9-11) These findings indicate that DNA strand breaks are involved in the events of alloxan-diabetogenesis. However, the complex sequence of events that eventually leads to the DNA strand breaks and death of pancreatic b-cells in alloxan diabetes mellitus is not clear.Cell death might occur by one of two fundamental processes, necrosis or apoptosis. The biochemical hallmarks of apoptosis are the distribution of phosphatidylserine (PS) at the external surface of the plasma membrane (PS exposure) in the early stages, and the cleavage of chromosomal DNA into nucleosomal units, which appears to be the final blow in the cell death process. Recent studies have shown that different trigger such as IL-1b 12) and streptozotocin 13) can induce apoptosis in pancreatic b-cells. Although detailed studies indicate that alloxan can induce insulin-dependent diabetes mellitus, nothing is known about apoptotic action or the sequence of cellular events of alloxan on the b-cells.According to current understanding, mitochondrial damage seems to occur in the early phase of apoptosis and to participate in the control of apoptosis. 14,15) Release of cytochrome c and apoptosis induced factor from mitochondria into cytoplasm during mitochondrial permeability transition cause to active caspase family, leading to the completion of apoptosis. 15,16) Isolated liver mitochondria incubated with alloxan alters respiration, decreases in the concentration of adenine nucleotides, causes Ca 2ϩ release, and changes in the Dy, 17,18) indicating that alloxan directly induces the mitochondrial damage. However, the relationship between diabetes, apoptosis and mitochondrial damage has remained elusive.INS-1 cells were established by X-ray-induced rat transplantable insulinoma, and have retained the similar ability of glucose-stimulated insulin release of native b-cells. 19) INS-1 ...

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Streptozotocin and alloxan induce DNA strand breaks and poly(ADP–ribose) synthetase in pancreatic islets

Cited by 485 publications

References 30 publications

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide

The mechanisms of alloxan- and streptozotocin-induced diabetes

Apoptosis and Mitochondrial Damage in INS-1 Cells Treated with Alloxan.

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