Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85547
Title:
Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice.
Authors:
Cardinal, John W; Margison, Geoffrey P; Mynett, Kurt J; Yates, Allen P; Cameron, Donald P; Elder, Rhoderick H
Abstract:
Type 1 diabetes is thought to occur as a result of the loss of insulin-producing pancreatic beta cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the beta cells, is used to trigger the initial cell death. High single doses of STZ cause extensive beta-cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), beta-cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in APNG(-/-) islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice. Apoptosis was not observed in PARP-inhibited APNG(+/+) mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta-cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG(-/-) and APNG(+/+) mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG(-/-) mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.
Affiliation:
Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, Brisbane 4102, Australia.
Citation:
Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice. 2001, 21 (16):5605-13 Mol. Cell. Biol.
Journal:
Molecular and Cellular Biology
Issue Date:
Aug-2001
URI:
http://hdl.handle.net/10541/85547
DOI:
10.1128/MCB.21.16.5605-5613.2001
PubMed ID:
11463841
Type:
Article
Language:
en
ISSN:
0270-7306
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorCardinal, John Wen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorMynett, Kurt Jen
dc.contributor.authorYates, Allen Pen
dc.contributor.authorCameron, Donald Pen
dc.contributor.authorElder, Rhoderick Hen
dc.date.accessioned2009-11-06T14:33:38Z-
dc.date.available2009-11-06T14:33:38Z-
dc.date.issued2001-08-
dc.identifier.citationIncreased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice. 2001, 21 (16):5605-13 Mol. Cell. Biol.en
dc.identifier.issn0270-7306-
dc.identifier.pmid11463841-
dc.identifier.doi10.1128/MCB.21.16.5605-5613.2001-
dc.identifier.urihttp://hdl.handle.net/10541/85547-
dc.description.abstractType 1 diabetes is thought to occur as a result of the loss of insulin-producing pancreatic beta cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the beta cells, is used to trigger the initial cell death. High single doses of STZ cause extensive beta-cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), beta-cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in APNG(-/-) islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice. Apoptosis was not observed in PARP-inhibited APNG(+/+) mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta-cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG(-/-) and APNG(+/+) mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG(-/-) mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshDNA Glycosylases-
dc.subject.meshDiabetes Mellitus, Type 1-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshIslets of Langerhans-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshN-Glycosyl Hydrolases-
dc.subject.meshStreptozocin-
dc.titleIncreased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice.en
dc.typeArticleen
dc.contributor.departmentDepartment of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, Brisbane 4102, Australia.en
dc.identifier.journalMolecular and Cellular Biologyen
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