Nicotinamide prevents the development of diabetes in the cyclophosphamide-induced NOD mouse model by reducing beta-cell apoptosis

O’Brien, Bronwyn A.; Harmon, Brian V.; Cameron, Donald P.; Allan, David J.

doi:10.1002/(sici)1096-9896(200005)191:1<86::aid-path573>3.0.co;2-0

Cited by 41 publications

(27 citation statements)

References 39 publications

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“…These results suggest that the protective effect of nicotinamide, a known PARP-1 inhibitor, which was reported for the spontaneous and cyclophosphamide-accelerated diabetes of the NOD mouse (26,27), could also result from other pharmacologic properties, such as scavenging of free oxygen radicals (30). However, the observed protective effects in BALB/c mice of a benzopyrone PARP inhibitor in the multiple low doses of streptozotocin diabetes model (22) suggest that islet immune destruction could be PARP-mediated in other mouse strains.…”

Section: Discussioncontrasting

confidence: 53%

“…2B). In addition, because nicotinamide had been reported to protect NOD mice from cyclophosphamide-accelerated diabetes (27), we analyzed the susceptibility of NOD Adprt1 Ϫ/Ϫ females to this accelerated disease (34). NOD Adprt1 Ϫ/Ϫ and control NOD mice developed diabetes from 10 days after intraperitoneal administration of a single high dose of cyclophosphamide (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, PARP-1-deficient islets (or islets treated with a specific PARP-1 inhibitor) are resistant in vitro to the toxic effects of nitric oxide or reactive oxygen intermediates (23)(24)(25), suggesting that PARP-1 deficiency could protect ␤-cells from inflammatory damage induced by activated macrophages. Consequently, nicotinamide, a weak PARP-1 inhibitor, has been reported to prevent both spontaneous and cyclophosphamide-accelerated diabetes in NOD mice (26,27). These latter studies prompted clinicians to launch nicotinamide trials in subjects either recently diagnosed or highly predisposed to diabetes (28 -30).…”

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confidence: 99%

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Unexpected Sensitivity of Nonobese Diabetic Mice With a Disrupted Poly(ADP-Ribose) Polymerase-1 Gene to Streptozotocin-Induced and Spontaneous Diabetes

et al. 2002

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic ␤-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced ␤-cell death.

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Section: Discussioncontrasting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Unexpected Sensitivity of Nonobese Diabetic Mice With a Disrupted Poly(ADP-Ribose) Polymerase-1 Gene to Streptozotocin-Induced and Spontaneous Diabetes

et al. 2002

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“…Injury to ␤ cells has also been implicated as a requirement for virus-accelerated diabetes (58,59). The earliest, CY-induced change previously reported is the rapid accumulation of monokines IL-12, TNF-␣, and IL-18 in the pancreas ϳ2 days after drug treatment (3), 1 day after the peak of drug-induced ␤ cell death (52). While it may ultimately not be trivial to separate cause and effect, the most obvious scenario would be that CY-induced ␤ cell death attracts and activates professional APCs, which then engender pathogenic competence in preexisting T cell pools with islet autoreactivity.…”

Section: Discussionmentioning

confidence: 68%

“…The unexpected resistance to CY-accelerated diabetes allowed a reevaluation of its mechanistic basis in vivo. There is previous evidence for acute, CY-mediated islet toxicity that peaks within a day of drug injection and removes a substantial proportion of ␤ cells (52). We have only begun mechanistic studies of how ICA69 might be involved in this process.…”

Section: Discussionmentioning

confidence: 99%

ICA69null Nonobese Diabetic Mice Develop Diabetes, but Resist Disease Acceleration by Cyclophosphamide

Winer

Astsaturov

Gaedigk

et al. 2002

The Journal of Immunology

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ICA69 (islet cell Ag 69 kDa) is a diabetes-associated autoantigen with high expression levels in β cells and brain. Its function is unknown, but knockout of its Caenorhabditis elegans homologue, ric-19, compromised neurotransmission. We disrupted the murine gene, ica-1, in 129-strain mice. These animals aged normally, but speed-congenic ICA69null nonobese diabetic (NOD) mice developed mid-life lethality, reminiscent of NOD-specific, late lethal seizures in glutamic acid decarboxylase 65-deficient mice. In contrast to wild-type and heterozygous animals, ICA69null NOD congenics fail to generate, even after immunization, cross-reactive T cells that recognize the dominant Tep69 epitope in ICA69, and its environmental mimicry Ag, the ABBOS epitope in BSA. This antigenic mimicry is thus driven by the endogenous self Ag, and not initiated by the environmental mimic. Insulitis, spontaneous, and adoptively transferred diabetes develop normally in ICA69null NOD congenics. Like glutamic acid decarboxylase 65, ICA69 is not an obligate autoantigen in diabetes. Unexpectedly, ICA69null NOD mice were resistant to cyclophosphamide (CY)-accelerated diabetes. Transplantation experiments with hemopoietic and islet tissue linked CY resistance to ICA69 deficiency in islets. CY-accelerated diabetes involves not only ablation of lymphoid cells, but ICA69-dependent drug toxicity in β cells that boosts autoreactivity in the regenerating lymphoid system.

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Textbook of Diabetes

2010

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Nicotinamide prevents the development of diabetes in the cyclophosphamide-induced NOD mouse model by reducing beta-cell apoptosis

Cited by 41 publications

References 39 publications

Unexpected Sensitivity of Nonobese Diabetic Mice With a Disrupted Poly(ADP-Ribose) Polymerase-1 Gene to Streptozotocin-Induced and Spontaneous Diabetes

Unexpected Sensitivity of Nonobese Diabetic Mice With a Disrupted Poly(ADP-Ribose) Polymerase-1 Gene to Streptozotocin-Induced and Spontaneous Diabetes

ICA69null Nonobese Diabetic Mice Develop Diabetes, but Resist Disease Acceleration by Cyclophosphamide

Textbook of Diabetes

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