Nitric oxide donors decrease the function and survival of human pancreatic islets

Eizirik, Décio L.; Delaney, Carol A.; Green, Michael H.L.; Cunningham, James M.; Thorpe, Julian R.; Pipeleers, Daniël; Hellerström, Claes; Green, Irene C.

doi:10.1016/0303-7207(96)03768-9

Cited by 74 publications

(53 citation statements)

References 58 publications

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“…We have previously observed that human pancreatic islets are less susceptible than rat or mouse pancreatic islets to the damaging effects of cytokines [9], nitric oxide donors [10,11], streptozotocin [10], alloxan [10], cycasin [22] and hydrogen peroxide [23]. Thus, it is noteworthy that in the present series of experiments peroxynitrite induced similar damage to human and rat pancreatic islets, as judged by a similar decrease in islet glucose oxidation and islet retrieval, and similar levels of DNA strand breakage.…”

Section: Discussionsupporting

confidence: 71%

“…Fax: (46) (18) 556401. E-mail: Carol Delaney@medcellbiol.uu.se the susceptibility to pancreatic ~-cell injury, with human islets being less susceptible to several different assaults than islets from rat or mouse [9][10][11]. More recently, we observed that human islets are more resistant than rodent islets to nitric oxide-induced DNA damage [12], although nitric oxide itself can decrease human islet survival [11].…”

Section: Introductionmentioning

confidence: 99%

“…E-mail: Carol Delaney@medcellbiol.uu.se the susceptibility to pancreatic ~-cell injury, with human islets being less susceptible to several different assaults than islets from rat or mouse [9][10][11]. More recently, we observed that human islets are more resistant than rodent islets to nitric oxide-induced DNA damage [12], although nitric oxide itself can decrease human islet survival [11]. The aim of the present study was to examine whether primary cultured human islets are susceptible to the deleterious effects of peroxynitrite or its decomposition products, and to compare the susceptibility of human and rodent islets to peroxynitrite exposure.…”

Section: Introductionmentioning

confidence: 99%

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Sensitivity of human pancreatic islets to peroxynitrite‐induced cell dysfunction and death

et al. 1996

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Nitric oxide and peroxynitrite (generated by the reaction of nitric oxide with the superoxide anion) may both be mediators of [$-ceH damage in early insulin-dependent diabetes mellitus. We observed that acute exposure of primary cultured human pancreatic islets to peroxynitrite results in a significant decrease in glucose oxidation and islet retrieval. DNA strand breaks in single human and rat islet cells are detectable after acute peroxynitrite exposure, followed by a decrease in islet cell survival after 1 h and 24 h. Cell death appeared to occur via a toxic cell death mechanism (necrosis) rather than apoptosis, as suggested by vital staining and ultrastructural evidence of early membrane and organelle degradation, mitochondrial swelling and loss of matrix. This study demonstrates for the first time that cultured human pancreatic islets are susceptible to the noxious effects of peroxynitrite.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sensitivity of human pancreatic islets to peroxynitrite‐induced cell dysfunction and death

et al. 1996

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“…We used two sources of nitric oxide in our study [20]. SNAP (S-Nitroso-N-acetyl-d,l-penicillamine) spontaneously decomposes to release nitric oxide.…”

Section: Adenoviral Vectorsmentioning

confidence: 99%

Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulin-secreting cells

et al. 2000

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It has been established from numerous studies that oxygen and nitrogen free radicals can contribute to the islet beta-cell destruction in Type I (insulin-dependent) diabetes mellitus models [1±2]. The deleterious actions of activated mononuclear cells could be mediated by cytokines through an increase in the intracellular generation of superoxide anions, nitric oxide (NO) and peroxynitrite [3±5]. Islet beta cells appear to have an exquisite sensitivity to these radicals because of constitutively low expression of antioxidant enzymes [6±7]. Several reports explained the rationale of increasing antioxidant enzyme expression Diabetologia (2000) AbstractAims/hypothesis. Vulnerability of pancreatic islets to oxygen free radicals and nitric oxide contributes to islet transplantation obstacles. This susceptibility can be linked to the low expression levels of antioxidant enzymes in islets. Our aim was to investigate the effect of overexpressing Cu/Zn superoxide dismutase in human islets through a simple procedure on the cytotoxic effects of two nitric oxide donors: 3-morpholinosydnonimine (SIN-1) and S-Nitroso-N-acetyl-d,lpenicillamine (SNAP). Methods. Cultured human islets and INS-1 rat-derived insulin-secreting cells were transfected by an E1-deleted adenovirus carrying Cu/Zn SOD cDNA under the control of a cytomegalovirus (CMV) promoter (AdSOD). The viability of the cells was tested by the WST-1 assay (Roche, Indianapolis, Ind., USA). Results. The AdSOD procedure allowed SOD activity to increase by twofold to threefold for 2 to 8 days following transfection. Adenovirus-driven SOD overexpression was associated with a significant reduction of SIN-1-induced cytotoxicity on human islets (69.9 ± 10.5 % protection at 200 mmol/l and 40.5 ± 8.9 % protection at 400 mmol/l) and INS-1 cells (82.2 ± 8.8 % protection at 200 mmol/l and 31.1 ± 5.8 % protection at 400 mmol/l). Protection against increasing doses of SNAP was AdSOD dose-dependent. Transfected islets released significantly more insulin than control islets in glucose-theophyllinstimulated conditions, without or following exposure to SNAP. Conclusions/interpretation. We thus established that adenoviral-induced overexpression of Cu/Zn SOD can be beneficial to human islet endocrine function and resistance to nitric oxide cytotoxicity. These data could be relevant for the development of new strategies aimed at preventing NO-induced beta-cell damage in an islet transplantation setting. [Diabetologia (2000) 43: 625±631] Keywords Islet transplantation, nitric oxide, oxidant stress, superoxide dismutase, reactive oxygen species, adenovirus, gene transfer. Corresponding author: Dr P. Y. Benhamou, Department of Endocrinology, CHU, BP 217X, 38 043 Grenoble, France Abbreviations: AdSOD, Adenovirus-driven superoxide dismutase; IEQ, equivalent number of islets; MOI, multiplicity of infection; NO, nitric oxide; pfu, plaque-forming units; ROS, reactive oxygen species; SIN-1, 3-Morpholino sydnonimine.HCl; SNAP, S-Nitroso-N-acetyl-d,l-penicillamine; SOD, superoxide dismutase.

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“…11 Finally, the NO-donor, Russian Black Salt, added in vitro to human islets has been shown to inhibit beta-cell function and induce DNA strand-breaks as well as beta-cell death. 12 On this basis, we consider the human NOS2 gene, which is the only gene responsible for NO production in betacells, to be a candidate gene for type 1 diabetes in man. We have used the extended transmission disequilibrium test (ETDT) as a test for linkage as: (i) the transmission disequilibrium test (TDT) was initially developed to identify linkage for minor susceptibility loci even when the loci did not appear in the genome scans, exemplified by the IDDM2 locus, 13 and (ii) the ETDT is a robust test for linkage in both multiplex and simplex families.…”

Section: Introductionmentioning

confidence: 99%

No evidence for linkage in the promoter region of the inducible nitric oxide synthase gene (NOS2) in a Danish type 1 diabetes population

et al. 2000

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Exposure of human pancreatic islets to a mixture of cytokines induces expression of inducible nitric oxide synthase (iNOS), impairs beta-cell function and induces apoptosis. Exposing human islets to high amounts of NO from chemical NO-donors causes DNA strand breaks and mitochondrial damage, suggesting that NO is deleterious to human beta-cells. Hence, we consider the gene encoding iNOS in beta-cells, NOS2, a candidate gene for type 1 diabetes in humans. In the present study we have tested three identified polymorphisms within the promoter sequence of the human NOS2 gene in a type 1 diabetic family material comprising 154 affected sib-pair families and 103 affected simplex families (1143 individuals in total). PCR-based amplification of the polymorphic loci were established. Linkage analysis was performed using the extended transmission disequilibrium testing (ETDT). A Bsal RFLP was found not to be polymorphic in 20 type 1 diabetic patients and 14 healthy control subjects and was not analysed further. In affected cases a nine allele CCTTT repeat and a bi-allelic TAAA repeat revealed allelewise P etdt of 0.52 and 0.60, respectively. ETDT applied to {(TAAA)n; (CCTTT)n} haplotypes demonstrated random transmission from heterozygous parents to affected offspring. In conclusion, the tested polymorphisms within the NOS2 gene promoter did not show evidence for linkage to type 1 diabetes in a Danish family material. Genes and Immunity (2000) 1, 362-366.

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Nitric oxide donors decrease the function and survival of human pancreatic islets

Cited by 74 publications

References 58 publications

Sensitivity of human pancreatic islets to peroxynitrite‐induced cell dysfunction and death

Sensitivity of human pancreatic islets to peroxynitrite‐induced cell dysfunction and death

Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulin-secreting cells

No evidence for linkage in the promoter region of the inducible nitric oxide synthase gene (NOS2) in a Danish type 1 diabetes population

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