Determinants of the selective toxicity of alloxan to the pancreatic B cell.

Malaisse, Willy; Malaisse‐Lagae, Francine; Sener, Abdullah; Pipeleers, Daniël

doi:10.1073/pnas.79.3.927

Cited by 248 publications

(151 citation statements)

References 24 publications

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“…Alloxan and streptozotocin cause a selective destruction of insulin-producing cells by overproduction of reactive oxygen and nitrogen intermediates [51,52,63]. Up to now there are no data on their influence on peroxiredoxin expression.…”

Section: Discussionmentioning

confidence: 99%

“…The beta cell toxin alloxan is used to generate animal models of Type I diabetes mellitus. The substance is able to destroy insulin-producing beta cells by generating oxygen radicals [51]. We investigated the effect of alloxan on Prxs expression in INS-1 cells using semiquantitative RT-PCR and western blot analysis.…”

Section: Up-regulation Of Prx I and Ii Expression By Allox-mentioning

confidence: 99%

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Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

et al. 2002

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Aims/hypothesis. Insulin-producing beta cells are destroyed by oxidative and nitrosative stress during the pathogenesis of Type I (insulin-dependent) diabetes mellitus. These cells are more sensitive than others due to their deficiency of well known antioxidant enzymes like superoxide dismutase, glutathione peroxidase and catalase. However the peroxiredoxins discovered in the past decade form a large family of highly conserved thioredoxin-dependent peroxide reductases, which are present in most tissues. We investigated whether peroxiredoxins I and II are present in pancreatic beta cells and if they are inducible by oxidative and nitrosative stress. Methods. To detect these enzymes in insulin-producing beta cells we used semiquantitative RT-PCR, western blots and immunohistochemistry. The expression of peroxiredoxins I and II was analysed after treatment with cytokines, hydrogen peroxide, alloxan or streptozotocin in the rat insulinoma cells INS-1 using RT-PCR and western blots. Results. We show that peroxiredoxins I and II are present in the cytoplasm of pancreatic islet cells as well as in insulinoma cell lines βTC6-F7 and INS-1. Peroxiredoxins I and II were up-regulated by all stress agents used. Conclusion/interpretation. Beta cells, undersupplied with well characterized antioxidant enzymes, possess an additional antioxidant system which is inducible by oxidative as well as nitrosative stress. [Diabetologia (2002) 45:867-876]

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Section: Discussionmentioning

confidence: 99%

Section: Up-regulation Of Prx I and Ii Expression By Allox-mentioning

confidence: 99%

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

et al. 2002

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“…Stimulation of oxygen free radical production in pancreatic islet cells, however, might be expected to have lethal consequences to islet cells since islet cells possess very low free radical scavenging enzyme activities [19,20], and therefore are exquisitely vulnerable to free radical-induced injury [20]. Cytokine-induced oxygen free radicals are primarily products of arachidonic acid metabolism in many cell types, and we have recently observed that inhibitors of arachidonic acid metabolism can protect islet cells from the cytotoxic effects of TNF and IFN-y.…”

Section: Free Radical Scavengers Protect Against Cytokinesmentioning

confidence: 99%

“…Such a mechanism for cytokinemediated islet cell injury was first suggested by Mandrup-Poulsen et al [18], and is based on the observations that islet cells possess very low oxygen free radical scavenging enzyme activities [19,20], and are exquisitely vulnerable to free radicals [20]. In the present report, we demonstrate that the oxygen free radical scavengers, dimethylthiourea and citiolone, can significantly protect islet cell monolayer cultures from lysis by the oxygen free radical generators, t-butylhydroperoxide and alloxan, as well as by toxic combinations of the cytokines, IL-1, TNF, and IFN-y..…”

mentioning

confidence: 99%

Oxygen free radical scavengers protect rat islet cells from damage by cytokines

1989

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Summary. A possible role for oxygen free radicals in mediating the cytotoxic effects of cytokines in islets was sought by the use of agents that scavenge free radicals. Rat islet cell monolayer cultures were incubated for 6 days with t-butylhydroperoxide, alloxan, streptozotocin, or the cytokines, interleukin 1, tumour necrosis factor, and interferon gamma, without and together with the oxygen free radical scavenger combination of dimethylthiourea and citiolone, and islet cell lysis was measured in a Slchromium cytotoxicity assay. The free radical scavengers significantly inhibited the islet cell cytotoxic effects of t-butylhydroperoxide and alloxan, but not streptozotocin. Similarly, the cytotoxic effects of the cytokine combinations of interleukin 1 plus tumour necrosis factor, interferon gamma plus tumour necrosis factor, and interferon gamma plus interleukin 1 were significantly inhibited by the free radical scavenger combination of dimethylthiourea and citiolone. These results suggest that the cytokine products of macrophages and lymphocytes infiltrating islets in Type 1 (insulin-dependent) diabetes may contribute to B-cell damage by inducing the production of oxygen free radicals in the islet cells.

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“…Also, there is an uptake of alloxan in liver mitochondria both in vivo and in vitro [17], and our preceding work has demonstrated that alloxan affects ion transport in isolated liver mitochondria [18,19]. Recent studies by others, not specifically directed to mitochondria, have verified a considerable, rapid accumulation [20] and cytotoxicity [21] of alloxan in hepatocytes. However, mitochondria from mouse endocrine pancreas can be isolated [17], and, to facilitate the interpretation of the data with regard to diabetogenicity of alloxan, some additional experiments were carried out on mitochondria from the endocrine pancreas.…”

mentioning

confidence: 95%

Alloxan effects on mitochondria: study of oxygen consumption, fluxes of Mg2+, Ca2+, K+ and adenine nucleotides, membrane potential and volume change in vitro

Boquist

1984

Diabetologia

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Summary. Isolated mouse liver mitochondria incubated with alloxan showed stimulated resting (state 4) respiration with succinate, and inhibited resting respiration with pyridinelinked substrates, whereas active (state 3) respiration was decreased with both kinds of substrates. The effects were dependent on the concentration of alloxan, on the energy state, and on transport of inorganic phosphate and uptake of Ca 2+. Using succinate as substrate, the effects of alloxan on endogenous Mg 2+, K + and adenine nucleotides, uptake of K +, accumulated Ca 2+, membrane potential and volume were studied in liver mitochondria, and in addition efflux of endogenous K + and accumulated Ca 2+ were investigated in mouse islet mitochondria. High concentrations of alloxan (> 3 mmol/1) induced efflux of endogenous Mg 2+, K + and adenine nucleotides, effiux of accumulated Ca 2+, inhibition of uptake of K +, loss of membrane potential, and swelling. Low concentrations of alloxan (< 3 mmol/1) had similar effects only in the presence of added Ca 2+ and inorganic phosphate. The influence of potentially protective agents was studied mainly with regard to alloxan induced swelling. Complete or partial protection was offered by antimycin A, malonate, La 3+, Ni 2+, ruthenium red, mersalyl and N-ethylmaleimide, suggesting requirement for energized transport of Ca 2+ and uptake of inorganic phosphate. The start of the respiratory changes, decrease of membrane potential and loss of MgZ+preceded the release of accumulated Ca 2+, which occurred in parallel with efflux of K + and swelling. The loss of Ca 2+ in association with swelling agrees with data previously obtained using qualitative and quantitative electron microscopy and X-ray microanalysis of islet fl cells from alloxan-treated mice. Since preceding studies in vivo have shown that alloxan passes across plasma membranes and is taken up in mitochondria of islet fl cells and hepatocytes, the combined data support the view that alloxan diabetes may be due to mitochondrial damage.

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Determinants of the selective toxicity of alloxan to the pancreatic B cell.

Cited by 248 publications

References 24 publications

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

Oxygen free radical scavengers protect rat islet cells from damage by cytokines

Alloxan effects on mitochondria: study of oxygen consumption, fluxes of Mg2+, Ca2+, K+ and adenine nucleotides, membrane potential and volume change in vitro

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