Cytotoxic effects of cytokines on rat islets: Evidence for involvement of free radicals and lipid peroxidation

Rabinovitch, Alex; Suarez, Wilma L.; Thomas, Panakkezhum D.; Strynadka, Ken; Simpson, Ian

doi:10.1007/bf02342435

Cited by 126 publications

(61 citation statements)

References 24 publications

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“…Cytokines like IL-1β, IFN-γ and TNF-α have been implicated in the pathogenesis of Type I diabetes and could be a major source of free radical insult in pancreatic islet cells [5,59,60]. An effect of cytokines (IFN-γ) on expression of peroxiredoxins has been shown only in rat Kupffer cells [37].…”

Section: Discussionmentioning

confidence: 99%

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%

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

et al. 2002

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“…It has also been shown that lipid peroxidation is involved in the cytotoxic effects of cytokines on rat islets and that the inhibition of this process protects islet beta cells from the combined cytotoxic effects of interleukin 1, tumor necrosis factor and interferon gamma (14). Furthermore, vitamin E has been shown to be effective in preventing severe complications in long-standing type 1 diabetic patients (15).…”

Section: Introductionmentioning

confidence: 99%

A randomized trial of nicotinamide and vitamin E in children with recent onset type 1 diabetes (IMDIAB IX)

Crinó

Schiaffini

Manfrini

et al. 2004

European Journal of Endocrinology

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Objective: Various adjuvant therapies have been introduced along with intensive insulin therapy in patients with recent onset type 1 diabetes. Nicotinamide (NA), administered at diagnosis of the disease, can have beneficial effects on the clinical remission rate, improve metabolic control and preserve or slightly increase beta-cell function, probably by reducing toxicity due to free oxygen radicals. Vitamin E, a known antioxidant, inhibits lipid peroxidation; this can lead to protection of islet beta cells from the combined effects of interleukin 1, tumor necrosis factor and gamma interferon. The aim of the present study was to investigate whether the addition of vitamin E to NA could improve metabolic control and the residual beta-cell function, as measured by C-peptide secretion, in children and adolescents with recent onset type 1 diabetes; patients were followed-up for 2 years after diagnosis. Patients and study design: Recent onset type 1 diabetes patients (n ¼ 64, mean age 8.8 years) were recruited by participating centres of the IMDIAB group. Thirty-two patients were randomized to NA (25 mg/kg body weight) plus vitamin E (15 mg/kg body weight); 32 patients acted as controls and received NA only at the same dose as above. Intensive insulin therapy was applied to both treatment groups. Results: There were three drop outs during the 2-year follow-up period. Overall, patients assigned to the NA þ vitamin E group or the NA group did not significantly differ in terms of glycated hemoglobin (HbA1c) levels, insulin requirement or baseline C-peptide secretion. Patients diagnosed at an age of less than 9 years showed significantly reduced C-peptide levels compared with those aged over 9 years at diagnosis and at the 2-year follow-up but there were no differences between the NA and NA þ vitamin E treated groups. However at 6 months, patients over 9 years of age treated with NA þ vitamin E showed significantly higher C-peptide compared with the NA group (P , 0.003). In both age groups and in the different treatment groups, C-peptide levels found at diagnosis were preserved 2 years later. Conclusions: The use of NA alone, or in combination with vitamin E, along with intensive insulin therapy is able to preserve baseline C-peptide secretion for up to 2 years after diagnosis. This finding is of particular interest for pre-pubertal children with type 1 diabetes and has never been reported before.

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“…Cytokine treatment of pancreatic islet cells in vitro results in generation of reactive oxygen species (Rabinovitch et al 1992) and nitric oxide (Southern et al 1990). In type 1 diabetes mellitus, where islet -cells are destroyed, there is evidence of increased cytokine production (Hussain et al 1996) and formation of peroxynitrite from reactive oxygen species and nitric oxide (Suarez-Pinzon et al 1997, Lakey et al 2001) -these can contribute to cell death by both apoptosis and necrosis (Eizirik et al 1996, Hadjivassiliou et al 1998, Hoorens et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells

Sigfrid¹,

Cunningham²,

Beeharry³

et al. 2003

Journal of Molecular Endocrinology

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Pancreatic -cells have low activities of the antioxidant enzyme catalase. Nitric oxide interacts with the haem group of catalase inhibiting its activity. We have studied the activity of catalase in -cells under conditions mimicking prediabetes and in which nitric oxide is generated from cytokine treatment in vitro. We also studied whether there is regulation of catalase enzyme activity by nitric oxide at the protein or gene expression level. RINm5F insulin-producing cells, treated for 24 h with cytokines, showed increased medium nitrite production (17±2·2 vs 0·3±0·2 pmol/µg protein) and significantly decreased cellular catalase activity (42·4±4·5%) compared with control cells. A similar reduction was seen in catalase-overexpressing RIN-CAT cells and in rat or human pancreatic islets of Langerhans. Catalase activity was also suppressed by the long-acting nitric oxide donor diethylenetriamine/nitric oxide adduct (Deta-NO) and this inhibition was reversible. The inhibition of catalase activity by cytokines in RINm5F cells was significantly reversed by the addition of the nitric oxide synthase 2 (NOS2) inhibitors nitro monomethylarginine or N-(3-(aminomethyl)benzyl)acetamidine (1400W). Protein expression was found to be unchanged in cytokine-or Deta-NO-treated RINm5F cells, while mRNA expression was marginally increased. We have shown that inhibition of catalase activity by cytokines is nitric oxide dependent and propose that this inhibition may confer increased susceptibility to cytokine-or nitric oxide-induced cell killing.

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Cytotoxic effects of cytokines on rat islets: Evidence for involvement of free radicals and lipid peroxidation

Cited by 126 publications

References 24 publications

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

A randomized trial of nicotinamide and vitamin E in children with recent onset type 1 diabetes (IMDIAB IX)

Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells

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