Free Radicals and the Pathogenesis of Type 1 Diabetes

Tabatabaie, Tahereh; Vasquez-Weldon, Angelica; Moore, Dennis; Kotake, Yashige

doi:10.2337/diabetes.52.8.1994

Cited by 55 publications

(43 citation statements)

References 51 publications

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“…Cytokines also increase intracellular levels of ROS (42,43). In control NOD islets, cytokine treatment elevated ROS, as indicated by increased CM-H 2 DCFDA fluorescence (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice

Chen

Epstein

2006

Diabetes

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It is widely proposed that reactive oxygen species (ROS) contribute to ␤-cell death in type 1 diabetes. We tested this in nonobese diabetic (NOD) mice using ␤-cell-specific overexpression of three antioxidant proteins: metallothionein (MT), catalase (Cat), or manganese superoxide dismutase (MnSOD). Unexpectedly, the cytoplasmic antioxidants, MT and catalase, greatly accelerated diabetes after cyclophosphamide and accelerated spontaneous diabetes in male NOD mice. This occurred despite the fact that they reduced cytokine-induced ROS production and MT reduced streptozotocin diabetes in NOD mice. Accelerated diabetes onset coincided with increased ␤-cell death but not with increased immune attack. Islets from MTNOD mice were more sensitive to cytokine injury. In vivo and in vitro studies indicated reduced activation of the Akt/pancreatic duodenal homeobox-1 survival pathway in MTNOD and CatNOD islets. Our study indicates that cytoplasmic ROS may have an important role for protecting the ␤-cell from autoimmune destruction. Diabetes 55:1592-1604, 2006

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“…Cytokines also increase intracellular levels of ROS (42,43). In control NOD islets, cytokine treatment elevated ROS, as indicated by increased CM-H 2 DCFDA fluorescence (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice

Chen

Epstein

2006

Diabetes

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“…It has been proven that both cytokines have direct and indirect toxic effects on beta cells through the induction of reactive oxygen intermediates and nitric oxide [4,38,39,40,41,42,43]. Besides its toxic effect, TNF-α could also influence adaptative immune responses directed against beta cells.…”

Section: Discussionmentioning

confidence: 99%

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Vosters

Beuneu

Nagy³

et al. 2004

Diabetologia

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Aims/hypothesis. Human pancreatic duct cells are closely associated with islet beta cells, and contaminate islet suspensions transplanted in Type 1 diabetes mellitus patients. Activated duct cells produce cytotoxic mediators and possibly contribute to the pathogenesis of Type 1 diabetes mellitus or islet graft rejection. As CD40 transduces activation signals involved in inflammatory and immune disorders, we investigated CD40 expression on duct cells and their response to CD40 engagement. Methods. CD40 expression on human pancreatic duct cells was analysed by flow cytometry and immunohistochemical analyses. To assess the function of CD40 expression on duct cells, activation of the transcription factor nuclear factor-kappa B was determined using electrophoretic mobility shift assay and ELISA. Cytokine mRNA levels were quantified by real-time RT-PCR, and protein levels by Luminex technology. Results. Isolated human pancreatic duct cells and Capan-2 cell lines were found to express constitutively CD40. The expression of CD40 on duct cells was confirmed in vivo on human normal and pathological pancreatic specimens. CD40 ligation on Capan-2 cells induced rapid nuclear factor-kappa B activation, and supershift assays demonstrated that p50/p65 heterodimers and p50/p50 homodimers were present in the activated complexes in the nucleus. This activation was accompanied by tumour necrosis factor-α and interleukin-1β mRNA accumulation. Tumour necrosis factor-α protein secretion was confirmed in CD40-activated Capan-2 cells and in isolated human pancreatic duct cells. Conclusions/interpretation. Interaction between activated T lymphocytes expressing CD40 ligand and duct cells expressing CD40 may contribute to the immune responses involved in Type 1 diabetes mellitus and islet graft rejection. Interfering with CD40-mediated duct cell activation could alleviate beta cell damage of immune origin.

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“…There are a few attempts to prove free radical formation in any of the diabetic models directly and thus offer mechanisms through which these species could affect the tissue environment as the disease progresses. One study used direct spin-trapping methods to show that free radical formation occurs in the pancreatic islets upon addition of exogenous cytokines [26]. Other studies have been performed to demonstrate the possibility of radical generation in a whole diabetic animal [27;28] through L-band EPR spectroscopy which used non-specific spin probes.…”

Section: Introductionmentioning

confidence: 99%

Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes

Stadler

Bonini

Dallas

et al. 2008

Free Radical Biology and Medicine

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Free radical production is implicated in the pathogenesis of diabetes mellitus, where several pathways and different mechanisms were suggested in the pathophysiology of the complications. In this study, we used electron paramagnetic resonance (EPR) spectroscopy combined with in vivo spin-trapping techniques to investigate the sources and mechanisms of free radical formation in streptozotocininduced diabetic rats. Free radical production was directly detected in the diabetic bile, which correlated with lipid peroxidation in the liver and kidney. EPR spectra showed the trapping of a lipidderived radical. Such radicals were demonstrated to be induced by hydroxyl radical through isotope labeling experiments. Multiple enzymes and metabolic pathways were examined as the potential source of the hydroxyl radicals using specific inhibitors. Neither xanthine oxidase, cytochrome P450s, the Fenton reaction, nor macrophage activation were required for the production of radical adducts. Interestingly, inducible nitric oxide synthase (apparently uncoupled) was identified as the major source of radical generation. The specific iNOS inhibitor 1400W as well as L-arginine pretreatment reduced the EPR signals to baseline levels, implicating peroxynitrite as the source of hydroxyl radical production. Applying immunological techniques, we localized iNOS overexpression in the liver and kidney of diabetic animals, which was closely correlated with the lipid radical generation and 4-hydroxynonenal-adducted protein formation, indicating lipid peroxidation. In addition, protein oxidation to protein free radicals occurred in the diabetic target organs. Taken together, our studies support inducible nitric oxide synthase as a significant source of EPR-detectable reactive intermediates, which leads to lipid peroxidation and may contribute to disease progression as well.

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Free Radicals and the Pathogenesis of Type 1 Diabetes

Cited by 55 publications

References 51 publications

Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice

Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes

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