Advertisement
Journal of Biological Chemistry
Open access logo
Advanced searchSave search
Letters to the Editor| Volume 290, ISSUE 16, P10570, April 17, 2015

Download started.

Ok

Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?

Open AccessPublished:April 17, 2015DOI:https://doi.org/10.1074/jbc.L115.648089
Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?
Previous ArticleInterleukin-2-inducible T-cell Kinase (ITK) Targeting by BMS-509744 Does Not Affect Cell Viability in T-cell Prolymphocytic Leukemia (T-PLL)
Next ArticleReply to Gurgul-Convey and Lenzen: Cytokines, Nitric Oxide, and β-Cells
      In their report (
      • Broniowska K.A.
      • Oleson B.J.
      • McGraw J.
      • Naatz A.
      • Mathews C.E.
      • Corbett J.A.
      How the location of superoxide generation influences the β-cell response to nitric oxide.
      J. Biol. Chem. 2015; 290: 7952-7960
      ), the authors strengthen doubts that peroxynitrite is a main culprit for β-cell dysfunction and death in type 1 diabetes, confirming previous studies (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ).
      Type 1 diabetes (T1DM) in humans and animal models is characterized by strong expression of the proinflammatory cytokines IL-1β and TNFα (
      • Jörns A.
      • Arndt T.
      • Meyer zu Vilsendorf A.
      • Klempnauer J.
      • Wedekind D.
      • Hedrich H.J.
      • Marselli L.
      • Marchetti P.
      • Harada N.
      • Nakaya Y.
      • Wang G.S.
      • Scott F.W.
      • Gysemans C.
      • Mathieu C.
      • Lenzen S.
      Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes.
      Diabetologia. 2014; 57: 512-521
      ). The reactive species generated by the cytokine action ultimately cause β-cell death through nitro-oxidative stress (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ). The very low expression of the H2O2-inactivating enzymes in β-cells, even though physiologically sufficient, is insufficient to prevent toxicity under pathophysiological conditions (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ).
      IL-1β alone with its dominant effect on NO generation causes β-cell dysfunction (
      • Weksler-Zangen S.
      • Raz I.
      • Lenzen S.
      • Jörns A.
      • Ehrenfeld S.
      • Amir G.
      • Oprescu A.
      • Yagil Y.
      • Yagil C.
      • Zangen D.H.
      • Kaiser N.
      Impaired glucose-stimulated insulin secretion is coupled with exocrine pancreatic lesions in the Cohen diabetic rat.
      Diabetes. 2008; 57: 279-287
      ). Only together with TNFα, a strong stimulator of mitochondrial reactive oxygen species formation (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ,
      • Lenzen S.
      Oxidative stress: the vulnerable beta-cell.
      Biochem. Soc. Trans. 2008; 36: 343-347
      ), does it cause β-cell death in T1DM (
      • Jörns A.
      • Arndt T.
      • Meyer zu Vilsendorf A.
      • Klempnauer J.
      • Wedekind D.
      • Hedrich H.J.
      • Marselli L.
      • Marchetti P.
      • Harada N.
      • Nakaya Y.
      • Wang G.S.
      • Scott F.W.
      • Gysemans C.
      • Mathieu C.
      • Lenzen S.
      Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes.
      Diabetologia. 2014; 57: 512-521
      ).
      Cytokine-treated β-cells show high manganese superoxide dismutase expression in the mitochondria (
      • Lenzen S.
      Oxidative stress: the vulnerable beta-cell.
      Biochem. Soc. Trans. 2008; 36: 343-347
      ). Thus, there is little chance for the superoxide radical to generate peroxynitrite through interaction with NO (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ). However, the authors ignore that these circumstances strongly favor the interaction between NO and H2O2, produced at high concentrations in cytokine-treated β-cell mitochondria, the primary site of cytokine toxicity (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ). This is the optimal precondition for formation of the highly toxic hydroxyl radical, because β-cell mitochondria express very little glutathione peroxidase (
      • Lenzen S.
      Oxidative stress: the vulnerable beta-cell.
      Biochem. Soc. Trans. 2008; 36: 343-347
      ), insufficient for quick H2O2 inactivation (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ,
      • Lenzen S.
      Oxidative stress: the vulnerable beta-cell.
      Biochem. Soc. Trans. 2008; 36: 343-347
      ).
      The authors overlook the crucial role of TNFα in the pathogenesis of β-cell death in T1DM and therefore their conclusion that NO is the primary mediator of cellular toxicity is inadequate. Experiments performed with a combination of IL-1β and TNFα confirm this (
      • Gurgul-Convey E.
      • Mehmeti I.
      • Lortz S.
      • Lenzen S.
      Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
      J. Mol. Med. 2011; 89: 785-798
      ).

      REFERENCES

        • Broniowska K.A.
        • Oleson B.J.
        • McGraw J.
        • Naatz A.
        • Mathews C.E.
        • Corbett J.A.
        How the location of superoxide generation influences the β-cell response to nitric oxide.
        J. Biol. Chem. 2015; 290: 7952-7960
        View in Article
        • Gurgul-Convey E.
        • Mehmeti I.
        • Lortz S.
        • Lenzen S.
        Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria.
        J. Mol. Med. 2011; 89: 785-798
        View in Article
        • Jörns A.
        • Arndt T.
        • Meyer zu Vilsendorf A.
        • Klempnauer J.
        • Wedekind D.
        • Hedrich H.J.
        • Marselli L.
        • Marchetti P.
        • Harada N.
        • Nakaya Y.
        • Wang G.S.
        • Scott F.W.
        • Gysemans C.
        • Mathieu C.
        • Lenzen S.
        Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes.
        Diabetologia. 2014; 57: 512-521
        View in Article
        • Weksler-Zangen S.
        • Raz I.
        • Lenzen S.
        • Jörns A.
        • Ehrenfeld S.
        • Amir G.
        • Oprescu A.
        • Yagil Y.
        • Yagil C.
        • Zangen D.H.
        • Kaiser N.
        Impaired glucose-stimulated insulin secretion is coupled with exocrine pancreatic lesions in the Cohen diabetic rat.
        Diabetes. 2008; 57: 279-287
        View in Article
        • Lenzen S.
        Oxidative stress: the vulnerable beta-cell.
        Biochem. Soc. Trans. 2008; 36: 343-347
        View in Article

      Article info

      Publication history

      Published online: April 17, 2015

      Identification

      DOI: https://doi.org/10.1074/jbc.L115.648089

      Copyright

      © 2015 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.

      User license

      Creative Commons Attribution (CC BY 4.0) |
      How you can reuse Information Icon
      Creative Commons Attribution (CC BY 4.0)

      Permitted

      • Read, print & download
      • Redistribute or republish the final article
      • Text & data mine
      • Translate the article
      • Reuse portions or extracts from the article in other works
      • Sell or re-use for commercial purposes

      Elsevier's open access license policy

      ScienceDirect

      Access this article on ScienceDirect

      ASBMB  ASBMB  ASBMB  ASBMB

      ISSN 0021-9258
      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the for this site.
      Copyright © 2022 Elsevier Inc. except certain content provided by third parties. The content on this site is intended for healthcare professionals.


      RELX