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A Role for Nitric Oxide and Other Inflammatory Mediators in Cytokine-Induced Pancreatic β-Cell Dysfunction and Destruction

  • Michael L. McDaniel
  • John A. Corbett
  • Guim Kwon
  • Jeanette R. Hill
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 426)

Abstract

Insulin-dependent diabetes mellitus is an autoimmune disease characterized by the selective destruction of the pancreatic β-cell. The autoimmune response that is ultimately responsible for the destruction of the β-cell consists of a number of complex components. Cytokines released during this inflammatory reaction have been implicated as effector molecules which mediate β-cell destruction1–3. Our studies have focused primarily in attempting to define the role of cytokines released by both T-lymphocytes and activated macrophages to produce deleterious effects directly on the β-cell during the initial inflammatory response associated with autoimmune diabetes. Our studies have described the ability of the cytokine, interleukin-1 (IL-1), to both inhibit insulin secretion from the β-cell and also to produce cytotoxic effects via the formation of the free radical nitric oxide (NO). Our more recent studies have revealed that the ability of cytokines such as IL-1 to produce nitric oxide by islets is also directly linked to the production of the proinflammatory prostaglandins and thromboxanes that may play an important role in the initial inflammatory response that is the hallmark of autoimmune diabetes.

Keywords

Nitric Oxide Nitric Oxide Insulin Secretion Autoimmune Diabetes Inhibit Insulin Secretion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    J.A. Corbett, and M.L. McDaniel, Perspectives in Diabetes: Does nitric oxide mediate autoimmune destruction of β-cells? Possible therapeutic interventions in IDDM, Diabetes 41:897 (1992).PubMedCrossRefGoogle Scholar
  2. 2.
    T. Mandrup-Poulsen, S. Helqvist, L.D. Wogensen, J. Molvig, F. Pociot, J. Johannesen, and J. Nerup, Cytokines and free radicals as effector molecules in the destruction of pancreatic beta cells, Curr. Top. Microbiol. Immunol. 164:169 (1990).PubMedCrossRefGoogle Scholar
  3. 3.
    A. Rabinovitch, Roles of cytokines in IDDM pathogenesis and islet β-cell destruction, Diabetes Rev. 1:215 (1993).Google Scholar
  4. 4.
    J.H. Hughes, J.R. Colca, R.A. Easom, J. Turk, and M.L. McDaniel, Interleukin-l inhibits insulin secretion from isolated rat pancreatic islets by a process that requires gene transcription and mRNA translation, J Clin Invest 86:856 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    U. Forstermann, H.H.H.W. Schmidt, J.S. Pollock, H. Sheng, J.A. Mitchell, T.D. Warner, M. Nakane, and F. Murad, Isoforms of nitric oxide synthase, Biochem. Pharmacol. 42:1849 (1991).PubMedCrossRefGoogle Scholar
  6. 6.
    J.A. Corbett, J.L. Wang, T.P. Misko, W. Zhao, W. Hickey, and M.L. McDaniel, Nitric oxide mediates IL-lβ-induced islet dysfunction and destruction: Prevention by dexamethasone, Autoimmunity 15:145 (1993).PubMedCrossRefGoogle Scholar
  7. 7.
    C. Nathan, Nitric oxide as a secretory product of mammalian cells, FASEB J. 6:3051 (1992).PubMedGoogle Scholar
  8. 8.
    C. Southern, D. Schulster, and I.C. Green, Inhibition of insulin secretion by interleukin-1 β and tumor necrosis factor a via an L-arginine-dependent nitric oxide generation mechanism, FEBS Lett. 276:42 (1990).PubMedCrossRefGoogle Scholar
  9. 9.
    N. Welsh, D.L. Eizirik, K. Bendtzen, and S. Sandier, Interleukin-l β induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of Krebs cycle enzyme aconitase, Endocrinol. 129:3167 (1991).CrossRefGoogle Scholar
  10. 10.
    J.A. Corbett, J.R. Lancaster, M.A. Sweetland, and M.L. McDaniel ML, Interleukin 1 induced inhibition of glucose stimulated insulin secretion and the formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans, J. Biol. Chem. 266:21351 (1991).PubMedGoogle Scholar
  11. 11.
    J.A. Corbett, J.L. Wang, J.H. Hughes, B.A. Wolf, M. Sweetland, J.R. Lancaster, and M.L. McDaniel, Nitric oxide and cGMP formation induced by interleukin-lβ in islets of Langerhans: Evidence for an effector role of nitric oxide in islet dysfunction, Biochem. J. 287:229 (1992).PubMedGoogle Scholar
  12. 12.
    J.A. Corbett, J.L. Wang, M.A. Sweetland, J.R. Lancaster, and M.L. McDaniel, IL-lβ induces the formation of nitric oxide by β-cells purified from rodent islets of Langerhans: Evidence for the β-cell as a source and site of action of nitric oxide, J. Clin. Invest. 90:2384 (1992).PubMedCrossRefGoogle Scholar
  13. 13.
    J.A. Corbett, G. Kwon, T.P. Misko, C.P. Rodi, and M.L. McDaniel, Tyrosine kinase involvement in IL-lβ expression of iNOS by β-cells purified from islets of Langerhans, Am. J. Physiol. 267:(Cell Physiol. 36) C48(1994).PubMedGoogle Scholar
  14. 14.
    J.A. Corbett, M.A. Sweetland, J.R. Lancaster, and M.L. McDaniel, A 1 hour pulse with IL-lβ induces the formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans: Evidence for a tyrosine kinase signaling mechanism, FASEB J. 7:369 (1993).PubMedGoogle Scholar
  15. 15.
    J.A. Corbett, G. Kwon, J. Turk, and M.L. McDaniel, IL-lβ induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: Activation of cyclooxygenase by nitric oxide, Biochemistry 32:13767 (1993).PubMedCrossRefGoogle Scholar
  16. 16.
    J. Turk, B.A. Wolf, and M.L. McDaniel, The role of phospholipid-derived mediators including arachidonic acid, its metabolites, inositoltrisphosphate and intracellular Ca2+ in glucose-induced insulin release by islets, Progress in Lipid Research, 26:125 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Michael L. McDaniel
    • 1
  • John A. Corbett
    • 1
  • Guim Kwon
    • 1
  • Jeanette R. Hill
    • 1
  1. 1.Department of PathologyWashington University School of MedicineSaint LouisUSA

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