Treatment of pancreatic islets with interleukin 1 (IL-1) results in a time-dependent inhibition of glucose-stimulated insulin secretion which has recently been demonstrated to be dependent on the metabolism of L-arginine to nitric oxide. In this report IL-1 beta is shown to induce the accumulation of cyclic GMP (cGMP) in a time-dependent fashion that mimics the time-dependent inhibition of insulin secretion by IL-1 beta. The accumulation of cGMP is dependent on nitric oxide synthase activity, since NG-monomethyl-L-arginine (a competitive inhibitor of nitric oxide synthase) prevents IL-1 beta-induced cGMP accumulation. cGMP formation and nitrite production induced by IL-1 beta pretreatment of islets are also blocked by the protein synthesis inhibitor, cycloheximide. The formation of cGMP does not appear to mediate the inhibitory effects of IL-1 beta on insulin secretion since a concentration of cycloheximide (1 microM) that blocks IL-1 beta-induced inhibition of glucose-stimulated insulin secretion and nitric oxide formation does not prevent cGMP accumulation, thus dissociating the two events. By using e.p.r. spectroscopy, IL-1 beta is shown to induce the formation of a g = 2.04 iron-nitrosyl feature in islets which is prevented by cycloheximide, demonstrating the requirement of protein synthesis for IL-1 beta-induced nitric oxide formation. Iron-nitrosyl complex-formation by islets confirms that IL-1 beta induces the generation of nitric oxide by islets, and provides evidence indicating that nitric oxide mediates destruction of iron-sulphur clusters of iron-containing enzymes. Consistent with the destruction of iron-sulphur centres is the finding that pretreatment of islets with IL-1 beta results in an approx. 60% inhibition of mitochondrial oxidation of D-glucose to CO2. Inhibition of islet glucose oxidation appears to be mediated by nitric oxide since both NMMA and cycloheximide prevent IL-1 beta-induced inhibition of glucose oxidation. These results show that IL-1 beta-induced nitric oxide formation parallels the ability of IL-1 beta to inhibit glucose-stimulated insulin secretion by islets, and that protein synthesis is required for IL-1 beta-induced nitric oxide formation. These results also suggest that nitric oxide mediates IL-1 beta-induced inhibitory effects on the pancreatic beta-cell by functioning as an effector molecule responsible for the destruction of iron-sulphur centres of iron-containing proteins, resulting in an impairment of mitochondrial function.
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October 1992
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Research Article|
October 01 1992
Nitric oxide and cyclic GMP formation induced by interleukin 1β in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction
J A Corbett;
J A Corbett
*Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
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J L Wang;
J L Wang
*Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
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J H Hughes;
J H Hughes
*Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
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B A Wolf;
B A Wolf
†Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, U.S.A
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M A Sweetland;
M A Sweetland
†Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, U.S.A
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J R Lancaster, Jr;
J R Lancaster, Jr
†Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, U.S.A
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M L McDaniel
M L McDaniel
*Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
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Publisher: Portland Press Ltd
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 1992 The Biochemical Society, London
1992
Biochem J (1992) 287 (1): 229–235.
Citation
J A Corbett, J L Wang, J H Hughes, B A Wolf, M A Sweetland, J R Lancaster, M L McDaniel; Nitric oxide and cyclic GMP formation induced by interleukin 1β in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction. Biochem J 1 October 1992; 287 (1): 229–235. doi: https://doi.org/10.1042/bj2870229
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