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
| Autor: | B A Wolf, Jonathan H. Hughes, Michael L. McDaniel, J R Lancaster, Jin Lin Wang, M A Sweetland, John A. Corbett |
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| Rok vydání: | 1992 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Cycloheximide Arginine Nitric Oxide Biochemistry Nitric oxide Rats Sprague-Dawley Islets of Langerhans chemistry.chemical_compound Internal medicine medicine Animals Secretion Cyclic GMP Molecular Biology Nitrites geography omega-N-Methylarginine geography.geographical_feature_category biology Pancreatic islets Insulin Biological Transport Cell Biology Islet Rats Nitric oxide synthase Glucose Endocrinology medicine.anatomical_structure chemistry Second messenger system biology.protein Amino Acid Oxidoreductases Nitric Oxide Synthase Oxidation-Reduction Research Article Interleukin-1 |
| Zdroj: | Biochemical Journal. 287:229-235 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj2870229 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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