Scientific article

A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion

Published inDiabetes, vol. 50, no. 6, p. 1311-1323
Publication date2001

Evidence is presented showing that a neuronal isoform of nitric oxide synthase (NOS) is expressed in rat pancreatic islets and INS-1 cells. Sequencing of the coding region indicated a 99.8% homology with rat neuronal NOS (nNOS) with four mutations, three of them resulting in modifications of the amino acid sequence. Double-immunofluorescence studies demonstrated the presence of nNOS in insulin-secreting beta-cells. Electron microscopy studies showed that nNOS was mainly localized in insulin secretory granules and to a lesser extent in the mitochondria and the nucleus. We also studied the mechanism involved in the dysfunction of the beta-cell response to arginine and glucose after nNOS blockade with N(G)-nitro-L-arginine methyl ester. Our data show that miconazole, an inhibitor of nNOS cytochrome c reductase activity, either alone for the experiments with arginine or combined with sodium nitroprusside for glucose, is able to restore normal secretory patterns in response to the two secretagogues. Furthermore, these results were corroborated by the demonstration of a direct enzyme-substrate interaction between nNOS and cytochrome c, which is strongly reinforced in the presence of the NOS inhibitor. Thus, we provide immunochemical and pharmacological evidence that beta-cell nNOS exerts, like brain nNOS, two catalytic activities: a nitric oxide production and an NOS nonoxidating reductase activity, both of which are essential for normal beta-cell function. In conclusion, we suggest that an imbalance between these activities might be implicated in beta-cell dysregulation involved in certain pathological hyperinsulinic states.

  • Animals
  • Arginine/pharmacology
  • Base Sequence/genetics
  • Cell Membrane/drug effects/physiology
  • Clotrimazole/pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Electrophysiology
  • Glucose/administration & dosage/pharmacology
  • Insulin/secretion
  • Islets of Langerhans/drug effects/metabolism/physiology
  • Male
  • Miconazole/pharmacology
  • Molecular Sequence Data
  • Nitric Oxide Synthase/antagonists & inhibitors/genetics/metabolism
  • Nitric Oxide Synthase Type I
  • Nitroprusside/pharmacology
  • Rats
  • Rats, Wistar
  • Subcellular Fractions/enzymology
  • Succinates/pharmacology
  • Tissue Distribution
Citation (ISO format)
LAJOIX, A D et al. A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion. In: Diabetes, 2001, vol. 50, n° 6, p. 1311–1323. doi: 10.2337/diabetes.50.6.1311
Main files (2)
Article (Published version)
Article (Published version)
ISSN of the journal0012-1797

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