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Scientific article
Open access
English

NADPH oxidase NOX2 defines a new antagonistic role for reactive oxygen species and cAMP/PKA in the regulation of insulin secretion

Published inDiabetes, vol. 61, no. 11, p. 2842-2850
Publication date2012
Abstract

In insulin-secreting cells, expression of NADPH oxidase (NOX), a potent source of ROS, has been reported, along with controversial findings regarding its function. Here, the role of NOXs was investigated: first by expression and cellular localization in mouse and human pancreatic islets, and then by functional studies in islets isolated from Nox isoform-specific knockout mice. Both human and mouse β-cells express NOX, in particular NOX2. With use of Nox isoform-specific knockout mice, functional analysis revealed Nox2 as the predominant isoform. In human islets, NOX2 colocalized with both insulin granules and endosome/lysosome membranes. Nox2-deficient islets stimulated with 22.8 mmol/L glucose exhibited potentiation of insulin release compared with controls, an effect confirmed with in vitro knockdown of Nox2. The enhanced secretory function in Nox2-deficient islets was associated with both lower superoxide levels and elevated cAMP concentrations. In control islets, GLP-1 and other cAMP inducers suppressed glucose-induced ROS production similarly to Nox2 deficiency. Inhibiting cAMP-dependent protein kinase reduced the secretory response in Nox2-null islets, although not in control islets. This study ascribes a new role for NOX2 in pancreatic β-cells as negative modulator of the secretory response, reducing cAMP/PKA signaling secondary to ROS generation. Results also show reciprocal inhibition between the cAMP/PKA pathway and ROS.

Keywords
  • Animals
  • Cells, Cultured
  • Cyclic AMP/agonists/antagonists & inhibitors/metabolism
  • Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/metabolism
  • Gene Silencing
  • Glucagon-Like Peptide 1/metabolism
  • Humans
  • Insulin/secretion
  • Insulin-Secreting Cells/cytology/drug effects/metabolism/secretion
  • Islets of Langerhans/cytology/drug effects/metabolism/secretion
  • Isoenzymes/antagonists & inhibitors/genetics/metabolism
  • Membrane Glycoproteins/antagonists & inhibitors/genetics/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase/antagonists & inhibitors/genetics/metabolism
  • Protein Kinase Inhibitors/pharmacology
  • RNA, Small Interfering
  • Reactive Oxygen Species/metabolism
  • Second Messenger Systems/drug effects
  • Secretory Vesicles/drug effects/metabolism
  • Tissue Culture Techniques
Citation (ISO format)
LI, Ning et al. NADPH oxidase NOX2 defines a new antagonistic role for reactive oxygen species and cAMP/PKA in the regulation of insulin secretion. In: Diabetes, 2012, vol. 61, n° 11, p. 2842–2850. doi: 10.2337/db12-0009
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal0012-1797
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450downloads

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