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

Deffert-Delbouille, Christine
Ma, Xiao-Juan
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Published in Diabetes. 2012, vol. 61, no. 11, p. 2842-50
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 AnimalsCells, CulturedCyclic AMP/agonists/antagonists & inhibitors/metabolismCyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/metabolismGene SilencingGlucagon-Like Peptide 1/metabolismHumansInsulin/secretionInsulin-Secreting Cells/cytology/drug effects/metabolism/secretionIslets of Langerhans/cytology/drug effects/metabolism/secretionIsoenzymes/antagonists & inhibitors/genetics/metabolismMembrane Glycoproteins/antagonists & inhibitors/genetics/metabolismMiceMice, Inbred C57BLMice, KnockoutNADPH Oxidase/antagonists & inhibitors/genetics/metabolismProtein Kinase Inhibitors/pharmacologyRNA, Small InterferingReactive Oxygen Species/metabolismSecond Messenger Systems/drug effectsSecretory Vesicles/drug effects/metabolismTissue Culture Techniques
PMID: 22933115
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Research groups Groupe Desmeules Jules (pharmacologie/toxicologie) (567)
Mitochondries et métabolisme énergétique (671)
Pharmaco-omiques et médecine de précision (1003)
Swiss National Science Foundation: 310030B_135704
(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. 2842-50. doi: 10.2337/db12-0009 https://archive-ouverte.unige.ch/unige:28039

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Deposited on : 2013-05-28

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