Glucose-Stimulated Insulin Secretion Fundamentally Requires H2O2 Signaling by NADPH Oxidase 4
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
32245800
DOI
10.2337/db19-1130
PII: db19-1130
Knihovny.cz E-zdroje
- MeSH
- draslíkové kanály fyziologie MeSH
- glukosa farmakologie MeSH
- inzulinová rezistence MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- NADPH-oxidasa 4 fyziologie MeSH
- peroxid vodíku metabolismus MeSH
- sekrece inzulinu * MeSH
- signální transdukce fyziologie MeSH
- vápník metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- draslíkové kanály MeSH
- glukosa MeSH
- mitochondrial K(ATP) channel MeSH Prohlížeč
- NADPH-oxidasa 4 MeSH
- Nox4 protein, mouse MeSH Prohlížeč
- peroxid vodíku MeSH
- vápník MeSH
NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islets (PIs) of β-cells through an as yet unknown mechanism. We found NADPH oxidase isoform 4 (NOX4) to be the main producer of cytosolic H2O2, which is essential for GSIS; an increase in ATP alone was insufficient for GSIS. The fast GSIS phase was absent from PIs from NOX4-null, β-cell-specific knockout mice (NOX4βKO) (though not from NOX2 knockout mice) and from NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H2O2 rescued GSIS in PIs from NOX4βKO mice. NOX4 silencing suppressed Ca2+ oscillations, and the patch-clamped KATP channel opened more frequently when glucose was high. Mitochondrial H2O2, decreasing upon GSIS, provided alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxides through electron-transfer flavoprotein:Q-oxidoreductase. Unlike GSIS, such insulin secretion was blocked with mitochondrial antioxidant SkQ1. Both NOX4 knockout and NOX4βKO mice exhibited impaired glucose tolerance and peripheral insulin resistance. Thus, the redox signaling previously suggested to cause β-cells to self-check hypothetically induces insulin resistance when it is absent. In conclusion, increases in ATP and H2O2 constitute an essential signal that switches on insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (it does so partially for fatty acids). Redox signaling could be impaired by cytosolic antioxidants; hence, those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.
Institut für Kardiovaskuläre Physiologie Goethe Universität Frankfurt Germany
Institute of Clinical and Experimental Medicine Prague Czech Republic
Klinik für Neurologie Universität Magdeburg Magdeburg Germany
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