Glucose-Stimulated Insulin Secretion Fundamentally Requires H(2)O(2)Signaling by NADPH Oxidase 4
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F20%3A00531109" target="_blank" >RIV/67985823:_____/20:00531109 - isvavai.cz</a>
Alternative codes found
RIV/00023001:_____/20:00079785
Result on the web
<a href="https://doi.org/10.2337/db19-1130" target="_blank" >https://doi.org/10.2337/db19-1130</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.2337/db19-1130" target="_blank" >10.2337/db19-1130</a>
Alternative languages
Result language
angličtina
Original language name
Glucose-Stimulated Insulin Secretion Fundamentally Requires H(2)O(2)Signaling by NADPH Oxidase 4
Original language description
NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islets (PIs) of beta-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, beta-cell-specific knockout mice (NOX4 beta KO) (though not from NOX2 knockout mice) and from NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H(2)O(2)rescued GSIS in PIs from NOX4 beta KO mice. NOX4 silencing suppressed Ca(2+)oscillations, and the patch-clamped K(ATP)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 NOX4 beta KO mice exhibited impaired glucose tolerance and peripheral insulin resistance. Thus, the redox signaling previously suggested to cause beta-cells to self-check hypothetically induces insulin resistance when it is absent. In conclusion, increases in ATP and H(2)O(2)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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30202 - Endocrinology and metabolism (including diabetes, hormones)
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Diabetes
ISSN
0012-1797
e-ISSN
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Volume of the periodical
69
Issue of the periodical within the volume
7
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
1341-1354
UT code for WoS article
000542843100006
EID of the result in the Scopus database
2-s2.0-85086740400