Plecita-Hlavata 2020 Diabetes: Difference between revisions
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Latest revision as of 22:34, 8 January 2021
PlecitΓ‘-HlavatΓ‘ L, JabΕ―rek M, HolendovΓ‘ B, Tauber J, Pavluch V, BerkovΓ‘ Z, CahovΓ‘ M, SchrΓΆder K, Brandes RP, Siemen D, JeΕΎek P (2020) Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4 . Diabetes 69:1341-54. |
Plecita-Hlavata Lydie, Jaburek Martin, Holendova Blanka, Tauber Jan, Pavluch Vojtech, Berkova Zuzana, Cahova Monika, Schroeder Katrin, Brandes Ralf P, Siemen Detlef, Jezek Petr (2020) Diabetes
Abstract: NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islets (PIs) of Ξ²-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, Ξ²-cell-specific knockout mice (NOX4Ξ²KO) (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 NOX4Ξ²KO 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 NOX4Ξ²KO mice exhibited impaired glucose tolerance and peripheral insulin resistance. Thus, the redox signaling previously suggested to cause Ξ²-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.
Β© 2020 by the American Diabetes Association.
β’ Bioblast editor: Plangger M β’ O2k-Network Lab: CZ Prague Jezek P
Labels: MiParea: Genetic knockout;overexpression
Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Islet cell;pancreas;thymus
2021-01