Plecita-Hlavata 2020 Diabetes

Plecitá-Hlavatá L, Jabůrek M, Holendová B, Tauber J, Pavluch V, Berková Z, Cahová M, Schröder K, Brandes RP, Siemen D, Ježek P (2020) Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4 . Diabetes 69:1341-54.

» PMID: 32245800 Open Access

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 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.

© 2020 by the American Diabetes Association.

• Bioblast editor: Plangger M • 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