We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS.

• Keywords
• Fatty acid-stimulated insulin secretion, GPR40, Mitochondrial fatty acids, Pancreatic β-cells, Redox signaling, Redox-activated phospholipase iPLA2γ,
• MeSH
• Insulin-Secreting Cells * metabolism   MeSH
• Cell Membrane * metabolism   MeSH
• Group VI Phospholipases A2 metabolism   genetics   MeSH
• Glucose metabolism   MeSH
• Insulin metabolism   MeSH
• Fatty Acids * metabolism   MeSH
• Mitochondria * metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Oxidation-Reduction * MeSH
• Hydrogen Peroxide metabolism   MeSH
• Receptors, G-Protein-Coupled MeSH
• Insulin Secretion * MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ffar1 protein, mouse MeSH Browser
• Group VI Phospholipases A2 MeSH
• Glucose MeSH
• Insulin MeSH
• Fatty Acids * MeSH
• Hydrogen Peroxide MeSH
• Pla2g6 protein, mouse MeSH Browser
• Receptors, G-Protein-Coupled MeSH