Abstract
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/H(2)O(2), providing: i) mitochondria-to-plasma-membrane redox signaling, closing K(ATP)-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H(2)O(2)-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA(2)γ/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 iPLA(2)γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H(2)O(2)-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 [Ca(2+)]-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.