Lecture „Redox mechanisms of insulin secretion“

RNDr. Petr Ježek, DrSc., Laboratory of Mitochondrial Physiology, IPHYS

RNDr. Petr Ježek, DrSc., Laboratory of Mitochondrial Physiology, IPHYS

Acute redox signaling from mitochondria has been sparsely reported. Fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic beta-cells has been questioned. We show that FA beta-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 iPLA2gamma (termed alsoPNPLA8), 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 iPLA2gamma-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 beta-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS. Moreover, upon glucose-stimulated insulin secretion, mitochondrial cristae became narrowed in 2D transmission electron microscopy sections, resulting from inflation of cristae volume, documented by 3D images of 2 nm resolution taken by focused-ion beam / scanning electron microscopy (FIB/SEM).  

Summary: Redox signal of beta-oxidation of fatty acids plus concomitant elevation of ATP is essential for fatty-acid stimulated insulin secretion at low glucose in pancreatic beta cells.