Lysine Potentiates Insulin Secretion via AASS-Dependent Catabolism and Regulation of GABA Content and Signaling

Background and aimLysine is an essential amino acid with insulinotropic effects in humans. In vitro, lysine also potentiates glucose-stimulated insulin secretion (GSIS) in {beta} cell lines and rodent pancreatic islets. For decades it has been assumed that insulinotropic action of lysine is mediated by plasma membrane depolarization similar to arginine. Aminoadipate-Semialdehyde Synthase (AASS) is a mitochondrial-located bifunctional enzyme engaged in the first two steps of the lysine catabolism. Whether AASS-dependent lysine catabolism occurs in {beta} cells and whether it is required for its insulinotropic action has not been investigated. MethodsmRNA expression of lysine catabolism pathway genes was assessed in human islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects. AASS was silenced in human pancreatic islets and in INS1 832/13 {beta} cells. {beta} cell metabolism and function were investigated by ELISA, extracellular flux analysis, live cell calcium imaging, transcriptomics and metabolomics analyses. ResultsExpression of genes involved in lysine catabolism, including AASS, ALDH7A1, DHTKD1 and HADH, was reduced in pancreatic islets from T2D donors. Silencing of AASS resulted in reduced lysine- and glucose-stimulated insulin secretion in human islets and INS1 832/13 {beta} cells. Surprisingly, transcriptomics and metabolomics analysis in Aass-KD {beta} cells with suppressed lysine catabolism identified reduced {gamma}-aminobutyric acid (GABA)/glutamate ratio as well as altered expression of genes implicated in GABA metabolism. This was accompanied by altered mitochondrial TCA cycle and oxidative phosphorylation (OXPHOS) activity, reflected by elevated lactate/pyruvate and reduced whole-cell ATP/ADP content as well as ATP-linked mitochondrial respiration. Glucose-and GABA-stimulated cytosolic calcium was also altered in Aass-KD {beta} cells. Strikingly, addition of GABA recovered impaired insulin secretion in Aass-KD {beta} cells. ConclusionAASS-dependent lysine catabolism is required to maintain adequate GABA shunt metabolism and signaling. In addition, lysine catabolism supports mitochondrial energy production, calcium uptake and insulin secretion. Reduced AASS-dependent lysine catabolism may contribute to {beta} cell GABA depletion and dysfunction in T2D patients.