Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress

Abstract

AbstractRenalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1Din vivo, and protects pancreatic β cells against autoimmune killing, ER and oxidative stressin vitro. The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of β cell mass and islet dysfunction in chronically stressed Akita micein vivo. We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human β cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress,in vitro. Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of β cells can rewire metabolism to protect against diabetogenic stress.