Renalase inhibition defends against acute and chronic β cell stress by regulating cell metabolism.

Abstract

Renalase (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 T1D in vivo, and protects pancreatic β cells against autoimmune killing, ER and oxidative stress in vitro. The molecular biochemistry and functions of Rnls are largely uncharted. Here we find that Rnls inhibition defends against loss of β cell mass and islet dysfunction in chronically stressed Akita mice in vivo. We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in a mouse β cell line and human stem cell-derived β cells and discovered a robust and conserved metabolic shift towards glycolysis to counter protein misfolding stress, in vitro. Our work illustrates metabolic functions 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.