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

• Published in: bioRxiv : the preprint server for biology
• Main Authors: MacDonald, Tara, Ryback, Birgitta, da Silva Pereira, Jessica Aparecida, Wei, Siying, Mendez, Bryhan, Cai, Erica, Ishikawa, Yuki, Weir, Gordon, Bonner-Weir, Susan, Kissler, Stephan, Yi, Peng
• Format: Journal Article
• Language: English
• Published: United States 13.06.2024

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 , and protects pancreatic β cells against autoimmune killing, ER and oxidative stress . 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 mice . 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, . 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.