Neuropeptide Y4 receptor activation delays autoimmune diabetes by reprogramming β-cell stress and immune tolerance

10 Jul 20264 min read0 viewsVerified Feed

GIST (Key Takeaways)

Type 1 diabetes (T1D) involves immune-mediated destruction of pancreatic {beta}-cells, yet current disease-modifying therapies mainly target immunity without enhancing {beta}-cell resilience. We show selective neuropeptide Y4 receptor (Y4R) agonism protects {beta}-cells while reshaping islet immunity across T1D models.
Multi-modal localisation using cell sorting, qPCR, RNAscope and fluorescent ligand competition demonstrated predominant Y4R expression and functional accessibility on mouse and human {beta}-cells. Selective Y4R agonism was non-toxic and did not impair islet network integrity, Ca{superscript 2} dynamics, glucose-stimulated insulin secretion or systemic glucose tolerance.
Y4R activation conferred cytoprotection against inflammatory cytokines, streptozotocin, lipotoxicity and ER stress, reducing caspase-3/7 activation and {beta}-cell loss whilst sustaining insulin release and promoting proliferation in both mouse and human islets. Bulk RNA-seq revealed a coordinated {beta}-cell resilience programme characterised by reinforced identity and insulin processing, KEAP1-NFE2L2-driven antioxidative and proteostatic activation, and suppression of EIF2 signalling and associated biosynthetic and ER stress pathways.
Concurrently, Y4R agonism dampened pathogenic chemokine and cytokine networks, including CXCL10, CCL3/4/7 and IL-6, while preserving IL-2 and Foxp3 signals, thereby limiting CD8 T cell, CD4 T cell and macrophage chemotaxis toward cytokine-stressed islets.

bioRxiv (Biomedical Preprints) published a clinical update in Research Highlights on 10 Jul 2026.

The item focuses on Neuropeptide Y4 receptor activation delays autoimmune diabetes by reprogramming β-cell stress and immune tolerance.

Review the original article for the full source wording and details.

Read the full original publication from the source journal or publisher link below.

Feed Metadata

Source

bioRxiv (Biomedical Preprints)