Work

NERP ‐4–Deleted VGF Impairs β‐Cell Granulogenesis and Insulin Secretion

Year: 2025

Type: article

Abstract: ABSTRACT Neuroendocrine regulatory peptide‐4 (NERP‐4) processed from the granin protein VGF functions as a positive allosteric modulator that acts on the amino acid transporter SNAT2 expressed on pancreatic β cells. NERP‐4 promotes insulin secretion and β‐cell maintenance. We studied the effects of NERP‐4–deleted VGF (VGF △NERP‐4 ) on β‐cell functions in MIN6‐K8 β cells and CRISPR‐Cas9–designed mouse islets. VGF △NERP‐4 exhibited reduced insulin secretion and disrupted β‐cell maintenance. Notably, VGF △NERP‐4 caused defective insulin granule formation via insulin accumulation in the trans ‐Golgi network, thereby reducing replenishment of insulin granule stores in the second‐phase insulin secretion. These findings are comparable to those obtained in Vgf knockdown. NERP‐4 administration to VGF △NERP‐4 β cells restored β‐cell maintenance but not insulin granule formation. NERP‐4 was reduced in the islets of patients with type 2 diabetes mellitus. NERP‐4 plays a role in β‐cell viability and the NERP‐4 region is critical for VGF structure in the context of granulogenesis, thereby providing new insights into the role of NERP‐4 in β‐cell biology.

Source: The FASEB Journal

DOI: 10.1096/fj.202502474r