NERP-4-Deleted VGF Impairs β-Cell Granulogenesis and Insulin Secretion

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.