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

  • FASEB J. 2025 Dec 31;39(24):e71365. doi: 10.1096/fj.202502474R.
Weidong Zhang  1  2 ,  Yuki Nakazato  3 ,  Naoto Minamino  4 ,  Nobuaki Okumura  2 ,  Ayako Miura  5 ,  Takefusa Tarusawa  6 ,  Hiroki Mizukami  6 ,  Hideyuki Sakoda  2 ,  Masamitsu Nakazato  7
Affiliations
  • 1. Department of Veterinary Anatomy, Faculty of Agriculture, University of Miyazaki, Miyazaki, Miyazaki, Japan.
  • 2. Laboratory of Biomolecular Analysis, Institute for Protein Research, The University of Osaka, Osaka, Japan.
  • 3. Division of Respirology, Rheumatology, Infectious Diseases, and Neurology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Miyazaki, Japan.
  • 4. Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
  • 5. Department of Bioregulatory Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Miyazaki, Japan.
  • 6. Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
  • 7. Forefront Research Center, Graduate School of Science, The University of Osaka, Osaka, Japan.
PMID: 41405840 DOI: 10.1096/fj.202502474R
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.

Keywords
NERP‐4; VGF; granulogenesis; insulin; β cell.
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