The NERP-4-SNAT2 axis regulates pancreatic β-cell maintenance and function

Insulin secretion from pancreatic beta cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on beta cells. The granin protein VGF has dual roles in beta cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and beta-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of beta-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into beta cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on beta-cell maintenance. These findings demonstrate a novel autocrine mechanism of beta-cell maintenance and function that is mediated by the peptide-amino acid transporter axis. Amino acids modulate insulin secretion via amino acid transporters expressed on beta cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to beta-cell maintenance and function.