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

Weidong Zhang, Ayako Miura, Md Moin Abu Saleh, Koichiro Shimizu, Yuichiro Mita, Ryota Tanida, Satoshi Hirako, Seiji Shioda, Valery Gmyr, Julie Kerr-Conte, Francois Pattou, Chunhuan Jin, Yoshikatsu Kanai, Kazuki Sasaki, Naoto Minamino, Hideyuki Sakoda and Masamitsu Nakazato ()
Additional contact information
Weidong Zhang: University of Miyazaki
Ayako Miura: University of Miyazaki
Md Moin Abu Saleh: University of Miyazaki
Koichiro Shimizu: University of Miyazaki
Yuichiro Mita: University of Miyazaki
Ryota Tanida: University of Miyazaki
Satoshi Hirako: University of Human Arts and Sciences
Seiji Shioda: Shonan University of Medical Sciences
Valery Gmyr: Université de Lille, Inserm, Campus Hospitalo-Universitaire de Lille, Institut Pasteur de Lille
Julie Kerr-Conte: Université de Lille, Inserm, Campus Hospitalo-Universitaire de Lille, Institut Pasteur de Lille
Francois Pattou: Université de Lille, Inserm, Campus Hospitalo-Universitaire de Lille, Institut Pasteur de Lille
Chunhuan Jin: Osaka University
Yoshikatsu Kanai: Osaka University
Kazuki Sasaki: Sasaki Foundation
Naoto Minamino: National Cerebral and Cardiovascular Center Research
Hideyuki Sakoda: University of Miyazaki
Masamitsu Nakazato: University of Miyazaki

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Insulin secretion from pancreatic β 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 β cells. The granin protein VGF has dual roles in β 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 β-cell–derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-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 β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide–amino acid transporter axis.

Date: 2023
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DOI: 10.1038/s41467-023-43976-8

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