The NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function
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Published:2023-12-09
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhang WeidongORCID, Miura Ayako, Abu Saleh Md Moin, Shimizu Koichiro, Mita Yuichiro, Tanida Ryota, Hirako Satoshi, Shioda Seiji, Gmyr Valery, Kerr-Conte Julie, Pattou FrancoisORCID, Jin Chunhuan, Kanai YoshikatsuORCID, Sasaki Kazuki, Minamino NaotoORCID, Sakoda HideyukiORCID, Nakazato MasamitsuORCID
Abstract
AbstractInsulin 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.
Funder
MEXT | Japan Society for the Promotion of Science Japan Agency for Medical Research and Development
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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