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Neuronatin regulates pancreatic beta cell insulin content and secretion

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Title: Neuronatin regulates pancreatic beta cell insulin content and secretion
Authors: Millership, S
Da Silva Xavier, G
Choudhury, A
Bertazzo, S
Chabosseau, PL
Pedroni, SMA
Irvine, E
Montoya, A
Faull, P
Taylor, WR
Kerr-Conte, J
Pattou, F
Ferrer, J
Christian, M
John, RM
Latreille, M
Liu, M
Rutter, G
Scott, J
Withers, DJ
Item Type: Journal Article
Abstract: Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.
Issue Date: 4-Jun-2018
Date of Acceptance: 17-May-2018
URI: http://hdl.handle.net/10044/1/60230
DOI: https://dx.doi.org/10.1172/JCI120115
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation
Start Page: 3369
End Page: 3381
Journal / Book Title: Journal of Clinical Investigation
Volume: 128
Issue: 8
Copyright Statement: © 2018 American Society for Clinical Investigation
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Medical Research Council
Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 093082/Z/10/Z
511377
MC-A654-5QB40
098424/Z/12/ZR
MR/K001981/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
SIGNAL PEPTIDASE COMPLEX
ENDOPLASMIC-RETICULUM
SACCHAROMYCES-CEREVISIAE
MEMBRANE TOPOLOGY
METABOLIC STATUS
GENE-EXPRESSION
INS GENE
PROTEIN
MICE
MUTATIONS
Beta cells
Cell Biology
Diabetes
Genetics
Insulin
Immunology
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2018-06-04
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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