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01.03.2014 | Article

β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice

verfasst von: Magalie A. Ravier, Michele Leduc, Joy Richard, Nathalie Linck, Annie Varrault, Nelly Pirot, Morgane M. Roussel, Joël Bockaert, Stéphane Dalle, Gyslaine Bertrand

Erschienen in: Diabetologia | Ausgabe 3/2014

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Abstract

Aims/hypothesis

Beta cell failure due to progressive secretory dysfunction and limited expansion of beta cell mass is a key feature of type 2 diabetes. Beta cell function and mass are controlled by glucose and hormones/neurotransmitters that activate G protein-coupled receptors or receptor tyrosine kinases. We have investigated the role of β-arrestin (ARRB)2, a scaffold protein known to modulate such receptor signalling, in the modulation of beta cell function and mass, with a specific interest in glucagon-like peptide-1 (GLP-1), muscarinic and insulin receptors.

Methods

β-arrestin2-knockout mice and their wild-type littermates were fed a normal or a high-fat diet (HFD). Glucose tolerance, insulin sensitivity and insulin secretion were assessed in vivo. Beta cell mass was evaluated in pancreatic sections. Free cytosolic [Ca²⁺] and insulin secretion were determined using perifused islets. The insulin signalling pathway was evaluated by western blotting.

Results

Arrb2-knockout mice exhibited impaired glucose tolerance and insulin secretion in vivo, but normal insulin sensitivity compared with wild type. Surprisingly, the absence of ARRB2 did not affect glucose-stimulated insulin secretion or GLP-1- and acetylcholine-mediated amplifications from perifused islets, but it decreased the islet insulin content and beta cell mass. Additionally, there was no compensatory beta cell mass expansion through proliferation in response to the HFD. Furthermore, Arrb2 deletion altered the islet insulin signalling pathway.

Conclusions/interpretation

ARRB2 is unlikely to be involved in the regulation of insulin secretion, but it is required for beta cell mass plasticity. Additionally, we provide new insights into the mechanisms involved in insulin signalling in beta cells.

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Titel: β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice
verfasst von: Magalie A. Ravier
Michele Leduc
Joy Richard
Nathalie Linck
Annie Varrault
Nelly Pirot
Morgane M. Roussel
Joël Bockaert
Stéphane Dalle
Gyslaine Bertrand
Publikationsdatum: 01.03.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 3/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-3130-7

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β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice