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

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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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Abbreviations

ACh:

Acetylcholine

ARRB:

β-Arrestin

AU:

Arbitrary units

[Ca2+]c :

Free cytosolic Ca2+ concentration

FOXO1:

Forkhead box O1

GIPR:

Gastric inhibitory polypeptide receptor

GLP-1R:

Glucagon-like peptide-1 receptor

GPCR:

G protein-coupled receptor

GSIS:

Glucose-stimulated insulin secretion

GSK3:

Glycogen synthase kinase 3

H&E:

Haematoxylin and eosin

HFD:

High-fat diet

IR:

Insulin receptor

ND:

Normal diet

PDX1:

Pancreas/duodenum homeobox protein 1

PI3K:

Phosphatidylinositol 3-kinase

RTK:

Receptor tyrosine kinase

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Acknowledgements

The authors thank R. J. Lefkowitz (Duke University Medical Center, Durham, USA) for kindly providing Arrb2 −/− mice, C. Bonnans (Institut de Génomique Fonctionnelle, Montpellier, France) for supplying and genotyping the animals, and L. Forichon and F. Rubio (Institut de Génomique Fonctionnelle, Montpellier, France) for technical assistance with the animals. The authors thank colleagues at the Reseau Histologie Expérimentale de Montpellier (Institut de Recherche en Cancérologie de Montpellier, Montpellier, France) and Montpellier Rio Imaging facilities (Institut des Neurosciences de Montpellier, Montpellier, France) for technical assistance.

Funding

This work was supported by the Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale (grant DRM20101220453), research allocation from SFD-ALFEDIAM.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

MAR contributed to the design, the acquisition, analysis and interpretation of the data and to the drafting/revision of the article. ML, JR, NL, AV, NP, MMR, SD and JB contributed to the acquisition and analysis of the data and to the revision of the manuscript. GB contributed to the conception and design of the study, the acquisition, analysis and interpretation of data and to drafting/revising the manuscript. All authors approved the final version to be published.

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Authors and Affiliations

  1. CNRS, UMR-5203, Institut de Génomique Fonctionnelle, 141 Rue de la Cardonille, 34094, Montpellier, France

    Magalie A. Ravier, Michele Leduc, Joy Richard, Nathalie Linck, Annie Varrault, Morgane M. Roussel, Joël Bockaert, Stéphane Dalle & Gyslaine Bertrand

  2. Inserm, U661, Institut de Génomique Fonctionnelle, Montpellier, France

    Magalie A. Ravier, Michele Leduc, Joy Richard, Nathalie Linck, Annie Varrault, Morgane M. Roussel, Joël Bockaert, Stéphane Dalle & Gyslaine Bertrand

  3. Institut de Génomique Fonctionnelle, Universités de Montpellier 1 & 2, Montpellier, France

    Magalie A. Ravier, Michele Leduc, Joy Richard, Nathalie Linck, Annie Varrault, Morgane M. Roussel, Joël Bockaert, Stéphane Dalle & Gyslaine Bertrand

  4. Inserm, U896, Institut de Recherche en Cancérologie de Montpellier, Centre Régional de Lutte Contre le Cancer Val d’Aurelle Paul Lamarque, Montpellier, France

    Nelly Pirot

  5. Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, Montpellier, France

    Nelly Pirot

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  1. Magalie A. Ravier
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  2. Michele Leduc
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  3. Joy Richard
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  7. Morgane M. Roussel
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  9. Stéphane Dalle
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  10. Gyslaine Bertrand
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Correspondence to Gyslaine Bertrand.

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Ravier, M.A., Leduc, M., Richard, J. et al. β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice. Diabetologia 57, 532–541 (2014). https://doi.org/10.1007/s00125-013-3130-7

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  • DOI: https://doi.org/10.1007/s00125-013-3130-7

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