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

Ravier, Magalie A.; Leduc, Michèle; Richard, J.; Linck, Nathalie; Varrault, Annie; Pirot, Nelly; Roussel, M.; Bockaert, Joël; Dalle, Stéphane; Bertrand, Gyslaine

doi:10.1007/s00125-013-3130-7

Cited by 49 publications

(41 citation statements)

References 51 publications

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“…Treatment of WT and ␤-arrestin 2 Ϫ/Ϫ islets with 16.7 mM glucose resulted in a similar induction of insulin secretion (Fig. 5B), as reported previously (22). PA or OA similarly potentiated glucose-stimulated insulin secretion from WT and ␤-arrestin 2 Ϫ/Ϫ islets.…”

Section: Tak-875- But Not Ffa-induced Insulin Secretion Is Reduced Isupporting

confidence: 87%

“…Further, ␤-arrestins negatively regulate the production of pro-inflammatory cytokines by interfering with NF-b signaling, a pathway implicated in ␤-cell dysfunction in T2D (41). Finally, ␤-arrestins have been implicated in compensatory ␤-cell proliferation and insulin signaling (22). It is therefore tempting to speculate that contrary to unbiased GPR40 agonists, which would simply act as insulin secretagogues, ␤-arrestin-biased GPR40 agonists may also afford additional cytoprotective, anti-inflammatory, and mitogenic actions, although this needs to be directly tested.…”

Section: Discussionmentioning

confidence: 99%

“…22. The original heterozygous ␤-arrestin 2 ϩ/Ϫ mice were from R. J. Lefkowitz (Duke University Medical Center, Durham, NC; described in Ref.…”

Section: Methodsmentioning

confidence: 99%

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β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1

Mancini

Bertrand

Vivot

et al. 2015

Journal of Biological Chemistry

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Background: FFAR1/GPR40 is a potential target to enhance insulin secretion in type 2 diabetes, yet knowledge of the pharmacobiology of GPR40 remains incomplete. Results: GPR40 functions via both G protein-mediated and ␤-arrestin-mediated mechanisms; endogenous and synthetic ligands differentially engage these pathways to promote insulin secretion. Conclusion: GPR40 is subject to functionally relevant biased agonism. Significance: Biased agonism at GPR40 could be exploited for therapeutic purposes.

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Section: Tak-875- But Not Ffa-induced Insulin Secretion Is Reduced Isupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1

Mancini

Bertrand

Vivot

et al. 2015

Journal of Biological Chemistry

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“…of βarr2 deletion on glucose-stimulated insulin secretion are controversial (11,14). This discrepancy may result from the islets isolated from different mice, as while we used islets from 12-wk-old male mice, Ravier et al used islets from 6-to 7-month-old female mice.…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 96%

“…βarr2 aggravated atherosclerosis after carotid injury through mechanisms involving smooth muscle cell proliferation (12) and exacerbated hepatic fibrosis induced by porcine serum through its effect on hepatic stellate cell proliferation (13), suggesting a role of βarr2 regulation of cell mass expansion under environmental stress. Interestingly, Ravier et al reported recently that knocking out βarr2 in female mice decreased the β-cell mass (14). However, how β-cell mass changes upon βarr2 deletion and its mechanism in regulating β-cell mass still remain largely unknown.…”

Section: Deletion Of A-arrestin2 In Mice Limited Pancreatic A-cell Exmentioning

confidence: 99%

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Lin

Zhao

Song

et al. 2016

Mol Med

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β-Arrestin2 (βarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that βarr2 was abundantly expressed in mouse pancreatic β-cells, and loss of βarr2 leads to impairment of acuteand late-phase insulin secretion. In the present study, we examined the dynamic changes of β-cell mass in barr2-deficient (barr2 -/-) mice in vivo and explored the underlying mechanisms involved. barr2-/-mice with exclusively luciferase overexpression in β-cellswere generated and fed a high-fat diet (HFD). β-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that β-cell mass was reduced dramatically in barr2 -/-mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU-and Ki67-positive cells reduced in islets from barr2 -/-mice. Exposure of barr2 -/-islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of βarr2 amplified β-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected β-cells from glucose-and FFA-induced cell death through JNK-activation inhibition.In conclusion, βarr2 plays roles in regulation of pancreatic β-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for βarr2 in the development of type 2 diabetes. China. Phone: +86-21-24058657; Fax: 86-21-64368031; E-mail: wangchen@sjtu.edu.cn. Submitted June 24, 2015; Accepted for publication February 22, 2016; Published Online (www.molmed.org) February 29, 2016. R E S E A R C H A R T I C L EM O L M E D 2 2 : 7 4 -8 4 , 2 0 1 6 | L i n E T A L . | 7 5Histology Study and Morphometric Analyses Pancreases were removed from 16-wk-old barr2 +/+ and barr2 -/-mice, immediately weighed, fixed and embedded. To determine the count and area of islets, 8-10 randomly chosen sections per mouse that were separated by at least 100 μm were stained with hematoxylin and eosin (H&E). The entire pancreatic sections were scanned using a Nikon Eclipse Ni-E Microscope (Nikon), and a tile image of the tissue section was generated using the NIS-Elements AR 4.20 (Nikon). The fractional area of the islet in the pancreas, islet count per unit pancreatic area (islet density) and islet size were manually quantified using Image-Pro Plus 6.0 (Media Cybernetics), as described previously (21). The average of all the sections was taken as a measure for the entire organ. The total islet mass was calculated as pancreatic weight × mean fractional pancreatic islet area. For immunofluorescence analysis, pan...

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Glucagon‐Like Peptide‐1 Receptor Activators

Wagner¹,

Evers²,

Bossart³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Type 2 diabetes (T2D) and obesity have reached pandemic levels and represent a major health burden to modern society. Peptidic GLP‐1 receptor agonists (GLP‐1RAs) have been established as an effective therapy with respect to glycemic control and provide moderate body weight reduction. Marketed first‐generation GLP‐1RAs are suitable for once‐ or twice‐daily subcutaneous dosing. Their substantial benefit on glucose control led to the discovery and development of longer lasting therapeutic options to improve patient convenience and compliance. Recently reported positive cardiovascular outcome studies for some GLP‐1RAs further underscore their therapeutic value. Besides long‐lasting action, alternative delivery formats for injectable GLP‐1RAs have been explored, for example oral formulations. One such oral formulation of a GLP‐1 analog has completed Phase 3 studies and is now approved for the treatment of T2D. In contrast, the discovery of orally available small molecule agonists of the GLP‐1R has been historically challenging, and only recently a few compounds have reached early clinical development. To further improve the efficacy of GLP‐1RAs, so‐called GLP‐1R dual or triple agonists have been developed. These peptides show promising results in early clinical trials but are awaiting confirmation of their therapeutic benefit in late‐stage development.

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

Abstract: 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.

Cited by 49 publications

References 51 publications

β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1

β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Glucagon‐Like Peptide‐1 Receptor Activators

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