β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion

Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-09, Vol.130 (9), p.3732-3737
Main Authors: Barella, Luiz F, Rossi, Mario, Zhu, Lu, Cui, Yinghong, Mei, Fang C, Cheng, Xiaodong, Chen, Wei, Gurevich, Vsevolod V, Wess, Jürgen
Format: Article
Language:English
Subjects:
Antidiabetics
Arrestin
Beta cells
Biomedical research
Concise Communication
Diabetes
Diabetes mellitus
Drug development
Drugs
Gene expression
Glibenclamide
Glucose
Homeostasis
Insulin
Insulin secretion
Intracellular signalling
Kinases
Metabolic disorders
Metabolism
Pancreas
Peptides
Phenotypes
Proteins
Rap1 protein
Rodents
Secretion
Sulfonylurea
Tolbutamide
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Summary:Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta-cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and co-immunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta-cells may prove useful for the development of efficacious antidiabetic drugs.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI126309