β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions

Lu Zhu, Joana Almaça, Prasanna K. Dadi, Hao Hong, Wataru Sakamoto, Mario Rossi, Regina J. Lee, Nicholas C. Vierra, Huiyan Lu, Yinghong Cui, Sara M. McMillin, Nicole A. Perry, Vsevolod V. Gurevich, Amy Lee, Bryan Kuo, Richard D. Leapman, Franz M. Matschinsky, Nicolai M. Doliba, Nikhil M. Urs, Marc G. Caron, David A. Jacobson, Alejandro Caicedo and Jürgen Wess ()
Additional contact information
Lu Zhu: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Joana Almaça: Diabetes and Metabolism, University of Miami Miller School of Medicine
Prasanna K. Dadi: Vanderbilt University
Hao Hong: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Wataru Sakamoto: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Mario Rossi: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Regina J. Lee: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Nicholas C. Vierra: Vanderbilt University
Huiyan Lu: Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases
Yinghong Cui: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Sara M. McMillin: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Nicole A. Perry: Vanderbilt University
Vsevolod V. Gurevich: Vanderbilt University
Amy Lee: University of Iowa
Bryan Kuo: Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering
Richard D. Leapman: Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering
Franz M. Matschinsky: University of Pennsylvania School of Medicine
Nicolai M. Doliba: University of Pennsylvania School of Medicine
Nikhil M. Urs: Duke University Medical Center
Marc G. Caron: Duke University Medical Center
David A. Jacobson: Vanderbilt University
Alejandro Caicedo: Diabetes and Metabolism, University of Miami Miller School of Medicine
Jürgen Wess: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.

Date: 2017
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DOI: 10.1038/ncomms14295

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