title: β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions.
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.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Joana
authors.initials: J
authors.lastname: Almaça
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Dadi
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.|Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sakamoto
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Regina J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Vierra
authors.affiliation: Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: McMillin
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Perry
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Vsevolod V
authors.identifier: 0000-0002-3950-5351
authors.initials: VV
authors.lastname: Gurevich
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
authors.affiliation: Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland 20892, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kuo
authors.affiliation: Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland 20892, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Leapman
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennslvania 19104, USA.
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennslvania 19104, USA.
authors.forename: Nicolai M
authors.initials: NM
authors.lastname: Doliba
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Nikhil M
authors.initials: NM
authors.lastname: Urs
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caicedo
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D059305:Diet, High-Fat; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics*; D000071560:beta-Arrestin 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007328:Insulin; D000071560:beta-Arrestin 2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2