title: Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway.
abstract: 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 acute- and late-phase insulin secretion. In the present study, we examined the dynamic changes of β-cell mass inβarr2-deficient (βarr2-/-) micein vivoand explored the underlying mechanisms involved.βarr2-/-mice with exclusively luciferase overexpression in β-cells were generated and fed a high-fat diet (HFD). β-Cell mass was determined byin vivononinvasive 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 inβarr2-/-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 fromβarr2-/-mice. Exposure ofβarr2-/-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.
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Lige
authors.initials: L
authors.lastname: Song
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Kaida
authors.initials: K
authors.lastname: Mu
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Biochemistry and Cell Biology, Laboratory of Molecular Cell Biology, Chinese Academy of Sciences, Institutes for Biological Sciences, Shanghai, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, and Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia