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

ABSTRACT: ?-Arrestin2 (?arr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that ?arr2 was abundantly expressed in mouse pancreatic ?-cells, and loss of ?arr2 leads to impairment of acute- and late-phase insulin secretion. In the present study, we examined the dynamic changes of ?-cell mass in ?arr2-deficient (?arr2^-/-) mice in vivo and explored the underlying mechanisms involved. ?arr2^-/- mice with exclusively luciferase overexpression in ?-cells were generated and fed a high-fat diet (HFD). ?-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 ?-cell mass was reduced dramatically in ?arr2^-/- 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 ?arr2^-/- mice. Exposure of ?arr2^-/- 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 ?arr2 amplified ?-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected ?-cells from glucose- and FFA-induced cell death through JNK-activation inhibition. In conclusion, ?arr2 plays roles in regulation of pancreatic ?-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for ?arr2 in the development of type 2 diabetes.

SUBMITTER: Lin Z 

PROVIDER: S-EPMC5005663 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature