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dc.contributor.authorLv, Lixia
dc.contributor.authorChen, Hewen
dc.contributor.authorSun, Jiaying
dc.contributor.authorLu, Di
dc.contributor.authorChen, Chen
dc.contributor.authorLiu, Dongfang
dc.date.accessioned2019-09-10T05:27:34Z
dc.date.available2019-09-10T05:27:34Z
dc.date.issued2015
dc.identifier.issn1355-008X
dc.identifier.doi10.1007/s12020-015-0543-8
dc.identifier.urihttp://hdl.handle.net/10072/387199
dc.description.abstractProtein N-arginine methyltransferase-1 (PRMT1), the major asymmetric arginine methyltransferase, plays important roles in various cellular processes. Previous reports have demonstrated that levels and activities of PRMT1 can vary in animals with type 2 diabetes mellitus. The aim of this study was to assess the expression and mechanism of action of PRMT1 during glucose toxicity-induced β cell dysfunction. Liposome-mediated gene transfection was used to transfect INS-1 cells with siPRMT1, which inhibits PRMT1 expression, and pALTER–FOXO1, which overexpresses forkhead box protein O1 (FOXO1). The cells were then cultured in media containing 5.6 or 25 mmol/L glucose with or without the small molecule PRMT1 inhibitor AMI-1 for 48 h. The protein levels of PRMT1, the arginine methylated protein α-metR, FOXO1, Phospho-FOXO1, pancreas duodenum homeobox-1 (PDX-1), and the intracellular localization of PDX-1 and FOXO1 were then measured by western blotting. FOXO1 methylation was detected by immunoprecipitated with anti-PRMT1 antibody and were immunoblotted with α-metR. The levels of insulin mRNA were measured by real-time fluorescence quantitative PCR. Glucose-stimulated insulin secretion (GSIS) and intracellular insulin content were measured using radioimmunoassays. Intracellular Ca2+ ([Ca2+]i) was detected using Fura-2 AM. Intracellular cAMP levels were measured using ELISA. Chronic exposure to high glucose impaired insulin secretion, decreased insulin mRNA levels and insulin content, increased intracellular [Ca2+]i and cAMP levels, and abolishes their responses to glucose. Inhibiting PRMT1 expression improved insulin secretion, increased mRNA levels and insulin content by regulating the intracellular translocation of PDX-1 and FOXO1, decreasing the methylation of FOXO1, and reducing intracellular [Ca2+]i and cAMP concentrations. Transient overexpression of constitutively active FOXO1 in nuclear reversed the AMI-1-induced improvement of β cell function without changing arginine methylation. It is concluded therefore that PRMT1 regulates GSIS in INS-1 cells, through enhanced methylation-induced nuclear localization of FOXO1, which subsequently suppresses the nuclear localization of PDX-1. Our results suggest a novel mechanism that might contribute to the deficient insulin secretion observed under conditions of chronically hyperglycemia.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherSpringer
dc.relation.ispartofpagefrom669
dc.relation.ispartofpageto682
dc.relation.ispartofissue3
dc.relation.ispartofjournalEndocrine
dc.relation.ispartofvolume49
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3202
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsEndocrinology & Metabolism
dc.subject.keywordsProtein N-arginine methyltransferase-1
dc.subject.keywordsForkhead box protein O1
dc.titlePRMT1 promotes glucose toxicity-induced beta cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationLv, L; Chen, H; Sun, J; Lu, D; Chen, C; Liu, D, PRMT1 promotes glucose toxicity-induced beta cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells, Endocrine, 2015, 49 (3), pp. 669-682
dcterms.dateAccepted2015-01-27
dc.date.updated2019-09-10T05:26:32Z
gro.hasfulltextNo Full Text
gro.griffith.authorChen, Chen


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