title: Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes.
abstract: Impaired beta-cell function is key to the development of type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART) is an islet peptide with insulinotropic and glucagonostatic properties. Here we studied the role of endogenous CART in beta-cell function. CART silencing in INS-1 (832/13) beta-cells reduced insulin secretion and production, ATP levels and beta-cell exocytosis. This was substantiated by reduced expression of several exocytosis genes, as well as reduced expression of genes important for insulin secretion and processing. In addition, CART silencing reduced the expression of a network of transcription factors essential for beta-cell function. Moreover, in RNAseq data from human islet donors, CARTPT expression levels correlated with insulin, exocytosis genes and key beta-cell transcription factors. Thus, endogenous beta-cell CART regulates insulin expression and secretion in INS-1 (832/13) cells, via actions on the exocytotic machinery and a network of beta-cell transcription factors. We conclude that CART is important for maintaining the beta-cell phenotype.
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Shcherbina
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Edlund
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: J L S
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Abels
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Ottosson-Laakso
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden; Department of Cell Physiology and Metabolism, University Medical Center, 1 Rue Michel-Servet, CH-1211 Genève 4, Switzerland.
authors.forename: C B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Jan Waldenströms Gata 35, 214 28 Malmö, Sweden. Electronic address: nils.wierup@med.lu.se.
authors.forename: N
authors.initials: N
authors.lastname: Wierup
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D005089:Exocytosis / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
keywords: Beta-cell; Cocaine- and amphetamine-regulated transcript; Exocytosis; Human islets; INS-1 (832/13); Insulin secretion