title: Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival.
abstract: Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells. In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse. This occurs through activation of the Ras-MAPK/ERK signaling pathway and up-regulation of the splicing factor SRSF1. Induction of exon 11 skipping by a splice-site competitive antisense oligonucleotide inhibited the MAPK-ERK signaling pathway downstream of the insulin receptor, sensitizing the pancreatic β-cell line MIN6 to stress-induced apoptosis and lipotoxicity. These results assign to insulin a regulatory role in INSR alternative splicing through the Ras-MAPK/ERK signaling pathway. We suggest that in beta cells, INSR-B has a protective role, while INSR-A expression sensitizes beta cells to programmed cell death.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Malakar
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Lital
authors.initials: L
authors.lastname: Chartarifsky
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Ayat
authors.initials: A
authors.lastname: Hija
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015703:Antigens, CD; D007328:Insulin; C435941:INSR protein, human; D011972:Receptor, Insulin