title: Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation.
abstract: Pancreatic β cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive β cells into more pliable states with reduced cellular insulin levels, increased β cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, β cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses β cell proliferation in a cell-autonomous manner.
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Marta
authors.initials: M
authors.lastname: Szabat
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Page
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Evgeniy
authors.initials: E
authors.lastname: Panzhinskiy
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Søs
authors.initials: S
authors.lastname: Skovsø
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Mojibian
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Juan
authors.initials: J
authors.lastname: Fernandez-Tajes
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bruin
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bround
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Jason T C
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Child and Family Research Institute, University of British Columbia, BC V5Z 4H4, Canada.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Xu
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Taghizadeh
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: O'Dwyer
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Centre for High-Throughput Biology, University of British Columbia, BC V6T 1Z3, Canada.
authors.forename: Kyung-Mee
authors.initials: KM
authors.lastname: Moon
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, BC V6T 1Z3, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: UVic-Genome BC Proteomics Centre, University of Victoria, BC V8Z 7X8, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212-4772, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Child and Family Research Institute, University of British Columbia, BC V5Z 4H4, Canada.
authors.forename: Francis C
authors.initials: FC
authors.lastname: Lynn
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212-4772, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.affiliation: UVic-Genome BC Proteomics Centre, University of Victoria, BC V8Z 7X8, Canada.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Borchers
authors.affiliation: Centre for High-Throughput Biology, University of British Columbia, BC V6T 1Z3, Canada.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Foster
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, BC V6T 1Z3, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada. Electronic address: James.D.Johnson@ubc.ca.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D055442:Metabolome; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D007328:Insulin; D020543:Proteome
keywords: ER stress; beta cells; dedifferentiation; diabetes; insulin; islets; metabolomic; proliferation; protein synthesis; proteomic; transcriptomic