PUBLICATION

IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation

Authors
Lu, J., Liu, K.C., Schulz, N., Karampelias, C., Charbord, J., Hilding, A., Rautio, L., Bertolino, P., Östenson, C.G., Brismar, K., Andersson, O.
ID
ZDB-PUB-160816-18
Date
2016
Source
The EMBO journal   35(18): 2026-44 (Journal)
Registered Authors
Charbord, Jeremie, Karampelias, Christos, Lu, Jing, Rautio, Linn, Schulz, Nadja
Keywords
diabetes, insulin, regeneration, zebrafish, β cell
MeSH Terms
  • Mice
  • Regeneration*
  • Cell Transdifferentiation*
  • Humans
  • Glucagon-Secreting Cells/physiology*
  • Animals
  • Zebrafish
  • Insulin-Like Growth Factor Binding Protein 1/metabolism*
  • Insulin-Secreting Cells/physiology*
(all 9)
PubMed
27516442 Full text @ EMBO J.
Abstract
There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of β cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during β-cell regeneration. We then tested the proteins' ability to potentiate β-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted β-cell regeneration by potentiating α- to β-cell transdifferentiation. Using various inhibitors and activators of the Igf pathway, we show that Igfbp1 exerts its regenerative effect, at least partly, by inhibiting Igf signaling. Igfbp1's effect on transdifferentiation appears conserved across species: Treating mouse and human islets with recombinant IGFBP1 in vitro increased the number of cells co-expressing insulin and glucagon threefold. Moreover, a prospective human study showed that having high IGFBP1 levels reduces the risk of developing type-2 diabetes by more than 85%. Thus, we identify IGFBP1 as an endogenous promoter of β-cell regeneration and highlight its clinical importance in diabetes.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
DsRedia1Tg; ki103Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IFL
DsRedia1Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IFL
GFPia1Tg; ki103Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IFL
GFPia1Tg; ki103Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IFL
GFPia1Tg; ki103Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IHC
GFPia1Tg; ki103Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IHC
GFPia1Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IFL
GFPia1Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IFL
GFPia1Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IHC
GFPia1Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6IHC
1 - 10 of 32
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Phenotype
Fish Conditions Stage Phenotype Figure
ia1Tg; ki103Tg; m1018Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; ki107Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; ki107Tg; s950Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s892Tg; zf5Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s892Tg; zf5Tg + MO3-arxachemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s892Tg; zf5Tg + MO3-arxachemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s892Tg; zf5Tg + MO3-arxachemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s939Tg; s950Tg; zf5Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s950Tg; s960Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
ki103Tg; s950Tg; s960Tgchemical ablation: pancreatic B cell, chemical treatment by environment: metronidazoleDay 6
1 - 10 of 13
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gz19TgTransgenic Insertion
    ia1TgTransgenic Insertion
      ki102TgTransgenic Insertion
        ki103TgTransgenic Insertion
          ki104TgTransgenic Insertion
            ki105TgTransgenic Insertion
              ki106TgTransgenic Insertion
                ki107TgTransgenic Insertion
                  m1018TgTransgenic Insertion
                    s892TgTransgenic Insertion
                      1 - 10 of 17
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      arxaMO3-arxaMRPHLNO
                      1 - 1 of 1
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                      Fish
                      Fish
                      gz19Tg; ki102Tg
                      ia1Tg; ki103Tg; m1018Tg; s950Tg
                      ia1Tg; ki103Tg; s950Tg
                      ia1Tg; m1018Tg; s950Tg
                      ia1Tg; s950Tg
                      ki103Tg/ki103Tg; s892Tg; zf5Tg
                      ki103Tg; ki107Tg; s950Tg
                      ki103Tg; s892Tg; zf5Tg
                      ki103Tg; s892Tg; zf5Tg + MO3-arxa
                      ki103Tg; s939Tg; s950Tg; zf5Tg
                      1 - 10 of 17
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                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab1-gcgmonoclonal
                        		IgG1Mouse
                        Ab1-igfbp1polyclonal
                          		IgGRabbit
                          Ab4-inspolyclonal
                            		Guinea pig
                            1 - 3 of 3
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                            Orthology
                            No data available
                            Engineered Foreign Genes
                            Marker Marker Type Name
                            CeruleanEFGCerulean
                            CFPEFGCFP
                            CreEFGCre
                            DsRedEFGDsRed
                            EGFPEFGEGFP
                            GFPEFGGFP
                            KaedeEFGKaede
                            mCherryEFGmCherry
                            NTREFGNTR
                            RFPEFGRFP
                            1 - 10 of 11
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                            Mapping
                            No data available
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                            Citation
                            Lu, J., Liu, K.C., Schulz, N., Karampelias, C., Charbord, J., Hilding, A., Rautio, L., Bertolino, P., Östenson, C.G., Brismar, K., Andersson, O. (2016) IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation. The EMBO journal. 35(18):2026-44.