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
  • Cell Transdifferentiation*
  • Regeneration*
  • Glucagon-Secreting Cells/physiology*
  • Insulin-Like Growth Factor Binding Protein 1/metabolism*
  • Zebrafish
  • Mice
  • Insulin-Secreting Cells/physiology*
  • Animals
  • Humans
(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
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
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Mutations / Transgenics
Human Disease / Model
No data available
Sequence Targeting Reagents
Target Reagent Reagent Type
arxaMO3-arxaMRPHLNO
1 - 1 of 1
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Fish
Antibodies
Orthology
No data available
Engineered Foreign Genes
Marker Marker Type Name
CeruleanEFGCerulean
CFPEFGCFP
CreEFGCre
DsRedEFGDsRed
EGFPEFGEGFP
GFPEFGGFP
KaedeEFGKaede
mCherryEFGmCherry
NTREFGNTR
RFPEFGRFP
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Mapping
No data available