title: IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation.
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.
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Jing
authors: J
authors: Lu
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Ka-Cheuk
authors: KC
authors: Liu
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Nadja
authors: N
authors: Schulz
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Christos
authors: C
authors: Karampelias
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Jérémie
authors: J
authors: Charbord
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
authors: Agneta
authors: A
authors: Hilding
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Linn
authors: L
authors: Rautio
authors: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors: Philippe
authors: P
authors: Bertolino
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
authors: Claes-Göran
authors: CG
authors: Östenson
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
authors: Kerstin
authors: K
authors: Brismar
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden olov.andersson@ki.se.
authors: Olov
authors: 0000-0001-6715-781X
authors: O
authors: Andersson
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D050416:Glucagon-Secreting Cells / Q000502:physiology*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D012038:Regeneration; D015027:Zebrafish
chemical_list: C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1
keywords: diabetes; insulin; regeneration; zebrafish; β cell