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

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. Synopsis Harnessing endogenous regenerative mechanisms for insulin‐producing β cells may offer a cure for diabetes. We identified Igfbp1 as a promoter of β‐cell regeneration in zebrafish, and in complementary human studies highlight IGFBP1's clinical importance in diabetes. In vivo screen in zebrafish for secreted proteins promoting β‐cell regeneration identified Igfbp1. Igfbp1 potentiates β‐cell regeneration by increasing conversion of α to β cells (transdifferentiation) in zebrafish and isolated mouse/human islets. Inhibition of the Igf pathway mimics Igfbp1a's regenerative effect. A prospective study of 1,190 humans shows that high levels of IGFBP1 correlate with reduced diabetes risk. Graphical Abstract In a zebrafish screen, insulin‐like growth factor binding protein 1 (Igfbp1) promotes β‐cell regeneration. Igfbp1 potentiates α‐ to β‐cell transdifferentiation in fish, mouse, and human islets. In humans, high IGFBP1 levels correlate with reduced type‐2 diabetes risk.