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 beta cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during beta-cell regeneration. We then tested the proteins' ability to potentiate beta-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted beta-cell regeneration by potentiating alpha -to beta-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 beta-cell regeneration and highlight its clinical importance in diabetes.