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Inducing beta-cell mass expansion in diabetic patients with the aim to restore glucose homeostasis is a promising therapeutic strategy. Although several  in vitro  studies have been carried out to identify modulators of beta-cell mass expansion, restoring endogenous beta-cell mass  in vivo  has yet to be achieved. To identify potential stimulators of beta-cell replication  in vivo , we established transgenic zebrafish lines that monitor and allow the quantification of cell proliferation by using the fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. Using these new reagents, we performed an unbiased chemical screen, and identified 20 small molecules that markedly increased beta-cell proliferation  in vivo . Importantly, these structurally distinct molecules, which include clinically-approved drugs, modulate three specific signaling pathways: serotonin, retinoic acid and glucocorticoids, showing the high sensitivity and robustness of our screen. Notably, two drug classes, retinoic acid and glucocorticoids, also promoted beta-cell regeneration after beta-cell ablation. Thus, this study establishes a proof of principle for a high-throughput small molecule-screen for beta-cell proliferation  in vivo , and identified compounds that stimulate beta-cell proliferation and regeneration.

Whole Organism High Content Screening Identifies Stimulators of Pancreatic Beta-Cell Proliferation