Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation

Pancreatic beta-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing beta-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of beta-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in beta-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis.