An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration

As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (beta) cells. However, little is known about how insulin signaling feedback might influence neogenesis of beta cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential beta cell genes insulin and pdx1, and promoted beta cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted beta cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for beta cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into beta cells. Furthermore, the extent of this differentiation was dependent on the function of the beta cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of beta cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in beta cell progenitors will reveal therapeutic targets for both in vivo and in vitro beta cell generation. (C) 2015 Elsevier Inc. All rights reserved.