ß-Cell MicroRNAs: Small but Powerful.

Noncoding RNA and especially microRNAs (miRs) have emerged as important regulators of key processes in cell biology, including development, differentiation, and survival. Currently, over 2,500 mature miRs have been reported in humans, and considering that each miR has multiple targets, the number of genes and pathways potentially affected is huge. Not surprisingly, many miRs have also been implicated in diabetes, and more recently, some have been discovered to play important roles in the pancreatic islet, including ß-cell function, proliferation, and survival. The goal of this Perspective is to offer an overview of this rapidly evolving field and the miRs involved, reveal novel networks of ß-cell miR signaling, and provide an outlook of the opportunities and challenges ahead.

MicroRNA-200 is induced by thioredoxin-interacting protein and regulates Zeb1 protein signaling and beta cell apoptosis.

Small noncoding microRNAs have emerged as important regulators of cellular processes, but their role in pancreatic beta cells has only started to be elucidated. Loss of pancreatic beta cells is a key factor in the pathogenesis of diabetes, and we have demonstrated that beta cell expression of thioredoxin-interacting protein (TXNIP) is increased in diabetes and causes beta cell apoptosis, whereas TXNIP deficiency is protective against diabetes. Recently, we found that TXNIP also impairs beta cell function by inducing microRNA (miR)-204. Interestingly, using INS-1 beta cells and primary islets, we have now discovered that expression of another microRNA, miR-200, is induced by TXNIP and by diabetes. Furthermore, we found that miR-200 targeted and decreased Zeb1 (zinc finger E-box-binding homeobox 1) and promoted beta cell apoptosis as measured by cleaved caspase-3 levels, Bax/Bcl2 ratio, and TUNEL. In addition, Zeb1 knockdown mimicked the miR-200 effects on beta cell apoptosis, suggesting that Zeb1 plays an important role in mediating miR-200 effects. Moreover, miR-200 increased beta cell expression of the epithelial marker E-cadherin, consistent with inhibition of epithelial-mesenchymal transition, a process thought to be involved in beta cell expansion. Thus, we have identified a novel TXNIP/miR-200/Zeb1/E-cadherin signaling pathway that, for the first time, links miR-200 to beta cell apoptosis and diabetes and also beta cell TXNIP to epithelial-mesenchymal transition. In addition, our results shed new light on the regulation and function of miR-200 in beta cells and show that TXNIP-induced microRNAs control various processes of beta cell biology.