Transcriptional regulation of α-cell differentiation

The development of the endocrine pancreas and the differentiation of its five cell types, alpha, beta, delta, epsilon and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of alpha- and beta-cells are critical for blood glucose homeostasis. These processes are governed by multiple transcription factors and other signalling systems, and its dysregulation results in diabetes. The differentiation of alpha-cells and the maintenance of alpha-cell function can be influenced at several stages during development and in the maturing islet. Many transcription factors, such as neurogenin 3 (Ngn3), pancreatic duodenal homeobox 1 (Pdxl) and regulatory factor x6 (Rfx6), play a crucial role in the determination of the endocrine cell fate, while other transcription factors, such as aristaless-related homeobox (Arx) and forkhead box A2 (Foxa2), are implicated in the initial or terminal differentiation of alpha-cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of alpha-cell function, is regulated by several factors, including forkhead box A1 (Foxal), paired box 6 (Pax6), brain4 (Brn4) End islet-1 (Isl-1). Detailed information about the regulation of normal and abnormal alpha-cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of alpha- to beta-cells for replacement therapy.