Transcriptional regulation of α-cell differentiation

The development of the endocrine pancreas and the differentiation of its five cell types, α, β, δ, ε and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of α- and β-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 α-cells and the maintenance of α-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 (Pdx1) 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 α-cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of α-cell function, is regulated by several factors, including forkhead box A1 (Foxa1), paired box 6 (Pax6), brain4 (Brn4) and islet-1 (Isl-1). Detailed information about the regulation of normal and abnormal α-cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of α- to β-cells for replacement therapy.