Notch signaling : A mediator of β-cell de-differentiation in diabetes?

Abstract Cytokines are mediators of pancreatic β-cell dysfunction and death in type 1 diabetes mellitus. Microarray analyses of insulin-producing cells exposed to interleukin-1β + interferon-γ showed decreased expression of genes related to β-cell-differentiated functions and increased expression of members of the Notch signaling pathway. Re-expression of this developmental pathway may contribute for loss-of-function of β-cells exposed to an autoimmune attack. In this study, we show that rat primary β-cells exposed to cytokines up-regulate several Notch receptors and ligands, and the target gene Hes1. Transfection of insulin-producing INS-1E cells and primary rat β-cells with a constitutively active form of the Notch receptor down-regulated Pdx1 and insulin expression in INS-1E cells but not in primary β-cells. Thus, activation of the Notch pathway inhibits differentiated functions in dividing but not in terminally differentiated β-cells.