Dysregulation of cis-regulatory elements that drive pancreatic islet cell gene transcription could underlie diabetes mellitus, a new study suggests. Researchers have identified genomic sequences that reside predominantly in clusters of enhancers and form functional 3D chromatin domains. These enhancers were bound by key β-cell transcription factors, such as FoxA2 and PDX-1, and drove islet-specific gene expression in human islet samples. Sequence variation in these regions was associated with an increased risk of type 2 diabetes mellitus and variation in fasting glycaemia levels.