Variants at the locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of mRNA in protective allele carriers. In the present study, combined allele-specific expression (cASE) analysis in human islets revealed multiple variants that influence expression. Epigenomic mapping identified an islet-selective enhancer cluster at the locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the promoter and additional neighbouring genes. Deletions of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowered the expression of and several neighbouring genes, and improved insulin secretion. Whilst down-regulation of had no effect on beta cell survival, loss of , markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the locus and enhanced stimulated insulin secretion.