Here, we used CRISPR–Cas9 technology to generate mice with partial deletions of the Ins1 and Ins2 promoters, which showed that only homozygous mice with mutations in the highly conserved C1 elements of the Ins1 and Ins2 promoters developed diabetes, indicating the value of genome editing in studying the regulation of insulin synthesis in vivo. Here, INS is linked to diabetes mellitus.