Following the identification of two new KIAA2022 variants in two subjects with non-autoimmune diabetes. In order to determine if Kiaa2022 could play a role in diabetes we performed in vitro studies in insulin-secreting INS-1E cells. Additionally, we generated Kiaa2022 knock out mice, which showed a reduced amount of proliferating β-cells. Interestingly, besides a pancreatic phenotype a variety of other phenotypes was observed in mutant and non-mutant progeny. RNAseq showed that down-regulated genes in Kiaa2022 mutant islets are associated to stress response and the disposition of epigenetic marks. We also observed an upregulation of LINE1 elements and not only in the pancreas, but also in the brain and testis. Activated LINE1 elements can cause genomic instability and genetic variation through retrotransposition into the genome. This suggests a mechanism by which genomic instability could be induced in Kiaa2022 mutant mice, which could cause phenotypic variability in all progeny.