Enhanced Expression of miR-199b-5p Promotes Proliferation of Pancreatic β-Cells by Down-Regulation of MLK3

Background: The initiation of β-cell proliferation to recover reduced β-cell mass is considered as one of the attractive therapeutic approaches for type 1 and 2 diabetes. In this study, we investigated the involvement of miRNAs in β-cell proliferation. Methods: Global miRNA array analysis of pancreas tissue was carried out using a 60% partial pancreatectomy (PPx) rodent model, which is a well-characterized model for pancreatic regeneration with accelerated proliferation of β-cells. To explore miRNAs with mitogenic activity on β-cells, precursors and antisense oligonucleotides (ASOs) for miRNAs were transfected into a primary islet monolayer cell cultures isolated from adult rats in order to modify their expression and proliferation of β-cells. Results: We found that miR-199b-5p, which was up-regulated 2.6 times in the pancreas of the PPx treated group, significantly enhanced the proliferation of β-cells when its precursor was over-expressed. Target genes of miR-199b-5p were investigated and Mixed lineage kinase-3 (MLK3) was identified as one of the candidates since its expression was down-regulated through an interaction with miR-199b-5p and siRNA treatment for MLK3 enhanced the proliferation of β-cells. Conclusion: Our data suggest that the up-regulation of miR-199b-5p enhances proliferation of β-cells at least in part through down-regulation of MLK3.