miR-375 gene dosage in pancreatic 13-cells: implications for regulation of β-cell mass and biomarker development

MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased beta-cell and increased a-cell mass and function. The relative importance of these processes for the overall phenotype of miR375K0 mice is unknown. Here, we show that mice overexpressing miR-375 exhibit noinial beta-cell mass and function. Selective re-expression of miR-375 in beta-cells of miR375K0 mice normalizes both, alpha- and 1 beta-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of beta-cells to the total plasma miR-375 levels. Only a small proportion z1 A) of circulating miR-375 originates from beta-cells. Furthermore, acute and profound 3cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type I diabetes TI D) subjects but not mature onset diabetes of the young MODY) and type 2 diabetes T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of beta-cell mass and provide in vivo evidence for release of miRNAs from pancreatic beta-cells. The small contribution of beta-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for beta-cell function but suggests a utility for the detection of acute beta-cell death for autoimmune diabetes.