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

Journal of molecular medicine (Berlin, Germany)

PubMedID: 26013143

Latreille M, Herrmanns K, Renwick N, Tuschl T, Malecki MT, McCarthy MI, Owen KR, Rülicke T, Stoffel M. miR-375 gene dosage in pancreatic ß-cells: implications for regulation of ß-cell mass and biomarker development. J Mol Med. 2015;.
UNLABELLED
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 ß-cell and increased a-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal ß-cell mass and function. Selective re-expression of miR-375 in ß-cells of miR-375KO mice normalizes both, a- and ß-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of ß-cells to the total plasma miR-375 levels. Only a small proportion (˜1 %) of circulating miR-375 originates from ß-cells. Furthermore, acute and profound ß-cell 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 1 diabetes (T1D) 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 ß-cell mass and provide in vivo evidence for release of miRNAs from pancreatic ß-cells. The small contribution of ß-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for ß-cell function but suggests a utility for the detection of acute ß-cell death for autoimmune diabetes.

KEY MESSAGES
Overexpression of miR-375 in ß-cells does not influence ß-cell mass and function. Increased a-cell mass in miR-375KO arises secondarily to loss of miR-375 in ß-cells. Only a small proportion of circulating miR-375 levels originates from ß-cells. Acute ß-cell destruction results in measurable increases of miR-375 in the blood. Circulating miR-375 levels are not a biomarker for pancreatic ß-cell function.