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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 β-cell and increased α-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 β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-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 β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes. KEY MESSAGES: • Overexpression of miR-375 in β-cells does not influence β-cell mass and function. • Increased α-cell mass in miR-375KO arises secondarily to loss of miR-375 in β-cells. • Only a small proportion of circulating miR-375 levels originates from β-cells. • Acute β-cell destruction results in measurable increases of miR-375 in the blood. Circulating miR-375 levels are not a biomarker for pancreatic β-cell function.

Original publication

DOI

10.1007/s00109-015-1296-9

Type

Journal article

Journal

J Mol Med (Berl)

Publication Date

10/2015

Volume

93

Pages

1159 - 1169

Keywords

Biomarker, Diabetes, MiRNA-375, Pancreatic β-cells, β-cell mass, Adult, Aged, Animals, Biomarkers, Blood Glucose, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Gene Dosage, Humans, Insulin, Insulin-Secreting Cells, Male, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Middle Aged, Young Adult