Title |
miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development
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Published in |
Journal of Molecular Medicine, May 2015
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DOI | 10.1007/s00109-015-1296-9 |
Pubmed ID | |
Authors |
Mathieu Latreille, Karolin Herrmanns, Neil Renwick, Thomas Tuschl, Maciej T. Malecki, Mark I. McCarthy, Katharine R. Owen, Thomas Rülicke, Markus Stoffel |
Abstract |
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. 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. |
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Student > Doctoral Student | 5 | 5% |
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