title: miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development.
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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH Zurich), Otto-Stern Weg. 7, 8093, Zurich, Switzerland.|MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Latreille
authors.affiliation: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH Zurich), Otto-Stern Weg. 7, 8093, Zurich, Switzerland.
authors.forename: Karolin
authors.initials: K
authors.lastname: Herrmanns
authors.affiliation: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 186, New York, NY, 10065, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Renwick
authors.affiliation: Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 186, New York, NY, 10065, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.|University Hospital, Krakow, Poland.
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Malecki
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Old Road, Headington, Oxford, OX3 7LJ, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ, UK.
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH Zurich), Otto-Stern Weg. 7, 8093, Zurich, Switzerland. stoffel@biol.ethz.ch.|Faculty of Medicine, University of Zurich, Zurich, Switzerland. stoffel@biol.ethz.ch.
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse
keywords: Biomarker; Diabetes; MiRNA-375; Pancreatic β-cells; β-cell mass