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.Key messagesOverexpression 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-015-1296-9) contains supplementary material, which is available to authorized users.

Biomarkers of β-Cell Stress and Death in Type 1 Diabetes

“…In the islet transplantation setting in humans where acute β-cell death is observed, Kanak et al [29••] showed that circulating miR-375 levels were elevated immediately post-transplantation and remained elevated up to 7 days later. In the T1D setting, C-peptide-negative individuals exhibited higher circulating miR-375 levels compared to individuals with more substantial β-cell mass, such as non-diabetic controls, individuals with T2D, and individuals with maturity onset diabetes of the young (MODY) [66••]. These findings suggest that steady-state circulating levels of miR-375 are more likely a reflection of dying β-cells rather than prevailing β-cell mass.…”

Future microfluidic and nanofluidic modular platforms for nucleic acid liquid biopsy in precision medicine

“…79,[82][83][84] As a result, often PCR cycle numbers (Cq) distributions are skewed relative to actual miRNA copy numbers, even with the latest locked nucleic acid (LNA) technology. [85][86][87][88][89][90][91][92][93] The same multiplex qRT-PCR test can have limits of detection that are different by several orders of magnitude for different virus serotypes. 94,95 The problem of discordant results between different platforms becomes worse in the case of low viral loads.…”

“…We took advantage of these effects at cones and wedges in the development of AC sprays and nano-aerosolization technologies. [84][85][86][87][88][89] Similarly, these effects may be used for thermal programming in PET conical nanopores. The local Joule heating density increases rapidly towards the tip due to field focusing, rE 2 ¼ rE 2 0 ðR=rÞ 4 , where r is the local conductivity, E 0 is the nominal field proportional to the applied voltage V, and R is the radial position of the base in the spherical coordinate r that traverses the cone axis.…”

Nucleic acid biomarkers of β cell stress and death in type 1 diabetes

“…However, this group also showed that β cell-derived miRNA-375 only contributes to about 1% of the total pool of circulating miRNA-375. Thus, while these authors speculated that increases in miR-375 may provide a reasonable assessment of β cell death, they questioned whether miRNA-375 was capable of providing insight into levels of β cell mass (31). …”