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Diabetologia

pp 1–13 | Cite as

miR-409-3p is reduced in plasma and islet immune infiltrates of NOD diabetic mice and is differentially expressed in people with type 1 diabetes

  • Giuliana Ventriglia
  • Francesca Mancarella
  • Guido Sebastiani
  • Dana P. Cook
  • Roberto Mallone
  • Chantal Mathieu
  • Conny Gysemans
  • Francesco DottaEmail author
Article

Abstract

Aims/hypothesis

MicroRNAs (miRNAs) are a novel class of potential biomarkers emerging in many diseases, including type 1 diabetes. Here, we aim to analyse a panel of circulating miRNAs in non-obese diabetic (NOD) mice and individuals with type 1 diabetes.

Methods

We adopted standardised methodologies for extracting miRNAs from small sample volumes to evaluate a profiling panel of mature miRNAs in paired plasma and laser-captured microdissected immune-infiltrated islets of recently diabetic and normoglycaemic NOD mice. Moreover, we validated the findings during disease progression and remission after anti-CD3 therapy in NOD mice, as well as in individuals with type 1 diabetes.

Results

Plasma levels of five miRNAs were downregulated in diabetic vs normoglycaemic mice. Of those, miR-409-3p was also downregulated in situ in the immune islet infiltrates of diabetic mice, suggesting an association with disease pathogenesis. Target-prediction tools linked miR-409-3p to immune- and metabolism-related signalling molecules. In situ miR-409-3p expression correlated with insulitis severity, and CD8+ central memory T cells were found to be enriched in miR-409-3p. Plasma miR-409-3p levels gradually decreased during diabetes development and improved with disease remission after anti-CD3 antibody therapy. Finally, plasma miR-409-3p levels were lower in people recently diagnosed with type 1 diabetes compared with a non-diabetic control group, and levels were inversely correlated with HbA1c levels.

Conclusions/interpretation

We propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.

Keywords

Anti-CD3 therapy Biomarker Inflammation MicroRNA Progression Type 1 diabetes 

Abbreviations

aCD3

Anti-CD3

LCM

Laser-captured microdissected

mAb

Monoclonal antibody

miRNA

MicroRNA

NOR

Non-obese resistant

SOP

Standard operating procedure

TCM

Central memory T cell

TEM

Effector memory T cell

3′-UTR

3′-Untranslated region

Notes

Acknowledgements

We would like to thank L. Dusaer and J. Laureys (Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Belgium) for their technical assistance.

Contribution statement

GV, FM and GS contributed to all aspects of this manuscript, including data acquisition and analysis and drafting and editing the manuscript. DPC, RM and CM were responsible for conception and experimental design, interpretation of the data and editing of the manuscript. FD and CG contributed to conception, experimental design and drafting the manuscript, provided final approval of the submitted manuscript and are guarantors of this work. All authors gave final approval of the version to be published.

Funding

This project has received funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement no. 115797 (INNODIA). This joint undertaking receives support from the Union’s Horizon 2020 research and innovation programme and EFPIA, JDRF and the Leona M. and Harry B. Helmsley Charitable Trust. FD is supported by the Italian Ministry of Research (grant no. 2015373Z39_007) and by Fondazione Roma. DPC is a PhD fellow of the FWO-Vlaanderen (Belgium) (11Y6716N).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_5026_MOESM1_ESM.pdf (1.3 mb)
ESM 1 (PDF 1.25 mb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Giuliana Ventriglia
    • 1
    • 2
    • 3
  • Francesca Mancarella
    • 1
    • 2
  • Guido Sebastiani
    • 1
    • 2
  • Dana P. Cook
    • 3
  • Roberto Mallone
    • 4
  • Chantal Mathieu
    • 3
  • Conny Gysemans
    • 3
  • Francesco Dotta
    • 1
    • 2
    Email author
  1. 1.Diabetes Unit, Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  2. 2.Fondazione Umberto Di Mario ONLUS c/o Toscana Life SciencesSienaItaly
  3. 3.Clinical and Experimental Endocrinology (CEE)Katholieke Universiteit Leuven (KU LEUVEN)LeuvenBelgium
  4. 4.Inserm, U1016, CNRS, UMR8104, Paris Descartes University, Sorbonne Paris Cité, Cochin InstituteParisFrance

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