Diabetologia

, Volume 57, Issue 5, pp 960–969

Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass

  • Latif Rachdi
  • Dulanjalee Kariyawasam
  • Fanny Guez
  • Virginie Aïello
  • Maria L. Arbonés
  • Nathalie Janel
  • Jean-Maurice Delabar
  • Michel Polak
  • Raphaël Scharfmann
Article

DOI: 10.1007/s00125-014-3174-3

Cite this article as:
Rachdi, L., Kariyawasam, D., Guez, F. et al. Diabetologia (2014) 57: 960. doi:10.1007/s00125-014-3174-3

Abstract

Aims/hypothesis

Growth factors and nutrients are important regulators of pancreatic beta cell mass and function. However, the signalling pathways by which these factors modulate these processes have not yet been fully elucidated. DYRK1A (also named minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family that has been conserved across evolution. A significant amount of data implicates DYRK1A in brain growth and function, as well as in neurodegenerative processes in Alzheimer’s disease and Down’s syndrome. We investigated here whether DYRK1A would be an attractive candidate for beta cell growth modulation.

Methods

To study the role of DYRK1A in beta cell growth, we used Dyrk1a-deficient mice.

Results

We show that DYRK1A is expressed in pancreatic islets and provide evidence that changes in Dyrk1a gene dosage in mice strongly modulate glycaemia and circulating insulin levels. Specifically, Dyrk1a-haploinsufficient mice show severe glucose intolerance, reduced beta cell mass and decreased beta cell proliferation.

Conclusions/interpretation

Taken together, our data indicate that DYRK1A is a critical kinase for beta cell growth as Dyrk1a-haploinsufficient mice show a diabetic profile.

Keywords

Beta cell Diabetes DYRK1A p27 Proliferation 

Abbreviations

BrdU

Bromodeoxyuridine

DYRK

Dual-specificity tyrosine phosphorylation-regulated kinase

EGCG

Epigallocatechin gallate

FOXO1

Forkhead box O1

mTOR

Mammalian TOR

TOR

Conserved target of rapamycin

Supplementary material

125_2014_3174_MOESM1_ESM.pdf (9 kb)
ESM Fig. 1Food intake and fat mass in Dyrk1a+/− mice (a) Lack of effect of Dyrk1A haploinsufficiency on food intake in male mice at 16 weeks. (b) Perigonadal fat mass in wild type and Dyrk1a+/− male mice of 16 weeks. Data are shown as the mean ± SEM of at least three independent experiments, ***p < 0.01. (PDF 9 kb)
125_2014_3174_MOESM2_ESM.pdf (66 kb)
ESM Fig. 2In vitro, DYRK1A inhibitors treatment impairs beta cell development. (a) Immunohistochemical analyses of E11.5 mice pancreata after 7 days in culture, with and without DYRK1A inhibitors (1 μmol/l harmine, or 10 μmol/l EGCG). Acinar cell and beta-cell development were evaluated using antibodies against amylase (green) and insulin (red), respectively. Nuclei were stained with Hoechst 33342 fluorescent stain (blue). Scale bar = 50 μm. (b) Absolute areas that were occupied by the nuclei, amylase- and insulin-positive cells were quantified using NIH Image J software. Data are mean ± SEM from at least three pancreata per condition. *p < 0.05; **p < 0.01. (PDF 66 kb)
125_2014_3174_MOESM3_ESM.pdf (91 kb)
ESM Fig. 3Islet proliferation in Dyrk1a +/- mice (a) BrdU and Insulin staining on pancreases from 12 weeks Dyrk1a+/− and control mice. Nuclei were stained with Hoechst 33342 fluorescent stain (blue). Scale bar: 12.5 μm. Proliferative index was established by measurement of at least 2,000 beta cells. (b) Ki67 and Glucagon staining of islet from 12 weeks Dyrk1a+/− and control mice. Scale bar: 25 μm. Proliferative index was established by measurement of at least 500 alpha cells. (c) Ki67 and Insulin staining of embryonic pancreas from Dyrk1a+/− and control mice at embryonic day 17. Nuclei were stained with Hoechst 33342 fluorescent stain (blue). Scale bar: 25 μm. Proliferative index was established by measurements of at least 500 beta cells. (d) Frequency of cell apoptosis was assessed by TUNEL staining in insulin-stained pancreatic sections from 12 weeks old Dyrk1a+/− and control mice. Data are mean ± SEM from at least three pancreata per condition. **p < 0.01. (PDF 90 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Latif Rachdi
    • 1
  • Dulanjalee Kariyawasam
    • 4
  • Fanny Guez
    • 1
  • Virginie Aïello
    • 1
  • Maria L. Arbonés
    • 3
  • Nathalie Janel
    • 2
  • Jean-Maurice Delabar
    • 2
  • Michel Polak
    • 4
  • Raphaël Scharfmann
    • 1
  1. 1.INSERM U1016, Institut Cochin, Faculté de Médecine CochinUniversité Paris DescartesParisFrance
  2. 2.Sorbonne Paris Cité, Unit of Functional and Adaptative Biology (BFA), CNRS UMR 8251University Paris DiderotParisFrance
  3. 3.Institut de Biologia Molecular de BarcelonaCSIC and Centro de Investigación Biomédica en Red de Enfermedades RarasBarcelonaSpain
  4. 4.Hôpital Universitaire Necker Enfants Malades, Endocrinologie gynécologie diabétologie pédiatriques, affilié IMAGINEUniversité Paris Descartes, INSERM U1016, Institut CochinParisFrance

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