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

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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.

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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

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Acknowledgements

The authors thank C. Mackenzie (Mackenzie Translation, Nantes, France), for his comments and editorial assistance in preparing this manuscript.

Funding

The research leading to these results received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115439, comprising financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies. The RS laboratory belongs to the Laboratoire d’Excellence consortium Revive. This work was supported by grants from Inserm ‘Junior 5-year Contract’ (LR).

Duality of interest

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

Contribution statement

LR and RS designed the research and wrote the manuscript. LR, DK, FG and VA performed the research and acquired the data. All authors made substantial contributions to the analysis and interpretation of data. All authors were involved in drafting the manuscript and all approved the final version. LR is responsible for the integrity of the work as a whole.

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Corresponding authors

Correspondence to Latif Rachdi or Raphaël Scharfmann.

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ESM Fig. 1

Food 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)

ESM Fig. 2

In 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)

ESM Fig. 3

Islet 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)

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Rachdi, L., Kariyawasam, D., Guez, F. et al. Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass. Diabetologia 57, 960–969 (2014). https://doi.org/10.1007/s00125-014-3174-3

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  • DOI: https://doi.org/10.1007/s00125-014-3174-3

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