Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass
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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.
To study the role of DYRK1A in beta cell growth, we used Dyrk1a-deficient mice.
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.
Taken together, our data indicate that DYRK1A is a critical kinase for beta cell growth as Dyrk1a-haploinsufficient mice show a diabetic profile.
KeywordsBeta cell Diabetes DYRK1A p27 Proliferation
Dual-specificity tyrosine phosphorylation-regulated kinase
Forkhead box O1
Conserved target of rapamycin
The authors thank C. Mackenzie (Mackenzie Translation, Nantes, France), for his comments and editorial assistance in preparing this manuscript.
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.
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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