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Abstract
Type 2 diabetes is caused by a limited capacity of insulin-producing pancreatic β cells to increase their mass and function in response to insulin resistance. The signaling pathways that positively regulate functional β cell mass have not been fully elucidated. DYRK1A (also called minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. A significant amount of data implicates DYRK1A in brain growth and Down syndrome, and recent data indicate that Dyrk1A haploinsufficient mice have a low functional β cell mass. Here we ask whether Dyrk1A upregulation could be a way to increase functional β cell mass.
We used mice overexpressing Dyrk1A under the control of its own regulatory sequences (mBACTgDyrk1A). These mice exhibit decreased glucose levels and hyperinsulinemia in the fasting state. Improved glucose tolerance is observed in these mice as early as 4 weeks of age. Upregulation of Dyrk1A in β cells induces expansion of β cell mass through increased proliferation and cell size. Importantly, mBACTgDyrk1A mice are protected against high-fat-diet-induced β cell failure through increase in β cell mass and insulin sensitivity.
These studies show the crucial role of the DYRK1A pathway in the regulation of β cell mass and carbohydrate metabolism in vivo. Activating the DYRK1A pathway could thus represent an innovative way to increase functional β cell mass.
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Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
The authors thank Colin Mackenzie (Mackenzie Translation) for his comments and editorial assistance in preparing this manuscript. The authors thank Sophie Berissi and the Necker Histology Facility for technical assistance.
Author Contribution
L.R. and R.S. designed the research and wrote the manuscript. L.R., D.K., and V.A. performed 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.
Funding
This work was supported by grants from INSERM “Junior 5-year Contract” and “la Société Francophone du Diabète” (SFD) (L.R.).The research leading to these results received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115439, financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and contribution from EFPIA companies. The RS laboratory belongs to the Laboratoire d’Excellence consortium Revive.
