Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass.
OBJECTIVE
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
Taken together, our data indicate that DYRK1A is a critical kinase for beta cell growth as Dyrk1a-haploinsufficient mice show a diabetic profile.
INSERM U1016, Institut Cochin, Faculté de Médecine Cochin, Université Paris Descartes, 24 Rue du Faubourg St Jacques, 75014, Paris, France, latif.rachdi@inserm.fr.
Latif
L
Rachdi
Dulanjalee
D
Kariyawasam
Fanny
F
Guez
Virginie
V
Aïello
Maria L
ML
Arbonés
Nathalie
N
Janel
Jean-Maurice
JM
Delabar
Michel
M
Polak
Raphaël
R
Scharfmann
D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D057895:Haploinsufficiency; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000097603:Dyrk Kinases
D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases