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

• Published in: Diabetologia Vol. 57; no. 5; pp. 960 - 969
• Main Authors: Rachdi, Latif, Kariyawasam, Dulanjalee, Guez, Fanny, Aïello, Virginie, Arbonés, Maria L., Janel, Nathalie, Delabar, Jean-Maurice, Polak, Michel, Scharfmann, Raphaël
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2014; Springer; Springer Nature B.V
• Subjects: Alzheimer's disease; Animals; Biological and medical sciences; Cell cycle; Cell growth; Cell Proliferation; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes. Impaired glucose tolerance; Dyrk Kinases; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Haploinsufficiency; Human Physiology; Insulin - metabolism; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - cytology; Internal Medicine; Islets of Langerhans - cytology; Kinases; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Transgenic; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Signal Transduction; France; United States > US; Paris France; DYRK1A; Diabetes; Proliferation; p27; Beta cell; Endocrinopathy; Cell proliferation; Diabetes mellitus; Langerhans islet; Rodentia; Vertebrata; Mammalia; Mouse; Animal; β Cell; Endocrine pancreas
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-014-3174-3

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.