title: Dyrk1A induces pancreatic β cell mass expansion and improves glucose tolerance.
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.
authors.affiliation: INSERM U1016; Institut Cochin; Faculté de Médecine Cochin; Université Paris Descartes; Paris, France.
authors.forename: Latif
authors.initials: L
authors.lastname: Rachdi
authors.affiliation: INSERM U1016; Institut Cochin; Faculté de Médecine Cochin; Université Paris Descartes; Paris, France; Hôpital Universitaire Necker Enfants Malades; Endocrinologie Gynécologie Diabétologie Pédiatriques; IMAGINE Institute; Paris, France.
authors.forename: Dulanjalee
authors.initials: D
authors.lastname: Kariyawasam
authors.affiliation: INSERM U1016; Institut Cochin; Faculté de Médecine Cochin; Université Paris Descartes; Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Aïello
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire; Translational Medicine and Neuroscience Program; IGBMC; CNRS; INSERM; Université de Strasbourg; UMR7104, UMR964, and Institut Clinique de la Souris; ICS; GIE CERBM; Illkirch, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Sorbonne Paris Cité; Unité de Biologie Fonctionnelle et Adaptative (BFA); CNRS UMR 8251; Paris Diderot University; Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.affiliation: Sorbonne Paris Cité; Unité de Biologie Fonctionnelle et Adaptative (BFA); CNRS UMR 8251; Paris Diderot University; Paris, France.
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Delabar
authors.affiliation: INSERM U1016; Institut Cochin; Faculté de Médecine Cochin; Université Paris Descartes; Paris, France; Hôpital Universitaire Necker Enfants Malades; Endocrinologie Gynécologie Diabétologie Pédiatriques; IMAGINE Institute; Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.affiliation: INSERM U1016; Institut Cochin; Faculté de Médecine Cochin; Université Paris Descartes; Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Scharfmann
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D049109:Cell Proliferation; D048429:Cell Size; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D059305:Diet, High-Fat; D005838:Genotype; D006946:Hyperinsulinism / Q000097:blood / Q000201:enzymology / Q000235:genetics; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D000097603:Dyrk Kinases
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: DYRK1A; beta cell; diabetes; growth; proliferation