title: Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action.
abstract: Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3'-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk-/-) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk-/- mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk-/- mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Llagostera
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: Luc
authors.initials: L
authors.lastname: Marti
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.forename: Marta
authors.initials: M
authors.lastname: Camps
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: Richard
authors.initials: R
authors.lastname: Kondo
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacin
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Perla
authors.initials: P
authors.lastname: Kaliman
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000502:physiology*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: C585516:DMPK protein, mouse; D007328:Insulin; D011972:Receptor, Insulin; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose