Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action.
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.
Llagostera
Esther
E
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Catalucci
Daniele
D
Marti
Luc
L
Liesa
Marc
M
Camps
Marta
M
Ciaraldi
Theodore P
TP
Kondo
Richard
R
Reddy
Sita
S
Dillmann
Wolfgang H
WH
Palacin
Manuel
M
Zorzano
Antonio
A
Ruiz-Lozano
Pilar
P
Gomis
Ramon
R
Kaliman
Perla
P
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
C585516:DMPK protein, mouse; D007328:Insulin; D011972:Receptor, Insulin; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose