[HTML][HTML] Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action

E Llagostera, D Catalucci, L Marti, M Liesa, M Camps… - PLoS …, 2007 - journals.plos.org
E Llagostera, D Catalucci, L Marti, M Liesa, M Camps, TP Ciaraldi, R Kondo, S Reddy…
PLoS One, 2007journals.plos.org
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 …
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.
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