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.
Highlights
Type 2 diabetes is a heterogeneous disease and a major international public health threat
Insulin resistance in DM1 has been associated with aberrant splicing of the insulin receptor RNA due to a toxic effect of the CUG-expanded repeats, which are transcribed from the mutated dmpk gene but are retained in the nucleus altering the normal metabolism of RNAs [10,11]
We show that DMPK plays a role in the regulation of whole-body glucose disposal and muscle insulin sensitivity through a mechanism that involves the intracellular trafficking of insulin and IGF-1 receptors
Summary
Type 2 diabetes is a heterogeneous disease and a major international public health threat. Insulin resistance, which is a major factor in the development of type 2 diabetes [2], is a common metabolic feature in myotonic dystrophy 1 (DM1), an autosomal dominant neuromuscular disorder [3]. Insulin resistance in DM1 has been associated with aberrant splicing of the insulin receptor RNA due to a toxic effect of the CUG-expanded repeats, which are transcribed from the mutated dmpk gene but are retained in the nucleus altering the normal metabolism of RNAs [10,11]. Dmpk gene is located on chromosome 19q13, in which quantitative trait loci (QTLs) for type 2 diabetes-associated phenotypes have been identified by two independent genome-wide linkage scans among large and multiple ethnicity populations [16,17]
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