Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease characterized by multi-system involvement. Affected organ system includes skeletal muscle, heart, gastro-intestinal system and the brain. In this review, we evaluate the evidence for alterations in insulin signaling and their relation to clinical DM1 features. We start by summarizing the molecular pathophysiology of DM1. Next, an overview of normal insulin signaling physiology is given, and evidence for alterations herein in DM1 is presented. Clinically, evidence for involvement of insulin signaling pathways in DM1 is based on the increased incidence of insulin resistance seen in clinical practice and recent trial evidence of beneficial effects of metformin on muscle function. Indirectly, further support may be derived from certain CNS derived symptoms characteristic of DM1, such as obsessive-compulsive behavior features, for which links with altered insulin signaling has been demonstrated in other diseases. At the basic scientific level, several pathophysiological mechanisms that operate in DM1 may compromise normal insulin signaling physiology. The evidence presented here reflects the importance of insulin signaling in relation to clinical features of DM1 and justifies further basic scientific and clinical, therapeutically oriented research.
Highlights
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a trinucleotide (i.e., CTG) repeat expansion in the 3′ untranslated region of the dystrophia myotonica protein kinase (i.e., DMPK) gene on chromosome 19q13.3
We have consolidated the clinical and molecular evidence for the involvement of insulin signaling in myotonic dystrophy type 1
Clear links have been established between pathophysiological concepts in DM1, such as spliceopathy and DMPK haploinsufficiency, and molecular alterations in insulin signaling
Summary
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a trinucleotide (i.e., CTG) repeat expansion in the 3′ untranslated region of the dystrophia myotonica protein kinase (i.e., DMPK) gene on chromosome 19q13.3. In contrast to other IGFBPs, IGFBP7 is predominantly expressed in the gastrointestinal tract, lung, and prostate [48] but is present in brain It has a 500fold higher binding affinity for free serum insulin than IGF1 and can regulate insulin tone and action at its receptor [48, 49]. The higher binding affinity of IGFBP7 to the IGF1 receptor leads to the blockade of the IRS1 intrinsic pathway which impairs activation of protein synthesis, cell proliferation and cell growth survival and apoptosis [50]. The hyper(pro-)insulinemia in DM1 reflects an appropriate and partly successful compensatory change in response to insulin resistance that may occur in DM1 This is reflected by impaired glucose tolerance and/or abnormal glucose tolerance curves and increased levels of HbA1c, but a relatively infrequent occurrence of type 2 diabetes. Besides type 2 diabetes mellitus and myotonic dystrophy, insulin resistance is a feature of several rare genetic diseases: Alström, Werner, Cockayne, Romano-Ward syndromes, and ataxia telangiectasia
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