Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

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.

Keywords: behavioral flexibility; diabetes type 2; insulin; insulin resistance; insulin-like growth factor 1 (IGF1); metformin; myotonic dystrophy (DM1); obsessive–compulsive disorder.

Figure 1

Schematic diagram of a cell with insulin/IGF signaling cascades depicted. Insulin may exert its effects through one of three transmembrane kinase receptors: IR, IGF1R or the IGFR/IR hybrid receptor. The IGF2R/M6P receptor has an unknown signaling potential. IGF1 can act alone or complexed with IGFBP3 or IGFBP5 and ALS and interacts with IGF1R and IR. IGF2 when bound to IGFBP2 or IGFBP6 interacts with the IGF2R (M6PR), IR or IGF1R. Insulin signaling is also regulated by IGFBP7, which can bind both IGF1 and insulin and bind with their receptors. IGFBP7 can also bind to the IGF1R which leads to the blockade of the IRS1 intrinsic pathway. Following ligand-receptor interaction, signal transduction to the cytosol is via the kinase domains of the IR, IGF1/IR and IGF1R receptors. The main targets for phosphorylation are the IRSs, which further transduce the signals through divergent messenger cascades, eventually leading to the various metabolic effects of insulin and IGFs. These effects can be metabolic or mitogenic and include lipid synthesis via PI3K/SREBP pathway, glycogen synthesis and protein synthesis and apoptosis regulation via the PI3K/AKT/GSK3/eIF2B pathway; and transcription and translation, cellular proliferation and synaptic plasticity via the RAS/MAPK/ERKS/RSK/Elk1 pathway. For an excellent review and more detail, see (23). IGF2 binds to the IGF2R (also known as the M6P receptor) and lacks intrinsic kinase activity but has been reported to regulate AKT activity. AKT acts to regulate multiple downstream targets including GSK3 and MTOR but is also involved in glucose uptake and the expression of GLUT4 which is a key player in glucose uptake. ALS, acid-labile subunit glycoprotein; eIF2B, eukaryotic initiation factor 2B; GSK3β, glycogen synthase kinase 3 beta; IGF1R, insulin growth factor receptor; IGFBP, insulin growth factor binding protein; IR, insulin receptor; IRS1, insulin receptor substrate-1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; RSK, ribosomal S6 kinase.

Figure 2

Schematic illustration of the link between altered insulin resistance/signaling and common symptoms across disorders (including DM1). The message is that some DM1 related symptoms are found in Metabolic syndrome, progeria and the rare genetic disease, while insulin resistance is an overlapping symptom seen all diseases. The common symptoms include but are not necessarily present in all overlapping disorders: cataracts, skull hyperostosis, early hair graying/loss, impaired muscular development or wasting, cardiac arrhythmia, hypogonadism, testicular atrophy and dyslipidemia. Insulin resistance is a key feature in some but not all DM1 cases and is present in 5–17% of DM1 cases. DM1 has symptomatic (and insulin resistance) overlap with certain rare diseases, including Alström-, Werner-, Romano-Ward, Cockayne syndromes, and ataxia telangiectasia. Both normal aging and DM1 are associated with increased insulin resistance. Moreover, DM1 is conceptualized as a disease with early-onset aging. Metabolic syndrome is also linked to insulin resistance (90), and is present in DM1 (87, 91).

Figure 3

Schematic diagram of the mechanisms associated with insulin resistance. The directionality of the arrow indicates if it is a cause or consequence of insulin resistance. This includes splice variation of IR/IGF1 receptor expression (e.g., IR-A isoform increase vs. IR-B), leading to insulin resistance. Diminished cell membrane IGFR and IR expression could result from the DMPK repeat length expansions blocking the nuclear pores, and also result in insulin resistance. Alterations in lipid metabolism as a consequence of insulin resistance may also lead to altered lipid/skeletal muscle ratios, as is seen in DM1. Reduced insulin sensitivity is also associated with diminished muscle protein synthesis, resulting in decreased muscle mass. Inflammation has a bidirectional relationship with insulin resistance and may in part underlie atherosclerosis in DM1. Mechanistically, inflammation increases mitochondrial oxidative stress and stress at the level of the pancreatic beta islet cells which also increases insulin resistance. Decreased IGFBP expression also reduces insulin sensitivity by reducing the half-life of any insulin-IGFBP complex to bind to the IR/IGF receptors. Insulin resistance also acts to alter leptin signaling which amongst others can regulate testosterone tone. Insulin resistance can also act at the level of (1) PPARγ/AMPK signaling and (2) AKT1/GSK3β signaling thereby regulating glucose turnover which may be linked to fatigue in DM1.