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.

Metabolic Alterations in Myotonic Dystrophy Type 1 and Their Correlation with Lipin

“…Abnormal lipid metabolism is frequently observed in patients with DM1, particularly in skeletal tissue. Additionally, the main cause of this abnormality is insulin resistance (increased levels of insulin at plasma, hyperinsulinemia) and dyslipidemia (hypertriglyceridemia, low HDL cholesterolemia, high LDL cholesterolemia, and abdominal obesity) [ 8 , 9 ]. MetS in patients with DM1 may be associated with lipin deficiency levels.…”

“…It is a major risk factor for cardiovascular disease, cerebrovascular disease accident and peripheral arterial disease [ 9 , 53 , 54 ]. Dyslipidemia is strongly associated to MetS, nonalcoholic fatty liver disease (NAFLD) and is closely related with insulin resistance, since alteration of lipid metabolism and the increase of free fatty acid (FFA) flux inhibits insulin signaling leading to insulin resistance [ 8 , 9 , 53 , 56 , 63 ].…”

“…These features were also in accordance with Table 2 , as with the downregulation of lipin the de novo lipogenesis was not inhibited and therefore there will be an increase of total cholesterol, LDL, and TAG secretion, as well as fatty acid synthesis [ 14 , 76 , 81 , 96 , 97 , 98 , 99 , 100 , 101 ]. Furthermore, the lipin deficiency may also, lead to insulin resistance, obesity, and amplification of the pro-inflammatory factors, influencing abnormal lipid metabolism, cell growth, SERCA function, endoplasmic reticulum stress, mitochondrial dysfunction, autophagosome accumulation, and lipid accumulation in skeletal muscle and liver, among other organs [ 8 , 9 , 14 , 81 , 96 ]. Therefore, it would be important to understand the correlation of lipin alteration in patients with DM1 with the high frequency of dyslipidemia and MetS.…”

“…The major targets of insulin are adipose tissue, muscle, liver, and heart. Insulin receptor can also be found in brain, lungs, kidneys, fibroblasts, and blood cells [ 8 ]. Insulin is also a key molecule in lipid metabolism and protein synthesis, and is involved in glucose uptake in skeletal muscle and adipocytes, promotion of glycogen synthesis, inhibiting lipolysis in adipocytes, reduction of hepatic gluconeogenesis process by lipolysis inhibition, regulation of muscle proteins synthesis, and promoting cell division and growth [ 8 , 70 ].…”

“…Metabolic syndrome (MetS) in patients with muscular disorders are significantly higher than in general population due to abnormal lipid metabolism, such as insulin resistance, hypertriglyceridemia, increased fat mass, high levels of low-density lipoprotein (LDL), low levels of high-density lipoproteins (HDL) and abdominal obesity [ 8 , 9 ]. These abnormalities seem to be related to lipin, since it is a key enzyme that regulates lipid metabolism and signaling, and is a transcriptional co-activator of fatty acid β-oxidation [ 10 , 11 , 12 , 13 , 14 ].…”