DM1 Pathogenesis Research Articles

Overexpression of CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 but Not from Myotonic Dystrophy Type 2

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested.

Compound loss of muscleblind‐like function in myotonic dystrophy

Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.

P.18.11 Nerve conduction alterations in Mexican patients with myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder with multisystemic clinical features. It is the most common type of muscular dystrophy in adults. The clinical phenotype varies with the age of presentation showing muscle weakness, wasting, myotonia, cardiac problems, cataracts, and central nervous system altetration. The peripheral nervous system involvement in the DM1 pathogenesis has not been clearly defined. To explore nerve conduction studies in DM1 Mexican patients and establish a relation with their clinical phenotype. A clinical, transversal, non-randomized study of consecutive cases was designed. Patients with molecular diagnosis of DM1 admitted between January 2010 and October 2012 with glycemic levels lower than 110 mg/dl and without concomitant diseases were part of the study. We documented the age, age at presentation and time of evolution. A nerve conduction study was performed in all patients recording motor and sensitive nerve conduction and F waves in the median, ulnar, tibial, peroneal and sural nerves of 4 extremities. We studied 39 patients, 25 male (64.1%) and 14 female (35.9%) between 6 and 57 years old. 35.9% classic, 28.2% early, 17.9% infant and 7.7% congenital DM1 form. A normal sensitive conduction was observed in 84.6% of the patients. Peroneal nerve was the most affected with decreased amplitude in 18 patients (42%). Median nerve showed prolonged latency in 3 patients (33%). Peroneal was the most affected nerve showing F waves with low persistence in 35.9% of patients, 25.6% had no response and 2.6% had prolonged latency. Tibial nerve showed alteration only in 12.9% of patients. DM1 patients presented electrophysiological data of motor neuropathy with axonal degeneration, mostly in peroneal nerve. These must be caused by muscular atrophy or neuropathic alteration. Sensitive nerve conduction abnormalities are infrequent.

Evaluating the effects of CELF1 deficiency in a mouse model of RNA toxicity

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by an expanded (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The toxic RNA transcripts produced from the mutant allele alter the function of RNA-binding proteins leading to the functional depletion of muscleblind-like (MBNL) proteins and an increase in steady state levels of CUG-BP1 (CUGBP-ETR-3 like factor 1, CELF1). The role of increased CELF1 in DM1 pathogenesis is well studied using genetically engineered mouse models. Also, as a potential therapeutic strategy, the benefits of increasing MBNL1 expression have recently been reported. However, the effect of reduction of CELF1 is not yet clear. In this study, we generated CELF1 knockout mice, which also carry an inducible toxic RNA transgene to test the effects of CELF1 reduction in RNA toxicity. We found that the absence of CELF1 did not correct splicing defects. It did however mitigate the increase in translational targets of CELF1 (MEF2A and C/EBPβ). Notably, we found that loss of CELF1 prevented deterioration of muscle function by the toxic RNA, and resulted in better muscle histopathology. These data suggest that while reduction of CELF1 may be of limited benefit with respect to DM1-associated spliceopathy, it may be beneficial to the muscular dystrophy associated with RNA toxicity.

P 170. Characterization of brain plasticity in Diabetes Type II and Alzheimer’s disease supports link between both diseases

Introduction Increased incidence of Alzheimer’s disease (AD) in individuals with Diabetes Type II (DM2) suggests a possible pathophysiologic link. Support for such a link comes from several experimental animal models. Insulin deficiency and resistance are major factors in the pathogenesis of DM2 and appear to be involved in the neurodegenerative processes of AD by altering synaptic brain plasticity. Transcranial magnetic stimulation (TMS) can be used to examine mechanisms of plasticity, and may thus reveal abnormalities in patients with DM2 that might resemble those in patients with AD. Objectives Evaluate cortical plasticity mechanisms in subjects with DM2 and compare them with those in patients with AD as assessed by TMS measures. Explore possible similarities in abnormal brain plasticity in order to investigate the link between DM2 and AD. Materials and methods To evaluate cortical brain plasticity we applied intermittent theta burst stimulation (iTBS) at 80% of active motor threshold (aMT) over the left primary motor cortex (M1) in patients with mild to moderate AD, DM2 and in healthy individuals. iTBS consisted of a total of 600 pulses divided into 20 trains, each including bursts of 3 pulses at 50 Hz repeated at 5 Hz for 2 s and with an 8 s interval between trains. Motor evoked potentials (MEPs) of the right first dorsal interosseus muscle (FDI) were triggered by neuronavigated single pulse transcranial magnetic stimulation (spTMS) over left M1 at 120% of resting motor threshold (rMT) before and after iTBS. Changes in MEP amplitudes after iTBS were examined as measures of long term potentiation (LTP) like plasticity. Results Within the first 20 min following iTBS baseline corrected MEPs were significantly larger for healthy subjects (1.32 ± 0.21 mV) compared to patients with AD (0.92 ± 0.08 mV; p = 0.023) and DM2 (0.69 ± 0.15 mV; p = 0.007) (Fig. 1). There was no significant difference between AD and DM2 (p = 0.63). Interestingly, while iTBS had almost no effect on AD patients it tended to have a paradoxically inhibitory effect in patients with DM2. Conclusion The iTBS-induced modulation of corticospinal excitability is impaired in both AD and DM2. This finding supports the notion of aberrant LTP-like mechanisms of plasticity in DM2 and AD, and suggests a pathophysiologic link between the two diseases. This link may account for the epidemiologically increased risk for patients with DM2 to develop AD. Further studies and longitudinal assessments are needed to explore such a link further, but in this context, TMS-methods appear promising and may become a valuable early biomarker for AD and individuals at risk. Acknowledgements The study was sponsored and supported by the Harvard Catalyst, Nexstim, Neuronix Ltd., the National Institutes of Health, and the Berenson-Allen Foundation. Download : Download high-res image (60KB) Download : Download full-size image

MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases

Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142–43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142–43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142–43, succeeded in reducing the nuclear localization of both Lyn and MBNL142–43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.

Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy

We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA–binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2α translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1.

Diabetes mellitus – um «continuum» fisiopatológico

IntroductionDiabetes mellitus is mainly subdivided into type 1 diabetes (DM1) or type 2 (DM2). The existence of genetic, metabolic and immunological mechanisms involving these two entities, and clinical evidence of an autoimmune form of diabetes diagnosed in adults (LADA), suggests the possibility of a pathophysiological continuity. ObjectiveTo describe the main genetic, immunological and metabolic mechanisms common to the development of DM1 and DM2. To support the hypothesis of a pathophysiological continuum between the two main subtypes of diabetes. MethodsSystematic search in PubMed database of the original articles or systematic reviews published until April 2013. The search terms used were: «type 1 diabetes mellitus», «type 2 diabetes mellitus», «latent auto-immune diabetes in adults», «pathophysiology». ConclusionsLADA assumes, under the pathophysiological point of view, an intermediate position between DM1 and DM2, sharing genetic and immunological mechanisms. It was found that self-reactivity and apoptosis of the β cell are not exclusive processes of DM1, and that insulin resistance, being a key factor in the pathogenesis of DM2, determines a more rapid progression of DM1. Phenotypic expression of diabetes results from the imbalance created between these pathophysiological mechanisms, along the course of the disease. More than the classification of the patient in a subtype of diabetes it is the recognition of mechanisms leading to metabolic changes that allows an adequate therapy. The definition of LADA as an isolated entity could be withdrawn.

Role of Potassium Channels in Myogenesis during Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder affecting 1 in 8000 people worldwide. DM1 is genetically identified as a mutation that contains expansion of CTG repeats in 3' UTR of the DM1 protein kinase gene. It is characterized by muscle wasting and multi-system failure including insulin resistance and major cardiac involvement.We have identified a switch in functional potassium channel expression from KCa1.1 to Kv1 channels when comparing myoblasts from healthy donors and from patients with DM1. Potassium channels are responsible for maintaining resting membrane potential and regulating cell volume, and play a role in cell proliferation. We hypothesize that this switch in potassium channel plays a role in the reduced myogenesis observed in patients with DM1, and that selective inhibition of Kv1 channels will rescue at least some of the pathological features of DM1 in skeletal muscle.We have found that pharmacological inhibition of Kv1 channel decreased proliferation of primary myoblasts from patients with DM1. This blockade also restored production of matrix metalloproteinase-2 (a protease necessary for myotube fusion) in DM1 myoblasts to levels obtained in cells from healthy controls. Blocking KCa1.1 channels induced an increase in the proliferative rate of healthy myoblasts. Our results do support the hypothesis that blocking Kv1 channels will be beneficial in DM1.Ongoing studies focus on the role of KCa1.1 and Kv1 channels in myoblast fusion to form myotubes. We also propose to study the inter-dependency of Kv and KCa1.1 channels by genetically or pharmacologically knocking down one channel and observing compensatory increase in expression of the other.Through this project, our goal is to better understand the roles of potassium channels in DM1 pathogenesis and to establish Kv1 channel as potential targets for therapy.

Immunohistochemical study of the pancreas of patients with long termed diabetes mellitus type 1

There has been a concept of the autoimmune pathogenesis of DM1 developed in the diabetology. The basic notion of the concept is that a root cause of a death of the insulin containing B-cells is in an autoimmune aggression against them (1, 2). There is a significant destruction of B-cells observed in patients with DM1 prior to diagnosis. In patients with recently diagnosed DM1 the autoimmune processes has manifested in a form of insulitis chronic inflammatory infiltration of mononuclear cells in the residual cells of the pancreatic islets (3). Although considered typical for recent onset disease, the insulitis has been described only in approximately 150 cases per 100 years (4). It is known that DM1 is accompaniedby peripheral nervous system lesions wich leads to a reduction of a life span and mortality enlargement. It has been suggested that peripheral nervous system lesions, as well as B-cell destruction, in DM1 patients also has an autoimmune nature. Moreover, experiments on DM1 animal models (NOD mice) shows the autoimmune destruction of pancreatic nerve terminals at a beginning of the DM1 progression (5-11). According to this model the autoimmune reaction on B-cells develops after T-cells infiltration into the pancreatic islets as a result of similarities between B-cells and neurons in some synthezied proteins and intracellular processes, and high sensitivity of B-cells to the cytokine induced destruction (5, 6, 12,13).

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8 % in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat.

Myotonic Dystrophy: From Bench to Bedside

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant disorders classically characterized by muscle weakness, myotonia, and early-onset cataracts. Patients may also experience dysfunction of the heart, brain, gastrointestinal, endocrine, skin, and respiratory systems. The pathogenesis of myotonic dystrophy is related to trinucleotide (DM1) and tetranucleotide (DM2) repeat expansions that produce toxic mutant mRNA with subsequent interference of RNA-splicing mechanisms. Optimal disease management includes symptomatic care, screens for asymptomatic disease, counseling, and a multidisciplinary approach. The authors review the pathogenesis, clinical features, diagnostic tests, and standard management of DM1 and DM2 and outline promising clinical research for patients with these disorders.

Myotonic dystrophy

The myotonic dystrophies (DM1 and DM2) are the paradigm for RNA toxicity in disease pathogenesis. The emphasis of this review will be on recent developments and issues in understanding the pathogenesis of DM1 and how this is driving the accelerated pace of translational and therapeutic developments. RNA toxicity in myotonic dystrophy is now associated with bi-directional antisense transcription, dysregulation of microRNAs and potentially non-ATG-mediated translation of homopolymeric toxic proteins. The role of other RNA-binding proteins beyond MBNL1 and CUGBP1, such as Staufen 1 and DDX5, are being identified and studied with respect to their role in myotonic dystrophy. New functions for MBNL1 in miR-1 biogenesis might have a clinically relevant role in myotonic dystrophy cardiac conduction defects and pathology. Advances are being made in identifying and characterizing small molecules with the potential to disrupt CUG-MBNL1 interactions. Mechanisms of RNA toxicity are moving beyond a simplistic 'foci-centric' view of DM1 pathogenesis as a spliceopathy due to MBNL1 sequestration. Therapeutic development for myotonic dystrophy is moving rapidly with the development of antisense and small molecule therapies. Clinically, significant emphasis is being placed on biomarker discovery and outcome measures as an essential prelude to clinical trials.

Transcriptome-wide Regulation of Pre-mRNA Splicing and mRNA Localization by Muscleblind Proteins

The muscleblind-like (Mbnl) family of RNA-binding proteins plays important roles in muscle and eye development and in myotonic dystrophy (DM), in which expanded CUG or CCUG repeats functionally deplete Mbnl proteins. We identified transcriptome-wide functional and biophysical targets of Mbnl proteins in brain, heart, muscle, and myoblasts by using RNA-seq and CLIP-seq approaches. This analysis identified several hundred splicing events whose regulation depended on Mbnl function in a pattern indicating functional interchangeability between Mbnl1 and Mbnl2. A nucleotide resolution RNA map associated repression or activation of exon splicing with Mbnl binding near either 3' splice site or near the downstream 5' splice site, respectively. Transcriptomic analysis of subcellular compartments uncovered a global role for Mbnls in regulating localization of mRNAs in both mouse and Drosophila cells, and Mbnl-dependent translation and protein secretion were observed for a subset of mRNAs with Mbnl-dependent localization. These findings hold several new implications for DM pathogenesis.

The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus

It is well established that genetic factors play an important role in the development of both type 2 diabetes mellitus (DM2) and obesity, and that genetically susceptible subjects can develop these metabolic diseases after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2 and/or obesity. Uncoupling protein 1 (UCP1) is mainly expressed in brown adipose tissue, and acts in thermogenesis, regulation of energy expenditure, and protection against oxidative stress. All these mechanisms are associated with the pathogenesis of DM2 and obesity. Hence, UCP1 is a candidate gene for the development of these disorders. Indeed, several studies have reported that polymorphisms -3826A/G, -1766A/G and -112A/C in the promoter region, Ala64Thr in exon 2 and Met299Leu in exon 5 of UCP1 gene are possibly associated with obesity and/or DM2. However, results are still controversial in different populations. Thus, the aim of this study was to review the role of UCP1 in the development of these metabolic diseases.

Over-nutrition, Obesity and Insulin Resistance in the Development of β-Cell Dysfunction

The incidence of type 2 diabetes mellitus (DM2) has increased dramatically over the last several decades, largely driven by equally worrisome growing rates of obesity. Chronic diabetic complications are leading causes of morbidity and mortality worldwide. Key players in the pathophysiology of DM2 are insulin resistance and β cell dysfunction, which in turn is a result of both β cell functional abnormality as well as reduced β cell mass. The mechanisms implicated are multifactorial and include genetic and environmental factors related to obesity. Glucose homeostasis is critically dependent on a finely regulated balance between insulin sensitivity and output in the pancreas, and insulin resistance demands a corresponding rise in insulin output in order to maintain normal glycemia. However, this compensation is lost in individuals predisposed to DM2, resulting in overt hyperglycemia. Furthermore, insulin resistance related to excess adiposity is linked to several abnormalities which impact β cell function and viability. These include glucotoxicity, lipotoxicity, increased oxidative stress, and inflammation. In addition, insulin signaling in the β cell is essential to its own functionality and viability, and obesity-related abnormalities in insulin signaling are known to induce failure of insulin secretion and hyperglycemia. Insulin resistance in the β cell arises from defects in phosphorylation/activation of insulin receptor substrates (IRS) proteins, which result in impairment in glucose sensing, glucose stimulated insulin secretion, and also in increased loss of β cells. This review intends to provide an update on the main characteristics and mechanisms that link obesity and insulin resistance to β cell dysfunction in the pathogenesis of DM2.

Repression of nuclear CELF activity can rescue CELF-regulated alternative splicing defects in skeletal muscle models of myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is caused by the expansion of CUG repeats in the 3’ UTR of DMPK transcripts. DM1 pathogenesis has been attributed in part to alternative splicing dysregulation via elevation of CUG-BP, Elav-like family member 1 (CELF1). Several therapeutic approaches have been tested in cells and mice, but no previous studies had specifically targeted CELF1. Here, we show that repressing CELF activity rescues CELF-dependent alternative splicing in cell culture and transgenic mouse models of DM1. CELF-independent splicing, however, remained dysregulated. These data highlight both the potential and limitations of targeting CELF1 for the treatment of DM1.

Two high-throughput screening assays for aberrant RNA–protein interactions in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1), the most prevalent form of adult muscular dystrophy, is caused by expansion of a CTG repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The pathogenic effects of the CTG expansion arise from the deleterious effects of the mutant transcript. RNA with expanded CUG tracts alters the activities of several RNA binding proteins, including muscleblind-like 1 (MBNL1). MBNL1 becomes sequestered in nuclear foci in complex with the expanded CUG-repeat RNA. The resulting loss of MBNL1 activity causes misregulated alternative splicing of multiple genes, leading to symptoms of DM1. The binding interaction between MBNL1 and mutant RNA could be a key step in the pathogenesis of DM1 and serves as a potential target for therapeutic intervention. We have developed two high-throughput screens suitable assays using both homogenous time-resolved fluorescence energy transfer and AlphaScreen technologies to detect the binding of a C-terminally His-tagged MBNL1 and a biotinylated (CUG)(12) RNA. These assays are homogenous and successfully miniaturized to 1,536-well plate format. Both assays were validated and show robust signal-to-basal ratios and Z' factors.

Misregulation of alternative splicing and microRNA processing in DM1 pathogenesis

Myotonic dystrophy of type I (DM1) is an autosomal dominant inherited disease caused by an unstable CTG expansion in the 3' non-coding region of the DMPK gene that confers to the mutant transcript a toxic RNA gain-of-function. Nuclear accumulation of DMPK transcripts containing expanded CUG repeats alters the activities of the splicing regulators MBNL1 and CUGBP1 resulting in alternative splicing misregulation of a numerous of transcripts in DM1 tissues. In collaboration with N. Charlet we identified a new mis-splicing event in the muscles of DM1 patients: BIN1 exon11 splicing mis-regulation due to MBNL1 loss-of-function results in the expression of an inactive form of BIN1. Reproducing similar BIN1 mis-splicing defect in the muscles of wild type mice is sufficient to promote T-tubule alterations and muscle strength decrease, suggesting that alteration of BIN1 splicing contributes to DM1 muscle weakness. Interestingly, the RNA binding protein MBNL1 regulates also the processing of the microRNA miR-1 that was found mis-regulated in the heart of DM1 patients. The consequences of miR-1 mis-regulation on DM1 heart conduction defects are not fully understood yet, however this work may shed light on the alteration of this class of non-coding RNA as an additional molecular mechanisms involved in DM1 pathophysiology.

Type 1 diabetes mellitus: An update

Globally, the number of children with Type 1 diabetes mellitus (T1DM) has been rising at a much faster pace than expected. Despite an advanced diabetes care system, we have not yet succeeded in either preventing the disease or treating complications of diabetes. Therefore, the negative effects tend to be greater among children with a young age at onset. Consequently, the global financial burden of diabetes is increasing at an exponential rate and accounts for about 11% of the total budget on health.Several studies have confirmed the increasing incidence of Type 1 diabetes mellitus, linking it with sedentary life style. T1DM, being one of the most prevalent chronic health conditions in children under the age of 18 years is considered as one of thrust areas of research. Hence, this article is aimed to provide an overview of the major advances in our understanding of the etiology, pathogenesis and clinical management of DM in children with the focus being on T1DM. The incidence, prevalence, burden on health budget and prevention and prediction of childhood diabetes, which may facilitate the researchers in the field of diabetes is documented in this review. Although T1DM cannot yet be prevented successfully, ongoing clinical trials on designer insulin and innovative strategies such as herbal formulae may bring some hope through advanced research techniques.