Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle

Abstract

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders caused by expansion of microsatellite repeats. In both forms, the mutant transcripts accumulate in nuclear foci altering the function of alternative splicing regulators which are necessary for the physiological mRNA processing. Missplicing of insulin receptor (IR) gene (INSR) has been associated with insulin resistance, however, it cannot be excluded that post-receptor signalling abnormalities could also contribute to this feature in DM. We have analysed the insulin pathway in skeletal muscle biopsies and in myotube cultures from DM patients to assess whether downstream metabolism might be dysregulated and to better characterize the mechanism inducing insulin resistance. DM skeletal muscle exhibits alterations of basal phosphorylation levels of Akt/PKB, p70S6K, GSK3β and ERK1/2, suggesting that these changes might be accompanied by a lack of further insulin stimulation. Alterations of insulin pathway have been confirmed on control and DM myotubes expressing fetal INSR isoform (INSR-A). The results indicate that insulin action appears to be lower in DM than in control myotubes in terms of protein activation and glucose uptake. Our data indicate that post-receptor signalling abnormalities might contribute to DM insulin resistance regardless the alteration of INSR splicing.

Cells of Matter—In Vitro Models for Myotonic Dystrophy

“…Cells obtained directly from patients are of great utility in modeling human genetic disorders if they reproduce molecular hallmarks of the disease. Regarding DM1 patients’ derived cells, they express the whole range of mutation lengths observed in affected individuals within their natural genomic context and reproduce other canonical features of the disease (Figure 1 ) such as CUGexp-RNA foci that colocalize with the MBNL family members ( 45 , 46 , 64 – 70 ), alternative splicing misregulations ( 48 , 65 , 67 , 70 – 73 ), and alterations of metabolic pathways ( 74 , 75 ). However, considering variable parameters, like for instance samples from patients with different forms of the disease (from congenital to adult), culture conditions, or replicative senescence of primary cells, one should be aware of experimental variability between them.…”

Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth

“…For instance, FOR increased muscle force in MKR mice, even in the absence of muscle hypertrophy, suggesting that strength gain is not causally related to muscle growth after β 2 ‐agonist treatment. This effect is clinically relevant for improving muscle function in INS‐resistant patients with type 2 diabetes mellitus or with myotonic dystrophies because they may not be beneficiated by growth‐promoting actions of β 2 ‐AR stimulation. The strength gain effect of FOR was associated with an increase in the quantity of type IIB fibre that, as expected, displayed faster contraction kinetics and an accumulation of carbohydrate to fuel glycolytic metabolism.…”

High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study

“…Determinants of fatty liver degeneration in DM1 are not yet clarified, and so far, only one study (7) analyzing a cohort of 36 DM1 patients, documented a high prevalence of NAFLD (about 38% of patients) and its strong association with markers of insulin resistance and features of the metabolic syndrome. NAFLD is strongly associated with insulin resistance and type 2 diabetes (23), which in turn are associated with DM1 (24), being likely related to the aberrant expression of the insulin receptor documented in DM1 peripheral tissues (25)(26)(27). To clarify this issue, we are going to evaluate in a further study prevalence and predictors of NAFLD in our cohort of DM1 patients, in comparison to a non-DM1-NAFLD cohort.…”

“…To clarify this issue, we are going to evaluate in a further study prevalence and predictors of NAFLD in our cohort of DM1 patients, in comparison to a non-DM1-NAFLD cohort. NAFLD is strongly associated with insulin resistance and type 2 diabetes (23): both these conditions are frequent features also in DM1 (24), being likely related to the aberrant expression of the insulin receptor in the peripheral tissues (25)(26)(27) and/or to the presence of other post-receptor signaling abnormalities in DM1 tissues (28).…”