P.274 - Post-receptor abnormalities contribute to peripheral insulin resistance in myotonic dystrophy type 1 and type 2

Abstract

Myotonic dystrophies are autosomal dominant disorders characterized by a variety of multisystemic features including metabolic dysfunctions such as insulin resistance, hyperinsulinemia and a fourfold higher risk of developing Diabetes mellitus type 2. DMs are caused by expanded CTG or CCTG repeats which lead to nuclear accumulation of mutant transcripts deregulating the activity of some splicing regulators and leading to aberrant alternative splicing of different genes. Splicing alteration of insulin receptor (IR) gene is considered one of the causes of metabolic dysfunctions, however it cannot be excluded that post-receptor signalling abnormalities could also contribute to this feature of DM. The aim of this work is to investigate the mechanisms that contribute to the peripheral insulin resistance in DMs. The basal activation of several proteins involved in the insulin pathway has been analysed by western blot in proximal and distal muscles from 6 DM1, 5 DM2 and 7 healthy subjects. Insulin receptor alternative splicing has been analysed by RT-PCR. Our results indicate that DM skeletal muscle exhibits high basal activation of some proteins involved in the insulin pathway. To study if these changes are accompanied by a lack of further insulin stimulation the analysis of insulin pathway activation was performed on myotubes derived from myoblasts isolated from muscle biopsies of 5 DM1, 5 DM2, 5 healthy 2 T2DM subjects. Our results indicate that, despite the similar expression of foetal IR isoform, insulin action appears to be impaired in DM myotoubes in terms of protein activation and glucose uptake. In conclusion, these data indicate that post receptor signalling abnormalities might contribute to DM insulin resistance. Further investigations will be necessary to identify novel biomarkers that could be target for therapeutic intervention to improve the quality of life of DM patients.