title: Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes.
abstract: This case-control study was designed to investigate the gene expression profile in skeletal muscle from severely insulin resistant patients with long-standing type 2 diabetes (T2D), and to determine associated signaling pathways. Gene expression profiles were examined by whole transcriptome, strand-specific RNA-sequencing and associated signaling was determined by western blot. We identified 117 differentially expressed gene transcripts. Ingenuity Pathway Analysis related these differences to abnormal muscle morphology and mitochondrial dysfunction. Despite a ~5-fold difference in plasma insulin, we did not observe any difference in phosphorylation of AKT or AS160, although other insulin-sensitive cascades, as mTOR/4EBP1, had retained their sensitivity. Autophagy-related gene (ATG14, RB1CC1/FIP200, GABARAPL1, SQSTM1/p62, and WIPI1) and protein (LC3BII, SQSTM1/p62 and ATG5) expression were decreased in skeletal muscle from the patients, and this was associated with a trend to increased phosphorylation of the insulin-sensitive regulatory transcription factor FOXO3a. These data show that gene expression is highly altered and related to mitochondrial dysfunction and abnormal morphology in skeletal muscle from severely insulin resistant patients with T2D, and that this is associated with decreased expression of autophagy-related genes and proteins. We speculate that prolonged treatment with high doses of insulin may suppress autophagy thereby generating a vicious cycle maintaining insulin resistance.
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Denmark.
authors.forename: Andreas Buch
authors.initials: AB
authors.lastname: Møller
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Kampmann
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hedegaard
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Thorsen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: Mikkel Holm
authors.initials: MH
authors.lastname: Vendelbo
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Denmark.|Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Denmark.|Department of Molecular Medicine, Aarhus University Hospital, Denmark.|Department of Clinical Pharmacology, Aarhus University Hospital, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
mesh_terms: D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000071183:Autophagy-Related Proteins; D015415:Biomarkers