Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes

TY - JOUR

T1 - Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes

AU - Møller, Andreas Buch

AU - Kampmann, Ulla

AU - Hedegaard, Jakob

AU - Thorsen, Kasper

AU - Nordentoft, Iver

AU - Vendelbo, Mikkel Holm

AU - Møller, Niels

AU - Jessen, Niels

PY - 2017/3/2

Y1 - 2017/3/2

N2 - 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.

AB - 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.

KW - Journal Article

UR - http://www.scopus.com/inward/record.url?scp=85014444197&partnerID=8YFLogxK

U2 - 10.1038/srep43775

DO - 10.1038/srep43775

M3 - Journal article

C2 - 28252104

SN - 2045-2322

VL - 7

SP - 1

EP - 11

JO - Scientific Reports

JF - Scientific Reports

M1 - 43775

ER -