Cited by 57Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismMitochondrial Function and Pathology

Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes.

Frederiksen, C. M., Højlund, K., Hansen, L., Oakeley, E. J., Hemmings, B., Abdallah, B. M., Brusgaard, K., Beck-Nielsen, H. +1 more·2008·Diabetologia

Abstract

Aims/hypothesis Microarray-based studies of skeletal muscle from patients with type 2 diabetes and high-risk individuals have demonstrated that insulin resistance and reduced mitochondrial biogenesis co-exist early in the pathogenesis of type 2 diabetes independently of hyperglycaemia and obesity. It is unknown whether reduced mitochondrial biogenesis or other transcriptional alterations co-exist with impaired insulin responsiveness in primary human muscle cells from patients with type 2 diabetes.Methods Using cDNA microarray technology and global pathway analysis with the Gene Map Annotator and Pathway Profiler (GenMapp 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1), we examined transcript levels in myotubes established from obese patients with type 2 diabetes and matched obese healthy participants, who had been extensively metabolically characterised both in vivo and in vitro. We have previously reported reduced basal lipid oxidation and impaired insulin-stimulated glycogen synthesis and glucose oxidation in these diabetic myotubes.Results No single gene was differently expressed after correction for multiple testing, and no biological pathway was differently expressed using either method of global pathway analysis. In particular, we found no evidence for differential expression of genes involved in mitochondrial oxidative metabolism. Consistently, there was no difference in mRNA levels of genes known to mediate the transcriptional control of mitochondrial biogenesis (PPARGC1A and NRF1) or in mitochondrial mass between diabetic and control myotubes.Conclusions/interpretation These results support the hypothesis that impaired mitochondrial biogenesis is not a primary defect in the sequence of events leading to insulin resistance and type 2 diabetes.

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  • Primary myotubes isolated from obese humans with type 2 DM display reduced basal lipid oxidation and insulin-stimulated glucose oxidation with no differences in OXPHOS gene expression.

    “For example, primary myotubes isolated from obese humans with type 2 DM display reduced basal lipid oxidation and insulinstimulated glucose oxidation with no differences in OXPHOS gene expression (126).”
  • PGC-1α expression may also be reduced as a consequence of promoter methylation or caused by insulin itself, obesity, and sustained lipid exposure.

    “In turn, PGC-1␣ expression may also be reduced as a consequence of promoter methylation (146) or caused by insulin itself (145), obesity (126), and sustained lipid exposure (126).”

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Authors
Frederiksen, C. M., Højlund, K., Hansen, L., Oakeley, E. J., Hemmings, B., Abdallah, B. M., Brusgaard, K., Beck-Nielsen, H., & Gaster, M.
Affiliations
  • Odense University Hospital (DK)
  • Friedrich Miescher Institute (CH)
  • University of Southern Denmark (DK)
Corresponding author
Højlund, K.
Venue
Diabetologia
Published
2008-08-22
Volume
51
Issue
11
Pages
2068-2077
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
OpenAlex
W2029631235
Cited by
57
References
44
Citations by year
2025: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 9
FWCI
2.88
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
type 2 diabetes, myotubes, skeletal muscle, insulin resistance, mitochondrial biogenesis, oxidative phosphorylation, PGC-1α, NRF1, gene expression profiling, lipid oxidation, glucose oxidation, glycogen synthesis, obesity
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Diabetes Mellitus, Type 2, Heat-Shock Proteins, Humans, Middle Aged, Obesity, Oxidative Phosphorylation, RNA, Transcription Factors, Transcription, Genetic, Body Mass Index, Muscle, Skeletal, Muscle Fibers, Skeletal, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Nuclear Respiratory Factor 1

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