CoChat
Sign Up
Cited by 81Metabolism, Diabetes, and CancerMitochondrial Function and PathologyAdipose Tissue and Metabolism

Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells

Open access
Lim, J. H., Lee, J. I., Suh, Y. H., Kim, W., Song, J. H., Jung, M. H.·2006·Diabetologia
DOI 10.1007/s00125-006-0278-4
Open this paper in CoChat — free accountOpen PDF

Abstract

Aims/hypothesis Mitochondrial dysfunction is considered a critical component in the development of diabetes. The aim of this study was to elucidate the molecular mechanisms involved in the development of insulin resistance and diabetes through investigation of mitochondrial retrograde signalling.Materials and methods Mitochondrial function of C2C12 myotube cells was impaired by genetic (ethidium bromide) and metabolic (oligomycin) stress, and changes in target molecules related to insulin signalling were analysed.Results Concomitant with reductions in mitochondrial membrane potential (DeltaPsim) and ATP synthesis, production of IRS1 and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) were reduced. Moreover, serine phosphorylation of IRS1 increased, resulting in decreased tyrosine phosphorylation. This indicates that mitochondrial dysfunction decreases insulin-stimulated SLC2A4 translocation and glucose uptake. Mitochondrial stress activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) signalling in a Ca(2+)-dependent manner, and removal of free Ca(2+) by BAPTA-AM, as well as inhibition of JNK and p38 MAPK, abrogated mitochondrial stress-induced reductions in IRS1 and SLC2A4 production. Mitochondrial dysfunction after oligomycin treatment significantly increased levels of activating transcription factor 3 (ATF3), which represses Irs1 promoter activity. Removal of the 5' flanking region of Irs1 demonstrated that the promoter region within 191 bases from the transcription site may be involved in the transcriptional repression of Irs1 by mitochondrial stress.Conclusions/interpretation We show distinct mitochondrial retrograde signalling, where Irs1 is downregulated through ATF3 in a Ca(2+)-, JNK- and p38 MAPK-dependent manner, and IRS1 is inactivated. Therefore, mitochondrial dysfunction causes aberrant insulin signalling and abnormal utilisation of glucose, as observed in many insulin resistance states.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s00125-006-0278-4

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Downregulation of mitochondrial function in myotubes with oligomycin or ethidium bromide increased intracellular fat content, impaired insulin signaling, and decreased insulin-stimulated glucose uptake.

    “Down regulation of mitochondrial function in myotubes with oligomycin, which inhibits mitochondrial ATP synthesis, and with ethidium bromide, which impairs mitochondrial DNA replication, caused an increase in intracellular fat content, impaired insulin signaling, and decreased insulin-stimulated glucose uptake [135].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [135]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 46 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Lim, J. H., Lee, J. I., Suh, Y. H., Kim, W., Song, J. H., & Jung, M. H.
Affiliations
Korea National Institute of Health (KR)
Corresponding author
Jung, M. H.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2006-05-31
Volume
49
Issue
8
Pages
1924-1936
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-006-0278-4
OpenAlex
W2047950907
Cited by
81
References
46
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 7 · 2012: 8
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Johns Hopkins University
  • National Institutes of Health
  • School of Medicine, Indiana University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
mitochondrial dysfunction, insulin resistance, insulin signaling, glucose uptake, IRS-1, GLUT4, serine phosphorylation, JNK, p38 MAPK, calcium signaling, ATF3, oligomycin, ethidium bromide, C2C12 myotubes, diabetes mellitus
MeSH terms
Animals, Cell Line, Glucose, Glycolysis, Insulin, Membrane Potentials, Mitochondria, Muscle, Transfection, Triglycerides, Signal Transduction, Muscle, Skeletal, Myoblasts, Glucose Transporter Type 4, Mitochondrial Membranes, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review