Cited by 101Metabolism, Diabetes, and CancerMitochondrial Function and PathologyAdipose Tissue and Metabolism

Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: evidence for an intrinsic oxidative enzyme defect

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Ørtenblad, Niels, Mogensen, Martin, Petersen, Ingrid, Højlund, Kurt, Levin, Klaus, Sahlin, Kent, Beck-Nielsen, Henning, Gaster, Michael·2005·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Abstract

In myotubes established from patients with type 2 diabetes (T2D), lipid oxidation and insulin-mediated glucose oxidation are reduced, whereas in myotubes from obese non-diabetic subjects, exposure to palmitate impairs insulin-mediated glucose oxidation. To determine the underlying mechanisms of these metabolic malfunctions, we studied mitochondrial respiration, uncoupled respiration and oxidative enzyme activities (citrate synthase (CS), 3-hydroxy-acyl-CoA-dehydrogenase activity (HAD)) before and after acute exposure to insulin and/or palmitate in myotubes established from healthy lean and obese subjects and T2D patients. Basal CS activity was lower (14%) in diabetic myotubes compared with myotubes from lean controls (P=0.03). Incubation with insulin (1 microM) for 4 h increased the CS activity (26-33%) in myotubes from both lean (P=0.02) and obese controls (P<0.001), but not from diabetic subjects. Co-incubation with palmitate (0.6 mM) for 4 h abolished the stimulatory effect of insulin on CS activity in non-diabetic myotubes. No differences were detected in mitochondrial respiration and HAD activity between myotubes from non-diabetic subjects and T2D patients, and none of these measures responded to high levels of insulin and/or palmitate. These results provide evidence for an intrinsic defect in CS activity, which may play a role in the pathogenesis of T2D. Moreover, the data suggest that insulin resistance at the CS level can be induced by exposure to high free fatty acid levels.

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Crossref · 10.1016/j.bbadis.2005.04.001

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Authors
Ørtenblad, N., Mogensen, M., Petersen, I., Højlund, K., Levin, K., Sahlin, K., Beck-Nielsen, H., & Gaster, M.
Affiliations
  • University of Southern Denmark (DK)
  • Odense University Hospital (DK)
Corresponding author
Gaster, Michael
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
2005-06
Volume
1741
Issue
1-2
Pages
206-214
ISSN
0925-4439 (ISSN-L)
OpenAlex
W2089721870
Cited by
101
References
36
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 9 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 12
FWCI
1.51
Type
journal article
Language
en
Open access
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
Funders
  • Diabetesforeningen
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • Novo Nordisk Fonden
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
type 2 diabetes, citrate synthase, insulin resistance, skeletal muscle, myotubes, palmitate, free fatty acids, mitochondrial respiration, 3-hydroxyacyl-CoA dehydrogenase, lipid oxidation, glucose oxidation, obesity
MeSH terms
Cells, Cultured, Citrate (si)-Synthase, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Insulin Resistance, Middle Aged, Obesity, Oxidation-Reduction, Oxygen Consumption, 3-Hydroxyacyl CoA Dehydrogenases, Muscle, Skeletal, Muscle Fibers, Skeletal, Palmitic Acid

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