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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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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It has generally been assumed that a reduction in muscle mitochondrial function will result in reductions in whole-body fat oxidative capacity.
“it has generally been assumed that a reduction in muscle mitochondrial function will result in reductions in whole-body fat oxidative capacity (3–5,42,43).”
From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [42]
Changes in skeletal muscle mitochondrial quality and quantity have been reported in people with type 2 diabetes.
“alterations in skeletal muscle mitochondrial quality and quantity have been observed in T2DM patients (2, 3).”
From Physical activity is the key determinant of skeletal muscle mitochondrial function in type 2 diabetes (2012) · cites this paper as [2]
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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
- bronze
- doi.org
- Licence
- 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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