Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle
Open accessAbstract
Insulin resistance correlates with intramyocellular lipid content (IMCL) and plasma free fatty acids (FFAs) and was recently linked to mitochondrial dysfunction. We examined the underlying relationships by measuring skeletal muscle ATP synthase flux, glucose transport/phosphorylation, and IMCL in response to different plasma insulin and plasma FFA concentrations. Healthy men were studied twice during hyperinsulinemic-euglycemic clamps with (LIP) or without (CON) lipid infusion (plasma FFA: CON ∼36 vs. LIP ∼1,034 μmol/l, P < 0.001). ATP synthase flux, glucose-6-phosphate (G6P), and IMCL were determined before and during the clamp in calf muscle using 31P and 1H magnetic resonance spectroscopy. Plasma lipid elevation resulted in ∼46% reduced whole-body glucose metabolism (180–360 min; P < 0.0001 vs. CON) and a 70% lower rise of G6P (P < 0.05 vs. CON) without significant changes in IMCL (LIP 117 ± 12% vs. CON 93 ± 3% of basal, P = 0.073). During the clamp, ATP synthase flux increased by ∼60% under control conditions (P = 0.02 vs. baseline) and was 24% lower during lipid infusion (LIP 11.0 ± 0.9 vs. CON 14.6 ± 1.2 μmol · g muscle−1 · min−1, P < 0.05). Physiologically increased plasma FFA concentrations reduce insulin-stimulated muscle ATP synthase flux in parallel with induction of insulin resistance.
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High levels of free fatty acids alter ATP synthesis in skeletal muscle.
“High levels of free FA (FFA) were shown to alter ATP synthesis in skeletal muscle (30).”
From TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet–Induced Insulin Resistance in Skeletal Muscle (2019) · cites this paper as [30]
Experimental induction of skeletal muscle insulin resistance by a physiological increase in plasma free fatty acid concentration in lean healthy insulin-sensitive individuals is associated with a decrease in oxidative phosphorylation flux in skeletal muscle.
“Lastly, experimental induction of insulin resistance in skeletal muscle, by a physiological increase in plasma FFA concentration in lean healthy insulin-sensitive individuals, is associated with a decrease in oxidative phosphorylation flux in skeletal muscle [110].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [110]
It cannot be completely excluded that the mitochondrial defect results secondary to insulin resistance.
“one cannot completely exclude the possibility that the mitochondrial defect results secondary to insulin resistance.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [110]
A mitochondrial defect similar to that in insulin-resistant individuals can be produced in young lean healthy subjects by physiologic elevation of plasma FFA concentration.
“a mitochondrial defect similar to that observed in insulin-resistant individuals can be produced in young lean healthy subjects by physiologic elevation of the plasma FFA concentration [110, 131]”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [110]
Short-term elevation of lipid availability reduces insulin-stimulated increase in ATP synthase flux in skeletal muscle.
“Moreover, it was shown in a comparable study that short-term elevation of lipid availability reduces insulin-stimulated increase in ATP synthase flux in skeletal muscle (10), although this may mainly reflect an effect of muscular insulin resistance on ATP flux.”
From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [10]
PGC-1α expression and the insulin-stimulated increase in skeletal muscle ATP synthesis were reduced upon lipid infusion.
“PGC-1α expression (9) and the insulin-stimulated increase in skeletal muscle ATP synthesis (10) were reduced upon lipid infusion.”
From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [10]
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BackgroundMitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus
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- Authors
- Brehm, A., Krssak, M., Schmid, A. I., Nowotny, P., Waldhäusl, W., & Roden, M.
- Affiliations
- Medical University of Vienna (AT)
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Hanusch Hospital (AT)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2006-01-01
- Volume
- 55
- Issue
- 1
- Pages
- 136-140
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2148020672
- Semantic Scholar
- b3a41abeca324733de403ba64f78380ee994679e
- Cited by
- 239
- References
- 47
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 7 · 2018: 14 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 19 · 2013: 20 · 2012: 15
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- UCLA - Biblioteca de Ciencias de la Salud (submittedVersion)
- Funders
- European Foundation for the Study of Diabetes
- Austrian Science Fund (P 15656)
- Universität Wien
- Novo Nordisk
- Medizinische Universität Wien
- 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 › Cell Biology › Muscle metabolism and nutrition
- Keywords
- insulin resistance, intramyocellular lipid, plasma free fatty acids, skeletal muscle, mitochondrial dysfunction, glucose transport, glucose-6-phosphate, hyperinsulinemic-euglycemic clamp, lipid infusion, glucose metabolism
- MeSH terms
- Adenosine Triphosphate, Adult, Biological Transport, Glucose, Humans, Insulin, Male, Glucose Clamp Technique, Muscle, Skeletal, Glucose-6-Phosphate, Lipid Metabolism
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