ArticleDiabetologia2012
Fat-induced membrane cholesterol accrual provokes cortical filamentous actin destabilisation and glucose transport dysfunction in skeletal muscle.
Article in Diabetologia, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 54 citations in OpenAlex.
- Trial
- Circulating Biomarkers as a Window into the Relationship between Sarcopenia and Diabetes: Implications for Effective Management.Current diabetes reviews · 2026Review
- GLUT4 Trafficking and Storage Vesicles: Molecular Architecture, Regulatory Networks, and Their Disruption in Insulin Resistance.International journal of molecular sciences · 2025Review
- Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression.International journal of molecular sciences · 2024Review
- Insulin signalling and GLUT4 trafficking in insulin resistance.Biochemical Society transactions · 2023Review
- A nexus of lipid andFrontiers in endocrinology · 2022Review
- Prior AICAR induces elevated glucose uptake concomitant with greater γ3-AMPK activation and reduced membrane cholesterol in skeletal muscle from 26-month-old rats.Facets (Ottawa) · 2022Article
- Reduced membrane cholesterol content in skeletal muscle is not essential for greater insulin-stimulated glucose uptake after acute exercise by rats.Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme · 2021Article
- Reconstructing the blood metabolome and genotype using long-range chromatin interactions.Metabolism open · 2020Article
- Role of High-Density Lipoproteins in Cholesterol Homeostasis and Glycemic Control.Journal of the American Heart Association · 2020Review
- Excess membrane cholesterol is an early contributing reversible aspect of skeletal muscle insulin resistance in C57BL/6NJ mice fed a Western-style high-fat diet.American journal of physiology. Endocrinology and metabolism · 2019Article
- The dysfunctional lipids in prostate cancer.American journal of clinical and experimental urology · 2019Review
- Inhibition of Adenosine Monophosphate-Activated Protein Kinase-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance.Hepatology communications · 2019Article
- β-Actin shows limited mobility and is required only for supraphysiological insulin-stimulated glucose transport in young adult soleus muscle.American journal of physiology. Endocrinology and metabolism · 2018Article
- The Nutrient-Sensing Hexosamine Biosynthetic Pathway as the Hub of Cancer Metabolic Rewiring.Cells · 2018Review
- Rac1 muscle knockout exacerbates the detrimental effect of high-fat diet on insulin-stimulated muscle glucose uptake independently of Akt.The Journal of physiology · 2018Article
- Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection.Cardiovascular diabetology · 2017Review
- The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)-mediated glucose uptake into skeletal muscle cells.The Journal of biological chemistry · 2017Article
- Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet.Physiological reports · 2017Article
- Membrane Cholesterol in Skeletal Muscle: A Novel Player in Excitation-Contraction Coupling and Insulin Resistance.Journal of diabetes research · 2017Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
aims/hypothesisDiminished cortical filamentous actin (F-actin) has been implicated in skeletal muscle insulin resistance, yet the mechanism(s) is unknown. Here we tested the hypothesis that changes in membrane cholesterol could be a causative factor, as organised F-actin structure emanates from cholesterol-enriched raft microdomains at the plasma membrane.
methodsSkeletal muscle samples from high-fat-fed animals and insulin-sensitive and insulin-resistant human participants were evaluated. The study also used L6 myotubes to directly determine the impact of fatty acids (FAs) on membrane/cytoskeletal variables and insulin action.
resultsHigh-fat-fed insulin-resistant animals displayed elevated levels of membrane cholesterol and reduced F-actin structure compared with normal chow-fed animals. Moreover, human muscle biopsies revealed an inverse correlation between membrane cholesterol and whole-body glucose disposal. Palmitate-induced insulin-resistant myotubes displayed membrane cholesterol accrual and F-actin loss. Cholesterol lowering protected against the palmitate-induced defects, whereas characteristically measured defects in insulin signalling were not corrected. Conversely, cholesterol loading of L6 myotube membranes provoked a palmitate-like cytoskeletal/GLUT4 derangement. Mechanistically, we observed a palmitate-induced increase in O-linked glycosylation, an end-product of the hexosamine biosynthesis pathway (HBP). Consistent with HBP activity affecting the transcription of various genes, we observed an increase in Hmgcr, a gene that encodes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. In line with increased HBP activity transcriptionally provoking a membrane cholesterol-based insulin-resistant state, HBP inhibition attenuated Hmgcr expression and prevented membrane cholesterol accrual, F-actin loss and GLUT4/glucose transport dysfunction. CONCLUSIONS/
interpretationOur results suggest a novel cholesterolgenic-based mechanism of FA-induced membrane/cytoskeletal disorder and insulin resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.