Cited by 395Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismLipid metabolism and biosynthesis

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Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance

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Amati, Francesca, Dubé, John J., Alvarez-Carnero, Elvis, Edreira, Martin M., Chomentowski, Peter, Coen, Paul M., Switzer, Galen E., Bickel, Perry E., Stefanovic-Racic, Maja, Toledo, Frederico G.S., Goodpaster, Bret H.·2011·Diabetes

DOI 10.2337/db10-1221PMC PMC3178290

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Abstract

OBJECTIVE: Chronic exercise and obesity both increase intramyocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercise-trained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite higher IMTGs and would account for its higher insulin sensitivity. We also hypothesized that the expression of key skeletal muscle proteins involved in lipid droplet hydrolysis, DAG formation, and fatty-acid partitioning and oxidation would be associated with the lipotoxic phenotype. RESEARCH DESIGN AND METHODS: A total of 14 normal-weight, endurance-trained athletes (NWA group) and 7 normal-weight sedentary (NWS group) and 21 obese sedentary (OBS group) volunteers were studied. Insulin sensitivity was assessed by glucose clamps. IMTGs, DAGs, ceramides, and protein expression were measured in muscle biopsies. RESULTS: DAG content in the NWA group was approximately twofold higher than in the OBS group and ~50% higher than in the NWS group, corresponding to higher insulin sensitivity. While certain DAG moieties clearly were associated with better insulin sensitivity, other species were not. Ceramide content was higher in insulin-resistant obese muscle. The expression of OXPAT/perilipin-5, adipose triglyceride lipase, and stearoyl-CoA desaturase protein was higher in the NWA group, corresponding to a higher mitochondrial content, proportion of type 1 myocytes, IMTGs, DAGs, and insulin sensitivity. CONCLUSIONS: Total myocellular DAGs were markedly higher in highly trained athletes, corresponding with higher insulin sensitivity, and suggest a more complex role for DAGs in insulin action. Our data also provide additional evidence in humans linking ceramides to insulin resistance. Finally, this study provides novel evidence supporting a role for specific skeletal muscle proteins involved in intramyocellular lipids, mitochondrial oxidative capacity, and insulin resistance.

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Authors: Amati, F., Dubé, J. J., Alvarez-Carnero, E., Edreira, M. M., Chomentowski, P., Coen, P. M., Switzer, G. E., Bickel, P. E., Stefanovic-Racic, M., Toledo, F. G. S., & Goodpaster, B. H.
Affiliations: University of Pittsburgh (US)
Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Corresponding author: Goodpaster, Bret H.
ORCID: Amati, Francesca
Dubé, John J.
Alvarez-Carnero, Elvis
Coen, Paul M.
Switzer, Galen E.
Bickel, Perry E.
Toledo, Frederico G.S.
Goodpaster, Bret H.
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2011-09-16
Volume: 60
Issue: 10
Pages: 2588-2597
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/db10-1221
PMC: PMC3178290
OpenAlex: W2032345647
Cited by: 395
References: 54
Citations by year: 2026: 13 · 2025: 18 · 2024: 13 · 2023: 17 · 2022: 18 · 2021: 16 · 2020: 28 · 2019: 27 · 2018: 38 · 2017: 32 · 2016: 41 · 2015: 41 · 2014: 29 · 2013: 35 · 2012: 27
FWCI: 12.09
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 3636 d)
Locations: Diabetes (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
IRIS (submittedVersion)
CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
SERVAL (Université de Lausanne) (submittedVersion, other-oa)
Funders: University of Pittsburgh (UL1RR024153, RR024153)
National Institutes of Health (5p30dk046204-15, RR024153, 1P30DK46204)
National Institute on Aging (R01 AG20128, P30AG024827)
National Institute of Diabetes and Digestive and Kidney Diseases (1P30DK-46204, R01DK068046, P30-DK046204)
National Center for Research Resources (RR-024153, UL1RR024153)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: insulin resistance, intramyocellular triglyceride, diacylglycerol, ceramide, endurance athletes, obesity, perilipin 5, adipose triglyceride lipase, stearoyl-CoA desaturase, mitochondrial oxidative capacity, fatty acid oxidation
MeSH terms: Aged, Ceramides, Diglycerides, Female, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Mitochondria, Muscle, Obesity, Oxygen Consumption, Physical Endurance, Triglycerides, Muscle, Skeletal, Athletes

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Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance

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