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Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans
Open accessAbstract
Significance: Muscle insulin resistance is a major factor in the pathogenesis of type 2 diabetes, but the underlying cellular mechanisms are yet unclear. This study found that muscle diacylglycerol content was temporally associated with protein kinase Cθ activation and impairment of insulin signaling in human skeletal muscle. A similar relationship between muscle diacylglycerol content and protein kinase Cθ activation was observed in insulin-resistant obese and type 2 diabetic individuals. In contrast, we observed no relationship between other putative mediators of muscle insulin resistance including ceramides, acylcarnitines, or circulating adipocytokines. These data support the hypothesis that diacylglycerol activation of protein kinase Cθ and subsequent impairment of insulin signaling plays a major role in the pathogenesis of muscle insulin resistance in humans.
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“Szendroedi et al. (2014) showed a strong relationship between muscle DAG content, PKCθ translocation and muscle insulin resistance in obese and type 2 diabetic patients, whereas no correlation with muscle ceramide content and muscle insulin resistance was seen in these subjects.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Szendroedi et al., 2014
In the citing paper
“Lipotoxicity is characterized by the accumulation of lipid metabolites (ceramides and diacylglycerol) that interfere with insulin signaling, thus impairing insulin action (26,28).”
From Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity (2018) · cites this paper as [28]
In the citing paper
“Similar to IKK and JNK pathways, it induces serine or threonine phosphorylation or IR or IRS-1, resulting in impairment of insulin signaling [80,81].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [80]
In the citing paper
“PKCθ is predominantly expressed in skeletal muscle and endothelium and is activated by increased DAG content in muscles, via elevated plasma fatty acid infusion in humans [80] or palmitate treatment in myocytes [64].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [80]
In the citing paper
“These findings have been replicated in animal studies (rodents and rats), further expanding our understanding of the defect involving insulin signaling and action (Griffin et al., 1999; Shulman, 2014; Szendroedi et al., 2014).”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Szendroedi et al., 2014
In the citing paper
“In particular, an overabundance of SFA (e.g., Palmitate) can induce IR through the accumulation of lipid derivatives including DAGs, ceramides and long chain acyl-CoAs in the cytosol, which in turn can interfere with IRS1-PKB signalling [113,114,115,116,117,118].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [113]
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Metadata
- Authors
- Szendroedi, J., Yoshimura, T., Phielix, E., Koliaki, C., Marcucci, M., Zhang, D., Jelenik, T., Müller, J., Herder, C., Nowotny, P., Shulman, G. I., & Roden, M.
- Affiliations
- Düsseldorf University Hospital (DE)
- Howard Hughes Medical Institute (US)
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;
- Deutsches Diabetes-Zentrum e.V. (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-06-16
- Volume
- 111
- Issue
- 26
- Pages
- 9597-9602
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4084449
- OpenAlex
- W2055608265
- Cited by
- 415
- References
- 51
- Citations by year
- 2026: 36 · 2025: 30 · 2024: 26 · 2023: 18 · 2022: 32 · 2021: 36 · 2020: 47 · 2019: 46 · 2018: 46 · 2017: 38 · 2016: 32 · 2015: 24 · 2014: 3
- FWCI
- 13.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- European Foundation for the Study of Diabetes
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Gesundheit
- Novo Nordisk
- Novo Nordisk Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research
- National Institutes of Health (UL1TR000142)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01DK049230, R01 DK-49230, R24DK085638, P30DK045735)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- muscle insulin resistance, diacylglycerol, protein kinase C theta, lipid infusion, intramyocellular lipid, IRS-1 serine phosphorylation, Akt2 phosphorylation, obesity, type 2 diabetes, inflammation, adipokines, ceramide, acylcarnitines, skeletal muscle
- MeSH terms
- Protein Kinase C-theta, Analysis of Variance, Blood Chemical Analysis, Calorimetry, Indirect, Diabetes Mellitus, Type 2, Diglycerides, Enzyme Activation, Humans, Insulin Resistance, Isoenzymes, Muscles, Protein Kinase C, Glucose Clamp Technique
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