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Cited by 1,390Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic Diseases

The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.

Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α

Itani, Samar I., Ruderman, Neil B., Schmieder, Frank, Boden, Guenther·2002·Diabetes
DOI 10.2337/diabetes.51.7.2005
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Abstract

The possibility that lipid-induced insulin resistance in human muscle is related to alterations in diacylglycerol (DAG)/protein kinase C (PKC) signaling was investigated in normal volunteers during euglycemic-hyperinsulinemic clamping in which plasma free fatty acid (FFA) levels were increased by a lipid/heparin infusion. In keeping with previous reports, rates of insulin-stimulated glucose disappearance (GRd) were normal after 2 h but were reduced by 43% (from 52.7 ± 8.2 to 30.0 ± 5.3 μmol · kg–1 · min–1, P < 0.05) after 6 h of lipid infusion. No changes in PKC activity or DAG mass were seen in muscle biopsy samples after 2 h of lipid infusion; however, at ∼6 h, PKC activity and DAG mass were increased approximately fourfold, as were the abundance of membrane-associated PKC-βII and -δ. A threefold increase in membrane-associated PKC-βII was also observed at ∼2 h but was not statistically significant (P = 0.058). Ceramide mass was not changed at either time point. To evaluate whether the fatty acid–induced insulin activation of PKC was associated with a change in the IkB kinase (IKK)/nuclear factor (NF)-κB pathway, we determined the abundance in muscle of IκB-α, an inhibitor of NF-κB that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IκB-α mass was observed after 2 h of lipid infusion, but at ∼6 h, IκB-α was diminished by 70%. In summary, the results indicated that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic-hyperinsulinemic clamping was associated with increases in DAG mass and membrane-associated PKC-βII and -δ and a decrease in IκB-α. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-β/IκB/NFκB pathway remains to be established.

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Metadata

Authors
Itani, S. I., Ruderman, N. B., Schmieder, F., & Boden, G.
Affiliations
  • Boston University (US)
  • Temple University Hospital (US)
ORCID
Ruderman, Neil B.
Venue
Diabetes
Publisher
American Diabetes Association
Published
2002-07-01
Volume
51
Issue
7
Pages
2005-2011
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.51.7.2005
OpenAlex
W2108462699
Cited by
1,390
References
46
Citations by year
2026: 17 · 2025: 23 · 2024: 44 · 2023: 22 · 2022: 28 · 2021: 43 · 2020: 64 · 2019: 51 · 2018: 46 · 2017: 63 · 2016: 58 · 2015: 67 · 2014: 71 · 2013: 77 · 2012: 82
FWCI
20.61
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ag007988-10)
  • National Institute on Aging (R01-AG07988)
  • National Heart, Lung, and Blood Institute (HL 07224-25, P01HL055854, T32HL007224)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
lipid-induced insulin resistance, skeletal muscle, diacylglycerol, protein kinase C, PKCβII, PKCδ, IκBα, NF-κB signaling, IκB kinase, free fatty acids, lipid infusion, insulin-stimulated glucose uptake, ceramide
MeSH terms
NF-KappaB Inhibitor alpha, Adult, Blood Glucose, Diglycerides, DNA-Binding Proteins, Fatty Acids, Nonesterified, Glucose, Humans, Infusions, Intravenous, Insulin, Insulin Resistance, Isoenzymes, Lipids, Male, Protein Kinase C, Glucose Clamp Technique, Signal Transduction, Body Mass Index, NF-kappa B, Muscle, Skeletal, I-kappa B Proteins, Protein Kinase C beta

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