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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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  • Activation of Protein Kinase C-δ was associated with the metabolomic changes and inhibits insulin signalling in muscle tissue.

    “This was associated with activation of Protein Kinase C (PKC)-δ [106] which inhibits insulin signalling in muscle tissue [107].”

    From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [107]

  • Both acute (4-hour) and chronic (4-day) physiological elevation of plasma free fatty acid concentration in insulin-sensitive individuals impairs insulin signalling and causes skeletal muscle insulin resistance.

    “Both acute (4 hours) and chronic (4 days) physiologic elevation of plasma FFA concentration in insulin sensitive individuals impairs insulin signaling and causes insulin resistance in skeletal muscle [28, 62–68].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [66]

  • An overabundance of saturated fatty acids such as palmitate can induce insulin resistance 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.

    “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 [116]

  • Many insulin-resistant states, including obesity, type 2 diabetes, and lipid/heparin infusion, are associated with increased JNK and/or IKK activation together with inhibitory IRS-1 serine phosphorylation.

    “Along these lines, numerous insulin-resistant states (e.g., obesity, type 2 diabetes, and lipid/heparin infusion) are associated with increased activation of JNK (18,21) and/or IKK (21)(22)(23)(24)(25) in parallel with inhibitory serine phosphorylation of IRS-1 (18,21).”

    From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [23]

  • Increasing fatty acid flux via lipid-plus-heparin infusion in humans or rodents increases the concentration of intramuscular triglycerides and/or fatty acid intermediates.

    “Accordingly, increasing fatty acid flux via a lipid-plus-heparin infusion in humans (23,46) or rodents (58) results in a corresponding increase in the concentration of IMTG and/or fatty acid intermediates.”

    From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [23]

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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 › Epidemiology › 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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