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Cited by 315Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismDiet, Metabolism, and Disease

Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats

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Dobbins, Robert L., Szczepaniak, Lidia S., Bentley, Brandon, Esser, Victoria, Myhill, Jeffrey, McGarry, J. Denis·2001·Diabetes
DOI 10.2337/diabetes.50.1.123
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Abstract

Cross-sectional studies in human subjects have used 1H magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (low-fat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle. Both the high-fat diet and drug treatment significantly impaired insulin sensitivity, as measured with the hyperinsulinemiceuglycemic clamp. Insulin-mediated glucose disposal (IMGD) fell from 12.57 ± 0.72 in the low-fat group to 9.79 ± 0.59, 8.96 ± 0.38, and 7.32 ± 0.28 μmol · min-1 · 100 g-1 in the low-fat + etoxomir, lard, and lard + etoxomir groups, respectively. We used HMRS, which distinguishes between fat within the myocytes and fat associated with contaminating adipocytes located in the muscle bed, to assess the IMCL content of isolated soleus muscle. A tight inverse relationship was found between IMGD and IMCL, the correlation (R = 0.96) being much stronger than that seen between IMGD and either fat mass or weight. In conclusion, either a diet rich in saturated fat or prolonged inhibition of fatty acid oxidation impairs IMGD in rats via a mechanism related to the accumulation of IMCL.

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  • In type 2 diabetic humans and obese rodents, oral CPT-1 inhibitors such as etomoxir and oxfenicine consistently elevate glucose oxidation and ameliorate hyperglycemia and hyperinsulinemia.

    “In type 2 diabetic humans and in obese rodents, oral administration of CPT-1 inhibitors such as etomoxir and oxfenicine consistently elevates glucose oxidation and ameliorates hyperglycemia and hyperinsulinemia (Barnett et al., 1992; Deems et al., 1998; Dobbins et al., 2001; Fragasso et al., 2009; Hubinger et al., 1997).”

    From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Dobbins et al., 2001

  • When insulin sensitivity is assessed by euglycemic clamp, some studies report improvements after etomoxir treatment while others find the opposite.

    “However, when insulin sensitivity was assessed by the euglycemic clamp technique, some studies reported improvements after etomoxir treatment whereas others found the opposite effect (Dobbins et al., 2001; Hubinger et al., 1997).”

    From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Dobbins et al., 2001

  • Inhibition of CPT1 by etomoxir increased lipid deposition in skeletal muscle and exacerbated insulin resistance in high fat-fed animals.

    “Inhibition of CPT1 by etomoxir, an irreversible inhibitor, increased lipid deposition in skeletal muscle and exacerbated insulin resistance in high fat-fed animals (40), indicating that alteration in LCFA flux into mitochondria is critical for regulating the deleterious effect of lipids on insulin sensitivity.”

    From Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis (2010) · cites this paper as [40]

  • Alteration in LCFA flux into mitochondria is critical for regulating the deleterious effect of lipids on insulin sensitivity.

    “Inhibition of CPT1 by etomoxir, an irreversible inhibitor, increased lipid deposition in skeletal muscle and exacerbated insulin resistance in high fat-fed animals (40), indicating that alteration in LCFA flux into mitochondria is critical for regulating the deleterious effect of lipids on insulin sensitivity.”

    From Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis (2010) · cites this paper as [40]

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Research works printed but not linked: 1

  1. Szczepaniak LS, Stein DT: Bulk magnetic susceptibility effects on the assess- ment of intra-and extra-cellular lipids in vivo. In Proceedings of the Inter- national Society for Magnetic Resonance in Medicine, Philadelphia, PA, May 22-28, 1999. Berkeley, CA, ISMRM, 1999, p. 1571

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Authors
Dobbins, R. L., Szczepaniak, L. S., Bentley, B., Esser, V., Myhill, J., & McGarry, J. D.
Affiliations
The University of Texas Southwestern Medical Center (US)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2001-01-01
Volume
50
Issue
1
Pages
123-130
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.50.1.123
OpenAlex
W2171699473
Cited by
315
References
73
Citations by year
2026: 2 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 13 · 2018: 7 · 2017: 5 · 2016: 10 · 2015: 13 · 2014: 13 · 2013: 14 · 2012: 15
FWCI
8.20
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 18573)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords
etomoxir, insulin resistance, insulin-stimulated glucose disposal, skeletal muscle, high-fat diet, saturated fat, fatty acid oxidation, soleus muscle, hyperinsulinemic-euglycemic clamp, 1H magnetic resonance spectroscopy
MeSH terms
Adipose Tissue, Animals, Body Weight, Carnitine O-Palmitoyltransferase, Dietary Fats, Eating, Enzyme Inhibitors, Epoxy Compounds, Glucose, Hyperinsulinism, Insulin Resistance, Isoenzymes, Male, Magnetic Resonance Spectroscopy, Time Factors, Glucose Clamp Technique, Rats, Sprague-Dawley, Adipocytes, Muscle, Skeletal, Lipid Metabolism, Rats, In Vitro Techniques

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