Paradoxical changes in muscle gene expression in insulin-resistant subjects after sustained reduction in plasma free fatty acid concentration

Mandeep Bajaj, Rafael Medina-Navarro, Swangjit Suraamornkul, Christian Meyer, Ralph A. DeFronzo, Lawrence J. Mandarino

    Research output: Contribution to journalArticlepeer-review

    25 Scopus citations

    Abstract

    Lipid oversupply plays a role in developing insulin resistance in skeletal muscle, decreasing expression of nuclear-encoded mitochondrial genes, and increasing extracellular matrix remodeling. To determine if a decrease in plasma lipid content reverses these abnormalities, insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Free fatty acids fell from 0.584 ± 0.041 to 0.252 ± 0.053 mmol/l (P < 0.001) and glucose disposal increased from 5.28 ± 0.46 to 6.31 ± 0.55 mg · kg-1 · min-1 (P < 0.05) after acipimox; intramuscular fatty acyl CoA decreased from 10.3 ± 1.9 to 4.54 ± 0.82 pmol/mg muscle (P < 0.01). Paradoxically, expression of PGC-1- and nuclear-encoded mitochondrial genes decreased after acipimox, and expression of collagens I and III α-subunits (82- and 21-fold increase, respectively, P < 0.05), connective tissue growth factor (2.5-fold increase, P < 0.001), and transforming growth factor-β1 increased (2.95-fold increase, P < 0.05). Therefore, a reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclear-encoded mitochondrial genes do not always correlate with changes in insulin sensitivity.

    Original languageEnglish (US)
    Pages (from-to)743-752
    Number of pages10
    JournalDiabetes
    Volume56
    Issue number3
    DOIs
    StatePublished - Mar 2007

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

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