Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 3; pp. 743 - 752
• Main Authors: Bajaj, Mandeep, Medina-Navarro, Rafael, Suraamornkul, Swangjit, Meyer, Christian, DeFronzo, Ralph A., Mandarino, Lawrence J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2007
• Subjects: Adult; Biological and medical sciences; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Acids, Nonesterified - metabolism; Female; Free Radical Scavengers - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Genetic aspects; Humans; Hypolipidemic Agents - pharmacology; Insulin - pharmacology; Insulin Resistance - physiology; Male; Medical sciences; Middle Aged; Mitochondrial DNA; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Pyrazines - pharmacology; RNA, Messenger - metabolism; Endocrinopathy; Human; Pancreatic hormone; Diabetes mellitus; Lipids; Muscle; Free fatty acid; Gene expression; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0840

Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration Mandeep Bajaj 1 2 , Rafael Medina-Navarro 3 , Swangjit Suraamornkul 2 , Christian Meyer 2 4 , Ralph A. DeFronzo 2 and Lawrence J. Mandarino 3 1 University of Texas Medical Branch, Galveston, Texas 2 University of Texas Health Science Center, San Antonio, Texas 3 Center for Metabolic Biology, Arizona State University, Tempe, Arizona 4 Carl T. Hayden VA Medical Center, Phoenix, Arizona Address correspondence and reprint requests to Lawrence J. Mandarino, PhD, Director, Center for Metabolic Biology, Professor and Chair, Department of Kinesiology, Professor, School of Life Sciences, Arizona State University, P.O. Box 874501, Tempe, AZ 85287-4501. E-mail: lawrence.mandarino{at}asu.edu 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. CTGF, connective tissue growth factor FFA, free fatty acid OGTT, oral glucose tolerance test TGF, transforming growth factor Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted December 18, 2006. Received June 20, 2006. DIABETES