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

Lipid oversupply plays a role in developing insulin resis-tance 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-resis-tant 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 kg1 min1 (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 col