Bajaj Mandeep, Medina-Navarro Rafael, Suraamornkul Swangjit, Meyer Christian, DeFronzo Ralph A, Mandarino Lawrence J
School of Life Sciences, Arizona State University, P.O. Box 874501, Tempe, AZ 85287-4501, USA.
Diabetes. 2007 Mar;56(3):743-52. doi: 10.2337/db06-0840.
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 alpha-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-beta1 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.
脂质供应过剩在骨骼肌胰岛素抵抗的发展中起作用，它会降低核编码的线粒体基因的表达，并增加细胞外基质重塑。为了确定血浆脂质含量的降低是否能逆转这些异常情况，对有2型糖尿病家族史的胰岛素抵抗受试者在阿西莫司治疗前后进行了正常血糖钳夹试验和肌肉活检，以抑制游离脂肪酸。阿西莫司治疗后，游离脂肪酸从0.584±0.041降至0.252±0.053 mmol/l（P<0.001），葡萄糖处置率从5.28±0.46增至6.31±0.55 mg·kg⁻¹·min⁻¹（P<0.05）；肌肉内脂肪酰基辅酶A从10.3±1.9降至4.54±0.82 pmol/mg肌肉（P<0.01）。矛盾的是，阿西莫司治疗后，PGC-1和核编码的线粒体基因的表达降低，而I型和III型胶原α亚基的表达（分别增加82倍和21倍，P<0.05）、结缔组织生长因子（增加2.5倍，P<0.001）和转化生长因子-β1增加（增加2.95倍，P<0.05）。因此，脂质供应的减少并不能完全逆转与肌肉脂质供应过剩相关的分子变化。核编码的线粒体基因表达的变化并不总是与胰岛素敏感性的变化相关。
