Cha Bong-Soo, Ciaraldi Theodore P, Park Kyong-Soo, Carter Leslie, Mudaliar Sunder R, Henry Robert R
Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Am J Physiol Endocrinol Metab. 2005 Jul;289(1):E151-9. doi: 10.1152/ajpendo.00141.2004. Epub 2005 Feb 22.
The impact of type 2 diabetes on the ability of muscle to accumulate and dispose of fatty acids and triglycerides was evaluated in cultured muscle cells from nondiabetic (ND) and type 2 diabetic (T2D) subjects. In the presence of 5 microM palmitate, T2D muscle cells accumulated less lipid than ND cells (11.5 +/- 1.2 vs. 15.1 +/- 1.4 nmol/mg protein, P < 0.05). Chronic treatment (4 days) with the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist troglitazone increased palmitate accumulation, normalizing uptake in T2D cells. There were no significant differences between groups with regard to the relative incorporation of palmitate into neutral lipid species. This distribution was also unaffected by troglitazone treatment. beta-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by approximately 40% compared with ND cells. Palmitate oxidation occurred primarily in mitochondrial ( approximately 40-50% of total) and peroxisomal (20-30%) compartments. The diabetes-related defect in palmitate oxidation was localized to the mitochondrial component. Both palmitate and octanoate oxidation were stimulated by a series of thiazolidinediones. Oxidation in T2D muscle cells was normalized after treatment. Troglitazone increased the mitochondrial component of palmitate oxidation. Skeletal muscle cells from T2D subjects express defects in free fatty acid metabolism that are retained in vitro, most importantly defects in beta-oxidation. These defects can be corrected by treatment with PPARgamma agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular triglyceride content, may represent one mechanism for the lipid-lowering and insulin-sensitizing effects of thiazolidinediones.
在来自非糖尿病（ND）和2型糖尿病（T2D）受试者的培养肌肉细胞中，评估了2型糖尿病对肌肉积累和处理脂肪酸及甘油三酯能力的影响。在存在5微摩尔棕榈酸的情况下，T2D肌肉细胞积累的脂质比ND细胞少（11.5±1.2对15.1±1.4纳摩尔/毫克蛋白质，P<0.05）。用过氧化物酶体增殖物激活受体γ（PPARγ）激动剂曲格列酮进行慢性治疗（4天）可增加棕榈酸积累，使T2D细胞的摄取正常化。在棕榈酸掺入中性脂质种类的相对比例方面，两组之间没有显著差异。这种分布也不受曲格列酮治疗的影响。与ND细胞相比，T2D肌肉细胞中长链（棕榈酸）和中链（辛酸）脂肪酸的β氧化均降低了约40%。棕榈酸氧化主要发生在线粒体（约占总量的40-50%）和过氧化物酶体（20-30%）区室。与糖尿病相关的棕榈酸氧化缺陷定位于线粒体部分。一系列噻唑烷二酮类药物均可刺激棕榈酸和辛酸的氧化。治疗后T2D肌肉细胞中的氧化恢复正常。曲格列酮增加了棕榈酸氧化的线粒体部分。T2D受试者的骨骼肌细胞在游离脂肪酸代谢方面存在缺陷，这些缺陷在体外仍然存在，最重要的是β氧化缺陷。这些缺陷可以通过用PPARγ激动剂治疗来纠正。增加骨骼肌中脂肪酸的处理，可能降低细胞内甘油三酯含量，这可能是噻唑烷二酮类药物降脂和胰岛素增敏作用的一种机制。
