Schrauwen Patrick, Schrauwen-Hinderling Vera, Hoeks Joris, Hesselink Matthijs K C
Maastricht University Medical Centre (MUMC), Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Human Biology, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Biochim Biophys Acta. 2010 Mar;1801(3):266-71. doi: 10.1016/j.bbalip.2009.09.011. Epub 2009 Sep 24.
Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-)diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial function in the pre-diabetic state, it cannot be excluded that mitochondrial dysfunction may in fact be the consequence of the insulin-resistant/diabetic state. Lipotoxicity, the deleterious effects of accumulating fatty acids in skeletal muscle cells, may lie at the basis of mitochondrial dysfunction: next to producing energy, mitochondria are also the major source of reactive oxygen species (ROS). Fatty acids accumulating in the vicinity of mitochondria are vulnerable to ROS-induced lipid peroxidation. Subsequently, these lipid peroxides could have lipotoxic effects on mtDNA, RNA and proteins of the mitochondrial machinery, leading to mitochondrial dysfunction. Indeed, increased lipid peroxidation has been reported in insulin resistant skeletal muscle and the mitochondrial uncoupling protein-3, which has been suggested to prevent lipid-induced mitochondrial damage, is reduced in subjects with an impaired glucose tolerance and in type 2 diabetic patients. These findings support the hypothesis that fat accumulation in skeletal muscle may precede the reduction in mitochondrial function that is observed in type 2 diabetes mellitus.
骨骼肌中的线粒体功能障碍被认为是胰岛素抵抗和2型糖尿病发生发展的基础。线粒体功能下降会导致脂质中间体的积累，使胰岛素信号脱敏并导致胰岛素抵抗。然而，目前尚不清楚在（预）糖尿病状态下线粒体功能为何会下降。尽管有人认为骨骼肌胰岛素抵抗可能是由于糖尿病前期状态下线粒体功能的遗传性或后天性降低所致，但也不能排除线粒体功能障碍实际上可能是胰岛素抵抗/糖尿病状态的结果。脂毒性，即骨骼肌细胞中脂肪酸积累的有害影响，可能是线粒体功能障碍的基础：线粒体除了产生能量外，也是活性氧（ROS）的主要来源。在线粒体附近积累的脂肪酸易受ROS诱导的脂质过氧化作用影响。随后，这些脂质过氧化物可能对线粒体机制的mtDNA、RNA和蛋白质产生脂毒性作用，导致线粒体功能障碍。事实上，在胰岛素抵抗的骨骼肌中已报道脂质过氧化增加，并且在糖耐量受损的受试者和2型糖尿病患者中，被认为可预防脂质诱导的线粒体损伤的线粒体解偶联蛋白-3减少。这些发现支持了这样一种假说，即骨骼肌中的脂肪积累可能先于2型糖尿病中观察到的线粒体功能下降。
