The role of FA metabolism in the impairment of insulin signalling

骨骼肌由于其质量的优势，负责胰岛素刺激的大部分葡萄糖处理，是调节血糖动态平衡的重要组织。人们普遍认为，脂肪酸(FA)代谢紊乱是骨骼肌胰岛素信号转导受损的原因之一。然而，这种骚乱的确切性质是一个有争议的问题。肌肉FA氧化受损被认为是肌肉内脂肪积累的根本原因，而肌肉内脂肪积累损害了对胰岛素的反应。然而，脂肪堆积是许多参数的函数，包括摄取和利用。至于肌肉中哪些脂质物种(如三酰甘醇(TAG)、二酰甘醇(DAG)、神经酰胺等)对胰岛素信号的损害负有责任，也存在争议。考虑到胰岛素敏感性和维持正常糖耐量对动物和人类整体健康的重要性，显然有必要对脂肪代谢如何调节肌肉中的胰岛素敏感性有更好的基础了解。因此，以下研究计划的总体目标是确定肌肉FA代谢中的哪些紊乱可能是扰乱细胞对胰岛素的反应(信号传递、葡萄糖运输)的最重要的原因。为实现这一目标而进行的实验扰动将检验：

Skeletal muscle, by virtue of its mass, is responsible for the majority of insulin-stimulated glucose disposal and an important tissue in the regulation of blood glucose homeostasis. It is generally accepted that disturbances in fatty acid (FA) metabolism are a contributor to the development of impaired insulin signalling in skeletal muscle. However, the exact nature of this disturbance is a matter of controversy. Impaired muscle FA oxidation is believed to be a fundamental cause in the accumulation of intramuscular lipids which impair the response to insulin. However, lipid accumulation is a function of many parameters including both uptake and utilization. It is also a matter of controversy as to which lipid species are responsible for impaired insulin signalling in muscle (e.g. triacylglyerol (TAG), diacylglyerol (DAG), ceramide, etc). Considering the importance of insulin sensitivity and maintenance of normal glucose tolerance to the overall health of animals and humans, there is a clear need to have a better BASIC understanding as to HOW lipid metabolism regulates insulin sensitivity in muscle. Thus, the general objective of the following research program is to determine which disturbances in muscle FA metabolism are likely to be the most important causative factors in disrupting the cellular response (signalling, glucose transport) to insulin. Experimental perturbations to achieve this objective will examine: