The role of FA metabolism in the impairment of insulin signalling

骨骼肌，由于其质量，负责大部分胰岛素刺激的葡萄糖处理和一个重要的组织在调节血糖稳态。人们普遍认为，脂肪酸（FA）代谢紊乱是骨骼肌胰岛素信号受损的一个原因。然而，这种干扰的确切性质是一个有争议的问题。受损的肌肉FA氧化被认为是肌内脂质积累的根本原因，从而损害了对胰岛素的反应。然而，脂质积累是许多参数的函数，包括摄取和利用。关于哪些脂质物种对肌肉中胰岛素信号受损负责（如三酰基甘油（TAG），二酰基甘油（DAG），神经酰胺等）也是一个有争议的问题。考虑到胰岛素敏感性和维持正常葡萄糖耐量对动物和人类整体健康的重要性，显然有必要对脂质代谢如何调节肌肉中的胰岛素敏感性有一个更好的基本理解。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破坏细胞对胰岛素反应（信号传导，葡萄糖运输）的最重要的致病因素。实现这一目标的实验扰动将检验：

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: