The role of FA metabolism in the impairment of insulin signalling

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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: