Insulin resistance: the role of intramuscular triglyceride and the importance of physical activity

In the Netherlands, the prevalence of diabetes is expected to rise from 480,000 to more than 650,000 patients by the year 2020. Numerous studies have reported a strong correlation between elevated plasma-free fatty-acid levels, the accumulation of intramuscular triglyceride (IMTG) and the development of insulin resistance. Traditionally, the Randle cycle was used to explain the mechanism behind fatty acid-induced insulin resistance in skeletal muscle. An alternative explanation is that the increased supply of free fatty acids leads to the accumulation of IMTG and fatty-acid metabolites, which can induce defects in the insulin signalling cascade, causing insulin resistance in skeletal muscle. However, this proposed relationship between elevated IMTG concentrations and skeletal-muscle insulin resistance does not always apply, as trained athletes have been shown to be markedly insulin-sensitive, despite having high levels of stored IMTG. This metabolic paradox is explained by the fact that it is not the size of the IMTG pool but rather the balance between fatty-acid availability, uptake and oxidation, i.e. the low turnover of the IMTG pool, that is instrumental in the development of skeletal-muscle insulin resistance. Physical exercise forms an effective strategy to improve the balance between skeletal-muscle fatty-acid uptake and oxidation and, as such, can prevent the development of skeletal-muscle insulin resistance