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Peroxisome proliferator activated receptors, fatty acids and muscle insulin resistance.

There is considerable interest in the mechanisms by which altered lipid metabolism might contribute to insulin resistance as is found in insulin resistance syndrome, also known as metabolic syndrome or syndrome X, which includes type 2 diabetes. The form of insulin resistance that is linked with abnormal lipid metabolism is arguably the most common form and contrasts with other forms that arise from relatively rare genetic mutations. Our research has been directed largely at examining a lipid supply hypothesis of muscle insulin resistance. This states that an oversupply and/or accumulation of lipid in muscle and liver leads to changes in metabolism at the level of substrate competition, enzyme regulation, intracellular signalling and/or gene transcription, which account for the insulin resistance seen in states such as metabolic syndrome and type 2 diabetes. The evidence for and against this hypothesis will be considered in this review. Strong support for the hypothesis comes from (1) increasing reports of accumulation of triglyceride (TG) in muscle in a variety of human insulinresistant states; (2) establishment of plausible mechanistic links based on in vitro and animal-based studies, whereby lipid accumulation could produce insulin resistance; (3) emerging studies in which causal links are more obvious, e.g. production of muscle insulin resistance in rodents by genetic manipulation aimed directly at increasing muscle fatty acid (FA) uptake, or by short-term elevation of FA, which produce insulin resistance and altered insulin signalling in muscle in a few hours; and (4) the pharmacological activity of agents such as the peroxisome proliferator activated receptor-g (PPARg) agonists, which significantly reduce muscle lipid accumulation and lessen insulin resistance. Nevertheless, several important issues have yet to be resolved, e.g. it is not clear exactly how lipids can accumulate excessively in muscle, or what their principal source is. Additionally, there may be technical limitations in determining the level and cellular localization of lipids in muscle tissue, and in some states high muscle TG levels exist without insulin resistance. These issues will be discussed in this review.