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The metabolic syndrome has been emphasized as affecting an important subset of individuals at high risk for cardiovascular disease leading the National Cholesterol Educational Program Adult Treatment Panel III in highlighting awareness of insulin-resistance syndrome. Insulin resistance is thought to be an underlying feature of the metabolic syndrome and in the last few years efforts have been performed to assess the effects of ectopic fat accumulation on whole-body glucose metabolism and on the pathogenesis of insulin resistance.Abnormality of fatty acid metabolism and ectopic fat accumulation within skeletal muscle has been measured using the traditional biopsy technique but this field of investigation has been exploited considerably more recently thanks to the use of non-invasive 1H-magnetic resonance spectroscopy. Initial data supported the hypothesis that a strong causal relationship between increased intra-myocellular lipid (IMCL) content and whole-body insulin resistance might exist. Indeed, experimental evidence is still controversial especially when the modulation of the IMCL content is induced by physical exercise and nutritional interventions.It has been suggested recently that the flux of muscular fatty acids as a source of oxidative energy may play a pivotal role into the development of the abnormalities of muscle and whole-body energy metabolism, potentially as the basis of the pathogenesis of obesity, the metabolic syndrome and type 2 diabetes.