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Elevated intramyocellular triglyceride (IMTG) is strongly associated with insulin resistance, though a cause and effect relationship has not been fully described. Insulin sensitivity and IMTG content are both dynamic and can alter rapidly in response to dietary variation, physical activity and thermoregulatory response. Physically active humans (athletes) display elevated IMTG content, but in contrast to obese persons, are insulin sensitive. This paradox has created confusion surrounding the role of IMTG in the development of insulin resistance. In this review we consider the modern athlete as the physiological archetype of the Late Palaeolithic hunter–gatherer to whom the selection pressures of food availability, predation and fluctuating environmental conditions applied and to whom the genotype of modern man is virtually identical. As food procurement by the hunter–gatherer required physical activity, ‘thrifty’ genes that encouraged immediate energy storage upon refeeding after food deprivation (Neel, 1962) must have been of secondary importance in survival to genes that preserved physical capacity during food deprivation. Similarly genes that enabled survival during cold exposure whilst starved would be of primary importance. In this context, we discuss the advantage afforded by an elevated IMTG content, and how under these conditions, a concomitant muscle resistance to insulin-mediated glucose uptake would also be advantageous. In sedentary modern man, adiposity is high and skeletal muscle appears to respond as if a state of starvation exists. In this situation, elevated plasma lipids serve to accrue lipid and induce insulin resistance in skeletal muscle. Reversal of this physiological state is primarily dependant on adequate contractile activity, however, in modern Western society, physical inactivity combined with abundant food and warmth has rendered IMTG a redundant muscle substrate.