The interaction between glucose and fat metabolism and insulin resistance in severely burned children and the metabolic effects of fenofibrate



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Insulin resistance occurs in conjunction with disturbances in fat and glucose metabolism and mitochondrial dysfunction. Four human studies were conducted to better understand this relationship in the settings of aging and burn trauma. \r\nThe first two studies focused on aging. Insulin resistance commonly occurs in aging, but it was unknown if this was accompanied by changes in fat metabolism. The first study examined tissue fat in healthy young and elderly in relation to insulin sensitivity. The second study attempted to decrease insulin sensitivity by increasing the mitochondrial oxidation rate of intracellular fat, and lower plasma lipids with the peroxisome proliferator activating receptor alpha agonist fenofibrate. \r\nThe final two studies focused on burn trauma in children. Children who experience severe flame burn rapidly develop insulin resistance and hyper-metabolic fat, protein and glucose regulation. This insulin resistance has been linked to increases in mortality and morbidities such as infection and delayed wound healing. It is hypothesized that the insulin resistance and metabolic dysregulation develop cumulatively for several weeks following a burn and that treatment between weeks 1 and 3 post-burn with fenofibrate will increase lipid oxidation and improve insulin sensitivity, as compared to changes seen in placebo treated children. Study three examined glucose kinetics including a) whole body glucose uptake during a hyperinsulinemic-euglycemic clamp, b) endogenous glucose production, c) glucose uptake across the leg and d) fasting glucose and insulin levels measured at 1 and 3 weeks post-burn, before and after treatment. Additionally, lipid kinetics, as reflected by a) free fatty acid oxidation b) fatty acid release c) intracellular triglyceride in the liver and muscle, and intracellular diacyglycerol and fatty acyl CoA were measured at these time points. Finally, the activity of the insulin signaling pathway in muscle was also measured, as was mitochondrial function. The last study served to quantitate the level of mitochondrial dysfunction following burn, by comparing the mitochondrial function in the burn trauma patients to that in healthy children. \r\n \r\n\r\n