Resistance to the hypoglycemic action of insulin develops within 7 days of bedrest in young, healthy volunteers. We propose that the same event occurs in elderly individuals confined to bed, that alterations in lipid metabolism are, at least in part, responsible for the insulin resistance associated with bedrest, and that individuals with greater disruptions in lipid metabolism before bedrest, as reflected by the accumulation of intracellular triglyceride (TG) in liver and muscle, will have a greater impairment of insulin action with bedrest. Further, we propose that the PPARa agonist fenofibrate will increase tissue fatty acid disposal by activating mitochondrial oxidative capacity, thereby improving insulin sensitivity. The accumulation of intracellular lipid reflects a dysregulation of tissue fatty acid metabolism involving abnormal relationships between tissue fatty acid uptake and oxidation. It has been postulated that such dysregulation of lipid metabolism causes insulin resistance as a direct consequence of the accumulated intracellular TG, or that the increased intracellular TG reflects an increase in active products of fatty acids, such as diacylglycerol, that inhibit the insulin signaling pathway. We recently found that both muscle and liver intracellular TG concentrations were elevated in more than one-half of otherwise healthy elderly individuals. We propose that an increase in tissue lipids in the elderly reflects altered tissue lipid metabolism that puts them at high risk for the development of insulin resistance with bedrest. We will investigate a series of specific hypotheses designed to examine the role of altered lipid metabolism in the development of insulin-resistance associated with bedrest. These studies will for the first time examine the rote of alterations in lipid metabolism in the development of insulin resistance that occurs with bedrest. Further, since inactivity is likely a principal factor in the development of insulin resistance in the elderly, the response to the inactivity imposed by bedrest represents an acceleration of the normal development of insulin resistance in elderly individuals. Therefore, the results of this study will also be pertinent to the understanding of the mechanisms responsible for the natural development of insulin resistance in free-living elderly.
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