Tissue Lipid Metabolism Clinical Trial
Official title:
Tissue Lipids and Insulin Resistance
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 the accumulation of intracellular triglyceride
(TG) in liver and muscle will play a role in impairing insulin action. Further, we propose
that the PPARĪ± (Peroxisome Proliferator-Activated Receptor Alpha) agonist fenofibrate will
increase tissue fatty acid disposal by activating mitochondrial oxidative capacity, thereby
improving insulin sensitivity.
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. 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.
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 triglyceride (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 hypothesize 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. Further, we propose that the PPARĪ± (Peroxisome Proliferator-Activated Receptor
Alpha) agonist fenofibrate will increase tissue fatty acid disposal by activating
mitochondrial oxidative capacity, thereby improving insulin sensitivity.
We will examine the role of alterations in lipid metabolism in the development of insulin
resistance that occurs with bedrest.
Methods: A total of 40 elderly subjects ranging in age from 60-85 will be studied. Subjects
will be randomized to one of two groups: 1) 10 days of bedrest or 2) 10 days of bedrest plus
fenofibrate. Each of the subjects will complete a 5- day diet stabilization period and have
a metabolic infusion study on day 5, followed by 10 days of bedrest and a metabolic study on
day 18. This will be followed by a 3 week rehabilitation program. Pre-test and post bedrest
measurements include body composition by DEXA, intracellular TG measurements by MRS,
strength testing.
The results will provide insight into the mechanisms responsible for the development of
insulin resistance with inactivity and strategies for ameliorating this response.
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Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment