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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG023591-01
Application #
6790875
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1 (J3))
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-04-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$25,606
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Coker, Robert H; Hays, Nicholas P; Williams, Rick H et al. (2015) Bed rest promotes reductions in walking speed, functional parameters, and aerobic fitness in older, healthy adults. J Gerontol A Biol Sci Med Sci 70:91-6
Coker, Robert H; Hays, Nicholas P; Williams, Rick H et al. (2014) Bed rest worsens impairments in fat and glucose metabolism in older, overweight adults. J Gerontol A Biol Sci Med Sci 69:363-70
Coker, Robert H; Wolfe, Robert R (2012) Bedrest and sarcopenia. Curr Opin Clin Nutr Metab Care 15:7-11
Tuvdendorj, Demidmaa; Chinkes, David L; Zhang, Xiao-Jun et al. (2011) Skeletal muscle is anabolically unresponsive to an amino acid infusion in pediatric burn patients 6 months postinjury. Ann Surg 253:592-7
Ferrando, Arny A; Paddon-Jones, Doug; Hays, Nicholas P et al. (2010) EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clin Nutr 29:18-23
Hays, Nicholas P; Roberts, Susan B (2008) Aspects of eating behaviors ""disinhibition"" and ""restraint"" are related to weight gain and BMI in women. Obesity (Silver Spring) 16:52-8
Kortebein, Patrick; Symons, T Brock; Ferrando, Arny et al. (2008) Functional impact of 10 days of bed rest in healthy older adults. J Gerontol A Biol Sci Med Sci 63:1076-81
Borsheim, Elisabet; Bui, Quynh-Uyen T; Tissier, Sandrine et al. (2008) Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clin Nutr 27:189-95
Kortebein, Patrick; Ferrando, Arny; Lombeida, Juan et al. (2007) Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA 297:1772-4
Wolfe, Robert R (2006) Optimal nutrition, exercise, and hormonal therapy promote muscle anabolism in the elderly. J Am Coll Surg 202:176-80

Showing the most recent 10 out of 12 publications