Metabolic dysregulation within skeletal muscle, including insulin resistance, is a major health problem facing older adults. This is a critical factor for type 2 diabetes mellitus (T2DM), a disease afflicting nearly one in every four older adults. Thus, studies concerning the etiology, prevention and treatment of these metabolic disorders specific to older men and women are crucial. To date, there has been a lack of studies, which have addressed whether alterations in skeletal muscle lipid content and the capacity for fat oxidation induced by intervention predict improvements in insulin resistance. Many studies suggest that elevated muscle triglyceride, or intramyocellular lipid (IMCL) content is associated with insulin resistance. However, recent evidence from our group as well as from others suggests a more complex association between IMCL and insulin resistance, one that likely involves the capacity for fat oxidation. Our studies support the hypothesis that dysregulated fatty acid metabolism and the accumulation of muscle lipid may be a mechanism of insulin resistance in previously sedentary older adults. Further, we will provide a detailed rationale regarding the potential therapeutic mechanisms by which exercise may improve insulin resistance in older adults through improved oxidative fatty acid metabolism. We will employ a randomized controlled exercise intervention trial to test the overall hypothesis that exercise-induced improvement in the capacity for fat oxidation in skeletal muscle is a primary factor which predicts improvements in insulin resistance. We will utilize novel magnetic resonance imaging (MRI), histochemical and biochemical approaches to quantify changes in muscle lipid content and distribution and also the amount of contractile tissue (muscle) itself. These changes in will be measured in conjunction with in vivo and in vitro measures of the capacity for fat oxidation and with in vivo measures of insulin resistance. This project will provide novel information concerning specific mechanisms by which exercise enhances the capacity for oxidative metabolism of fatty acids and improves insulin resistance in older adults who are at high risk for the development of T2DM. Ultimately this should help identify mechanisms and therapeutic targets implicated in skeletal muscle metabolic dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021961-04
Application #
7248606
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Tian, Ying
Project Start
2004-08-15
Project End
2008-12-30
Budget Start
2007-07-01
Budget End
2008-12-30
Support Year
4
Fiscal Year
2007
Total Cost
$307,779
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Goodpaster, Bret H; Sparks, Lauren M (2017) Metabolic Flexibility in Health and Disease. Cell Metab 25:1027-1036
Summers, Scott A; Goodpaster, Bret H (2016) CrossTalk proposal: Intramyocellular ceramide accumulation does modulate insulin resistance. J Physiol 594:3167-70
Coen, Paul M; Goodpaster, Bret H (2012) Role of intramyocelluar lipids in human health. Trends Endocrinol Metab 23:391-8
Dubé, John J; Allison, Katelyn F; Rousson, Valentin et al. (2012) Exercise dose and insulin sensitivity: relevance for diabetes prevention. Med Sci Sports Exerc 44:793-9
Dubé, J J; Amati, F; Toledo, F G S et al. (2011) Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia 54:1147-56