INSULIN RESISTANCE AND PROTEIN METABOLISM

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Aging is associated with decreased skeletal muscle mass and increased total body and visceral fat. Elderly people are the most likely segment of the population to remain in bed for extended periods of time for a variety of reasons. Considerable literature exists on the effects of prolonged bedrest in healthy young people---accelerated loss of muscle and the development of insulin resistance--but very little is known about the physiological, metabolic, and functional consequences of bedrest in older people. Therefore, the effects of 10 days of bedrest will be examined in two groups of elderly men and women: normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). The overall goal is to examine the effects of reduced insulin action on skeletal muscle protein metabolism. Five hypotheses will be tested. (1) Insulin resistance exerts an important effect on muscle protein metabolism. (2) Hepatic insulin resistance plays a role in the bedrest-induced peripheral insulin resistance with IGT, Increased hepatic glucose production, even during conditions of elevated insulin levels will result in hyperglycemia and reduced muscle fat oxidation. It is clear that bedrest increases tissue sensitivity to cortisol, potentially exacerbating the hepatic insulin resistance and accelerating loss of muscle protein. (3) Reduced insulin-stimulated glucose disposal results in a decreased rate of muscle protein synthesis and an accelerated loss of muscle during bedrest. Specifically, individuals with NGT will demonstrate reduced loss of muscle compared with those individuals with IGT. (4) Insulin resistance and bedrest will result in an alteration in the skeletal muscle insulin signaling cascade ultimately affecting the rate of muscle protein synthesis. (5) Metformin, a powerful hypoglycemic agent, will prevent many of the bedrest induced adaptations in subjects with IGT. Dietary intake during bedrest will be carefully controlled (eucaloric with 0.8 g protein ? kg-1 ? d-1) so that nitrogen balance may be measured during the entire 10-day period. This project and the interaction with the other projects in this PPG will, for the first time, examine the effect of bedrest in elderly people and provide critical information for the clinical management of bedrest-induced metabolic abnormalities in this vulnerable population.