Approximately 40 percent of the elderly in the United States possess some degree of impaired glucose tolerance, which may lead to coronary artery disease, stroke, and noninsulin-dependant diabetes mellitus. Impairments in peripheral insulin action with aging are commonly associated with these complications. The proposed studies will investigate the following two hypotheses concerning peripheral insulin action and aging: 1. The decrement in insulin sensitivity that occurs with aging is related to a reduction in insulin-responsive glucose transporter protein (GLUT4) levels in skeletal muscle. 2. The cellular mechanism responsible for the improvement in insulin sensitivity with exercise intervention (i.e., endurance training) in older humans is, at least in part, an increase in the skeletal muscle GLUT4 protein. The hypotheses will be investigated by addressing the following questions in humans: 1. With aging, is the loss of insulin sensitivity associated with a reduction in GLUT4 protein levels and expression? 2. Do skeletal muscle GLUT4 levels and expression increase in conjunction with insulin sensitivity after short (7 days) and/or long-term (24 week) endurance-oriented exercise training in older subjects? 3. If GLUT4 levels and expression are elevated with exercise training, is this adaptation lost with exercise cessation, yet maintained with a reduction in training volume in older, exercise-trained individuals? Methods to achieve these goals will involve assessments of body composition, cardiorespiratory fitness level, in-vivo insulin sensitivity (minimal model), and analysis of skeletal muscle samples. The broad, long-term objectives of this proposal are to: 1. Increase the knowledge of the aging process in relation to insulin action at the cellular level in humans. 2. Elucidate the biochemical mechanisms involved with improving insulin sensitivity in older subjects. 3. Demonstrate that exercise training can serve as a deterrent to the decrement in insulin action associated with aging.
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