Non-insulin-dependent diabetes (NIDDM) is one of the most common chronic diseases in older persons, with a prevalence of approximately 10 percent among person 65+years. Most epidemiologic studies have shown that the transition from the normal state to overt NIDDM in aging is characterized by a deterioration in glucose tolerance. This deterioration is due initially to imparied peripheral glucose disposal, primarily related to insulin resistance in the skeltetal muscle. There is evidence, however, that the life-time deterioration in glucose tolerance may not be solely a consequence of aging. In fact, the contribution of aging per se may be relatively modest. Data from several studies suggest that while there is some degree of mandatory (i.e., biological) decline in glucose tolerance with aging, the degree to which this occurs is modulated by several other factors, namely, body composition and physical activity. With age, lean mass and physical activity level level decrease, while excess adiposity increases. Because each of these aging-related factors is associated with glucose homeostasis, it is important to differentiate their relative contribution to glucose intolerance from that of mandatory aging. Previous studies in subjects with moderate to severe NIDDM have demonstrated that impairment in peripheral glucose disposal can be attributed to a defect in muscle glycogen synthesis. Muscle glucose transport and glycogen synthase are both insulin stimulated, and each has been linked to the reduced rate of insulin stimulated glucose disposal in NIDDM. Other studies have shown that exercise improves insulin sensitivity. We recently observed significant improvements in insulin sensitivity after 6 weeks of areobic exercise training in a sample of younger adults, comprising both normal subjects and insulin-resistant offspring of diabetic parent(s). These improvements were explained primarily by training-related increases in glucose transport-phosphorylation and muscle glucogen synthesis. In this IDS, we planto study insulin resistance in healthy older persons. Specifically, we will use 13C and 31p NMR spectroscopy to investigate the effect of aerobic exercise training on: 1) insulin sensitivity; 2) muscle glycogen synthetic rates; 3) muscle glucose-6-phosphate concentrations; and 4) insulin secretion. We hypothesize that: 1) glucose transport/phosphorylation is the rate limiting step for insulin stimulated muscle glycogen synthesism and alterations in its activity is primaryly responsible for the insulin resistance that occurs with aging; and 2) this defect in insulin stimulated glucose transport/phosphorylation and insulin stimulated muscle glycogen synthesis will be partially (or totally) reversed with an intensive, 12-week aerobic exercise training program. To distinguish the training effect from the effect of a single bout of exercise, insulin sesitivity, muscle glycogen synthetic rates and muscle glucose-6-phosphate concentrations will be measured not only before and after a training program, but also 48 hours after the first bout of exercise. The results from these studies will provide new insights into the pathogenesis of insulin resistance in aging as well the mechanism by which exercise might reverse insulin resistance and, in turn, prevent the deveopment of NIDDM.
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