The proposed research is intended to study insulin resistance as a marker identifying obese individuals at higher risk for co-morbid conditions as well as a marker for metabolic changes responsible for obesity treatment failure. The objectives of this study are: (1) to differentiate, at weight stability, between the impact of adiposity (percent fat) and that of insulin resistance on abnormalities of carbohydrate and lipid substrate availability and oxidation as they relate to atherogenic risk factors such as hyperinsulinemia, blood lipids and lipoproteins; (2) to determine if, in obese individuals, the degree of insulin resistance at a certain level of adiposity, could predict the individual's response to weight loss. In Experiment (1), four groups of obese, premenopausal women, characterized by measurements of body composition and of insulin sensitivity (assessed from oral and the frequently-sampled intravenous glucose tolerance) will be matched at 2 levels of insulin resistance and 2 levels of adiposity and will be studied initially, at weight stability. The following studies are planned: a. measurements of the degree of hyperinsulinemia and blood lipids and lipoproteins; b. in vivo measurements of total body glucose disposal and systemic lipolysis in the basal state and during an euglycemic insulin clamp; c. in vitro measurements of the insulin action at gluteal and abdominal fat cell levels (antilipolytic action and stimulation of glucose transport). In Experiment (2), two groups of obese women matched by adiposity but with different degrees of insulin resistance will lose 10 kg, in the metabolic ward, on a diet of constant caloric deficit. a. Weight loss- induced energy expenditure changes (resting and 24 hr measurements) and accompanying body composition changes (amount of fat, extra and intracellular water, total body potassium, total body nitrogen), and b. weight loss-induced changes in glucose disposal in vivo (as a reflection of changes in muscle insulin sensitivity) and changes in insulin sensitivity at the adipose tissue level (glucose transport and anti- lipolytic action) will be compared within and between groups. this will establish whether initial differing insulin resistance has an impact on subsequent metabolic events after weight loss.
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