The major goal of this study is to determine whether exercise training and dietary restriction can reduce the suppressive effects of free fatty acids (FFA) on insulin-mediated glucose disposal in a group (N=40) of moderately obese (BMI, 27-32 kg/m) older men and women (60-80 yr) with impaired glucose tolerance. Subjects will perform either 12 weeks of exercise training (walking/jogging, stationary cycling, at 80-85% HRmax, 60 min/day, 5 days/week) while consuming a eucaloric diet (N=20), or 12 weeks of similar exercise training while consuming a hypocaloric diet designed to reduce body weight by 10-15% (N=20). Three-day food records and daily body weight measurements will be obtained, and a dietitian will carefully monitor and advise on diets, including appropriate behavioral modifications that may be necessary to facilitate adherence to the diet. To assess whether the metabolic adaptations to exercise and weight loss are related to varying body fat distribution, half of the subjects (N=20) will have predominantly upper body obesity (waist/hip ratio (WHR) greater than 0.95 for men and greater than 0.85 for women) while half will have predominantly lower body obesity (WHR less than 0.95 for men and less than 0.85 for women). Adaptations to the exercise and dietary interventions will be determined during euglycemic hyperinsulinemic (40 mU/m2/min) clamps with normal (saline infusion) and elevated (approximately 4 mmol/L) FFA levels (intralipid/heparin infusion). Infusion of [3-3H] glucose and [1-14C] palmitate will be used to measure hepatic glucose production and FFA turnover, respectively. Indirect calorimetry will be used to examine changes in carbohydrate and fat oxidation. Muscle biopsies of the vastus lateralis will be performed before and after each clamp/infusion to quantify changes in pyruvate dehydrogenase, acetyl CoA, and citrate concentrations. Body composition changes will be determined by hydrodensitometry, urinary creatinine and anthropometric measurements. Computed tomography scans will be used to measure changes in the amount of subcutaneous and deep adipose tissue in the abdominal region. Maximal oxygen consumption (VO2max) will be used to assess the effectiveness of the training program. Changes in total energy expenditure will be determined from 24-hour measurements in a whole body calorimeter. Data from this project will provide information on the extent to which glucose-FFA interactions on insulin action can be ameliorated by exercise and weight loss in older moderately obese men and women with impaired glucose tolerance. The results from this study can contribute to understanding the mechanism by which alterations in life-style factors can improve metabolic control and ultimately enhance the quality of life of a sizeable number of older overweight Americans.
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