The candidate is an Exercise Physiologist whose initial research and funded pilot projects focused on the effects of diet and exercise on obesity and glucose metabolism in sedentary normals and patients with diabetes. The proposed MRSDA will allow her to gain training in the areas of muscle and fat metabolism while investigating the interactions of aging and glucose metabolism in women with a high risk of developing diabetes. Research: Gestational diabetes mellitus (GDM) affects 90,000 women per yr in the U.S. Within 10-20 y of pregnancy, 40-65% of these women develop non-insulin dependent diabetes mellitus (NIDDM); a disease linked to obesity, physical inactivity and characterized by abnormalities in glucose and fatty acid metabolism. We hypothesize that women with a history of GDM who present with impaired glucose tolerance (IGT) or NIDDM after the menopause will be sedentary, have visceral obesity and abnormalities in their glucose, fat and muscle metabolism. A structured weight loss and aerobic exercise program (WL+AEX) will be more effective than weight loss (WL) alone in reducing visceral obesity and increasing aerobic capacity to 1) decrease free fatty acid (FFA) levels and increase fat oxidation; 2) increase muscle GLUT-4 protein and glycogen storage; and 3) enhance insulin sensitivity thereby improving glucose tolerance. This study will investigate glucose homeostasis in IGT or NIDDM (N=80) postmenopausal women (50-60 y) with a history of GDM. Measurements will be performed at baseline and after 6 months of WL or WL+AEX. Follow-up of patients will occur 1 yr after the intervention(s) to evaluate the patient's glucose tolerance, body composition and VO2max. Total and regional percent body fat, fat mass, lean tissue mass and hone mineral content will be determined by dual-energy x-ray absorptiometry. Computed tomography will quantify' intraabdominal and subcutaneous adipose tissue areas and mid-thigh muscle and adipose tissue area. VO2 max will be measured during a progressive treadmill test. Hyperinsulinemic-euglycemic clamps with tritiated glucose will assess glucose utilization, insulin sensitivity, and quantitate the role of the liver with respect to glucose production. During the clamp, plasma FFA levels and fat oxidation will be determined. Muscle biopsies of the vastus lateralis will be obtained for measurement of fiber characteristics, GLUT-4 transporters, and oxidative enzyme levels. The effects of WL or WL+AEX program on glucose homeostasis in IGT or NlDDM postmenopausal women with prior GDM are unknown. The projected study will contribute valuable information to help develop guidelines for the management of the metabolic control in the obese glucose intolerant and diabetic patient. Environment: Receipt of this MSRDA with the guidance of Drs. Goldberg and Nagey will allow the candidate to launch a career in gerontology studying disorders of glucose homeostasis in women at a high risk for NIDDM, and investigate the mechanisms by which WL or WL+AEX improve carbohydrate metabolism. The interdisciplinary environment in the School of Medicine provides excellent training and resources for advanced learning in gerontology and metabolism. The proposed work will provide the candidate with the requisite skills and training to embark on an independent research career.
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