Obesity, Weight Loss, and Cardiovascular Disease Risk

• Lipid/lipoprotein changes [ Designated as safety issue: No ]
• Blood pressure changes [ Designated as safety issue: No ]
• Insulin resistance changes [ Designated as safety issue: No ]
• Endothelial function changes [ Designated as safety issue: No ]

• 1. Lipid/lipoprotein changes
• 2. Blood pressure changes
• 3. Insulin resistance changes
• 4. Endothelial function changes

While obesity, insulin resistance, and diabetes are highly associated, it is not clear whether insulin resistance and compensatory hyperinsulinemia play important roles in the tendency to gain weight and/or inability to lose weight. The role of hyperinsulinemia in coronary heart disease (CHD)is also unclear. The specific aims of the proposed research are as follows:

1. To compare insulin resistant versus insulin sensitive nondiabetic overweight individuals with respect to their ability to lose weight on a low calorie diet. CHD risk factors before and after weight loss will also be assessed to determine the degree to which insulin resistance is associated with CHD risk, as well as the impact that differences in insulin resistance have on the metabolic benefits of weight loss
2. To determine if weight loss and its associated metabolic benefits vary as a function of the relative amounts of dietary fat and carbohydrate in hypocaloric diets. Because high carbohydrate diets increase insulin secretion, the relationship between dietary composition and change in circulating insulin concentrations will be analyzed with respect to both weight loss and CHD risk factors.
3. To quantify and compare the improvement in glycemic control and CHD risk factors associated with weight loss in obese type 2 diabetics, while being treated with 1) an insulin secretagogue (sulfonylurea) or 2) an insulin sensitizer (thiazolidinedione). Manipulation of plasma insulin concentrations with these medications will provide a mechanism by which to evaluate the impact of circulating insulin concentrations on the described outcome measures.
4. A subgroup of overweight/obese premenopausal women with PCOS will be studied using two diets in crossover design with regard to macronutrient effects on endogenous hyperinsulinism. For this subgroup age range will be 18-50 years, BMI 25-50 kg/m2.
5. In order to increase our data and therefore increase our better understanding of fat cells and insulin resistance and changes in fat cells with weight loss we would like to increase our participant enrollment to 550 all to be enrolled at Stanford University Medical Center recruiting Bariatric participants:

Age for Bariatric patients 30-65 men and women BMI 27-no upper limit Currently we have completed all participants except the bariatric and post bariatric population and those with hypoglycemia following bariatric surgery.

The ethnic background of subjects reflects Stanford's patient population.

Inclusion Criteria:

• BMI 30-35
• age 35-65
• nondiabetic by fasting plasma glucose concentration
• no active major organ diseases
• insulin resistant or insulin sensitive

Exclusion Criteria:

• anemia
• pregnant
• major organ disease
• active malignancy
• eating disorder
• active psychiatric illness
• chronic inflammatory conditions