Obesity, Inflammation and Thrombosis: LOOK AHEAD

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DESCRIPTION (provided by applicant): The increased number of obese diabetic individuals, coupled with their high cardiovascular morbidity, mortality, and healthcare expenditures, poses an enormous public health problem for the United States. Obese diabetic patients have increased inflammation and impaired coagulant balance, which are both thought to contribute to increased risk for atherothrombotic events. Although lifestyle modification with diet therapy, exercise, and weight management is recommended as foundation therapy by multiple national organizations, there are no prospective clinical trials that have shown significant cardiovascular event reduction by weight loss achieved by any modality. The Look AHEAD (Action for Health in Diabetes) study is a large multicenter trial designed to examine whether weight loss through intensive lifestyle intervention (ILI) with both diet and exercise will reduce cardiovascular events in obese diabetic individuals compared with a control group that receives diabetes support and education (DSE). The Look AHEAD trial has quantitatively assessed which aspects of lifestyle were modified by individuals (diet, physical activity) and effects on adiposity, fitness, and traditional risk factors (blood pressure, lipids, glycemic control). The proposed aims have been designed in conjunction with the Look AHEAD investigators to examine the effects of diet and exercise on inflammation and impaired coagulant balance. In this grant, we propose the following aims: 1) examine the association between measurements of obesity (weight, body mass index, waist, etc.) at baseline and levels of proinflammatory (IL-6, CRP) and anti-inflammatory (adiponectin isoforms) adipocytokines and parameters of impaired coagulant balance (PAI-1, fibrinogen, D-dimer, TAFI) in 50% of patients enrolled in the Look AHEAD trial and how this relationship is influenced by dietary intake, physical activity, fitness, gender, ethnicity, and presence of cardiovascular risk factors and disease; 2) compare the effects of ILI versus DSE on changes in inflammatory markers and impaired coagulant balance between baseline and year 1 and examine how changes are related to changes in adiposity, dietary intake, fitness, and physical activity; 3) examine how greater reductions in weight loss lead to greater changes in parameters that measure pathways of inflammation, oxidative stress, neurohormonal regulation, and impaired coagulant balance in a case-control study.