Abdominal obesity and its associated insulin resistance play a key role in the clustering of vascular risk factors, known as Metabolic Syndrome. Subjects with Metabolic Syndrome are at increased risk for the development of both type 2 diabetes and cardiovascular disease. Type 2 diabetes and atherosclerosis have shared pathogenetic pathways in which insulin resistance and abdominal obesity play a central role. The imbalanced production of pro- and anti-inflammatory cytokines by abdominal adipose tissue, often referred to as adipose tissue dysfunction, induces insulin resistance and also directly leads to atherosclerosis. Insulin resistance increases the risk for type 2 diabetes and induces several metabolic changes as hyperglycemia, dyslipidemia and hypertension, all contributing to the development of atherosclerosis. The clustering of these vascular risk factors is known as Metabolic Syndrome. Metabolic Syndrome may be regarded as a reflection of adipose tissue dysfunction. The main aim of this thesis was to determine the role of abdominal obesity and Metabolic Syndrome in the development of type 2 diabetes and recurrent vascular events in high-risk patients with clinically manifest atherosclerosis. Patients with manifest atherosclerosis are at high risk for recurrent vascular events. Among these patients, Metabolic Syndrome was found to identify those patients at higher risk for future vascular events and all cause mortality, independently of the presence of type 2 diabetes. Also in patients at treatment goals for systolic blood pressure or LDL-cholesterol, presence of Metabolic Syndrome points to a higher vascular risk. It was also shown that prediction models based on Metabolic Syndrome are able to discriminate patients with manifest atherosclerosis at the highest risk from those at lower risk for future vascular events. These data indicate that patients with manifest atherosclerosis and Metabolic Syndrome may benefit from more aggressive treatment of cardiovascular risk factors than recommended by current guidelines. Screening for Metabolic Syndrome may direct therapy, focusing on treatment of insulin resistance by intensive lifestyle changes. Risk reduction in patients with manifest atherosclerosis focuses on preventing new vascular events and not on prevention of type 2 diabetes. It was found that patients with manifest atherosclerosis are at high risk of developing type 2 diabetes and that Metabolic Syndrome identifies those at the highest risk. Abdominal obesity was found to be a strong individual predictor of type 2 diabetes. Thus, patients with manifest atherosclerosis and Metabolic Syndrome may derive particular benefit from lifestyle interventions focusing on reduction of abdominal obesity in order to prevent the development of type 2 diabetes. Although abdominal obesity plays a central role in the shared pathophysiological pathway of type 2 diabetes and atherosclerosis, only less than half of all obese individuals develop type 2 diabetes. It was found that the combined presence of abdominal adiposity and ?3 metabolic risk factors was associated with a more than additive risk of developing type 2 diabetes, indicating that underlying mechanisms are separate. Thus, to identify those patients with manifest atherosclerosis who are at the highest risk of developing type 2 diabetes, fat distribution in combination with metabolic risk factors should be considered
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