Res. 2003;11:1048 -1054. Objective: To study the effect of weight loss in response to a lifestyle modification program on the circulating levels of adipose tissue derived cytokines (adipokines) in obese individuals with insulin resistance. Research Methods and Procedures: Twenty-four insulinresistant obese subjects with varying degrees of glucose tolerance completed a 6-month program consisting of combined hypocaloric diet and moderate physical activity. Adipokines [leptin, adiponectin, resistin, tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6)] and highly sensitive C-reactive protein were measured before and after the intervention. Insulin sensitivity index was evaluated by the frequently sampled intravenous glucose tolerance test. Results: Participants had a 6.9 Ϯ 0.1 kg average weight loss, with a significant improvement in sensitivity index and reduction in plasma leptin (27.8 Ϯ 3 vs. 23.6 Ϯ 3 ng/mL, p ϭ 0.01) and IL-6 (2.75 Ϯ 1.51 vs. 2.3 Ϯ 0.91 pg/mL, p ϭ 0.012). TNF-␣ levels tended to decrease (2.3 Ϯ 0.2 vs. 1.9 Ϯ 0.1 pg/mL, p ϭ 0.059). Adiponectin increased significantly only among diabetic subjects. The reductions in leptin were correlated with the decreases in BMI (r ϭ 0.464, p Ͻ 0.05) and with changes in highly sensitive C-reactive protein (r ϭ 0.466, p Ͻ 0.05). Discussion: Weight reduction in obese individuals with insulin resistance was associated with a significant decrease in leptin and IL-6 and a tendency toward a decrease in circulating TNF-␣, whereas adiponectin was increased only in diabetic subjects. Further studies are needed to elucidate the relationship between changes of adipokines and the health benefits of weight loss.

OBJECTIVE -Endothelial dysfunction has been reported in type 2 diabetic patients and in obese subjects with insulin resistance syndrome (IRS). This study evaluates the effects of weight reduction and exercise on vascular reactivity of the macro-and the microcirculation in obese subjects with IRS.RESEARCH DESIGN AND METHODS -We studied 24 obese subjects (9 men and 15 women, age 49.3 Ϯ 1.9 years, BMI 36.7 Ϯ 0.94 kg/m 2 , mean Ϯ SEM) with IRS at baseline and after 6 months of weight reduction and exercise. Brachial artery flow-mediated dilation (FMD) and response to sublingual glyceryltrinitrate (GTN) were assessed by high-resolution ultrasound. Microvascular reactivity was evaluated by the laser-Doppler perfusion imaging after iontophoresis of acetylcholine and sodium nitroprusside. We also measured plasma levels of soluble intercellular adhesion molecule (sICAM), vascular adhesion molecule, von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1) antigen, and tissue plasminogen activator antigen.RESULTS -This intervention resulted in 6.6 Ϯ 1% reduction in body weight (P Ͻ 0.001) and significant improvement of insulin sensitivity index (2.9 Ϯ 0.36 vs. 1.9 Ϯ 0.33 [10 Ϫ4 ⅐ min Ϫ1 ⅐ (U ml Ϫ1 )], P Ͻ 0.001). FMD significantly improved (12.9 Ϯ 1.2% vs. 7.9 Ϯ 1.0%, P Ͻ 0.001), whereas response to GTN and microvascular reactivity did not change. Similar observations were seen when the subjects were subclassified according to their glucose tolerance to normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. sICAM and PAI-1 significantly decreased (251.3 Ϯ 7.7 vs. 265.6 Ϯ 9.3 ng/ml, P ϭ 0.018 and 36.2 Ϯ 3.6 vs. 48.6 Ϯ 3.9 ng/ml, P ϭ 0.001, respectively). The relationship between percentage weight reduction and improved FMD was linear (R 2 ϭ 0.47, P ϭ 0.001).CONCLUSIONS -We conclude that 6 months of weight reduction and exercise improve macrovascular endothelial function and reduces selective markers of endothelial activation and coagulation in obese subjects with IRS regardless of the degree of glucose tolerance. Diabetes Care 26:2119 -2125, 2003O besity and insulin resistance are often associated with hyperinsulinemia, glucose intolerance, hypertension, dyslipidemia, premature atherosclerosis, and increased risk for coronary artery disease (1). This cluster of abnormalities is known as the insulin resistance syndrome (IRS) or the metabolic syndrome (2). According to the recently suggested Adult Treatment Panel-III clinical guidelines of the National Cholesterol Education Program, it is estimated that the age-adjusted prevalence of the metabolic syndrome is ϳ23.7% of the adult population (3). This population has an overall excess coronary artery disease risk of ϳ70% (4).Endothelial dysfunction, an early step in the development of atherosclerosis (5), has been reported in patients with type 2 diabetes (6) and in obese nondiabetic individuals (7). It also exists in subjects at high risk for developing diabetes, including subjects with impaired glucose tolerance and normoglycemic first-degree relati...

Risk of type 1 diabetes at 3 years is high for initially multiple and single Ab+ IT and multiple Ab+ NT. Genetic predisposition, age, and male sex are significant risk factors for development of Ab+ in twins.