Insulin Resistance as a Determinant of Platelet Activation in Obese Women

ObjectivesWe tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation.BackgroundObesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women.MethodsWe performed a cross-sectional study in 40 obese and 20 non-obese healthy women using urinary thromboxane metabolite excretion as a non-invasive index of platelet activation. An index of insulin sensitivity, SI, and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured.ResultsObese women had significantly (p < 0.0001) higher 11-dehydro-thromboxane B2(11-dehydro-TXB2) excretion (median 718 vs. 211 pg/mg creatinine), CRP (1.13 vs. 0.48 mg/l), and CD40L levels (4.45 vs. 0.90 ng/ml) than controls. Obese women had lower SI(median 2.51 vs. 5.0 104min−1/[μU/ml], p < 0.002) and adiponectin (6.3 vs. 10 μg/ml, p < 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio (β = 0.27, p < 0.05) and SI(β = −0.72, p < 0.04) predicted 11-dehydro-TXB2excretion rate, independently of adiponectin, CRP, CD40L, and lipid patterns. In order to investigate the cause-effect relationship of these associations, we examined the effects of a 12-week weight loss program or a 3-week pioglitazone treatment on urinary 11-dehydro-TXB2in 10 women with impaired SIand visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased SI(+92%) and decreased CD40L (−27%), CRP (−37%), and 11-dehydro-TXB2(−53%) (p < 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB2excretion (−43%, p < 0.05) without changes in body weight.ConclusionsInsulin resistance is a major determinant of platelet activation in female obesity.