Insulin Resistance as a Determinant of Platelet Activation in Obese Women

Insulin Resistance as a Determinant of Platelet Activation in Obese Women Stefania Basili, Giovanni Pacini, Maria Teresa Guagnano, Maria Rosaria Manigrasso, Francesca Santilli, Caterina Pettinella, Giovanni Ciabattoni, Carlo Patrono, Giovanni Davì Insulin resistance, per se, might contribute to increased platelet activation observed in obesity, independently of underlying inflammation. Forty obese women had significantly higher 11-dehydro-thromboxane B2(11-dehydro-TXB2) excretion, an index of platelet activation, C-reactive protein, and CD40 ligand levels and lower SI, an index of insulin sensitivity and adiponectin, than healthy controls. Waist-to-hip ratio and SIpredicted 11-dehydro-TXB2, independently of adiponectin, inflammatory, and lipid patterns. Improved insulin sensitivity achieved with either successful weight loss or pioglitazone treatment significantly decreased thromboxane biosynthesis in obese women. Thus, insulin resistance is a major determinant of platelet activation in female obesity. We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. Obesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women. We 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. Obese 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.