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CLINICAL RESEARCH: INSULIN RESISTANCE, PLATELETS, AND OBESITY

Insulin Resistance as a Determinant of Platelet Activation in Obese Women

Stefania Basili, MD, Giovanni Pacini, DSC, Maria Teresa Guagnano, MD^_*, Maria Rosaria Manigrasso, MD^_*, Francesca Santilli, MD^_*, Caterina Pettinella, BS^_*, Giovanni Ciabattoni, MD^_*, Carlo Patrono, MD and Giovanni Davì, MD^_*,_*

^_* Center of Excellence on Aging and Departments of Medicine and Drug Sciences, University of Chieti "G. D’Annunzio" Schools of Medicine and Pharmacy, Chieti, Italy
Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy
Department of Medical Therapy, University of Rome "La Sapienza," Rome, Italy
Department of Pharmacology, University of Rome "La Sapienza," Rome, Italy

Manuscript received May 15, 2006; revised manuscript received August 2, 2006, accepted August 7, 2006.

^_* Reprint requests and correspondence: Dr. Giovanni Davì, Center of Excellence on Aging, "G. D’Annunzio" University Foundation, Via Colle dell’Ara, 66013 Chieti, Italy. (Email: gdavi{at}unich.it).

OBJECTIVES: We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation.

BACKGROUND: 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.

METHODS: 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, S_I, and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured.

RESULTS: 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 S_I (median 2.51 vs. 5.0 10⁴ min^–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 (ß = 0.27, p < 0.05) and S_I (ß = –0.72, p < 0.04) predicted 11-dehydro-TXB₂ excretion 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-TXB₂ in 10 women with impaired S_I and visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased S_I (+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-TXB₂ excretion (–43%, p < 0.05) without changes in body weight.

CONCLUSIONS: Insulin resistance is a major determinant of platelet activation in female obesity.

Abbreviations and Acronyms   11-dehydro-TXB2 = 11-dehydro-thromboxane B2   AUC = area under the response curve   BMI = body mass index   CD40L = CD40 ligand   CRP = C-reactive protein   DI = disposition index   FSIGT = insulin-modified frequently sampled intravenous glucose tolerance test   OGIS = oral glucose insulin sensitivity   OGTT = oral glucose tolerance test   SI = insulin sensitivity index   WHR = waist-to-hip ratio   AIRG = incremental acute insulin response

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