doi: 10.1161/hq0102.101546
© 2002 American Heart Association, Inc.
Thrombosis |
Inhibition of Platelet-Collagen Interaction
An In Vivo Action of Insulin Abolished by Insulin Resistance in Obesity
From the Department of Medicine (J.W., H.Y.-J., S.V.), Division of Diabetes, the Department of Applied Chemistry and Microbiology (A.T.), and the Department of Clinical Chemistry (M.S.), University of Helsinki; the Obesity Research Group (A.R.); and the Wihuri Research Institute (R.L.), Helsinki, Finland.
Correspondence to Jukka Westerbacka, MD, University of Helsinki, Department of Medicine, Haartmaninkatu 4, FIN-00029 HUCH, Helsinki, Finland. E-mail jukka.westerbacka{at}huch.fi
Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42±2 years, body mass index 24.0±0.4 kg/m2) and 14 obese (aged 43±1 years, body mass index 37.2±1.5 kg/m2) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU · kg-1 · min-1) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of 
4000 s-1) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s-1); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6±0.2 mg · kg-1 · min-1) than in the nonobese subjects (5.4±0.4 mg · kg-1 · min-1, P<0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3±0.6x106 to 3.5±0.4x106 per square centimeter in the nonobese subjects (P<0.05) but failed to do so in the obese subjects (5.2±0.8x106 versus 5.5±0.7x106 per square centimeter, P=NS; P<0.01 versus nonobese subjects). Epinephrine- and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (P<0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5±0.3 versus 3.2±0.5 pmol/109 for before versus after insulin, respectively; P<0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9±0.2 versus 1.8±0.1 pmol/109 for before versus the end of in vivo hyperinsulinemia, respectively; P=NS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease.
Key Words: insulin • collagen • nitric oxide • obesity • cGMP
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