title: Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity.
abstract: 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/m(2)) and 14 obese (aged 43+/-1 years, body mass index 37.2+/-1.5 kg/m(2)) 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 approximately 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+/-0.6x10(6) to 3.5+/-0.4x10(6) per square centimeter in the nonobese subjects (P<0.05) but failed to do so in the obese subjects (5.2+/-0.8x10(6) versus 5.5+/-0.7x10(6) 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/10(9) 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/10(9) 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.
authors.affiliation: Department of Medicine, University of Helsinki, Finland. jukka.westerbacka@huch.fi
authors.forename: Jukka
authors.initials: J
authors.lastname: Westerbacka
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.forename: Anu
authors.initials: A
authors.lastname: Turpeinen
authors.forename: Aila
authors.initials: A
authors.lastname: Rissanen
authors.forename: Satu
authors.initials: S
authors.lastname: Vehkavaara
authors.forename: Martti
authors.initials: M
authors.lastname: Syrjälä
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D015992:Body Mass Index; D003094:Collagen / Q000494:pharmacology*; D006152:Cyclic GMP / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D004837:Epinephrine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006487:Hemostasis; D006801:Humans; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D007333:Insulin Resistance; D009765:Obesity / Q000097:blood*; D010446:Peptide Fragments / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology
chemical_list: D007328:Insulin; D010446:Peptide Fragments; C086309:thrombin receptor peptide SFLLRNP; D000244:Adenosine Diphosphate; D003094:Collagen; D006152:Cyclic GMP; D005947:Glucose; D004837:Epinephrine