title: Platelet inhibition by insulin is absent in type 2 diabetes mellitus.
abstract: OBJECTIVE
  ADP-induced P2y12 signaling is crucial for formation and stabilization of an arterial thrombus. We demonstrated recently in platelets from healthy subjects that insulin interferes with Ca2+ increases induced by ADP-P2y1 contact through blockade of the G-protein Gi, and thereby with P2y12-mediated suppression of cAMP.
  
  
  RESULTS
  Here we show in patients with type 2 diabetes mellitus (DM2) that platelets have lost responsiveness to insulin leading to increased adhesion, aggregation, and procoagulant activity on contact with collagen. Using Ser473 phosphorylation of protein kinase B as output for insulin signaling, a 2-fold increase is found in insulin-stimulated normal platelets, but in DM platelets there is no significant response. In addition, DM2 platelets show increased P2y12-mediated suppression of cAMP and decreased P2y12 inhibition by the receptor antagonist AR-C69931MX.
  
  
  CONCLUSIONS
  The loss of responsiveness to insulin together with increased signaling through P2y12 might explain the hyperactivity of platelets in patients with DM2.
authors.affiliation: Department of Hematology, University Medical Center Utrecht, Utrecht University, The Netherlands.
authors.forename: Irlando Andrade
authors.initials: IA
authors.lastname: Ferreira
authors.forename: Astrid I M
authors.initials: AI
authors.lastname: Mocking
authors.forename: Marion A H
authors.initials: MA
authors.lastname: Feijge
authors.forename: Gertie
authors.initials: G
authors.lastname: Gorter
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.forename: Jan-Willem N
authors.initials: JW
authors.lastname: Akkerman
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins / Q000378:metabolism; D010477:Perfusion; D010750:Phosphoproteins / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D003094:Collagen; D000242:Cyclic AMP; D011972:Receptor, Insulin; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium