title: Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment.
abstract: OBJECTIVE
  This study sought to assess the influence of type 2 diabetes mellitus (T2DM) and the impact of hypoglycemic treatment (insulin vs. noninsulin) on platelet function profiles in patients treated with dual oral antiplatelet therapy.
  
  
  BACKGROUND
  Insulin inhibits platelet aggregation by suppressing the P2Y12 pathway. However, T2DM patients have a loss of responsiveness to insulin that leads to upregulation of the P2Y12 pathway, increased platelet reactivity, and reduced responsiveness to antiplatelet agents. Patients with insulin-treated diabetes mellitus (ITDM) have a more advanced disease status and higher atherothrombotic risk compared with non-ITDM (NITDM). However, the impact of insulin therapy on platelet dysfunction in patients treated with P2Y12 antagonists is unknown.
  
  
  METHODS
  A total of 201 T2DM and 65 nondiabetic patients with coronary artery disease in a steady phase of aspirin and clopidogrel treatment were studied. Platelet aggregation was assessed using agonists specific (6 and 20 microM adenosine diphosphate [ADP]) and nonspecific (6 microg/ml collagen and 20 microM epinephrine) for the P2Y12 pathway. High shear-induced platelet reactivity was assessed by means of the PFA-100 system (Dade-Behring International, Miami, Florida).
  
  
  RESULTS
  The T2DM patients had platelet aggregation and shear-induced platelet function significantly increased compared with nondiabetic patients using all assays. Platelet aggregation was increased in ITDM (n = 68) compared with NITDM (n = 133) patients after P2Y12-specific stimuli. Insulin treatment was the strongest predictor of ADP-induced aggregation. Platelet function profiles were similar between ITDM and NITDM using assays nonspecific to the P2Y12 pathway. Platelet dysfunction was independent of glycemic control and inflammatory status.
  
  
  CONCLUSIONS
  The P2Y12-dependent and -independent pathways of platelet reactivity are altered in T2DM compared with nondiabetic patients, and ITDM have greater ADP-induced platelet aggregation compared with NITDM.
authors.affiliation: Division of Cardiology, University of Florida, Shands Jacksonville, Jacksonville, Florida 32209, USA. dominick.angiolillo@jax.ufl.edu
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Esther
authors.initials: E
authors.lastname: Bernardo
authors.forename: Celia
authors.initials: C
authors.lastname: Ramírez
authors.forename: Marco A
authors.initials: MA
authors.lastname: Costa
authors.forename: Manel
authors.initials: M
authors.lastname: Sabaté
authors.forename: Pilar
authors.initials: P
authors.lastname: Jimenez-Quevedo
authors.forename: Rosana
authors.initials: R
authors.lastname: Hernández
authors.forename: Raul
authors.initials: R
authors.lastname: Moreno
authors.forename: Javier
authors.initials: J
authors.lastname: Escaned
authors.forename: Fernando
authors.initials: F
authors.lastname: Alfonso
authors.forename: Camino
authors.initials: C
authors.lastname: Bañuelos
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Bass
authors.forename: Carlos
authors.initials: C
authors.lastname: Macaya
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernandez-Ortiz
mesh_terms: D000368:Aged; D001241:Aspirin / Q000627:therapeutic use; D000077144:Clopidogrel; D003327:Coronary Disease; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010979:Platelet Function Tests; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D001241:Aspirin; D000077144:Clopidogrel; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine