Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment.
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.
Angiolillo
Dominick J
DJ
Division of Cardiology, University of Florida, Shands Jacksonville, Jacksonville, Florida 32209, USA. dominick.angiolillo@jax.ufl.edu
Bernardo
Esther
E
Ramírez
Celia
C
Costa
Marco A
MA
Sabaté
Manel
M
Jimenez-Quevedo
Pilar
P
Hernández
Rosana
R
Moreno
Raul
R
Escaned
Javier
J
Alfonso
Fernando
F
Bañuelos
Camino
C
Bass
Theodore A
TA
Macaya
Carlos
C
Fernandez-Ortiz
Antonio
A
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
D001241:Aspirin; D000077144:Clopidogrel; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine