Therefore, we propose that PDI could be a potential culprit of MetS-induced platelet hyperactivity, possibly through a deficient PDI denitrosation activity, decreased PDI S-nitrosylation and/or less PDI needed for transnitrosation reactions, an increase in TF activation, and insulin resistance caused by increased quantity and/or activity of secreted platelet PDI. The gene discussed is INS; the disease is metabolic syndrome.