The main novel findings of this study are: (1) the heart pretreatment with platelets of healthy humans (healthy-PLTs) reduces infarct size, (2) the cardioprotective properties of healthy-PLTs depend on myocardial S1P receptor and RISK (PI3K-ERK-1/2-PKC) pathway activation, (3) the cardioprotective properties are lost by platelets from T2DM patients (diabetic-PLTs), which release less S1P than healthy-PLTs after mechanical and chemical stimulation, in vitro, and (4) the higher is the ROS level in PLTs the higher is infarct size in hearts pretreated with diabetic PLTs. This evidence concerns the gene PRRT2 and type 2 diabetes mellitus.