Objective— ADP-induced P2y ₁₂ signaling is crucial for formation and stabilization of an arterial thrombus. We demonstrated recently in platelets from healthy subjects that insulin interferes with Ca ²⁺ increases induced by ADP-P2y ₁ contact through blockade of the G-protein G _i , and thereby with P2y ₁₂ -mediated suppression of cAMP. Methods and 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 Ser ⁴⁷³ 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 P2y ₁₂ -mediated suppression of cAMP and decreased P2y ₁₂ inhibition by the receptor antagonist AR-C69931MX. Conclusion— The loss of responsiveness to insulin together with increased signaling through P2y ₁₂ might explain the hyperactivity of platelets in patients with DM2.