Platelet inhibition by insulin is absent in type 2 diabetes mellitus

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 Ca2+ 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.