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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:417.)
© 2006 American Heart Association, Inc.

Thrombosis

Platelet Inhibition by Insulin Is Absent in Type 2 Diabetes Mellitus

Irlando Andrade Ferreira; Astrid I.M. Mocking; Marion A.H. Feijge; Gertie Gorter; Timon W. van Haeften; Johan W.M. Heemskerk; Jan-Willem N. Akkerman

From the Laboratory for Thrombosis and Haemostasis (I.A.F., A.I.M.M., G.G., J.-W.N.A.), Department of Hematology, University Medical Center Utrecht and the Institute for Biomembranes (I.A.F., A.I.M.M., G.G., J.-W.N.A.), Utrecht University, the Netherlands; Department of Biochemistry and Human Biology (M.A.H.F., J.W.M.H.), University of Maastricht, the Netherlands; Department of Internal Medicine (T.W.v.H.), University Medical Center Utrecht, the Netherlands.

Correspondence to Dr J.W.N. Akkerman, Thrombosis and Haemostasis, Department of Hematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. E-mail j.w.n.akkerman{at}azu.nl

Objective— ADP-induced P2y₁₂ 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-P2y₁ contact through blockade of the G-protein G_i, and thereby with P2y₁₂-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 Ser⁴⁷³ 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 P2y₁₂-mediated suppression of cAMP and decreased P2y₁₂ inhibition by the receptor antagonist AR-C69931MX.

Conclusion— The loss of responsiveness to insulin together with increased signaling through P2y₁₂ might explain the hyperactivity of platelets in patients with DM2.

Insulin inhibits Ca²⁺ mobilization in platelets by interfering with P2y₁₂-mediated cAMP suppression. Here we show that DM2 platelets have lost responsiveness to insulin and also show increased P2y₁₂ signaling. This might explain the increased platelet deposition and procoagulant activity under flow of DM2 platelets on contact with collagen.

Key Words: P2y₁₂ receptor • Ca²⁺ regulation • clopidogrel • protein kinase B/Akt • IRS-1

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