Platelet inhibition by insulin is absent in type 2 diabetes mellitus
Platelet inhibition by insulin is absent in type 2 diabetes mellitus
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DOI：
10.1161/01.atv.0000199519.37089.a0
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发表时间：
2006-02-01
影响因子：
8.7
通讯作者：
Akkerman, JWN
中科院分区：
文献类型：
--
作者：
Ferreira, IA;Mocking, AIM;Akkerman, JWN
目的：ADP诱导的P2y(12)信号对动脉血栓的形成和稳定至关重要。我们最近在健康人的血小板上证实，胰岛素通过阻断G蛋白G(I)而干扰ADP-P2y(1)接触引起的钙离子增加，从而干扰P2y(12)介导的cAMP抑制。方法和结果-在这里，我们显示在2型糖尿病(DM2)患者中，血小板对胰岛素失去了反应性，导致与胶原接触时的粘附性、聚集性和促凝血活性增加。使用蛋白激酶B的Ser(473)磷酸化作为胰岛素信号的输出，在胰岛素刺激的正常血小板中被发现增加了2倍，但在糖尿病患者中没有显著的反应。受体拮抗剂AR-C69931MX可使DM2血小板对p2y(12)介导的cAMP抑制作用增强，对p2y(12)的抑制作用减弱。结论：DM2患者血小板对胰岛素的反应性丧失，并通过P2y(12)信号转导途径增强，这可能是DM2患者血小板过度活动的原因之一。
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.