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 Gi, 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. CONCLUSIONS: The loss of responsiveness to insulin together with increased signaling through P2y12 might explain the hyperactivity of platelets in patients with DM2.
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 Gi, 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. CONCLUSIONS: The loss of responsiveness to insulin together with increased signaling through P2y12 might explain the hyperactivity of platelets in patients with DM2.
Authors: Antonio J López Farré; Juan Tamargo; Petra J Mateos-Cáceres; Luís Azcona; Carlos Macaya Journal: Pharm Res Date: 2010-07-14 Impact factor: 4.200
Authors: Monica Periasamy; David C Lieb; Matthew J Butcher; Norine Kuhn; Elena Galkina; Mark Fontana; Stephen Wohlgemuth; Jerry L Nadler; Yuliya Dobrydneva Journal: Obes Surg Date: 2014-08 Impact factor: 4.129