Enhanced platelet activity and thrombosis in a murine model of type I diabetes are partially insulin-like growth factor 1-dependent and phosphoinositide 3-kinase-dependent


Correspondence: Donna S. Woulfe, Biological Sciences, University of Delaware, Rm 329, Wolf Hall, 105 The Green, Newark, DE 19716, USA.

Tel.: +1 302 831 0850; fax: +1 302 831 2281.

E-mail: dswoulfe@udel.edu



To determine whether dysregulation of platelet signaling mechanisms contributes to the increased risk of thrombosis associated with diabetes, using a type I diabetes mouse model.

Methods and Results

Type I diabetes was induced in C57Bl6 mice following streptozotocin injection. Arterial thrombosis, platelet signaling and function were assessed 4 weeks later in comparison with non-diabetic control mice. Fifty-seven per cent of diabetic mice (glucose level of > 250 mg dL−1) developed stable occlusive thrombi after FeCl3 injury, as compared with 5% of their non-diabetic counterparts, suggesting that diabetic mice are more sensitive to arterial injury (P ≤ 0.02). Platelets from diabetic mice were more sensitive to protease-activated receptor 4 (PAR4) agonist-induced fibrinogen binding than platelets from non-diabetic mice, and the average Akt phosphorylation induced by PAR4 agonist peptide was greater (P ≤ 0.01) in platelets from diabetic mice. Recent studies suggest that insulin-like growth factor 1 (IGF-1) potentiates Akt phosphorylation in platelets. To determine whether IGF-1 signaling contributes to the increase in PAR4 sensitivity in platelets from diabetic mice, platelet signaling and function were evaluated in the presence of inhibitors of the IGF-1 receptor. IGF-1 receptor inhibition reduced Akt phosphorylation and fibrinogen binding in platelets from diabetic mice to levels consistent with those seen in normoglycemic platelets, but had no significant effect on platelets from non-diabetic mice.


The results suggest that platelets from mice with streptozotocin-induced diabetes show enhanced platelet Akt phosphorylation and activity resulting from IGF-1-dependent mechanisms. Increases in platelet Akt activation may explain the enhanced sensitivity to thrombotic insult seen in diabetic mice.