Premium
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
Author(s) -
Stolla M. C.,
Li D.,
Lu L.,
Woulfe D. S.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12170
Subject(s) - platelet , medicine , endocrinology , streptozotocin , diabetes mellitus , protein kinase b , agonist , platelet activation , fibrinogen , protease activated receptor , receptor , phosphorylation , chemistry , thrombin , biochemistry
Summary Objectives 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 C 57 B l6 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 FeCl 3 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 ( PAR 4) agonist‐induced fibrinogen binding than platelets from non‐diabetic mice, and the average A kt phosphorylation induced by PAR 4 agonist peptide was greater ( P ≤ 0.01) in platelets from diabetic mice. Recent studies suggest that insulin‐like growth factor 1 ( IGF ‐1) potentiates A kt phosphorylation in platelets. To determine whether IGF ‐1 signaling contributes to the increase in PAR 4 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 A kt 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. Conclusions The results suggest that platelets from mice with streptozotocin‐induced diabetes show enhanced platelet A kt phosphorylation and activity resulting from IGF ‐1‐dependent mechanisms. Increases in platelet A kt activation may explain the enhanced sensitivity to thrombotic insult seen in diabetic mice.