Pleiotropic Effects of PPAR gamma Agonist on Hemostatic Activation in Type 2 Diabetes Mellitus

Thiazolidinediones (TZDs) represent a class of peroxisome proliferator-activated receptor (PPAR)gamma agonists widely used as insulin-sensitizers in the treatment of type 2 diabetes mellitus (T2DM). The beneficial effects of hypoglycemic drugs, including TZDs, on the hemostatic abnormalities associated to T2DM have been formerly related to improved metabolic control, rather than to direct effects. However, in recent years the pleiotropic effects of PPAR gamma agonists on hemostatic function have become evident. In particular, the role of platelets as a pivotal player in diabetes complications by stimulating and sustaining inflammation has been lately acknowledged. Upon activation platelets synthesize and release many bioactive substances such as thromboxane A(2) (TXA(2)) or pro-inflammatory mediators including CD40 ligand (CD40L) that exert autocrine and paracrine activation processes in vascular inflammation leading to cardiovascular disease (CVD). Although PPAR gamma is a nuclear hormone receptor, anucleate platelets also highly express this receptor and treatment with synthetic PPAR gamma ligands dampens the release of soluble(s) CD40L and TXA(2) in thrombin-activated platelets. Moreover, PPAR gamma through Sirtuin1 pathway has been implicated in modulating inflammatory and atherosclerotic processes in patients with T2DM. Therefore, in T2DM, where platelet activation contributes to the pathogenesis of CVD, TZDs may have an enhanced therapeutic role, despite some potentially serious adverse side effects. This review will discuss the pleiotropic effects of PPAR gamma treatment on the hemostatic abnormalities associated with T2DM, with particular focus on platelet activation.