C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice

Aims/hypothesis: Diabetic macro- and microangiopathy are associated with a high risk of vascular complications. The diabetic patient exhibits a pathological coagulation state, with an increased synthesis of coagulation factors and plasminogen activator inhibitor 1 (PAI-1) as well as an enhanced aggregation of platelets. Previous studies have shown that C-peptide can reduce leucocyte-endothelial cell interaction and improve microvascular blood flow in patients with type 1 diabetes. In the present study, we examined in vivo whether C-peptide is able to reduce platelet activation and through that microvascular thrombus formation. Materials and methods: In the microvessels of cremaster muscle preparations taken from normal and diabetic mice, ferric chloride-induced thrombus formation was analysed using intravital fluorescence microscopy. Results: I.V. administration of C-peptide in high dose (70 nmol/kg), but not in low dose (7 nmol/kg), caused a significant delay in arteriolar and venular thrombus growth in normal and diabetic mice. This effect was repressed by cremaster muscle superfusion with insulin (100 mu U/ml) in diabetic animals, but particularly in normal animals. In parallel, immunohistochemistry demonstrated a higher number of PAI-1-expressing vessels in cremaster muscle tissue from control animals and from animals treated with C-peptide and insulin compared with tissue from animals with C-peptide treatment application alone. Conclusions/interpretation: We conclude that C-peptide possesses antithrombotic actions in vivo. A causal role of PAI-1 in this scenario needs to be further addressed. However, the reversal of C-peptide action by insulin may invalidate the use of this peptide as a treatment option to improve rheology and microcirculation in diabetic patients.