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

Abstract

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 leucocyteendothelial 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 μU/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.

C-Peptide: A New Mediator of Atherosclerosis in Diabetes

“…In contrast to this it has been revealed that C-peptide demonstrates antithrombotic effects in vivo . Administration of C-peptide in high doses caused delay in arteriolar and venular thrombus growth in normal and diabetic mice [43]. …”

The dual effect of C‐peptide on cellular activation and atherosclerosis: Protective or not?

“…Both normal and diabetic animals showed a significant deceleration of microvascular thrombus formation after administration of high dose of C‐peptide. However, subsequent administration of insulin reversed this effect, suggesting that C‐peptide may not help the treatment and/or prevention of thrombosis when in combination with insulin . In contrast, it was demonstrated that C‐peptide or insulin alone inhibits low oxygen (O 2 )‐induced ATP release from healthy human erythrocytes.…”

“…In addition, clinical trials in humans with T1DM and T2DM suggested beneficial impact of C‐peptide on kidney, retina, and nerve . High doses of C‐peptide were capable to reduce thrombus formation . It increases microvascular blood flow in the skin of T1DM patients, possibly by stimulating Na + , K + ‐ATPase activity and nitric oxide (NO) production .…”

“…[12][13][14] High doses of C-peptide were capable to reduce thrombus formation. 15 It increases microvascular blood flow in the skin of T1DM patients, possibly by stimulating Na + , K + -ATPase activity and nitric oxide (NO) production. 16 NO production stimulated by C-peptide has beneficial effects on reduction of erythrocytes and leukocyte-endothelium interaction in vitro, which has been found beneficial for cardiovascular complications.…”

C‐Peptide and Atherogenesis: C‐Peptide as a Mediator of Lesion Development in Patients with Type 2 Diabetes Mellitus?

“…Such mechanisms were most likely mediated by a reduction in endothelial plasminogen activator inhibitor 1 (PAI-1) expression in arterioles and venules, but not by an effect on platelet activation. Interestingly, concomitant treatment with insulin abolished the effect of C-peptide on microvascular thrombus formation [21]. These data suggest that C-peptide could exhibit antithrombotic actions in vivo.…”