High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis in Type-2 Diabetic Mice

Abstract

Abstract Introduction Metformin is the most prescribed medication in Type 2 Diabetes(T2D). Metformin has shown to decrease mean platelet volume, with promising antiplatelet effects. High doses of Metformin have also been associated with hypercoagulation. We hypothesize that Metformin will protect T2D mice from occlusive arterial thrombus formation by altering platelet activation and mitochondrial bioenergetics. Methods T2D was developed by low dose of Streptozotocin, non-T2D (healthy) mice are controls. Either vehicle or Metformin was administered twice daily via oral gavage for 7-days. Ferric chloride (FeCl3) arterial thrombosis and tail bleeding time were performed. Whole blood aggregometry, platelet activation/adhesion and mitochondrial bioenergetics were evaluated. Results Metformin decreased susceptibility of T2D mice to arterial thrombosis. Platelet bioenergetics show T2D mice have increased platelet mitochondrial respiration, but no differences were observed with Metformin treatment. In non-T2D mice, Metformin modulated ADP-dependent increase in platelet adhesion. In non-T2D mice, Metformin shortens bleeding time with faster thrombotic occlusion. Metformin also increased platelet mitochondrial maximal respiration and spare respiratory capacity uniquely in non-T2D mice. Conclusion Metformin regulates platelet bioenergetics and ADP-mediated platelet function in T2D mice which attenuates susceptibility to arterial thrombosis. Future studies will evaluate clinically relevant doses of Metformin that regulates thrombotic function in diabetic platelets.