The role of complement C3 in diabetes

The prevalence of diabetes worldwide continues to rise and with it the burden of cardiovascular disease (CVD). This is related to clustering of cardiovascular risk factors in diabetes, coupled with a deranged haemostatic system, generating a pro-thrombotic environment. Matters are compounded further by increased incorporation of proteins such as plasmin inhibitor (PI) and complement C3 into the clot contributing to a hypofibrinolytic state. C3 is a key component of the complement pathways and elevated plasma levels are seen in diabetes and correlate with clot lysis time in type 1 patients, which may relate to increased incorporation of C3 into the clot compared to controls. Ex-vivo analysis demonstrates that C3 causes a prolongation in clot lysis, and this is more pronounced in diabetes. Targeted interference with fibrinolysis, such as inhibition of fibrinogen interactions with C3, may lead to the development of diabetes specific therapeutic agents. The aims of my work were therefore to i) further study the role of C3 in hypofibrinolysis in relation to diabetes ii) elucidate potential binding sites between fibrinogen and C3 and iii) modulate fibrin clot lysis by targeted interference with fibrinogen-PI and fibrinogen-C3 interactions. My work has helped demonstrate that complement C3 plays an important role in hypofibrinolysis in type 2 as well as type 1 diabetes, an effect that shows wide inter-individual variability and may relate to differing rates of glycation of C3 in diabetes. I have also identified potential interaction sites of this protein with the β chain of fibrinogen. Moreover, I have helped develop a new method, using Adhiron technology, for the identification of novel therapeutic targets that can be used to enhance the fibrinolytic process and reduce thrombosis risk.