The H2S-releasing metformin hybrid Met-ITC protects against diabetes-associated vascular dysfunction preserving glycaemic control

Background and Purpose: Patients undergoing metformin (Met) therapy for the treatment of type 2 diabetes remain at high cardiovascular risk. Hydrogen sulphide (H2S)-releasing molecules offer antioxidant, anti-senescence and vasoactive properties that may complement Met activity. This study investigated whether metformin–isothiocyanate (Met-ITC), a H2S-releasing metformin hybrid, preserves the antidiabetic activity of Met while providing H2S-derived vascular protection. Experimental Approach: The predicted Absorption, Distribution, Metabolism and Excretion (ADME) properties of Met and Met-ITC were evaluated in silico. Maintenance of Met antidiabetic properties was assessed in vitro by evaluating glucose uptake in HepG2 cells and in vivo through oral glucose tolerance tests in db/db mice. The ability of Met-ITC to release H2S and its ability to preserve cell viability and contrast ROS formation and cellular senescence were evaluated in human aortic endothelial cells (HAECs) and smooth muscle cells (HASMCs) exposed to hydrogen peroxide, homocysteine or high-glucose concentrations. The hyperpolarizing effect of Met-ITC was tested on HASMCs and its direct vasorelaxing effect as well as its ability to inhibit noradrenaline-induced vasoconstriction were tested on endothelium-intact or -denuded rat aortic rings. Key Results: Met-ITC showed a more favourable permeability profile than Met and maintained its antidiabetic profile. It provided better protection against oxidative stress, loss of cell viability and senescence compared with Met. Moreover, Met-ITC produced a concentration-dependent hyperpolarization of HASMCs, restricted noradrenaline-induced contraction and induced vasodilatation in endothelium-denuded and -intact rat aortic rings. Conclusion and Implications: These findings identify Met-ITC as a potential candidate for the treatment of diabetes-associated vascular dysfunction.